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Both vitamin D deficiency and single nucleotide polymorphisms (SNPs) in the gene encoding the vitamin D receptor (VDR) have been widely reported to associate with susceptibility to polycystic ovarian syndrome (PCOS). A case-control study was conducted to study the influence of vitamin D status and genotpye for 24 SNPs in four genes in the vitamin D pathway (VDR, DBP, CYP27B1, CYP24A1) on PCOS. Statistical analyses were conducted to identify phenotypic and genotypic factors associated with risk of pcoS and to test for interactions between genotype and vitamin D status. pcoS was independently associated with lower age, higher body mass index, lower waist-hip ratio, vitamin D deficiency (serum 25-hydroxyvitamin D concentration <10 ng/mL), lack of outdoor exercise, increased fasting glucose and a family history of PCOS in at least one first degree relative. No statistically significant association was observed between the genotype of any SNP investigated and risk of PCOS, either as a main effect or in interaction with vitamin D status. We report a strong and independent association between vitamin D deficiency and risk of PCOS in Pakistan, that was not modified by genetic variation in the vitamin D pathway.Polycystic ovary syndrome (PCOS) is the most common reproductive, endocrine and metabolic disorder in women of reproductive age 1 . Globally, the prevalence of PCOS ranges from 4 to 21%, as defined using NIH 1990 and Rotterdam 2003 criteria 2 . Epidemiological data from Pakistan are scarce, but the prevalence of PCOS has been reported to be particularly high among women of South Asian ethnic origin 3,4 .PCOS is thought to arise as a result of the interplay between genetic and environmental factors 5 . A growing body of literature indicates that vitamin D deficiency may be a risk factor: meta-analyses of observational studies reveal independent associations between PCOS and low serum concentrations of 25-hydroxyvitamin D (25[OH] D, the major circulating vitamin D metabolite) as well as single nucleotide polymorphisms [SNPs] in the gene encoding the vitamin D receptor (VDR) 6-11 . However, data relating to vitamin D status among women with PCOS in Pakistan are lacking. Moreover, studies in the field have not yet tested for main effects of SNPs in the genes encoding the 1-alpha hydroxylase enzyme CYP27B1 (which converts 25[OH]D to its active metabolite 1,25-dihydroxy vitamin D) or the vitamin D 24-hydroxylase enzyme CYP24A1 (which converts 25[OH]D to its major inactive catabolite 24R,25-dihydroxy vitamin D). Neither have they tested for interactions between SNPs in the vitamin D pathway and vitamin D status in influencing the risk of PCOS.We have previously demonstrated that genetic variation in the vitamin D pathway can modify the influence of vitamin D deficiency and supplementation on clinical phenotype in the context of tuberculosis 12-14 . We, therefore, conducted a case control study in Lahore, Pakistan, to determine whether vitamin D deficiency and SNPs in four vitamin D pathway genes might influence the risk ...