MLH1 rs63749795 variant confers increased risk for endometriosis: a genetic association study

Aims The present study aimed to investigate the association between two MutL homolog 1 (MLH1) single-nucleotide polymorphisms (SNPs), rs63749795 and rs63749820, and the risk of endometriosis.

This case-control study included 150 patients with endometriosis and 150 matched healthy controls. Genotyping of the MLH1 polymorphisms was performed using the tetra-primer ARMS-PCR methods.

The frequency of alleles and genotypes for the MLH1 rs63749820 polymorphism and the allelic distribution of MLH1 rs63749795 did not differ significantly between patients with endometriosis and healthy controls. However, the MLH1 rs63749795 polymorphism was found to be significantly associated with increased susceptibility to endometriosis in individuals carrying the CT genotype (OR = 2.42, 95% CI = 1.39–4.23, p = 0.001). Furthermore, analysis of the MLH1 rs63749795 and rs63749820 haplotypes revealed that CC and TT were associated with an increased risk of endometriosis. After applying Bonferroni correction for multiple comparisons (adjusted p < 0.0125), the association for TT remained statistically significant. In contrast, the TC haplotype (OR = 0.50, p = 0.0003) demonstrated a robust protective effect against the disease.

In the present study, we report for the first time a significant association between the MLH1 rs63749795 polymorphism and susceptibility to endometriosis. Article highlights This is the first genetic association study to report a significant link between the MLH1 rs63749795 polymorphism and an increased risk of endometriosis, suggesting a novel genetic factor in disease susceptibility. The CT genotype of the MLH1 rs63749795 variant was associated with a 2.42-fold higher risk of developing endometriosis in the studied Iranian population. Haplotype analysis revealed that the TT haplotype confers increased risk, while the TC haplotype has a protective effect against endometriosis, highlighting the complex interplay of genetic variants. The findings emphasize the potential role of DNA mismatch repair pathway genes in the pathogenesis of endometriosis, bridging genetic susceptibility with biological mechanisms like genomic instability and inflammation. The study underscores the importance of population-specific research and calls for larger, multi-ethnic studies to validate these associations and explore their functional consequences. Acknowledgments The present study is reflective of the thesis of Niloofar Nazarikhah (MSc student of Genetic). We extend our sincere appreciation to Dr. Tahereh Poordast for her valuable contribution to the selection of patients and control subjects. Moreover, the authors wish to thank all of the participants in the current research. The authors did not receive any specific grant from any funding source. Author contributions N.N. and M.J.M conceived and planned the presented experiment, performed experiments and analyzed the data. M.J.M. wrote the paper, designed experiments and supervised the research. All authors have read and approved the manuscript. Disclosure statement The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Ethical approval statement The study was approved by the Regional Ethics Committee of Islamic Azad University, Arsanjan Branch (IR.IAU.A.REC.1402.034). Data availability statement The datasets generated and analyzed during the current study are not publicly available due to ethical and legal restrictions. The study involved human participants diagnosed with endometriosis, and the data contain sensitive clinical information that could compromise participant confidentiality. In accordance with the ethical approval granted by the Ethics Committee of Islamic Azad University, Arsanjan Branch, and institutional data protection policies, the data cannot be shared openly. However, de-identified data may be made available from the corresponding author upon reasonable request, subject to approval by the ethics committee and completion of a data-sharing agreement.