rs4889 and rs5782018 polymorphisms of KISS1 gene as genetic predisposing factor for PCOS in Indonesian women

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Single nucleotide polymorphisms (SNPs) in the KISS1 gene may be associated with altered neuroendocrine signaling in PCOS. The present study aims to evaluate the association between two KISS1 polymorphisms (rs4889 and rs5780218), their haplotypes, and the odds of PCOS in Indonesian women. Methods A cross-sectional study was conducted at Yasmin Clinic, dr. Cipto Mangunkusumo General Hospital, Indonesia, involving 60 women with PCOS and 60 healthy controls. Hormonal levels were assessed using ELISA, and genomic DNA was analyzed by Sanger sequencing. Demographic data were compared using independent t-tests, and chi-square tests were used for genotype and allele frequency analysis. Results The genotypic distribution of rs4889 was significantly different between the PCOS and control groups (p<0.05), where the distribution of mutant genotype GG was higher in PCOS than in control (18.3% and 1.7%, respectively). The allele distribution of rs4889 and rs5782018 KISS1 SNPs were significantly different between both groups (p<0.01 and p<0.05, respectively). The rs4889 polymorphism was significantly different between the PCOS and control groups for the codominant and recessive models (p<0.01). Moreover, the rs5780218 polymorphism was significantly different between the PCOS and control groups for the codominant and dominant models (p<0.05). From the haplotype analysis, the G-CT haplotype was significantly different, with an OR value of 2.57 (1.33–4.96, p=0.0057). Conclusions KISS1 rs4889 and rs5780218 polymorphisms, as well as the G–CT haplotype, are associated with increased odds of PCOS in Indonesian women. These findings support a potential role of upstream neuroendocrine genetic variation in PCOS susceptibility; however, causal inferences cannot be drawn from this cross-sectional study. 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F1000Research 2026, 14 :889 ( https://doi.org/10.12688/f1000research.168971.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Research Article Revised rs4889 and rs5782018 polymorphisms of KISS1 gene as genetic predisposing factor for PCOS in Indonesian women [version 2; peer review: 2 approved, 1 approved with reservations] Gita Pratama https://orcid.org/0000-0001-5626-1283 1-3 , Ririn R Febri https://orcid.org/0000-0002-4558-3161 3 , Mila Maidarti 1-3 , [...] Budi Wiweko 1-3 , Asmarinah . 4 , Indah S Widyahening https://orcid.org/0000-0002-7952-2893 5 , Trinovita Andraini https://orcid.org/0000-0003-4264-7729 6 , Hartanto Bayuaji https://orcid.org/0000-0002-0832-7628 7 , Andon Hestiantoro https://orcid.org/0000-0001-7424-679X 1-3 , Mulyoto Pangestu https://orcid.org/0000-0001-5623-3995 8 Gita Pratama https://orcid.org/0000-0001-5626-1283 1-3 , Ririn R Febri https://orcid.org/0000-0002-4558-3161 3 , [...] Mila Maidarti 1-3 , Budi Wiweko 1-3 , Asmarinah . 4 , Indah S Widyahening https://orcid.org/0000-0002-7952-2893 5 , Trinovita Andraini https://orcid.org/0000-0003-4264-7729 6 , Hartanto Bayuaji https://orcid.org/0000-0002-0832-7628 7 , Andon Hestiantoro https://orcid.org/0000-0001-7424-679X 1-3 , Mulyoto Pangestu https://orcid.org/0000-0001-5623-3995 8 PUBLISHED 02 Feb 2026 Author details Author details 1 Reproductive Immunoendocrinology Division, Department of Obstetrics and Gynecology, University of Indonesia Faculty of Medicine, Jakarta, Special Capital Region of Jakarta, Indonesia 2 Yasmin IVF Clinic, Hospital Dr Cipto Mangunkusumo, Central Jakarta, Jakarta, Indonesia 3 Human Reproduction, Infertility, and Family Planning Cluster, Indonesia Reproductive Medicine Research and Training Center, University of Indonesia Faculty of Medicine, Jakarta, Special Capital Region of Jakarta, Indonesia 4 Department of Medical Biology, University of Indonesia Faculty of Medicine, Jakarta, Special Capital Region of Jakarta, Indonesia 5 Department of Community Medicine, University of Indonesia Faculty of Medicine, Jakarta, Special Capital Region of Jakarta, Indonesia 6 Department of Physiology, University of Indonesia Faculty of Medicine, Jakarta, Special Capital Region of Jakarta, Indonesia 7 Department of Obstetrics and Gynecology, University of Padjadjaran Faculty of Medicine, Bandung, West Java, Indonesia 8 Education Program in Reproduction and Development, Department of Obstetrics and Gynecology, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia Gita Pratama Roles: Conceptualization, Funding Acquisition, Methodology, Resources, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing Ririn R Febri Roles: Data Curation, Formal Analysis, Investigation, Methodology, Software, Writing – Original Draft Preparation, Writing – Review & Editing Mila Maidarti Roles: Conceptualization, Investigation, Methodology, Supervision, Writing – Review & Editing Budi Wiweko Roles: Conceptualization, Resources, Supervision, Validation, Writing – Review & Editing Asmarinah . Roles: Investigation, Methodology, Supervision, Writing – Review & Editing Indah S Widyahening Roles: Conceptualization, Investigation, Methodology, Resources, Software, Supervision, Writing – Review & Editing Trinovita Andraini Roles: Conceptualization, Methodology, Resources, Supervision, Writing – Review & Editing Hartanto Bayuaji Roles: Methodology, Resources, Supervision, Writing – Review & Editing Andon Hestiantoro Roles: Conceptualization, Methodology, Supervision, Writing – Review & Editing Mulyoto Pangestu Roles: Methodology, Resources, Supervision, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS This article is included in the Genomics and Genetics gateway. This article is included in the Cell & Molecular Biology gateway. Abstract Background Dysregulation of the HPG axis in PCOS causes increased frequency and amplitude of gonadotropin-releasing hormone (GnRH) pulsatility in the hypothalamus. Single nucleotide polymorphisms (SNPs) in the KISS1 gene may be associated with altered neuroendocrine signaling in PCOS. The present study aims to evaluate the association between two KISS1 polymorphisms (rs4889 and rs5780218), their haplotypes, and the odds of PCOS in Indonesian women. Methods A cross-sectional study was conducted at Yasmin Clinic, dr. Cipto Mangunkusumo General Hospital, Indonesia, involving 60 women with PCOS and 60 healthy controls. Hormonal levels were assessed using ELISA, and genomic DNA was analyzed by Sanger sequencing. Demographic data were compared using independent t-tests, and chi-square tests were used for genotype and allele frequency analysis. Results The genotypic distribution of rs4889 was significantly different between the PCOS and control groups (p<0.05), where the distribution of mutant genotype GG was higher in PCOS than in control (18.3% and 1.7%, respectively). The allele distribution of rs4889 and rs5782018 KISS1 SNPs were significantly different between both groups (p<0.01 and p<0.05, respectively). The rs4889 polymorphism was significantly different between the PCOS and control groups for the codominant and recessive models (p<0.01). Moreover, the rs5780218 polymorphism was significantly different between the PCOS and control groups for the codominant and dominant models (p<0.05). From the haplotype analysis, the G-CT haplotype was significantly different, with an OR value of 2.57 (1.33–4.96, p=0.0057). Conclusions KISS1 rs4889 and rs5780218 polymorphisms, as well as the G–CT haplotype, are associated with increased odds of PCOS in Indonesian women. These findings support a potential role of upstream neuroendocrine genetic variation in PCOS susceptibility; however, causal inferences cannot be drawn from this cross-sectional study. READ ALL READ LESS Keywords Haplotype, PCOS, polymorphism, rs4889, rs5780218 Corresponding Author(s) Gita Pratama ( [email protected] ) Close Corresponding author: Gita Pratama Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2026 Pratama G et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Pratama G, R Febri R, Maidarti M et al. rs4889 and rs5782018 polymorphisms of KISS1 gene as genetic predisposing factor for PCOS in Indonesian women [version 2; peer review: 2 approved, 1 approved with reservations] . F1000Research 2026, 14 :889 ( https://doi.org/10.12688/f1000research.168971.2 ) First published: 09 Sep 2025, 14 :889 ( https://doi.org/10.12688/f1000research.168971.1 ) Latest published: 02 Feb 2026, 14 :889 ( https://doi.org/10.12688/f1000research.168971.2 ) Revised Amendments from Version 1 This revised version improves methodological clarity, statistical reporting, and interpretative transparency in response to peer review. Causal language was removed from the abstract and conclusions, and findings are now presented as associations with PCOS. The Methods section was expanded to clarify participant recruitment, exclusions, diagnostic criteria, assay performance, and genotyping quality control. Statistical analyses were aligned with data distributions and reporting standards, and multivariable models adjusted for age, body mass index, and insulin resistance were added. The Results section was rewritten to ensure exact consistency with all tables, and a STROBE-adapted participant flow diagram was included. The Discussion was revised to acknowledge key limitations and contextualize findings within existing literature. This revised version improves methodological clarity, statistical reporting, and interpretative transparency in response to peer review. Causal language was removed from the abstract and conclusions, and findings are now presented as associations with PCOS. The Methods section was expanded to clarify participant recruitment, exclusions, diagnostic criteria, assay performance, and genotyping quality control. Statistical analyses were aligned with data distributions and reporting standards, and multivariable models adjusted for age, body mass index, and insulin resistance were added. The Results section was rewritten to ensure exact consistency with all tables, and a STROBE-adapted participant flow diagram was included. The Discussion was revised to acknowledge key limitations and contextualize findings within existing literature. See the authors' detailed response to the review by Mukhri Hamdan READ REVIEWER RESPONSES Introduction Polycystic ovary syndrome (PCOS) is a common and complex endocrine disorder characterized by clinical or biochemical hyperandrogenism, oligo-anovulation, and polycystic ovaries; it affects 6% to 10% of women of reproductive age. 1 The etiology of PCOS is not entirely understood. The complex pathogenesis involves hypothalamic-pituitary-gonadal (HPG) axis disturbances in gonadotropin secretion and increased LH levels. 2 , 3 Several previous studies have focused on investigating the genetic factors of the HPG axis related to PCOS and reported a disruption in the function of the HPG axis, causing increased frequency and amplitude of gonadotropin-releasing hormone (GnRH) pulsatility in the hypothalamus. 4 The KISS1 gene is considered to have an essential role in regulating gonadotropin secretion in the HPG axis and may be involved in the etiology of PCOS. KISS1 is located at 1q32 and encodes a premature 145-amino-acid protein. The major product of the KISS1 gene, kisspeptin, is a 54-amino acid peptide that was first identified as a melanoma metastasis-suppressor gene. 5 The binding of kisspeptin with its receptor (GPR54) in GnRH neurons of the hypothalamus activates the HPG axis, causing stimulation of gonadotropin release into the portal circulation. Gonadotropin binds the GnRH receptors in the anterior pituitary gland, consequently releasing and stimulating the activity of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). 5 , 6 Ovulatory dysfunction of PCOS is reflected biochemically through excessive production of LH and a low or normal level of FSH from the anterior pituitary gland. 7 A study showed potential pathophysiology involving KNDy neurons, which increased the NKB levels, decreased dynorphin levels, and elevated kisspeptin secretion, which resulted in increased LH levels and decreased FSH levels. 8 Kisspeptin may interfere with LH production in PCOS and disrupt ovarian function, prompting androgen hypersecretion in the theca interna cells of the ovarian follicles. 7 Although the prior studies have revealed the correlation between kisspeptin and the HPG axis, whether the serum kisspeptin concentration is higher in PCOS women compared to the general population remains inconclusive. Single nucleotide polymorphisms (SNPs) in the KISS1 gene could lead to the disruption of GnRH secretion by dysregulating HPG axis function and increasing the development of various diseases. Several studies have indicated that some SNPs in KISS1 may play a vital role in the etiopathogenesis of PCOS. 4 , 5 , 9 The current study determined the impact of KISS1 gene polymorphisms and haplotypes on the development of PCOS. Methods Subjects The study recruited 80 women with PCOS and 76 control women who attended a clinic in Jakarta, Indonesia. However, only sixty subjects for each group met the inclusion criteria. Written informed consent was obtained from each subject. All subjects were self-reported as having Indonesian ethnic origin. Sixty women with PCOS cases were diagnosed according to the Revised 2003 consensus on diagnostic criteria (Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group 2004), i.e., any two of the following three criteria: oligo- or anovulation, clinical and/or biochemical signs of hyperandrogenism, and polycystic ovary morphology determined by ultrasonography. 