PCOS is a multifactorial disorder that has been linked to genetic and environmental factors, including obesity and insulin resistance. A growing body of evidence suggests that PCOS has a genetic background and various biochemical pathways as well as their related genes in these pathways –including those involved in steroidogenesis, lipid metabolism, gonadotropin and sex hormones metabolism and many others- have crucial roles in the pathological development of PCOS (3, 6). Vitamin D is recognized for its vital roles in the metabolic and endocrine pathways linked to PCOS, including the insulin signaling pathway (34) and the production of sex hormones (35).
The GC gene contains instructions for a polymorphic plasma protein called GC, also referred to as group-specific component or vitamin D binding protein (VDBP). This protein, synthesized in the liver, serves as a carrier for vitamin D and its metabolites. The rs7041 polymorphism is one of the genetic variations associated with the VDBP gene, and various studies have investigated its correlation with several diseases, including diabetes (20, 36),obesity (21, 37), pulmonary obstruction (22, 38), asthma (23, 39), Parkinson's disease (25, 40), and MS (26). The results of these studies suggest that this polymorphism significantly impacts various aspects of diseases. To date, only a limited number of studies have addressed the association of the rs7041 polymorphism with PCOS (27, 28).
The findings of this study reveal a significant association between the GT genotype and PCOS. Analysis of the alleles related to this polymorphism indicates that the T allele significantly increases the risk of PCOS. Vitamin D deficiency and its metabolism disruption play a crucial role in the pathogenesis of PCOS (27, 28). In this context, studies have indicated the beneficial effects of vitamin D supplementation on insulin secretion and serum lipid profiles in PCOS patients (41, 42). The serum level of vitamin D is influenced by various factors, with one of the main factors being VDBP. Numerous studies have shown a significant association between the rs7041 polymorphism and serum 25(OH)D levels (18, 43). In this regard, some studies have reported that the T allele in this polymorphism is associated with vitamin D deficiency (44, 45). Therefore, the T allele of rs7041 polymorphism may be involved in the pathogenesis and progression of PCOS in women through decreased vitamin D levels. In this regard, a study conducted in India on 50 PCOS women showed that the GT genotype of the rs7041 polymorphism increases the risk of PCOS in women with vitamin D deficiency (27). However, two other studies did not report any association between genotypes of this polymorphism and the risk of PCOS (28, 46). Besides, in a study by Santos and colleagues (2017), it was shown that PCOS women with the TT genotype had a higher prevalence of metabolic syndrome, indicating a significant association between this genotype and metabolic syndrome (18). Therefore, the T allele of rs7041 polymorphism may play a role in the development of metabolic symptoms and potentially contribute to the pathogenesis of PCOS through this pathway.
This study, for the first time, investigated the association of the rs7041 polymorphism in the VDBP gene with infertility and RPL in women with PCOS. According to the results, the GT genotype and T allele show a significant association with infertility in women with PCOS. However, no association was observed between genotypes and alleles with RPL in women with PCOS. The differing results in the two subgroups suggest that different pathological pathways may be involved in infertility and RPL in PCOS patients, and this polymorphism may only affect specific metabolic pathways related to infertility.
PCOS is associated with a significantly higher risk of infertility, with a prevalence ranging from 70–80% among affected women (9). In this regard, studies have demonstrated that an elevated level of LH in women with PCOS is linked to infertility, as increased LH levels can disrupt ovulation (47). The present study revealed that women with the TT + GT genotype have higher LH levels compared to women with the GG genotype. Therefore, it can be suggested that the T allele may increase the risk of infertility in women with PCOS by elevating LH levels.
Moreover, individuals with the GG genotype were found to have higher FBS levels compared to those with the GT and TT genotypes. Consistent with these findings, Zhao et al. (2020) also indicated that individuals with the G allele have higher FBS levels than those with the T allele (20). Thus, it is plausible that individuals with the G allele may have a higher risk of insulin resistance and type 2 diabetes. However, some studies have reported conflicting results or found different outcomes. Kiani and colleagues (2019) reported that cardiovascular patients with the TT genotype have higher FBS levels (48). Given these contradictory results, further investigation in larger populations and different ethnicities is necessary.
All clinical features, except BMI, FBS, TC, and LDL showed significant differences between PCOS and its associated subgroups when compared to the non-PCOS group. These results have also been detailed in our earlier publications (31–33). No significant difference in BMI, FBS, TC, and LDL was observed in some studies (18, 28). However, certain studies reported significant variations in the level of FBS and BMI between PCOS and non-PCOS subjects (46, 49). These differences could stem from factors such as race, age, and sample size.
The present study has some limitations that should be taken into consideration. This research was conducted on a relatively small population of women. Therefore, to confirm the results of this study, further research with a larger sample size is needed. Additionally, this study was exclusively carried out on Iranian women and does not encompass racial and environmental diversity. Future studies should focus on larger and more diverse populations to validate the findings of this study. Another limitation of this study is not having measured serum vitamin D levels.