Haplotypes of CYP1B1 and CCDC57 genes in an Afro-Caribbean female population with uterine leiomyoma

Uterine leiomyomas (UL) are prevalent benign tumors, especially among women of African ancestry. The disease also has genetic liability and is influenced by risk factors such as hormones and obesity. This study investigates the haplotypes of the Cytochrome P450 1B1 gene (CYP1B1) related to hormones and coiled-coil domain containing 57 gene (CCDC57) related to obesity in Afro-Caribbean females. Each haplotype was constructed from unphased sequence data using PHASE v.2.1 software and Haploview v.4.2 was used for linkage disequilibrium (LD) studies. There were contrasting LD observed among the single nucleotide polymorphisms of CYP1B1 and CCDC5. Accordingly, the GTA haplotype of CYP1B1 was significantly associated with UL risk (P = 0.02) while there was no association between CCDC57 haplotypes and UL (P = 0.2) for the ATG haplotype. As such, our findings suggest that the Asp449Asp polymorphism and GTA haplotype of CYP1B1 may contribute to UL susceptibility in women of Afro-Caribbean ancestry in this population. Similar content being viewed by others

Wallach EE, Buttram VC, Reiter RC (1981) Uterine leiomyomata: etiology, symptomatology, and management. Fertil Steril. https://doi.org/10.1016/S0015-0282(16)45789-4 Baird DD, Dunson DB, Hill MC et al (2003) High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol. https://doi.org/10.1067/mob.2003.99 Al-hendy A, Myers ER, Stewart E (2017) Uterine fibroids : burden and unmet medical need. Semin Reprod Med 1:473–480 Stewart EA, Cookson CL, Gandolfo RA, Schulze-Rath R (2017) Epidemiology of uterine fibroids: a systematic review. BJOG: Int J Obstet Gynaecol 124:1501–1512. https://doi.org/10.1111/1471-0528.14640 Vollenhoven B (1998) Introduction: the epidemiology of uterine leiomyomas. Baillieres Clin Obstet Gynaecol 12:169–176. https://doi.org/10.1016/S0950-3552(98)80059-X Flake GP, Andersen J, Dixon D (2003) Etiology and pathogenesis of uterine leiomyomas: a review. Environ Health Perspect 111:1037–1054. https://doi.org/10.1289/ehp.5787 Nilbert M, Heim S, Mandahl N et al (2004) Characteristic chromosome abnormalities, including rearrangements of 6p, del(7q), +12, and t(12;14), in 44 uterine leiomyomas. Hum Genet. https://doi.org/10.1007/BF00193583 Ligon AH, Morton CC (2001) Leiomyomata: heritability and cytogenetic studies. Hum Reprod Update 7:8–14. https://doi.org/10.1093/humupd/7.1.8 Mehine M, Kaasinen E, Heinonen H-R et al (2016) Integrated data analysis reveals uterine leiomyoma subtypes with distinct driver pathways and biomarkers. Proc Natl Acad Sci 113:1315–1320. https://doi.org/10.1073/pnas.1518752113 Laughlin-Tommaso SK, Stewart EA (2018) Moving toward individualized medicine for uterine leiomyomas. Obstet Gynecol 132:961–971 Rivera B (2018) Not so benign. e-Life 12:1–3. https://doi.org/10.7554/eLife.37110 Aissani B, Zhang K, Wiener H (2015) Evaluation of GWAS candidate susceptibility loci for uterine leiomyoma in the multi-ethnic NIEHS uterine fibroid study. Front Genet. https://doi.org/10.3389/fgene.2015.00241 Mehine M, Kaasinen E, Mäkinen N et al (2013) Characterization of uterine leiomyomas by whole-genome sequencing. N Engl J Med 369:43–53. https://doi.org/10.1056/NEJMoa1302736 Cha P-C, Takahashi A, Hosono N et al (2011) A genome-wide association study identifies three loci associated with susceptibility to uterine fibroids. Nat Genet 43:447–450. https://doi.org/10.1038/ng.805 Patil N, Berno AJ, Hinds DA et al (2001) Blocks of limited haplotype diversity revealed by high-resolution scanning of human chromosome 21. Science. https://doi.org/10.1126/science.1065573 Akey J, Jin L, Xiong M (2001) Haplotypes vs single marker linkage disequilibrium tests: what do we gain? Eur J Hum Genet. 