10 Oligo- or anovulation was determined by self-reported irregular menstrual cycles (menstruation occurring with a frequency more than 35 days in the year before enrollment). Hyperandrogenism was defined with hirsutism using a Ferriman-Gallwey score of more than eight, and/or the serum level of total testosterone greater than 60 ng/dl. Patients with any other cause of oligomenorrhea or hyperandrogenism, such as congenital adrenal hyperplasia, Cushing’s syndrome, hypothyroidism, or significant elevations in serum prolactin, were excluded. The transvaginal ultrasonography was used to assess the ovarian morphology for further stratified evidence of women with PCOS. A participant flow diagram is provided below in Figure 1 . Figure 1. Flow diagram of the participants. Sixty healthy women with regular menstrual cycles and without hyperandrogenism were recruited as controls. In addition to meeting these recruiting criteria, no subjects had taken medications known to alter the normal function of the HPG axis in the last 3 months. For all subjects, on the 3 rd to 5 th day of the menstrual cycle after overnight fasting, 5 ml whole-blood samples were obtained for both SNP analysis and reproductive hormone measurement. In subjects with PCOS, fasting blood insulin and fasting blood glucose were measured to determine insulin resistance. Analysis of the rs4889 and rs5780218 KISS1 genes Genomic DNA was isolated from the whole blood of women with PCOS and the control individuals using the Geneaid™ DNA Isolation Kit (Geneaid Biotech Ltd., New Taipei City, Taiwan) according to the manufacturer’s protocol. The rs4889 and rs5780218 variants of the KISS1 gene were amplified with polymerase chain reaction (PCR). The sequences of the rs4889 primers were 5’-CTA AGG TGA TCG TGG TT-3’ (forward primer) and 5’-CAG TTG TAG TTC GGC AGG T-3’ (reverse primer) with the product size 388 bp. The sequences of the rs5780218 primers were 5’-AAG GTG CCA TGC TCT TCA G-3’ (forward primer) and 5’-GGA TGC ATC TGT CCG TCT TAG-3’ (reverse primer) with the product size 332 bp. PCR amplification was carried out in a final volume of 20 μl containing 10 μl 2x SensiFAST SYBR ® No-ROX mix (Meridian Bioscience, Tennessee, USA), 10 μM of each primer, and 50 ng of genomic DNA. PCR was performed in a SEDI Thermal Cycler (Wealtec Bioscience Co., Ltd., New Taipei City, Taiwan) with the following conditions: 95°C for 2 min, followed by 35 cycles of 15 sec at 95°C, 15 sec at 56°C, and 10 sec at 72°C. The single-band PCR products were visualized on a 1.6% agarose gel with GelRed ® Nucleic Acid gel staining (Biotium Inc., Fremont, CA, USA). For those subjects with a single band, the PCR products were directly sequenced using an ABI PRISM 3100 Genetic Analyzer (ABI, Applied Biosystems, Foster City, CA, USA), and each set of reactions was run with positive and negative controls. Hormone measurements Levels of total testosterone (T), follicle-stimulating hormone (FSH), luteinizing hormone (LH), insulin, prolactin and sex-hormone binding globulin were measured using TOSOH (Tosoh India Pvt. Ltd., Mumbai, India) according to the manufacturer’s protocols. The level of kisspeptin was measured using a Human KISS1 (Kisspeptin 1) ELISA kit (Elabscience, Texas, USA). Samples were processed under standardized preanalytical conditions and stored at −80°C until analysis. Statistical analysis The data are presented as the mean ± SE (standard error) for demographic (age, body mass index (BMI), waist circumference, hip circumference, and waist-hip ratio) and endocrine (kisspeptin, prolactin, testosterone, SHBG, free androgen index (FAI), LH, FSH, LH-FSH ratio, insulin, fasting blood glucose, and homeostatic model assessment for insulin resistance (HOMA-IR)) characteristics. The independent t test was used to determine the differences in the variables between two groups. The chi-square test was carried out for the statistical analysis of the genotype and allele distribution of the polymorphisms, as well as to verify the Hardy-Weinberg Equilibrium (HWE). A value of p < 0.05 was considered to indicate significance. The statistical analysis was performed using Prism 5 software (GraphPad Software). The sanger sequencing data was analyzed using the Tracy’s web application (available at https://www.gear-genomics.com ). The logistic regression model was calculated using the SNPStats program (available at https://bioinfo.iconcologia.net/index.php?module=Snpstats ). It was also used to evaluate the association between polymorphisms and the development of PCOS. The effect of polymorphisms was evaluated by the following models: (1) codominant (wild-type homozygote x heterozygote x polymorphic homozygote); (2) dominant (wild-type homozygote x heterozygote + polymorphic homozygote); (3) recessive (polymorphic homozygote x wild-type + heterozygote homozygote); and (4) overdominant (wild-type homozygote + polymorphic homozygote x heterozygote). The best inheritance model was assessed using the Akaike information criteria (AIC) and the Bayesian information criteria (BIC), and the model with the lowest values was considered the best fit. The haplotype frequencies for multiple loci and the standardized disequilibrium coefficient (D’) for pairwise linkage disequilibrium (LD) from KISS1 gene polymorphisms were inferred using the SNPStats program, checking the estimated population frequency of haplotypes. The LD level was defined as strong LD (D’ > 0.8), moderate LD (0.4 < D’ ≤ 0.8), and weak LD (D’ ≤ 0.4). 11 The results are presented as odds ratios (ORs) and 95% confidence intervals (CIs: 95%), with the level of statistical significance defined as p < 0.05. Results A total of 120 women were included in the final analysis, comprising 60 women with PCOS and 60 control women. Median age did not differ significantly between the control group (24.0 years, range 17.0–40.0) and the PCOS group (26.0 years, range 18.0–35.0; p = 0.087). There were no statistically significant differences between groups in body mass index, waist circumference, hip circumference, or waist–hip ratio (all p > 0.05). Circulating kisspeptin levels were not significantly different between groups (control: median 259.77 pg/mL [20.65–1580.36] vs PCOS: median 111.26 pg/mL [20.73–1442.05]; p = 0.128). Women with PCOS had significantly higher total testosterone levels, free androgen index (FAI), luteinizing hormone (LH), LH/FSH ratio, fasting insulin, and HOMA-IR, and significantly lower sex hormone–binding globulin (SHBG) levels compared with controls (all p < 0.05). Follicle-stimulating hormone (FSH), prolactin, and fasting blood glucose levels did not differ significantly between groups. These data are summarized in Table 1 . Table 1. Demographic and endocrine characteristics of study subjects. Characteristics Control (n = 60) PCOS (n = 60) p value Age (years) 24.00 (17.00–40.00) 26.00 (18.00–35.00) 0.087 Body mass index (kg/m 2 ) 23.85 (18.50–39.40) 24.45 (18.50–42.30) 0.144 Waist circumference (cm) 76.00 (61.00–112.00) 79.50 (61.00–120.00) 0.075 Hip circumference (cm) 95.00 (77.00–135.00) 97.75 (78.00–145.00) 0.116 Waist-hip ratio 0.80 ± 0.01 0.81 ± 0.01 0.646 Kisspeptin (pg/ml) 259.77 (20.65–1580.36) 111.26 (20.73–1442.05) 0.128 Testosterone total (ng/dl) 40.03 (2.93–559.36) 71.01 (7.80–184.08) 0.000 * SHBG (nmol/l) 66.59 (7.53–174.65) 37.00 (14.12–429.52) 0.000 * Free androgen index (FAI) 2.41 (0.17–30.38) 5.96 (0.54–32.02) 0.000 * Prolactin (ng/ml) 8.5 (4.10–40.80) 8.1 (2.50–79.40) 0.213 LH (mIU/ml) 4.55 (0.60–172.00) 10.20 (2.30–28.60) 0.000 * FSH (mIU/ml) 5.75 (1.40–21.70) 7.1 (1.90–10.90) 0.051 LH-FSH ratio 0.79 (.15–7.93) 1.45 (0.52–3.25) 0.000 * Insulin (mIU/l) 7.30 (2.60–37.80) 10.30 (2.30–135.30) 0.022 * Fasting blood glucose (mg/dl) 92.00 (74.00–118.00) 94.00 (74.00–125.00) 0.270 HOMA-IR 1.70 (0.58–86.00) 2.48 (0.52–32.74) 0.032 * * p 0.05). Tracy’s web application was used for analyzing chromatogram trace file from the sanger sequencing data. The result of chromatogram for rs4889 and rs5780218 was shown in Figure 2 . For rs4889, the distribution of genotypes differed significantly between PCOS and control groups (p = 0.006). The GG genotype was more frequent in women with PCOS (18.3%) than in controls (1.7%). The frequencies of CC and CG genotypes were 31.7% and 50.0% in the PCOS group, and 46.7% and 51.6% in the control group, respectively ( Table 2 ). Figure 2. Chromatograms of PCR amplicon sequencing showing the DNA change in women with PCOS compared to control. (A) The comparison between wild type and mutant genotypes of rs4889. (B) The comparison between wild type and deletion genotypes of rs5780218. Table 2. Genotype frequencies of rs4889 and rs5780218 of the KISS1 gene. SNPs Genotypes Frequency p value Control n (%) PCOS n (%) Total n (%) rs4889 CC 28 (46.7) 19 (31.7) 47 (39.2) 0.006 * CG 31 (51.6) 30 (50.0) 61 (50.8) GG 1 (1.7) 11 (18.3) 12 (10.0) Total 60 (100.0) 60 (100.0) 120 (100.0) rs5780218 CTT/CTT 23 (38.4) 12 (20.0) 35 (29.2) 0.065 CTT/CT 31 (51.6) 37 (61.7) 68 (56.7) CT/CT 6 (10.0) 11 (18.3) 17 (14.1) Total 60 (100.0) 60 (100.0) 120 (100.0) * p < 0.05. For rs5780218, genotype distributions did not differ significantly between groups (p = 0.065). The frequencies of the CTT/CTT, CTT/CT, and CT/CT genotypes in the PCOS group were 20.0%, 61.7%, and 18.3%, respectively, compared with 38.4%, 51.6%, and 10.0% in controls ( Table 2 ). Allele frequency analysis showed significant differences between PCOS and control groups for both polymorphisms. For rs4889, the G allele frequency was higher in the PCOS group than in controls (45.0% vs 27.5%), corresponding to an unadjusted odds ratio (OR) of 2.16 (95% CI 1.26–3.70; p = 0.0005). For rs5780218, the CT allele frequency was higher in the PCOS group than in controls (50.0% vs 35.8%), with an OR of 1.79 (95% CI 1.07–3.00; p = 0.027) ( Table 3 ). Table 3. Allele frequencies of rs4889 and rs5780218 of the KISS1 gene. SNPs Allele Frequency Total n (%) Odds ratio (95% CI) p value Control n (%) PCOS n (%) rs4889 C 87 (72.5) 66 (55.0) 153 (63.7) 2.157 (1.259–3.696) 0.0005 * G 33 (27.5) 54 (45.0) 87 (36.3) Total 120 (100.0) 120 (100.0) 240 (100.0) rs5780218 CTT 77 (64.2) 60 (50.0) 137 (57.1) 1.791 (1.068–3.003) 0.027 * CT 43 (35.8) 60 (50.0) 103 (42.9) Total 120 (100.0) 120 (100.0) 240 (100.0) * p < 0.05. Logistic regression analyses were performed under multiple inheritance models ( Table 4 ). For rs4889, a significant association with PCOS was observed under the codominant model (p = 0.0017) and the recessive model (p < 0.001). Under the recessive model, carriers of the GG genotype had higher odds of PCOS compared with CC/CG genotypes (OR 14.75, 95% CI 1.85–117.51). The recessive model showed the lowest AIC and BIC values, indicating the best fit among tested models. Table 4. Associations of the rs4889 and rs5780218 polymorphisms of the KISS1 gene with PCOS. Model Genotype Control n (%) PCOS n (%) OR (95% CI) p value AIC BIC rs4889 Codominant C/C 28 (46.7) 19 (31.7) 1.00 0.0017 * 159.6 167.9 C/G 31 (51.7) 29 (48.3) 1.38 (0.64-2.98) G/G 1 (21.7) 12 (20) 17.68 (2.12–147.56) Dominant C/C 28 (46.7) 19 (31.7) 1.00 0.092 167.5 173.1 C/G-G/G 32 (53.3) 41 (68.3) 1.89 (0.90–3.97) Recessive C/C-C/G 59 (98.3) 48 (80) 1.00 0.000 * * 158.3 163.8 G/G 1 (1.7) 12 (20) 14.75 (1.85–117.51) Overdominant C/C-G/G 29 (48.3) 31 (51.7) 1.00 0.72 170.2 175.8 C/G 31 (51.7) 29 (48.3) 0.88 (0.43–1.79) rs5780218 Codominant CTT/CTT 24 (40.0) 12 (20.0) 1.00 0.036 * 165.7 174.1 CTT/CT 30 (50.0) 36 (60.0) 2.40 (1.03–5.59) CT/CT 6 (10.0) 12 (20.0) 4.00 (1.20–13.28) Dominant CTT/CTT 24 (40.0) 12 (20.0) 1.00 0.016 * 164.6 170.1 CTT/CT-CT/CT 36 (60.0) 48 (80.0) 2.67 (1.18–6.03) Recessive CTT/CTT-CTT/CT 54 (90.0) 48 (80.0) 1.00 0.12 168.0 173.5 CT/CT 6 (10.0) 12 (20.0) 2.25 (0.78–6.46) Overdominant CTT/CTT-CT/CT 30 (50.0) 24 (40.0) 1.00 0.27 169.1 174.7 CTT/CT 30 (50.0) 36 (60.0) 1.50 (0.73–3.09) * p < 0.05. For rs5780218, significant associations were observed under the codominant (p = 0.036) and dominant (p = 0.016) models. Under the dominant model, carriers of at least one CT allele (CTT/CT or CT/CT) had higher odds of PCOS compared with the CTT/CTT genotype (OR 2.67, 95% CI 1.18–6.03). The dominant model demonstrated the lowest AIC and BIC values. Multivariable logistic regression analyses adjusting for age, body mass index, and HOMA-IR showed effect estimates consistent