Variability in genes regulating vitamin D metabolism is associated with vitamin D levels in type 2 diabetes

Abstract

Mortality rate is increased in type 2 diabetes (T2D). Low vitamin D levels are associated with increased mortality risk in T2D. In the general population, genetic variants affecting vitamin D metabolism (DHCR7 rs12785878, CYP2R1 rs10741657, GC rs4588) have been associated with serum vitamin D. We studied the association of these variants with serum vitamin D in 2163 patients with T2D from the "Sapienza University Mortality and Morbidity Event Rate (SUMMER) study in diabetes". Measurements of serum vitamin D were centralised. Genotypes were obtained by Eco™ Real-Time PCR. Data were adjusted for gender, age, BMI, HbA1c, T2D therapy and sampling season. DHCR7 rs12785878 (p = 1 x 10-4) and GC rs4588 (p = 1 x 10-6) but not CYP2R1 rs10741657 (p = 0.31) were significantly associated with vitamin D levels. One unit of a weighted genotype risk score (GRS) was strongly associated with vitamin D levels (p = 1.1 x 10-11) and insufficiency (<30 ng/ml) (OR, 95%CI = 1.28, 1.16-1.41, p = 1.1 x 10-7). In conclusion, DHCR7 rs12785878 and GC rs4588, but not CYP2R1 rs10741657, are significantly associated with vitamin D levels. When the 3 variants were considered together as GRS, a strong association with vitamin D levels and vitamin D insufficiency was observed, thus providing robust evidence that genes involved in vitamin D metabolism modulate serum vitamin D in T2D.

Keywords: CYP2R1 (Cytochrome P450 Family 2 Subfamily R Member 1); DHCR7 (7-dehydrocholesterol reductase); GC (Vitamin D Binding Protein); SUMMER Study in Diabetes; genetic risk score.

Figure 1. Combined effect of risk alleles, as indicated by quartiles of a weighted genotype risk score (w-GRS), on Vitamin D levels

Mean Vitamin D levels significantly decreased as a function of the number of risk alleles (p = 1.1 × 10⁻⁷). In the x-axis, the score range in each quartile is indicated in parenthesis.