Polycystic Ovarian Syndrome (PCOS) and its association with VDR gene variants Cdx2 (rs11568820) and ApaI (rs7975232): Systematic review, meta-analysis and in silico analysis

Polycystic ovary syndrome (PCOS) is a multifactorial and polygenic disorder of women in the reproductive-age group. Vitamin D serum level and Vitamin D receptor (VDR) polymorphism which may have an indirect role in the availability of Vit D have been investigated as one of the predisposing causes. The study aims to investigate the association between VDR polymorphism and PCOS susceptibility. Online databases (PubMed, Science Direct, and Google Scholar) were searched up to 30th December 2023 with suitable syntax. Odds Ratios (OR) with 95% Confidence Interval (CI) and Chi-square (chi 2) tests were applied under different genetic models to find the association between VDR gene Cdx2 G > A (rs11568820) and ApaI C > A(rs7975232) polymorphisms, and PCOS risk. All the statistical calculations were performed using Review Manager 5.3 software (Cochrane Collaboration, Oxford, UK). To understand the molecular effect of variants in the untranslated region, in silico analysis was performed using Regulome DB, FATHMM-MKL, and Haploreg v4.1 web tools. A total of seventeen case-control studies were identified with 2337 PCOS patients and 1779 healthy controls. VDR variant Cdx2 (rs11568820) was found to be significantly associated (OR = 0.47, 95% CI = 0.25-0.87, p = 0.02) after the one-out analysis with one major study. VDR variant ApaI is significantly associated with PCOS under all four genetic models: Dominant Model (AA + AC vs CC): OR = 0.69, 95% CI = 0.52-0.93, p = 0.01, Recessive model (AA vs. AC + CC): OR = 0.78, 95% CI = 0.68-0.89, p = 0.0004; Additive model (AA vs. AA +CC): OR = 0.65, 95% CI = 0.53-0.80, p = 0.0001 and Allele model (A vs. C): OR = 0.80, 95%CI = 0.72-0.88, p = 0.0001 indicating 'A' allele as protective factor. However, the association became insignificant after subgroup analysis which is based on the stratification of data according to ethnicity. In silico analysis also suggested the deleterious effect of these intronic variants. The study suggested a significant role of these two variants as risk factors for PCOS.