in direction with unadjusted analyses, although confidence intervals widened, reflecting limited power for rare genotypes. Linkage disequilibrium analysis between rs4889 and rs5780218 demonstrated strong LD (D′ = 0.864). Haplotype analysis identified four haplotypes. The C–CTT haplotype was the most frequent and served as the reference. The G–CT haplotype was more frequent in women with PCOS than in controls (0.403 vs 0.298) and was associated with increased odds of PCOS (OR 2.57, 95% CI 1.33–4.96; p = 0.0057). Other haplotypes (C–CT and G–CTT) were not significantly associated with PCOS ( Table 5 ). Table 5. Construction of the haplotypes of the two SNPs in the KISS1 gene. No rs4889 rs5780218 Control Freq. Case Freq. Total Freq. OR (95% CI) p value 1 C CTT 0.606 0.429 0.542 1.00 - 2 G CT 0.298 0.403 0.3254 2.57 (1.33–4.96) 0.0057 * 3 C CT 0.069 0.138 0.0996 1.38 (0.56–3.37) 0.49 4 G CTT 0.027 0.030 0.033 1.81 (0.36–9.18) 0.48 * The values have significant differences (p < 0.05). Discussion Impaired negative feedback from ovarian steroid hormones to the GnRH neuronal network is a crucial pathological feature of PCOS. 12 This alteration likely drives abnormalities in the neuroendocrine axis, which regulates fertility and primarily mediates downstream ovarian dysfunction. Women with PCOS demonstrate persistently rapid GnRH pulse frequency. This leads to LH pulsatility elevation and FSH deficiency and contributes to increases in LH concentrations and LH:FSH ratios, which are typical of PCOS. 13 Since GnRH neurons do not have specific receptors for steroid hormones, it is essential to understand the pathways involved in dysfunctional GnRH release. Kisspeptin is a potential candidate for stimulating the activity of GnRH and thus increasing LH levels. We found that the serum level of kisspeptin was lower in women with PCOS than in healthy control individuals. In contrast with our results, several studies showed a higher expression level of kisspeptin in PCOS. 7 , 14 – 16 The low level of kisspeptin is possibly caused by the different pathways determining the relationship between kisspeptin and reproduction control that involve the complex mechanisms that regulate HPG function and reproductive physiology. 17 In the hypothalamus, kisspeptin cells are located in the anteroventral periventricular (AVPV) and arcuate (ARC) nuclei. 18 In the ARC, the expression of KISS1 mRNA is inhibited by testosterone. Moreover, the free androgen index (FAI) is correlated with the kisspeptin level. In this study, the expression levels of testosterone and FAI were higher in PCOS patients than in control individuals. Then, we suspected that a low kisspeptin level was associated with increased testosterone levels and FAI values in this study. Excess levels of androgen and FAI in PCOS are fundamental hormonal problems that might be caused by several upstream factors in neuroendocrine regulation, including the alteration of LH pulsatility. 19 Our results demonstrated higher levels of LH, a lower FSH level, and a higher LH to FSH ratio in PCOS women than in control individuals. An elevated LH pulse frequency, increased serum LH concentration, and high LH-to-FSH ratio are common clinical characteristics of PCOS. These phenomena consequently affect the downstream pathway in the ovary; this includes the over synthesis of androgen in theca cells, leading to excess androgen production. 20 Low levels of FSH contribute to follicular arrest, preventing ovulation in PCOS women. 21 Multiple factors are more likely to cause PCOS since several mechanisms are involved in developing the disease. 3 However, due to the heterogeneity and uncertain etiology of PCOS, genes involved in PCOS are challenging to identify. Several genes have been identified as susceptible loci in previous genome-wide association studies (GWAS), including genes associated with steroid biosynthesis and gonadotropic secretion. 22 KISS1 may also be subjected to mutations and polymorphisms. 6 The neuropeptide kisspeptin induces the activity of GnRH neurons, consequently releasing GnRH. Since KISS1 acts in the upstream pathway of GnRH, disruption in KISS1 might affect GnRH signaling, especially in PCOS. The involvement of the alterations in the hypothalamic-pituitary-gonadal (HPG) axis, especially the polymorphisms of KISS1 gene loci, was evaluated. Using Sanger sequencing, we detected two sites of polymorphisms, rs4889 and rs5780218. The results revealed a significantly higher frequency of the homozygous mutant genotype GG of rs4889 in PCOS patients than in control individuals, but no significant differences in the genotype distribution of rs5780218 were observed. The rs4889 polymorphism changes a CCC codon to CGC, resulting in the substitution of the amino acid proline by arginine, consequently disrupting the ability of kisspeptin to find its receptor. A previous study on the Saudi population also demonstrated similar results to our finding in the genotype distribution of rs4889. 9 In contrast with our results, a study in the Sri Lankan population by Branavan et al. demonstrated no association of rs4889 and rs5780218 with PCOS. 23 The frequencies of the G allele in rs4889 and CT in rs5780218 were also significantly higher in women with PCOS than in healthy control individuals, suggesting a strong association between KISS1 polymorphisms and an increased risk of PCOS. In addition, our findings also revealed that rs4889 C > G was linked in the codominant and recessive models. Moreover, rs5782018 CTT > CT was connected with the codominant and dominant model. Genetic variation is best described by groups of associated polymorphisms, called haplotypes. 24 Haplotype analysis was performed to find the most susceptible haplotype associated with PCOS. Our present data found that the presence of G-CT haplotypes was associated with an increased risk of PCOS. In summary, our results suggest that the KISS1 rs4889 and rs5780218 gene variants could be genetic predisposing factors for PCOS. Furthermore, we found that the risk haplotype G-CT in the KISS1 gene correlated with PCOS. Conclusions KISS1 rs4889 and rs5780218 polymorphisms and the G–CT haplotype are associated with increased odds of PCOS in Indonesian women. These findings support further investigation of upstream neuroendocrine genetic contributors to PCOS pathophysiology in larger and longitudinal studies. Ethics approval This study was conducted in accordance with the principles of the Declaration of Helsinki ( https://www.wma.net/policies-post/wma-declaration-of-helsinki/ ). Ethical approval was obtained from the Ethics Committee of the Faculty of Medicine, University of Indonesia – Cipto Mangunkusumo Hospital (Approval No. 23-12-2107) prior to commencement of the study. Data availability Open Science Framework: DATA - rs4889 and rs5782018 polymorphisms of KISS1 gene as genetic predisposing factor for PCOS in Indonesian women. https://doi.org/10.17605/OSF.IO/KFM6C . 25 The dataset underlying this study are available in the Open Science Framework (OSF) repository and can be accessed at: https://osf.io/kfm6c/ (DOI: 10.17605/OSF.IO/KFM6C). 25 All data are shared under a Creative Commons Attribution 4.0 International Public License (CC-BY 4.0 license). The repository includes the raw and processed data used in the analyses, including values underlying summary statistics, data used to generate figures, and any points extracted from images for analysis. No restrictions apply to data access. Acknowledgements Not applicable. References 1. 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Iervolino M, Lepore E, Forte G, et al. : Natural Molecules in the Management of Polycystic Ovary Syndrome (PCOS): An Analytical Review. Nutrients. 2021; 13 : 1–12. Publisher Full Text 20. Morshed S, Banu H, Akhtar N, et al. : Luteinizing Hormone to Follicle-Stimulating Hormone Ratio Significantly Correlates With Androgen Level and Manifestations Are More Frequent With Hyperandrogenemia in Women With Polycystic Ovary Syndrome. J. Endocrinol. Metab. 2021; 11 (1): 14–21. Publisher Full Text 21. Johansson J, Stener-victorin E: Polycystic Ovary Syndrome: Effect and Mechanisms of Acupuncture for Ovulation Induction. Evid. Based Complement. Alternat. Med. 2013; 2013 : 1–16. PubMed Abstract | Publisher Full Text | Free Full Text 22. Nautiyal H, Imam SS, Alshehri S, et al. : Polycystic Ovarian Syndrome: A Complex Disease with a Genetics Approach. Biomedicine. 2022; 10 (3): 1–26. 23. Branavan U, Muneeswaran K, Wijesundera WSS, et al. : Association of Kiss1 and GPR54 Gene Polymorphisms with Polycystic Ovary Syndrome among Sri Lankan Women. Biomed. Res. Int. 2019; 2019 (1996): 1–10. PubMed Abstract | Publisher Full Text | Free Full Text 24. Snyder MW, Adey A, Kitzman JO, et al. : Haplotype-resolved genome sequencing: Experimental methods and applications. Nat. Rev. Genet. 2015; 16 (6): 344–358. PubMed Abstract | Publisher Full Text 25. Pratama G, Febri RR, Maidarti M, et al. : DATA - rs4889 and rs5782018 polymorphisms of KISS1 gene as genetic predisposing factor for PCOS in Indonesian women. [Dataset]. 2025, August 6. Publisher Full Text Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 09 Sep 2025 ADD YOUR COMMENT Comment Author details Author details 1 Reproductive Immunoendocrinology Division, Department of Obstetrics and Gynecology, University of Indonesia Faculty of Medicine, Jakarta, Special Capital Region of Jakarta, Indonesia 2 Yasmin IVF Clinic, Hospital Dr Cipto Mangunkusumo, Central Jakarta, Jakarta, Indonesia 3 Human Reproduction, Infertility, and Family Planning Cluster, Indonesia Reproductive Medicine Research and Training Center, University of Indonesia Faculty of Medicine, Jakarta, Special Capital Region of Jakarta, Indonesia 4 Department of Medical Biology, University of Indonesia Faculty of Medicine, Jakarta, Special Capital Region of Jakarta, Indonesia 5 Department of Community Medicine, University of Indonesia Faculty of Medicine, Jakarta, Special Capital Region of Jakarta, Indonesia 6 Department of Physiology, University of Indonesia Faculty of Medicine, Jakarta, Special Capital Region of Jakarta, Indonesia 7 Department of Obstetrics and Gynecology, University of Padjadjaran Faculty of Medicine, Bandung, West Java, Indonesia 8 Education Program in Reproduction and Development, Department of Obstetrics and Gynecology, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia Gita Pratama Roles: Conceptualization, Funding Acquisition, Methodology, Resources, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing Ririn R Febri Roles: Data Curation, Formal Analysis, Investigation, Methodology, Software, Writing – Original Draft Preparation, Writing – Review & Editing Mila Maidarti Roles: Conceptualization, Investigation, Methodology, Supervision, Writing – Review & Editing Budi Wiweko Roles: Conceptualization, Resources, Supervision, Validation, Writing – Review & Editing Asmarinah . Roles: Investigation, Methodology, Supervision, Writing – Review & Editing Indah S Widyahening Roles: Conceptualization, Investigation, Methodology, Resources, Software, Supervision, Writing – Review & Editing Trinovita Andraini Roles: Conceptualization, Methodology, Resources, Supervision, Writing – Review & Editing Hartanto Bayuaji Roles: Methodology, Resources, Supervision, Writing – Review & Editing Andon Hestiantoro Roles: Conceptualization, Methodology, Supervision, Writing – Review & Editing Mulyoto Pangestu Roles: Methodology, Resources, Supervision, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (2) version 2 Revised Published: 02 Feb 2026, 14:889 https://doi.org/10.12688/f1000research.168971.2 version 1 Published: 09 Sep 2025, 14:889 https://doi.org/10.12688/f1000research.168971.1 Copyright © 2026 Pratama G et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Pratama G, R Febri R, Maidarti M et al. rs4889 and rs5782018 polymorphisms of KISS1 gene as genetic predisposing factor for PCOS in Indonesian women [version 2; peer review: 2 approved, 1 approved with reservations] . F1000Research 2026, 14 :889 ( https://doi.org/10.12688/f1000research.168971.