Association of FSHR rs6165 and ADIPOQ rs2241766 variants with polycystic ovary syndrome (PCOS) in Pakistani women: a two-locus genetic risk analysis

Abstract Background Polycystic ovary syndrome (PCOS) is a common multifactorial endocrine disorder with reproductive and metabolic manifestations. The contribution of variants involved in ovarian folliculogenesis and metabolic regulation remains incompletely understood in South Asian populations. This study investigated the association of follicle-stimulating hormone receptor ( FSHR ) rs6165 and adiponectin ( ADIPOQ ) rs2241766 polymorphisms with PCOS susceptibility in Pakistani women and evaluated their combined genetic contribution using a cumulative genetic risk score. Methods A hospital-based case-control study included 55 PCOS patients (Rotterdam 2003 criteria) and 60 healthy controls. Genotyping of ADIPOQ rs2241766 was performed using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP), whereas FSHR rs6165 was genotyped using allele-specific PCR. Associations were evaluated using logistic regression under allelic and codominant models after adjustment for age and body mass index (BMI). A two-locus genetic risk score based on total risk alleles was constructed and categorized into tertiles. Results The FSHR rs6165 AG genotype was associated with significantly increased PCOS risk compared with AA homozygotes (adjusted odds ratio (OR) = 7.56, 95% confidence interval (CI): 3.10–18.43, p < 0.001), and the G allele was more frequent among cases (adjusted OR = 2.32, 95% CI: 1.52–3.56, p < 0.001). The ADIPOQ rs2241766 G allele showed a non-significant trend toward increased risk (adjusted OR = 1.78, 95% CI: 0.88–3.58, p = 0.09). Participants in the highest genetic risk score tertile had significantly greater odds of PCOS than those in the lowest tertile (adjusted OR = 3.80, 95% CI: 1.80–8.02, p < 0.001), with moderate discriminatory performance (area under the curve (AUC) = 0.71, 95% CI: 0.63–0.79). Conclusions The FSHR rs6165 variant is associated with increased PCOS susceptibility in Pakistani women, whereas ADIPOQ rs2241766 showed only a modest, non-significant association. Combining variants from reproductive and metabolic pathways may improve genetic risk assessment compared with single-variant analyses. Replication in larger, ethnically diverse cohorts is warranted to validate these exploratory findings.