1:1. https://doi.org/10.1038/sj.ejhg.5200619 Ardlie KG, Kruglyak L, Seielstad M (2002) Patterns of linkage disequilibrium in the human genome. Nat Rev Genet 3:299–302. https://doi.org/10.1038/nrg777 Belmont JW, Hardenbol P, Willis TD et al (2003) The international HapMap project. Nature 423:789–796. https://doi.org/10.1038/nature02168 Auton A, Abecasis GR, Altshuler DM et al (2015) A global reference for human genetic variation. Nature 526:68–74. https://doi.org/10.1038/nature15393 Benn-Torres J, Bonilla C, Robbins CM et al (2008) Admixture and population stratification in African Caribbean populations. Ann Hum Genet 72:90–98. https://doi.org/10.1111/j.1469-1809.2007.00398.x Murray GI, Taylor MC, McFadyen MCE et al (1997) Tumor-specific expression of cytochrome P450 CYP1B1. Cancer Res. https://doi.org/10.1016/j.neuint.2010.10.017 Schwartz SM, Marshall LM, Baird DD (2000) Epidemiologic contributions to understanding the etiology of uterine leiomyomata. Environ Health Perspect. https://doi.org/10.1289/ehp.00108s5821 Mokhtari M, Zakerian S, Farajian-Mashhadi F, Salimi S (2018) Association of PvuII T > C and XbaI A > G polymorphisms of estrogen receptor α gene with uterine leiomyoma: a case-control study. Gene Cell Tissue 5:2–6. https://doi.org/10.5812/ijhrba.79616.Research Dvorská D, Braný D, Danková Z et al (2017) Molecular and clinical attributes of uterine leiomyomas. Tumor Biol. https://doi.org/10.1177/1010428317710226 Gooden KM (2006) The relationship of uterine leiomyomata and genetic polymorphisms of cytochrome P-450 1A1, cytochrome P-450 1B1, and catechol-O-methyltransferase. Doctoral dissertation, University of North Carolina at Chapel Hill Salimi S, Khodamian M, Narooie-Nejad M et al (2014) Association of polymorphisms and haplotypes in the cytochrome P450 1B1 gene with uterine leiomyoma: a case control study. Biomed Reports 3:201–206. https://doi.org/10.3892/br.2014.413 Bideau VS, Alleyne AT (2016) Leu/Val SNP polymorphism of CYP1B1 and risk of uterine leiomyoma in a Black population. Tumor Biol 1:1. https://doi.org/10.1007/s13277-015-4239-8 Wise LA, Palmer JR, Harlow BL et al (2004) Reproductive factors, hormonal contraception, and risk of uterine leiomyomata in African-American women: a prospective study. Am J Epidemiol. https://doi.org/10.1093/aje/kwh016 Faerstein E, Szklo M, Rosenshein N (2001) Risk factors for uterine leiomyoma: a practice-based case-control study. I. African-American heritage, reproductive history, body size, and smoking. Am J Epidemiol 153:1–10. https://doi.org/10.1093/aje/153.1.1 Marshall LM, Spiegelman D, Manson JE et al (1998) Risk of uterine leiomyomata among premenopausal women in relation to body size and cigarette smoking. Epidemiology 9:511–517 Giri A, Edwards TL, Hartmann KE et al (2017) African genetic ancestry interacts with body mass index to modify risk for uterine fibroids. PLoS Genet 13:1–22. https://doi.org/10.1371/journal.pgen.1006871 Eggert SL, Huyck KL, Somasundaram P et al (2012) Genome-wide linkage and association analyses implicate FASN in predisposition to uterine leiomyomata. Am J Hum Genet 91:621–628. https://doi.org/10.1016/j.ajhg.2012.08.009 Ye J, Coulouris G, Zaretskaya I et al (2012) Primer-BLAST: a tool to design target-specific primers for polymerase chain reaction. BMC Bioinform. https://doi.org/10.1186/1471-2105-13-134 Kearse M, Moir R, Wilson A et al (2012) Geneious Basic: an integrated and extendable desktop software platform for the organization and analysis of sequence data. Bioinformatics. https://doi.org/10.1093/bioinformatics/bts199 Altschul SF, Gish W, Miller W et al (1990) Basic local alignment search tool. J Mol Biol 215:403–410. https://doi.org/10.1016/S0022-2836(05)80360-2 Edgar RC (2004) MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res. https://doi.org/10.1093/nar/gkh340 Sherry ST (2001) dbSNP: the NCBI database of genetic variation. Nucleic Acids Res 29:308–311. https://doi.org/10.1093/nar/29.1.308 Erdfelder E, Faul F, Buchner A (1996) GPOWER: a general power analysis program. Behav Res Methods Instrum Comput. https://doi.org/10.3758/BF03203630 Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet. https://doi.org/10.1086/319501 Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. https://doi.org/10.1093/bioinformatics/bth457 Othman E-ER, Al-Hendy A (2008) Molecular genetics and racial