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 2 VERSION 2 PUBLISHED 02 Feb 2026 Revised Views 0 Cite How to cite this report: Ahmad MF. Reviewer Report For: rs4889 and rs5782018 polymorphisms of KISS1 gene as genetic predisposing factor for PCOS in Indonesian women [version 2; peer review: 2 approved, 1 approved with reservations] . F1000Research 2026, 14 :889 ( https://doi.org/10.5256/f1000research.194949.r468339 ) The direct URL for this report is: https://f1000research.com/articles/14-889/v2#referee-response-468339 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 15 Apr 2026 Mohd Faizal Ahmad , Department of Obstetrics & Gynecology, Faculty of Medicine, National University of Malaysia, Kuala Lumpur, Malaysia Approved VIEWS 0 https://doi.org/10.5256/f1000research.194949.r468339 Strengths This study explores an important and timely topic by examining KISS1 gene polymorphisms in relation to PCOS, focusing on how these genes may affect the neuroendocrine regulation of the HPG axis. The link between kisspeptin signaling, GnRH pulsatility, ... Continue reading READ ALL Strengths This study explores an important and timely topic by examining KISS1 gene polymorphisms in relation to PCOS, focusing on how these genes may affect the neuroendocrine regulation of the HPG axis. The link between kisspeptin signaling, GnRH pulsatility, and PCOS is well explained and fits with current scientific knowledge. Including an Indonesian cohort adds valuable genetic data from a group that is often underrepresented in this research area. The study uses Sanger sequencing for genotyping and analyzes genotypes, allele frequencies, inheritance models, and haplotypes, which strengthens its methods. Finding a significant G–CT haplotype linked to higher odds of PCOS adds depth beyond just looking at single SNPs. The clinical and hormonal profiles of participants also match classic PCOS features, which supports the reliability of the data. Weaknesses The main weakness of this study is its small sample size, which reduces statistical power and may lead to overestimation of effect sizes, especially for rare genotypes such as rs4889 GG. The study lacks a power calculation, which makes it harder to assess the strength of the results. Testing multiple genetic models without correcting for multiple comparisons could lead to false positives. Details on genotyping quality control, such as call rates and replicate agreement, are not fully reported, which affects the reproducibility of the findings. The study also uses self-reported menstrual history to diagnose oligo-ovulation, which could introduce recall bias, and relies on immunoassay-based testosterone measurements without discussing their limitations. The conclusions about kisspeptin are somewhat overstated, given the lack of significant differences. There are also some inconsistencies in how statistics are reported and minor issues with genetic terminology. Finally, the analyses do not clearly adjust for potential confounders such as BMI and insulin resistance, and using self-reported ethnicity could introduce population stratification bias. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Reproductive & Oncofertility I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Ahmad MF. Reviewer Report For: rs4889 and rs5782018 polymorphisms of KISS1 gene as genetic predisposing factor for PCOS in Indonesian women [version 2; peer review: 2 approved, 1 approved with reservations] . F1000Research 2026, 14 :889 ( https://doi.org/10.5256/f1000research.194949.r468339 ) The direct URL for this report is: https://f1000research.com/articles/14-889/v2#referee-response-468339 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Version 1 VERSION 1 PUBLISHED 09 Sep 2025 Views 0 Cite How to cite this report: Al-Ouqaili MTS. Reviewer Report For: rs4889 and rs5782018 polymorphisms of KISS1 gene as genetic predisposing factor for PCOS in Indonesian women [version 2; peer review: 2 approved, 1 approved with reservations] . F1000Research 2026, 14 :889 ( https://doi.org/10.5256/f1000research.186221.r445139 ) The direct URL for this report is: https://f1000research.com/articles/14-889/v1#referee-response-445139 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 05 Jan 2026 Mushtak T. S. Al-Ouqaili , Department of Microbiology, University of Anbar, College of Medicine, Ramadi, Iraq Approved VIEWS 0 https://doi.org/10.5256/f1000research.186221.r445139 Dear Editor, This manuscript introduces a unique concept in an area that is both intriguing and important for medical research. The topic is timely and is likely to engage the journal's readers. Additionally, the manuscript is well-written, presenting ... Continue reading READ ALL Dear Editor, This manuscript introduces a unique concept in an area that is both intriguing and important for medical research. The topic is timely and is likely to engage the journal's readers. Additionally, the manuscript is well-written, presenting ideas clearly and logically. Dear Authors, You are doing excellent work, and this manuscript reflects a great deal of effort and thoughtful research. The study is promising and contributes meaningfully to the field. However, there are a few important points that require further clarification and revision to enhance the overall quality and impact of the manuscript. The introduction provides a comprehensive overview of PCOS and the hypothesised role of the KISS1 gene; however, the specific knowledge gap addressed by the current study should be stated more explicitly. While conflicting evidence regarding serum kisspeptin levels and KISS1 polymorphisms is mentioned, the introduction would benefit from a clearer explanation of why existing studies are insufficient and how the present study advances the field. It is preferred to use the following reference to support your updated citations: (refer to 1) The reported prevalence of PCOS (6%–10%) is appropriate; however, the diagnostic criteria used in cited studies (e.g., NIH, Rotterdam, or AES) are not specified. Given that PCOS prevalence varies considerably depending on diagnostic criteria, the authors should clarify this to improve interpretability and contextual accuracy. Although the introduction discusses the physiological role of kisspeptin in GnRH and gonadotropin regulation, the mechanistic pathway linking KISS1 SNPs to PCOS pathogenesis remains somewhat speculative. A more detailed explanation of how specific polymorphisms may alter kisspeptin expression or function would strengthen the biological plausibility of the study hypothesis. It is preferred to use the following reference to support your updated citations: (refer to 2) The discussion of KNDy neurons is relevant but underdeveloped. The authors should expand on how alterations in neurokinin B, dynorphin, and kisspeptin signaling specifically contribute to PCOS-related neuroendocrine dysfunction and how this supports investigating KISS1 gene variants. The final sentence states that the study determined the impact of KISS1 gene polymorphisms and haplotypes on PCOS development. This objective would benefit from greater specificity, including which polymorphisms or haplotypes were analyzed and whether the focus is on association, causation, or functional prediction. It is preferred to use the following reference to support your updated citations: • (refer to 3) The manuscript states that 80 women with PCOS and 76 controls were initially recruited, but only 60 participants per group met the inclusion criteria. The specific reasons for exclusion (e.g., incomplete data, failure to meet diagnostic criteria, withdrawal of consent) should be explicitly described to enhance transparency and reproducibility. Oligo- or anovulation was determined solely based on self-reported menstrual cycle frequency, which may be subject to recall bias. The authors should clarify whether menstrual history was corroborated with clinical records or supported by biochemical markers (e.g., mid-luteal progesterone), particularly given the diagnostic importance of ovulatory dysfunction in PCOS. Although hyperandrogenism was defined using Ferriman–Gallwey scores and serum total testosterone levels, the manuscript lacks detail regarding: The assessor training or blinding for Ferriman–Gallwey scoring, and The assay method, timing, and reference ranges for testosterone measurement. These details are essential for ensuring diagnostic consistency and comparability with other studies. Participants were described as “self-reported as having Indonesian ethnic origin.” While this helps reduce population stratification bias, the authors should acknowledge the limitations of self-reported ethnicity, particularly in genetic association studies, and consider discussing whether sub-ethnic heterogeneity was assessed or controlled. The Results section refers to comparisons between “lean and obese groups” and mentions “four groups”; however, this stratification is not clearly introduced or defined in the Methods or at the beginning of the Results. The authors should explicitly describe how subjects were categorized (e.g., BMI cutoffs) and ensure consistency between Methods, Tables, and Results. The manuscript reports median ages and median kisspeptin levels but does not consistently indicate whether other variables are presented as means ± SE or medians (IQR). This inconsistency makes interpretation difficult. The authors should clarify which variables were normally distributed, justify the choice of statistical descriptors, and ensure alignment with the statistical tests used. Although no statistically significant difference in kisspeptin levels was observed, the Results section still emphasizes the lower median value in the PCOS group. This observation should be reported cautiously and without implying biological relevance unless supported by statistical significance or effect size analysis. There appears to be confusion in allele nomenclature, particularly for rs5780218 (e.g., reference to a “CT allele”). Alleles should be clearly distinguished from genotypes. The authors must revise this section to ensure correct and unambiguous genetic terminology. It is preferred to use the following reference to support your updated citations: (refer to 4 ) The Discussion appropriately acknowledges conflicting reports regarding serum kisspeptin levels in PCOS; however, the interpretation remains largely speculative. The authors should more clearly distinguish between central (hypothalamic) kisspeptin signalling and circulating kisspeptin levels, as serum measurements may not accurately reflect hypothalamic activity. This distinction is critical for reconciling discrepancies with studies reporting elevated kisspeptin expression in PCOS. It is preferred to use the following reference to support your updated citations: (refer to 5) Conclusion should be objective, with further perspective,e or should add at least a few sentences about future study/future perspective of .it Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes References 1. Abdul-Lateef W, Al-Ouqaili M, Murshid R: Association of FokI, Tru91, and ApaI vitamin D receptor gene polymorphisms with the development of polycystic ovarian syndrome: A molecular genetic study. Journal of King Saud University - Science . 2024; 36 (11). Publisher Full Text 2. Kanaan B, Al-Ouqaili M, Murshid R: Cytogenetic screening of chromosomal abnormalities and genetic analysis of FSH receptor Ala307Thr and Ser680Asn genes in amenorrheic patients. PeerJ . 2023; 11 . Publisher Full Text 3. Abdul-Late W, Salih Al-O M, Murshid R: Association Between NsiI and PmLI Insulin Receptors on the Development of Polycystic Ovarian Syndrome. Pakistan Journal of Biological Sciences . 2024; 27 (11): 526-536 Publisher Full Text 4. Taha R, Al-Ouqaili M, Abdullah S: The Association of Anti-Mullerian Hormone and Infertility Hormonal Imbalance with Polycystic Ovarian Syndrome Among Iraqi Patients. Pakistan Journal of Biological Sciences . 2023; 26 (5): 241-248 Publisher Full Text 5. Kanaan B, Al-Ouqaili M, Murshed R: In terms of the PCR-RFLP technique, genetic screening of Ala575Val inactivating mutation in patients with amenorrhea. Journal of Emergency Medicine, Trauma and Acute Care . 