Our findings suggest that VDR gene polymorphisms may influence the severity of MetSyn component disorder. In individuals with MetSyn, the VDR 2228570 C > T (FokI) polymorphism appeared to be associated with insulin sensitivity and iPTH concentration. Additionally, in individuals without MetSyn, this polymorphism was associated with higher triglycerides and lower HDL levels. Furthermore, when considering all individuals, HDL cholesterol varied independently with VDR FokI polymorphism. In support of the findings, Oh and Barrett-Connor (2002) investigating VDR gene polymorphisms in individuals with type 2 diabetes in the Rancho Bernando Cohort, observed that individuals with the mutant recessive homozygous genotype, the VDR 1544410 A > G (BsmI) polymorphism, presented significantly higher levels of HOMA-IR compared to those with heterozygous or normal homozygous genotypes .
Since the early 1980’s, it has been demonstrated that pancreatic insulin secretion is inhibited by vitamin D deficiency, suggesting a role for this vitamin in the regulation of endocrine pancreatic function, especially in the β cell . In addition, the non-genomic pathway dependent on membrane VDR protein promotes rapid calcium fluxes important in inducing effects of vitamin D on insulin release [31–34]. It is already known that 1,25(OH)2D3 directly influences β cell insulin secretion through the induction of increases in intracellular free calcium concentration through voltage-dependent Ca2+ channels . Moreover, though glycemia is a major major characteristic of diabetes mellitus type 2, no association was found between fasting glycemia and VDR gene polymorphisms evaluated in this cohort. Similarly, Malecki and coworkers (2003) have investigated BsmI, TaqI, and FokI VDR gene polymorphisms in 548 Polish individuals with and without T2DM and did not found any association of glycemia with any of the VDR gene polymorphisms either .
On the other hand, the association of MetSyn with increased cardiovascular disease may be modulated by non-bony effects of vitamin D such as those on lipid profiles. This possibility is supported by an investigation on whether lack of vitamin D has effect on cholesterol metabolism where serum concentrations of HDL cholesterol was found to be 22% higher in VDR knockout compared to wild type mice . In contrast, different results were observed in humans in the NHANES 2000–2004 survey, which demonstrated that vitamin D deficiency (< 15 ng/mL) was associated with lower concentrations of HDL cholesterol in adults . Results of this study corroborate the latter study, in suggesting that VDR gene polymorphism associated with lower serum 25(OH)D3, may be linked to lower HDL-cholesterol in adults.
There are three mechanisms by which our data suggests that the vitamin D-VDR axis could affect lipid profiles. First: Vitamin D induced suppression of PTH secretion, and it has been reported that PTH could reduce lipolysis . Second: Vitamin D increases intestinal calcium absorption and this can trigger a decrease in serum triglycerides levels by reducing the hepatic triglyceride formation and secretion , and Third: Vitamin D might improve insulin secretion and insulin sensitivity, thereby indirectly influencing lipid metabolism .
In the present study, important associations were also identified for both VDR 2228570 C > T (FokI) or VDR 1544410 A > G (BsmI) polymorphism in individuals without MetSyn. The higher triglycerides and lower HDL in heterozygous VDR 2228570 C > T (FokI) as well lower 25(OH)D3 in homozygous recessive VDR 1544410 A > G (BsmI), could be related to the overweight/obese condition of the individuals. There are likely to be many genetic factors in addition to the VDR 1544410 A > G and VDR 2228570 C > T gene polymorphisms that are involved in determination of MetSyn risk. Despite this our data suggests that VDR polymorphisms may contribute to MetSyn component severity such as insulin secretion, insulin resistance and HDL-cholesterol, findings that warrant further examination in larger cohorts with data permitting genome wide association studies to be made.