Phenotype-Specific Association of LHCGR rs13405728 Polymorphism with Anovulatory Infertility in Malay Women with Polycystic Ovary Syndrome: A Case-Control Study.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is a multifactorial, polygenic endocrinopathy with an incompletely understood aetiology that accounts for approximately 80% of female anovulatory infertility. Both genetic and environmental factors contribute significantly to its pathogenesis. This study is the first to investigate the association of DENN/MADD domain-containing 1A (DENND1A rs2479106 and rs10986105), luteinising hormone/choriogonadotropin receptor (LHCGR rs13405728), follicle-stimulating hormone receptor (FSHR rs6166), thyroid adenomaassociated protein I (THADA rs13429458), and cytochrome P450 17A1 (CYP17A1 rs743572) gene polymorphisms with PCOS-related anovulatory infertility in Malay women. MATERIALS AND METHODS: In this case-control study, 96 participants were recruited - 48 anovulatory infertile-PCOS patients and 48 infertile non-PCOS controls. Single nucleotide polymorphisms (SNPs) were detected using highresolution melting (HRM) analysis, with sequencing performed for validation. RESULTS: The LHCGR rs13405728 polymorphism was strongly associated with an increased risk of PCOS-related anovulatory infertility, with each minor G allele conferring an odds ratio (OR) of 2.63 and 95% confidence interval (95% CI) of 1.11-6.27, P= 0.020). Conversely, the THADA rs7568365 T allele exhibited a protective effect, reducing the risk by 72% (OR=0.28; 95% CI: 0.08-0.90; P=0.020). No significant associations were observed for DENND1A rs2479106 and rs10986105, FSHR rs6166, THADA rs13429458, or CYP17A1 rs743572. Haplotype analysis revealed that the A-T (rs13429458-rs1317772225-rs7568365) and ATA and ACA (rs13405728-rs6166-rs13429458) haplotypes were protective, with ORs of 0.13, 0.19, and 0.30, respectively (P<0.05). CONCLUSION: The LHCGR rs13405728 polymorphism is significantly associated with the risk of PCOS-related anovulatory infertility in Malay women and may serve as a potential early prognostic biomarker for the development of PCOS-related infertility.