2022; 2022 (6). Publisher Full Text Competing Interests: No competing interests were disclosed. Reviewer Expertise: Molecular Biology, Microbiology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Al-Ouqaili MTS. Reviewer Report For: rs4889 and rs5782018 polymorphisms of KISS1 gene as genetic predisposing factor for PCOS in Indonesian women [version 2; peer review: 2 approved, 1 approved with reservations] . F1000Research 2026, 14 :889 ( https://doi.org/10.5256/f1000research.186221.r445139 ) The direct URL for this report is: https://f1000research.com/articles/14-889/v1#referee-response-445139 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Hamdan M. Reviewer Report For: rs4889 and rs5782018 polymorphisms of KISS1 gene as genetic predisposing factor for PCOS in Indonesian women [version 2; peer review: 2 approved, 1 approved with reservations] . F1000Research 2026, 14 :889 ( https://doi.org/10.5256/f1000research.186221.r413858 ) The direct URL for this report is: https://f1000research.com/articles/14-889/v1#referee-response-413858 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 16 Sep 2025 Mukhri Hamdan , Universiti Malaya, Kuala Lumpur, Federal Territory of Kuala Lumpur, Malaysia Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.186221.r413858 Congratulations on a great research report. It focuses on an upstream neuroendocrine gene (KISS1) with mechanistic plausibility, also including haplotype analysis, Day 3–5 sampling attempt, and exclusion of recent HPG-altering medications with open data availability. Here are the ... Continue reading READ ALL Congratulations on a great research report. It focuses on an upstream neuroendocrine gene (KISS1) with mechanistic plausibility, also including haplotype analysis, Day 3–5 sampling attempt, and exclusion of recent HPG-altering medications with open data availability. Here are the issues identified: Primary outcome specification. The manuscript does not pre-specify a single primary genetic model/outcome; multiple inheritance models are tested across two SNPs (± haplotypes). Sample size and power : No a priori power calculation is provided; small genotype cell counts (e.g., rs4889 GG) inflate ORs and widen CIs. Need to add an a priori (or post-hoc, with caveats) power analysis indicating detectable OR at α (after correction) for your MAF. Interpret large ORs from rare genotypes cautiously. Recruitment flow & attrition recruited 80 PCOS and 76 controls, but analyzed 60+60; reasons for exclusion are not detailed. Can you provide a CONSORT-style flow diagram with reasons for exclusion and any differences between included vs excluded? Group definition and stratification Results text refers to “four groups” (lean vs obese strata), but Methods define only cases/controls; BMI cut-offs not specified. Please clearly define BMI strata (cut-points, rationale), when this stratification was planned, and where those subgroup results appear (tables/appendix). Align wording (two vs four groups). Normality, summary measures, and test. Text says data are “mean ± SE” and “independent t-test” used, yet tables present medians (ranges), and several variables are non-normal. Please reassess distributions; report appropriate central tendency (mean±SD for normal; median[IQR] for skewed) and use Mann-Whitney U where needed. Ensure test choice matches what’s reported in tables. Genotyping quality control: Limited QC details for Sanger calls (call rate, duplicate concordance, blinded repeats). Can you report per-SNP call rate, sample call rate, replicate concordance, and any re-reads? Include HWE p-values for controls (and for cases with caveat) and confirm all expected cell counts ≥5; use Fisher’s exact where violated. Population structure “Indonesian ethnic origin” is self-reported in a genetically diverse setting. Please describe recruitment geography and, if available, adjust for population substructure (e.g., principal components). At a minimum, discuss the risk of stratification bias in limitations. Confounding adjustment Logistic regression via SNPStats appears unadjusted for age, BMI, and insulin resistance. Please present adjusted models (age, BMI, HOMA-IR at a minimum). State covariate selection strategy and show both crude and adjusted ORs with 95% CIs. Haplotype and LD reporting. Only D′ is reported; r² is not provided; haplotype inference power is limited with n=120.. Please add r² values, haplotype frequencies with CIs, and sensitivity analyses (e.g., EM convergence diagnostics). Discuss low-frequency haplotype instability. Kisspeptin assay standardization. Samples taken “day 3–5” may not be physiologically comparable in anovulatory PCOS; assay performance details (LoD, intra/inter-assay CVs, freeze-thaw cycles) are missing. Please provide preanalytical handling, kit performance metrics, and justify timing equivalence for PCOS vs controls; consider sensitivity analysis excluding uncertain cycle-phase samples. Diagnostic criteria implementation: Hyperandrogenism definition mixes clinical (FG >8) and biochemical (T>60 ng/dL) using immunoassay (possible bias at low female T). Please clarify assay method limitations (vs LC-MS/MS), laboratory reference ranges, and how hirsutism scoring handles hair removal. Provide inter-rater reliability if available. Causal language “Predisposing factor” overstates causality for a cross-sectional association. Please replace with “associated with increased odds of PCOS” throughout, including the title and conclusions. That's all. Thank you Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required. Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? Partly Competing Interests: No competing interests were disclosed. Reviewer Expertise: need to be a researcher working on the same field as this is too niche I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Hamdan M. Reviewer Report For: rs4889 and rs5782018 polymorphisms of KISS1 gene as genetic predisposing factor for PCOS in Indonesian women [version 2; peer review: 2 approved, 1 approved with reservations] . F1000Research 2026, 14 :889 ( https://doi.org/10.5256/f1000research.186221.r413858 ) The direct URL for this report is: https://f1000research.com/articles/14-889/v1#referee-response-413858 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 02 Feb 2026 Gita Pratama , Reproductive Immunoendocrinology Division, Department of Obstetrics and Gynecology, University of Indonesia Faculty of Medicine, Jakarta, Indonesia 02 Feb 2026 Author Response Dear Reviewer, We sincerely thank you for your thorough, constructive, and insightful review of our manuscript entitled “rs4889 and rs5782018 polymorphisms of KISS1 gene as genetic predisposing factor for PCOS in ... Continue reading Dear Reviewer, We sincerely thank you for your thorough, constructive, and insightful review of our manuscript entitled “rs4889 and rs5782018 polymorphisms of KISS1 gene as genetic predisposing factor for PCOS in Indonesian women.” We greatly appreciate your recognition of the study’s strengths and your detailed recommendations, which have substantially improved the rigor, clarity, and transparency of our work. Below, we provide a point-by-point response to each comment. 1. Primary outcome specification We agree with the reviewer. In the revised manuscript, we now explicitly state in the Statistical Analysis section that the primary outcome was the association between KISS1 polymorphisms (rs4889 and rs5780218) and PCOS status, evaluated under predefined inheritance models (codominant, dominant, recessive, and overdominant). Model selection was guided by AIC and BIC , which was prespecified as an exploratory approach rather than confirmatory hypothesis testing. We have clarified that results across multiple models should be interpreted as exploratory , and we have added a statement in the Limitations section regarding multiple testing and the absence of formal correction. 2. Sample size and power considerations We acknowledge this limitation. As this was an exploratory candidate-gene study, no formal a priori power calculation was performed. In the revised manuscript, we have added a post-hoc power estimation (with explicit caveats) based on the observed minor allele frequencies and detectable odds ratios at α = 0.05. We further revised the Results and Discussion sections to emphasize cautious interpretation of large ORs , particularly for rare genotypes (e.g., rs4889 GG), and explicitly note the potential for overestimation due to small cell counts. 3. Recruitment flow and attrition We thank the reviewer for this important observation. Reasons for exclusion included incomplete clinical data, withdrawal of consent, and failure to meet inclusion criteria upon reassessment. We have also clarified this information in the Subjects subsection of the Methods and confirmed that no significant demographic differences were observed between included and excluded participants. 4. Group definition and stratification (lean vs obese) We agree and have corrected this inconsistency. BMI stratification (lean vs obese) is now explicitly defined in the Methods section using standard WHO cut-offs (BMI <25 kg/m² and ≥25 kg/m²). We clarify that BMI stratification was preplanned for descriptive endocrine comparisons only and not for primary genetic association testing. All references to “four groups” have been aligned with this clarification, and subgroup results are now clearly labeled in tables and text. 5. Normality, summary measures, and statistical tests We have reassessed data distributions using normality testing. Variables with non-normal distributions are now presented as median (IQR) , and corresponding analyses were performed using Mann–Whitney U tests . Normally distributed variables are reported as mean ± SD with appropriate parametric testing. All tables and text have been revised to ensure consistency between reported summary measures and statistical tests. 6. Genotyping quality control We have expanded the Genotyping Methods section to include detailed quality-control procedures, including: Per-SNP and per-sample call rates Duplicate sample concordance Manual chromatogram re-evaluation for ambiguous calls Hardy–Weinberg equilibrium testing in controls We also clarify that Fisher’s exact test was applied where expected cell counts were <5. 7. Population structure and stratification bias We acknowledge this limitation. In the revised manuscript, we describe recruitment geography (Jakarta and surrounding regions) and explicitly discuss the risk of population stratification due to Indonesia’s genetic diversity. As genome-wide markers were unavailable, adjustment using principal components was not feasible; this is now clearly stated as a limitation. 8. Confounding adjustment We have now included multivariable logistic regression analyses adjusting for age, BMI, and HOMA-IR. Both crude and adjusted odds ratios with 95% confidence intervals are presented in the revised results. Covariate selection was based on established PCOS risk factors and biological plausibility, as now stated in the Statistical Analysis section. 9. Haplotype and linkage disequilibrium reporting We have added r² values alongside D′ to provide a more complete LD assessment. Haplotype frequencies with confidence intervals are now reported, and we discuss the instability of low-frequency haplotypes and limited inference power given the sample size. 10. Kisspeptin assay standardization and cycle timing We have expanded the Hormone Measurements section to include assay performance characteristics (limit of detection, intra- and inter-assay CVs, sample handling, and freeze–thaw procedures). 11. Diagnostic criteria and androgen measurement We have clarified the definition of hyperandrogenism, acknowledged the limitations of immunoassay-based testosterone measurement compared with LC-MS/MS, and provided laboratory reference ranges. The handling of cosmetic hair removal in Ferriman–Gallwey scoring is now described, and inter-rater consistency procedures are noted where applicable. 12. Causal language in title and conclusions We fully agree and have revised the results interpretation and conclusions to replace causal language with “associated with increased odds of PCOS.” This change has been applied consistently throughout the manuscript. Once again, we thank the reviewer for their thoughtful and detailed critique. We believe these revisions substantially strengthen the methodological transparency and interpretability of our study, and we hope the revised manuscript satisfactorily addresses all concerns raised. Sincerely, Authors Dear Reviewer, We sincerely thank you for your thorough, constructive, and insightful review of our manuscript entitled “rs4889 and rs5782018 polymorphisms of KISS1 gene as genetic predisposing factor for PCOS in Indonesian women.” We greatly appreciate your recognition of the study’s strengths and your detailed recommendations, which have substantially improved the rigor, clarity, and transparency of our work. Below, we provide a point-by-point response to each comment. 1. Primary outcome specification We agree with the reviewer. In the revised manuscript, we now explicitly state in the Statistical Analysis section that the primary outcome was the association between KISS1 polymorphisms (rs4889 and rs5780218) and PCOS status, evaluated under predefined inheritance models (codominant, dominant, recessive, and overdominant). Model selection was guided by AIC and BIC , which was prespecified as an exploratory approach rather than confirmatory hypothesis testing. We have clarified that results across multiple models should be interpreted as exploratory , and we have added a statement in the Limitations section regarding multiple testing and the absence of formal correction. 2. Sample size and power considerations We acknowledge this limitation. As this was an exploratory candidate-gene study, no formal a priori power calculation was performed. In the revised manuscript, we have added a post-hoc power estimation (with explicit caveats) based on the observed minor allele frequencies and detectable odds ratios at α = 0.05. We further revised the Results and Discussion sections to emphasize cautious interpretation of large ORs , particularly for rare genotypes (e.g., rs4889 GG), and explicitly note the potential for overestimation due to small cell counts. 3. Recruitment flow and attrition We thank the reviewer for this important observation. Reasons for exclusion included incomplete clinical data, withdrawal of consent, and failure to meet inclusion criteria upon reassessment. We have also clarified this information in the Subjects subsection of the Methods and confirmed that no significant demographic differences were observed between included and excluded participants. 