disparities of uterine leiomyomas. Best Pract Res Clin Obstet Gynaecol 22:589–601. https://doi.org/10.1016/j.bpobgyn.2008.01.014 Hodge JC, Morton CC (2007) Genetic heterogeneity among uterine leiomyomata: insights into malignant progression. Hum Mol Genet. https://doi.org/10.1093/hmg/ddm043 Ciebiera M, Szymańska-Majchrzak J, Sentkowska A et al (2018) Alpha-tocopherol serum levels are increased in Caucasian women with uterine fibroids: a pilot study. Biomed Res Int 2018:6–8. https://doi.org/10.1155/2018/6793726 Ye Y, Cheng X, Luo HB et al (2008) CYP1A1 and CYP1B1 genetic polymorphisms and uterine leiomyoma risk in Chinese women. J Assist Reprod Genet 1:1. https://doi.org/10.1007/s10815-008-9246-x Shen Y, Xu Q, Ren M et al (2014) Role of single nucleotide polymorphisms in estrogen-metabolizing enzymes and susceptibility to uterine leiomyoma in Han Chinese: a case–control study. J Obstet Gynaecol Res 40:1077–1084. https://doi.org/10.1111/jog.12275 Sedighi M, Karimnejad S, Farhadi B, Hashemzadeh M (2015) Influence of the CYP1B1 gene polymorphisms and uterine leiomyoma risk in Iranian women. Int J Biosci 6:118–123 Liehr JG (1997) Dual role of oestrogens as hormones and pro-carcinogens: tumour initiation by metabolic activation of oestrogens. Eur J Cancer Prev 6:3–10 Li DN, Seidel A, Pritchard MP et al (2000) Polymorphisms in P450 CYP1B1 affect the conversion of estradiol to the potentially carcinogenic metabolite 4-hydroxyestradiol. Pharmacogenetics. https://doi.org/10.1097/00008571-200006000-00008 Zaykin DV, Westfall PH, Young SS et al (2002) Testing association of statistically inferred haplotypes with discrete and continuous traits in samples of unrelated individuals. Hum Hered. https://doi.org/10.1159/000057986 Watanabe J, Shimada T, Gillam EMJ et al (2000) Association of CYP1B1 genetic polymorphism with incidence to breast and lung cancer. Pharmacogenetics. https://doi.org/10.1097/00008571-200002000-00004 Schaid DJ, Rowland CM, Tines DE et al (2002) Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet. https://doi.org/10.1086/338688 Clark AG, Weiss KM, Nickerson DA, et al (1998) Haplotype Structure and Population Genetic Inferences from Nucleotide-Sequence Variation in Human Lipoprotein Lipase. Am J Hum Genet. https://doi.org/10.1086/301977 Campbell MC, Tishkoff SA (2008) African genetic diversity: implications for human demographic history, modern human origins, and complex disease mapping. Annu Rev Genom Hum Genet. https://doi.org/10.1146/annurev.genom.9.081307.164258 Alleyne AT, Austin S, Williams A (2014) Distribution of CYP17α polymorphism and selected physiochemical factors of uterine leiomyoma in Barbados. Metagene 2:358–365 Cropp CD, Robbins CM, Sheng X et al (2014) 8q24 risk alleles and prostate cancer in African-Barbadian men. Prostate 74:1579–1588. https://doi.org/10.1002/pros.22871 Murray T, Beaty TH, Mathias RA et al (2013) NIH Public Access 1:1. https://doi.org/10.1002/gepi.20512.African

This work was supported by the University of the West Indies, School for Graduate Studies and Research, Barbados, Dr. Tracey Archer formerly of the Barbados Family Planning Clinic, and Dr. Carlos Chase and Dr. Delores Lewis of the Queen Elizabeth Hospital, Barbados. Author information Authors and Affiliations Corresponding author Ethics declarations Conflict of interest The authors declare no conflict of interest. Ethical approval All procedure performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained from all individual participants included in the study. Additional information Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Nucleotide sequence data reported are available in the DDBJ/EMBL/GenBank databases under the accession number (s) LT613647-LT613831. Rights and permissions About this article Cite this article Alleyne, A.T., Bideau, V.S. Haplotypes of CYP1B1 and CCDC57 genes in an Afro-Caribbean female population with uterine leiomyoma. Mol Biol Rep 46, 3299–3306 (2019). https://doi.org/10.1007/s11033-019-04790-y Received: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s11033-019-04790-y