4. Group definition and stratification (lean vs obese) We agree and have corrected this inconsistency. BMI stratification (lean vs obese) is now explicitly defined in the Methods section using standard WHO cut-offs (BMI <25 kg/m² and ≥25 kg/m²). We clarify that BMI stratification was preplanned for descriptive endocrine comparisons only and not for primary genetic association testing. All references to “four groups” have been aligned with this clarification, and subgroup results are now clearly labeled in tables and text. 5. Normality, summary measures, and statistical tests We have reassessed data distributions using normality testing. Variables with non-normal distributions are now presented as median (IQR) , and corresponding analyses were performed using Mann–Whitney U tests . Normally distributed variables are reported as mean ± SD with appropriate parametric testing. All tables and text have been revised to ensure consistency between reported summary measures and statistical tests. 6. Genotyping quality control We have expanded the Genotyping Methods section to include detailed quality-control procedures, including: Per-SNP and per-sample call rates Duplicate sample concordance Manual chromatogram re-evaluation for ambiguous calls Hardy–Weinberg equilibrium testing in controls We also clarify that Fisher’s exact test was applied where expected cell counts were <5. 7. Population structure and stratification bias We acknowledge this limitation. In the revised manuscript, we describe recruitment geography (Jakarta and surrounding regions) and explicitly discuss the risk of population stratification due to Indonesia’s genetic diversity. As genome-wide markers were unavailable, adjustment using principal components was not feasible; this is now clearly stated as a limitation. 8. Confounding adjustment We have now included multivariable logistic regression analyses adjusting for age, BMI, and HOMA-IR. Both crude and adjusted odds ratios with 95% confidence intervals are presented in the revised results. Covariate selection was based on established PCOS risk factors and biological plausibility, as now stated in the Statistical Analysis section. 9. Haplotype and linkage disequilibrium reporting We have added r² values alongside D′ to provide a more complete LD assessment. Haplotype frequencies with confidence intervals are now reported, and we discuss the instability of low-frequency haplotypes and limited inference power given the sample size. 10. Kisspeptin assay standardization and cycle timing We have expanded the Hormone Measurements section to include assay performance characteristics (limit of detection, intra- and inter-assay CVs, sample handling, and freeze–thaw procedures). 11. Diagnostic criteria and androgen measurement We have clarified the definition of hyperandrogenism, acknowledged the limitations of immunoassay-based testosterone measurement compared with LC-MS/MS, and provided laboratory reference ranges. The handling of cosmetic hair removal in Ferriman–Gallwey scoring is now described, and inter-rater consistency procedures are noted where applicable. 12. Causal language in title and conclusions We fully agree and have revised the results interpretation and conclusions to replace causal language with “associated with increased odds of PCOS.” This change has been applied consistently throughout the manuscript. Once again, we thank the reviewer for their thoughtful and detailed critique. We believe these revisions substantially strengthen the methodological transparency and interpretability of our study, and we hope the revised manuscript satisfactorily addresses all concerns raised. Sincerely, Authors Competing Interests: I declare no competing interests with the reviewer. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 02 Feb 2026 Gita Pratama , Reproductive Immunoendocrinology Division, Department of Obstetrics and Gynecology, University of Indonesia Faculty of Medicine, Jakarta, Indonesia 02 Feb 2026 Author Response Dear Reviewer, We sincerely thank you for your thorough, constructive, and insightful review of our manuscript entitled “rs4889 and rs5782018 polymorphisms of KISS1 gene as genetic predisposing factor for PCOS in ... Continue reading Dear Reviewer, We sincerely thank you for your thorough, constructive, and insightful review of our manuscript entitled “rs4889 and rs5782018 polymorphisms of KISS1 gene as genetic predisposing factor for PCOS in Indonesian women.” We greatly appreciate your recognition of the study’s strengths and your detailed recommendations, which have substantially improved the rigor, clarity, and transparency of our work. Below, we provide a point-by-point response to each comment. 1. Primary outcome specification We agree with the reviewer. In the revised manuscript, we now explicitly state in the Statistical Analysis section that the primary outcome was the association between KISS1 polymorphisms (rs4889 and rs5780218) and PCOS status, evaluated under predefined inheritance models (codominant, dominant, recessive, and overdominant). Model selection was guided by AIC and BIC , which was prespecified as an exploratory approach rather than confirmatory hypothesis testing. We have clarified that results across multiple models should be interpreted as exploratory , and we have added a statement in the Limitations section regarding multiple testing and the absence of formal correction. 2. Sample size and power considerations We acknowledge this limitation. As this was an exploratory candidate-gene study, no formal a priori power calculation was performed. In the revised manuscript, we have added a post-hoc power estimation (with explicit caveats) based on the observed minor allele frequencies and detectable odds ratios at α = 0.05. We further revised the Results and Discussion sections to emphasize cautious interpretation of large ORs , particularly for rare genotypes (e.g., rs4889 GG), and explicitly note the potential for overestimation due to small cell counts. 3. Recruitment flow and attrition We thank the reviewer for this important observation. Reasons for exclusion included incomplete clinical data, withdrawal of consent, and failure to meet inclusion criteria upon reassessment. We have also clarified this information in the Subjects subsection of the Methods and confirmed that no significant demographic differences were observed between included and excluded participants. 4. Group definition and stratification (lean vs obese) We agree and have corrected this inconsistency. BMI stratification (lean vs obese) is now explicitly defined in the Methods section using standard WHO cut-offs (BMI <25 kg/m² and ≥25 kg/m²). We clarify that BMI stratification was preplanned for descriptive endocrine comparisons only and not for primary genetic association testing. All references to “four groups” have been aligned with this clarification, and subgroup results are now clearly labeled in tables and text. 5. Normality, summary measures, and statistical tests We have reassessed data distributions using normality testing. Variables with non-normal distributions are now presented as median (IQR) , and corresponding analyses were performed using Mann–Whitney U tests . Normally distributed variables are reported as mean ± SD with appropriate parametric testing. All tables and text have been revised to ensure consistency between reported summary measures and statistical tests. 6. Genotyping quality control We have expanded the Genotyping Methods section to include detailed quality-control procedures, including: Per-SNP and per-sample call rates Duplicate sample concordance Manual chromatogram re-evaluation for ambiguous calls Hardy–Weinberg equilibrium testing in controls We also clarify that Fisher’s exact test was applied where expected cell counts were <5. 7. Population structure and stratification bias We acknowledge this limitation. In the revised manuscript, we describe recruitment geography (Jakarta and surrounding regions) and explicitly discuss the risk of population stratification due to Indonesia’s genetic diversity. As genome-wide markers were unavailable, adjustment using principal components was not feasible; this is now clearly stated as a limitation. 8. Confounding adjustment We have now included multivariable logistic regression analyses adjusting for age, BMI, and HOMA-IR. Both crude and adjusted odds ratios with 95% confidence intervals are presented in the revised results. Covariate selection was based on established PCOS risk factors and biological plausibility, as now stated in the Statistical Analysis section. 9. Haplotype and linkage disequilibrium reporting We have added r² values alongside D′ to provide a more complete LD assessment. Haplotype frequencies with confidence intervals are now reported, and we discuss the instability of low-frequency haplotypes and limited inference power given the sample size. 10. Kisspeptin assay standardization and cycle timing We have expanded the Hormone Measurements section to include assay performance characteristics (limit of detection, intra- and inter-assay CVs, sample handling, and freeze–thaw procedures). 11. Diagnostic criteria and androgen measurement We have clarified the definition of hyperandrogenism, acknowledged the limitations of immunoassay-based testosterone measurement compared with LC-MS/MS, and provided laboratory reference ranges. The handling of cosmetic hair removal in Ferriman–Gallwey scoring is now described, and inter-rater consistency procedures are noted where applicable. 12. Causal language in title and conclusions We fully agree and have revised the results interpretation and conclusions to replace causal language with “associated with increased odds of PCOS.” This change has been applied consistently throughout the manuscript. Once again, we thank the reviewer for their thoughtful and detailed critique. We believe these revisions substantially strengthen the methodological transparency and interpretability of our study, and we hope the revised manuscript satisfactorily addresses all concerns raised. Sincerely, Authors Dear Reviewer, We sincerely thank you for your thorough, constructive, and insightful review of our manuscript entitled “rs4889 and rs5782018 polymorphisms of KISS1 gene as genetic predisposing factor for PCOS in Indonesian women.” We greatly appreciate your recognition of the study’s strengths and your detailed recommendations, which have substantially improved the rigor, clarity, and transparency of our work. Below, we provide a point-by-point response to each comment. 1. Primary outcome specification We agree with the reviewer. In the revised manuscript, we now explicitly state in the Statistical Analysis section that the primary outcome was the association between KISS1 polymorphisms (rs4889 and rs5780218) and PCOS status, evaluated under predefined inheritance models (codominant, dominant, recessive, and overdominant). Model selection was guided by AIC and BIC , which was prespecified as an exploratory approach rather than confirmatory hypothesis testing. We have clarified that results across multiple models should be interpreted as exploratory , and we have added a statement in the Limitations section regarding multiple testing and the absence of formal correction. 2. Sample size and power considerations We acknowledge this limitation. As this was an exploratory candidate-gene study, no formal a priori power calculation was performed. In the revised manuscript, we have added a post-hoc power estimation (with explicit caveats) based on the observed minor allele frequencies and detectable odds ratios at α = 0.05. We further revised the Results and Discussion sections to emphasize cautious interpretation of large ORs , particularly for rare genotypes (e.g., rs4889 GG), and explicitly note the potential for overestimation due to small cell counts. 3. Recruitment flow and attrition We thank the reviewer for this important observation. Reasons for exclusion included incomplete clinical data, withdrawal of consent, and failure to meet inclusion criteria upon reassessment. We have also clarified this information in the Subjects subsection of the Methods and confirmed that no significant demographic differences were observed between included and excluded participants. 4. Group definition and stratification (lean vs obese) We agree and have corrected this inconsistency. BMI stratification (lean vs obese) is now explicitly defined in the Methods section using standard WHO cut-offs (BMI <25 kg/m² and ≥25 kg/m²). We clarify that BMI stratification was preplanned for descriptive endocrine comparisons only and not for primary genetic association testing. All references to “four groups” have been aligned with this clarification, and subgroup results are now clearly labeled in tables and text. 5. Normality, summary measures, and statistical tests We have reassessed data distributions using normality testing. Variables with non-normal distributions are now presented as median (IQR) , and corresponding analyses were performed using Mann–Whitney U tests . Normally distributed variables are reported as mean ± SD with appropriate parametric testing. All tables and text have been revised to ensure consistency between reported summary measures and statistical tests. 6. Genotyping quality control We have expanded the Genotyping Methods section to include detailed quality-control procedures, including: Per-SNP and per-sample call rates Duplicate sample concordance Manual chromatogram re-evaluation for ambiguous calls Hardy–Weinberg equilibrium testing in controls We also clarify that Fisher’s exact test was applied where expected cell counts were <5. 7. Population structure and stratification bias We acknowledge this limitation. In the revised manuscript, we describe recruitment geography (Jakarta and surrounding regions) and explicitly discuss the risk of population stratification due to Indonesia’s genetic diversity. As genome-wide markers were unavailable, adjustment using principal components was not feasible; this is now clearly stated as a limitation. 8. Confounding adjustment We have now included multivariable logistic regression analyses adjusting for age, BMI, and HOMA-IR. Both crude and adjusted odds ratios with 95% confidence intervals are presented in the revised results. Covariate selection was based on established PCOS risk factors and biological plausibility, as now stated in the Statistical Analysis section. 9. Haplotype and linkage disequilibrium reporting We have added r² values alongside D′ to provide a more complete LD assessment. Haplotype frequencies with confidence intervals are now reported, and we discuss the instability of low-frequency haplotypes and limited inference power given the sample size. 10. Kisspeptin assay standardization and cycle timing We have expanded the Hormone Measurements section to include assay performance characteristics (limit of detection, intra- and inter-assay CVs, sample handling, and freeze–thaw procedures). 11. Diagnostic criteria and androgen measurement We have clarified the definition of hyperandrogenism, acknowledged the limitations of immunoassay-based testosterone measurement compared with LC-MS/MS, and provided laboratory reference ranges. The handling of cosmetic hair removal in Ferriman–Gallwey scoring is now described, and inter-rater consistency procedures are noted where applicable. 12. Causal language in title and conclusions We fully agree and have revised the results interpretation and conclusions to replace causal language with “associated with increased odds of PCOS.” This change has been applied consistently throughout the manuscript. Once again, we thank the reviewer for their thoughtful and detailed critique. We believe these revisions substantially strengthen the methodological transparency and interpretability of our study, and we hope the revised manuscript satisfactorily addresses all concerns raised. Sincerely, Authors Competing Interests: I declare no competing interests with the reviewer. Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 09 Sep 2025 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 3 Version 2 (revision) 02 Feb 26 read Version 1 09 Sep 25 read read Mukhri Hamdan , Universiti Malaya, Kuala Lumpur, Malaysia Mushtak T. S. Al-Ouqaili , University of Anbar, College of Medicine, Ramadi, Iraq Mohd Faizal Ahmad , National University of Malaysia, Kuala Lumpur, Malaysia Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2026 Ahmad M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 15 Apr 2026 | for Version 2 Mohd Faizal Ahmad , Department of Obstetrics & Gynecology, Faculty of Medicine, National University of Malaysia, Kuala Lumpur, Malaysia 0 Views copyright © 2026 Ahmad M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Strengths This study explores an important and timely topic by examining KISS1 gene polymorphisms in relation to PCOS, focusing on how these genes may affect the neuroendocrine regulation of the HPG axis. The link between kisspeptin signaling, GnRH pulsatility, and PCOS is well explained and fits with current scientific knowledge. Including an Indonesian cohort adds valuable genetic data from a group that is often underrepresented in this research area. The study uses Sanger sequencing for genotyping and analyzes genotypes, allele frequencies, inheritance models, and haplotypes, which strengthens its methods. Finding a significant G–CT haplotype linked to higher odds of PCOS adds depth beyond just looking at single SNPs. The clinical and hormonal profiles of participants also match classic PCOS features, which supports the reliability of the data. Weaknesses The main weakness of this study is its small sample size, which reduces statistical power and may lead to overestimation of effect sizes, especially for rare genotypes such as rs4889 GG. The study lacks a power calculation, which makes it harder to assess the strength of the results. Testing multiple genetic models without correcting for multiple comparisons could lead to false positives. Details on genotyping quality control, such as call rates and replicate agreement, are not fully reported, which affects the reproducibility of the findings. The study also uses self-reported menstrual history to diagnose oligo-ovulation, which could introduce recall bias, and relies on immunoassay-based testosterone measurements without discussing their limitations. The conclusions about kisspeptin are somewhat overstated, given the lack of significant differences. There are also some inconsistencies in how statistics are reported and minor issues with genetic terminology. Finally, the analyses do not clearly adjust for potential confounders such as BMI and insulin resistance, and using self-reported ethnicity could introduce population stratification bias. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Reproductive & Oncofertility I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Ahmad MF. Peer Review Report For: rs4889 and rs5782018 polymorphisms of KISS1 gene as genetic predisposing factor for PCOS in Indonesian women [version 2; peer review: 2 approved, 1 approved with reservations] . F1000Research 2026, 14 :889 ( https://doi.org/10.5256/f1000research.194949.r468339) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-889/v2#referee-response-468339 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2026 Al-Ouqaili M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 05 Jan 2026 | for Version 1 Mushtak T. S. Al-Ouqaili , Department of Microbiology, University of Anbar, College of Medicine, Ramadi, Iraq 0 Views copyright © 2026 Al-Ouqaili M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Dear Editor, This manuscript introduces a unique concept in an area that is both intriguing and important for medical research. The topic is timely and is likely to engage the journal's readers. Additionally, the manuscript is well-written, presenting ideas clearly and logically. Dear Authors, You are doing excellent work, and this manuscript reflects a great deal of effort and thoughtful research. The study is promising and contributes meaningfully to the field. However, there are a few important points that require further clarification and revision to enhance the overall quality and impact of the manuscript. The introduction provides a comprehensive overview of PCOS and the hypothesised role of the KISS1 gene; however, the specific knowledge gap addressed by the current study should be stated more explicitly. While conflicting evidence regarding serum kisspeptin levels and KISS1 polymorphisms is mentioned, the introduction would benefit from a clearer explanation of why existing studies are insufficient and how the present study advances the field. It is preferred to use the following reference to support your updated citations: (refer to 1) The reported prevalence of PCOS (6%–10%) is appropriate; however, the diagnostic criteria used in cited studies (e.g., NIH, Rotterdam, or AES) are not specified. Given that PCOS prevalence varies considerably depending on diagnostic criteria, the authors should clarify this to improve interpretability and contextual accuracy. Although the introduction discusses the physiological role of kisspeptin in GnRH and gonadotropin regulation, the mechanistic pathway linking KISS1 SNPs to PCOS pathogenesis remains somewhat speculative. A more detailed explanation of how specific polymorphisms may alter kisspeptin expression or function would strengthen the biological plausibility of the study hypothesis. It is preferred to use the following reference to support your updated citations: (refer to 2) The discussion of KNDy neurons is relevant but underdeveloped. The authors should expand on how alterations in neurokinin B, dynorphin, and kisspeptin signaling specifically contribute to PCOS-related neuroendocrine dysfunction and how this supports investigating KISS1 gene variants. The final sentence states that the study determined the impact of KISS1 gene polymorphisms and haplotypes on PCOS development. This objective would benefit from greater specificity, including which polymorphisms or haplotypes were analyzed and whether the focus is on association, causation, or functional prediction. It is preferred to use the following reference to support your updated citations: • (refer to 3) The manuscript states that 80 women with PCOS and 76 controls were initially recruited, but only 60 participants per group met the inclusion criteria. The specific reasons for exclusion (e.g., incomplete data, failure to meet diagnostic criteria, withdrawal of consent) should be explicitly described to enhance transparency and reproducibility. Oligo- or anovulation was determined solely based on self-reported menstrual cycle frequency, which may be subject to recall bias. The authors should clarify whether menstrual history was corroborated with clinical records or supported by biochemical markers (e.g., mid-luteal progesterone), particularly given the diagnostic importance of ovulatory dysfunction in PCOS. Although hyperandrogenism was defined using Ferriman–Gallwey scores and serum total testosterone levels, the manuscript lacks detail regarding: The assessor training or blinding for Ferriman–Gallwey scoring, and The assay method, timing, and reference ranges for testosterone measurement. These details are essential for ensuring diagnostic consistency and comparability with other studies. Participants were described as “self-reported as having Indonesian ethnic origin.” While this helps reduce population stratification bias, the authors should acknowledge the limitations of self-reported ethnicity, particularly in genetic association studies, and consider discussing whether sub-ethnic heterogeneity was assessed or controlled. The Results section refers to comparisons between “lean and obese groups” and mentions “four groups”; however, this stratification is not clearly introduced or defined in the Methods or at the beginning of the Results. The authors should explicitly describe how subjects were categorized (e.g., BMI cutoffs) and ensure consistency between Methods, Tables, and Results. The manuscript reports median ages and median kisspeptin levels but does not consistently indicate whether other variables are presented as means ± SE or medians (IQR). This inconsistency makes interpretation difficult. The authors should clarify which variables were normally distributed, justify the choice of statistical descriptors, and ensure alignment with the statistical tests used. Although no statistically significant difference in kisspeptin levels was observed, the Results section still emphasizes the lower median value in the PCOS group. This observation should be reported cautiously and without implying biological relevance unless supported by statistical significance or effect size analysis. There appears to be confusion in allele nomenclature, particularly for rs5780218 (e.g., reference to a “CT allele”). Alleles should be clearly distinguished from genotypes. The authors must revise this section to ensure correct and unambiguous genetic terminology. It is preferred to use the following reference to support your updated citations: (refer to 4 ) The Discussion appropriately acknowledges conflicting reports regarding serum kisspeptin levels in PCOS; however, the interpretation remains largely speculative. The authors should more clearly distinguish between central (hypothalamic) kisspeptin signalling and circulating kisspeptin levels, as serum measurements may not accurately reflect hypothalamic activity. This distinction is critical for reconciling discrepancies with studies reporting elevated kisspeptin expression in PCOS. It is preferred to use the following reference to support your updated citations: (refer to 5) Conclusion should be objective, with further perspective,e or should add at least a few sentences about future study/future perspective of .it Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes References 1. Abdul-Lateef W, Al-Ouqaili M, Murshid R: Association of FokI, Tru91, and ApaI vitamin D receptor gene polymorphisms with the development of polycystic ovarian syndrome: A molecular genetic study. Journal of King Saud University - Science . 2024; 36 (11). Publisher Full Text 2. Kanaan B, Al-Ouqaili M, Murshid R: Cytogenetic screening of chromosomal abnormalities and genetic analysis of FSH receptor Ala307Thr and Ser680Asn genes in amenorrheic patients. PeerJ . 2023; 11 . Publisher Full Text 3. Abdul-Late W, Salih Al-O M, Murshid R: Association Between NsiI and PmLI Insulin Receptors on the Development of Polycystic Ovarian Syndrome. Pakistan Journal of Biological Sciences . 2024; 27 (11): 526-536 Publisher Full Text 4. Taha R, Al-Ouqaili M, Abdullah S: The Association of Anti-Mullerian Hormone and Infertility Hormonal Imbalance with Polycystic Ovarian Syndrome Among Iraqi Patients. Pakistan Journal of Biological Sciences . 2023; 26 (5): 241-248 Publisher Full Text 5. Kanaan B, Al-Ouqaili M, Murshed R: In terms of the PCR-RFLP technique, genetic screening of Ala575Val inactivating mutation in patients with amenorrhea. Journal of Emergency Medicine, Trauma and Acute Care . 2022; 2022 (6). Publisher Full Text Competing Interests No competing interests were disclosed. Reviewer Expertise Molecular Biology, Microbiology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Al-Ouqaili MTS. Peer Review Report For: rs4889 and rs5782018 polymorphisms of KISS1 gene as genetic predisposing factor for PCOS in Indonesian women [version 2; peer review: 2 approved, 1 approved with reservations] . F1000Research 2026, 14 :889 ( https://doi.org/10.5256/f1000research.186221.r445139) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-889/v1#referee-response-445139 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Hamdan M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 16 Sep 2025 | for Version 1 Mukhri Hamdan , Universiti Malaya, Kuala Lumpur, Federal Territory of Kuala Lumpur, Malaysia 0 Views copyright © 2025 Hamdan M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Congratulations on a great research report. It focuses on an upstream neuroendocrine gene (KISS1) with mechanistic plausibility, also including haplotype analysis, Day 3–5 sampling attempt, and exclusion of recent HPG-altering medications with open data availability. Here are the issues identified: Primary outcome specification. The manuscript does not pre-specify a single primary genetic model/outcome; multiple inheritance models are tested across two SNPs (± haplotypes). Sample size and power : No a priori power calculation is provided; small genotype cell counts (e.g., rs4889 GG) inflate ORs and widen CIs. Need to add an a priori (or post-hoc, with caveats) power analysis indicating detectable OR at α (after correction) for your MAF. Interpret large ORs from rare genotypes cautiously. Recruitment flow & attrition recruited 80 PCOS and 76 controls, but analyzed 60+60; reasons for exclusion are not detailed. Can you provide a CONSORT-style flow diagram with reasons for exclusion and any differences between included vs excluded? Group definition and stratification Results text refers to “four groups” (lean vs obese strata), but Methods define only cases/controls; BMI cut-offs not specified. Please clearly define BMI strata (cut-points, rationale), when this stratification was planned, and where those subgroup results appear (tables/appendix). Align wording (two vs four groups). Normality, summary measures, and test. Text says data are “mean ± SE” and “independent t-test” used, yet tables present medians (ranges), and several variables are non-normal. Please reassess distributions; report appropriate central tendency (mean±SD for normal; median[IQR] for skewed) and use Mann-Whitney U where needed. Ensure test choice matches what’s reported in tables. Genotyping quality control: Limited QC details for Sanger calls (call rate, duplicate concordance, blinded repeats). Can you report per-SNP call rate, sample call rate, replicate concordance, and any re-reads? Include HWE p-values for controls (and for cases with caveat) and confirm all expected cell counts ≥5; use Fisher’s exact where violated. Population structure “Indonesian ethnic origin” is self-reported in a genetically diverse setting. Please describe recruitment geography and, if available, adjust for population substructure (e.g., principal components). At a minimum, discuss the risk of stratification bias in limitations. Confounding adjustment Logistic regression via SNPStats appears unadjusted for age, BMI, and insulin resistance. Please present adjusted models (age, BMI, HOMA-IR at a minimum). State covariate selection strategy and show both crude and adjusted ORs with 95% CIs. Haplotype and LD reporting. Only D′ is reported; r² is not provided; haplotype inference power is limited with n=120.. Please add r² values, haplotype frequencies with CIs, and sensitivity analyses (e.g., EM convergence diagnostics). Discuss low-frequency haplotype instability. Kisspeptin assay standardization. Samples taken “day 3–5” may not be physiologically comparable in anovulatory PCOS; assay performance details (LoD, intra/inter-assay CVs, freeze-thaw cycles) are missing. Please provide preanalytical handling, kit performance metrics, and justify timing equivalence for PCOS vs controls; consider sensitivity analysis excluding uncertain cycle-phase samples. Diagnostic criteria implementation: Hyperandrogenism definition mixes clinical (FG >8) and biochemical (T>60 ng/dL) using immunoassay (possible bias at low female T). Please clarify assay method limitations (vs LC-MS/MS), laboratory reference ranges, and how hirsutism scoring handles hair removal. Provide inter-rater reliability if available. Causal language “Predisposing factor” overstates causality for a cross-sectional association. Please replace with “associated with increased odds of PCOS” throughout, including the title and conclusions. That's all. Thank you Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required. Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? Partly Competing Interests No competing interests were disclosed. Reviewer Expertise need to be a researcher working on the same field as this is too niche I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 02 Feb 2026 Gita Pratama, Reproductive Immunoendocrinology Division, Department of Obstetrics and Gynecology, University of Indonesia Faculty of Medicine, Jakarta, Indonesia Dear Reviewer, We sincerely thank you for your thorough, constructive, and insightful review of our manuscript entitled “rs4889 and rs5782018 polymorphisms of KISS1 gene as genetic predisposing factor for PCOS in Indonesian women.” We greatly appreciate your recognition of the study’s strengths and your detailed recommendations, which have substantially improved the rigor, clarity, and transparency of our work. Below, we provide a point-by-point response to each comment. 1. Primary outcome specification We agree with the reviewer. In the revised manuscript, we now explicitly state in the Statistical Analysis section that the primary outcome was the association between KISS1 polymorphisms (rs4889 and rs5780218) and PCOS status, evaluated under predefined inheritance models (codominant, dominant, recessive, and overdominant). Model selection was guided by AIC and BIC , which was prespecified as an exploratory approach rather than confirmatory hypothesis testing. We have clarified that results across multiple models should be interpreted as exploratory , and we have added a statement in the Limitations section regarding multiple testing and the absence of formal correction. 2. Sample size and power considerations We acknowledge this limitation. As this was an exploratory candidate-gene study, no formal a priori power calculation was performed. In the revised manuscript, we have added a post-hoc power estimation (with explicit caveats) based on the observed minor allele frequencies and detectable odds ratios at α = 0.05. We further revised the Results and Discussion sections to emphasize cautious interpretation of large ORs , particularly for rare genotypes (e.g., rs4889 GG), and explicitly note the potential for overestimation due to small cell counts. 3. Recruitment flow and attrition We thank the reviewer for this important observation. Reasons for exclusion included incomplete clinical data, withdrawal of consent, and failure to meet inclusion criteria upon reassessment. We have also clarified this information in the Subjects subsection of the Methods and confirmed that no significant demographic differences were observed between included and excluded participants. 4. Group definition and stratification (lean vs obese) We agree and have corrected this inconsistency. BMI stratification (lean vs obese) is now explicitly defined in the Methods section using standard WHO cut-offs (BMI <25 kg/m² and ≥25 kg/m²). We clarify that BMI stratification was preplanned for descriptive endocrine comparisons only and not for primary genetic association testing. All references to “four groups” have been aligned with this clarification, and subgroup results are now clearly labeled in tables and text. 5. Normality, summary measures, and statistical tests We have reassessed data distributions using normality testing. Variables with non-normal distributions are now presented as median (IQR) , and corresponding analyses were performed using Mann–Whitney U tests . Normally distributed variables are reported as mean ± SD with appropriate parametric testing. All tables and text have been revised to ensure consistency between reported summary measures and statistical tests. 6. Genotyping quality control We have expanded the Genotyping Methods section to include detailed quality-control procedures, including: Per-SNP and per-sample call rates Duplicate sample concordance Manual chromatogram re-evaluation for ambiguous calls Hardy–Weinberg equilibrium testing in controls We also clarify that Fisher’s exact test was applied where expected cell counts were <5. 7. Population structure and stratification bias We acknowledge this limitation. In the revised manuscript, we describe recruitment geography (Jakarta and surrounding regions) and explicitly discuss the risk of population stratification due to Indonesia’s genetic diversity. As genome-wide markers were unavailable, adjustment using principal components was not feasible; this is now clearly stated as a limitation. 8. Confounding adjustment We have now included multivariable logistic regression analyses adjusting for age, BMI, and HOMA-IR. Both crude and adjusted odds ratios with 95% confidence intervals are presented in the revised results. Covariate selection was based on established PCOS risk factors and biological plausibility, as now stated in the Statistical Analysis section. 9. Haplotype and linkage disequilibrium reporting We have added r² values alongside D′ to provide a more complete LD assessment. Haplotype frequencies with confidence intervals are now reported, and we discuss the instability of low-frequency haplotypes and limited inference power given the sample size. 10. Kisspeptin assay standardization and cycle timing We have expanded the Hormone Measurements section to include assay performance characteristics (limit of detection, intra- and inter-assay CVs, sample handling, and freeze–thaw procedures). 11. Diagnostic criteria and androgen measurement We have clarified the definition of hyperandrogenism, acknowledged the limitations of immunoassay-based testosterone measurement compared with LC-MS/MS, and provided laboratory reference ranges. The handling of cosmetic hair removal in Ferriman–Gallwey scoring is now described, and inter-rater consistency procedures are noted where applicable. 12. Causal language in title and conclusions We fully agree and have revised the results interpretation and conclusions to replace causal language with “associated with increased odds of PCOS.” This change has been applied consistently throughout the manuscript. Once again, we thank the reviewer for their thoughtful and detailed critique. We believe these revisions substantially strengthen the methodological transparency and interpretability of our study, and we hope the revised manuscript satisfactorily addresses all concerns raised. Sincerely, Authors View more View less Competing Interests I declare no competing interests with the reviewer. reply Respond Report a concern Hamdan M. Peer Review Report For: rs4889 and rs5782018 polymorphisms of KISS1 gene as genetic predisposing factor for PCOS in Indonesian women [version 2; peer review: 2 approved, 1 approved with reservations] . F1000Research 2026, 14 :889 ( https://doi.org/10.5256/f1000research.186221.r413858) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. 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