Inherited Variation in Vitamin D Genes Is Associated With Predisposition to Autoimmune Disease Type 1 Diabetes

Abstract

OBJECTIVEVitamin D deficiency (25-hydroxyvitamin D [25(OH)D] <50 nmol/L) is commonly reported in both children and adults worldwide, and growing evidence indicates that vitamin D deficiency is associated with many extraskeletal chronic disorders, including the autoimmune diseases type 1 diabetes and multiple sclerosis.RESEARCH DESIGN AND METHODSWe measured 25(OH)D concentrations in 720 case and 2,610 control plasma samples and genotyped single nucleotide polymorphisms from seven vitamin D metabolism genes in 8,517 case, 10,438 control, and 1,933 family samples. We tested genetic variants influencing 25(OH)D metabolism for an association with both circulating 25(OH)D concentrations and disease status.RESULTSType 1 diabetic patients have lower circulating levels of 25(OH)D than similarly aged subjects from the British population. Only 4.3 and 18.6% of type 1 diabetic patients reached optimal levels (≥75 nmol/L) of 25(OH)D for bone health in the winter and summer, respectively. We replicated the associations of four vitamin D metabolism genes (GC, DHCR7, CYP2R1, and CYP24A1) with 25(OH)D in control subjects. In addition to the previously reported association between type 1 diabetes and CYP27B1 (P = 1.4 × 10−4), we obtained consistent evidence of type 1 diabetes being associated with DHCR7 (P = 1.2 × 10−3) and CYP2R1 (P = 3.0 × 10−3).CONCLUSIONSCirculating levels of 25(OH)D in children and adolescents with type 1 diabetes vary seasonally and are under the same genetic control as in the general population but are much lower. Three key 25(OH)D metabolism genes show consistent evidence of association with type 1 diabetes risk, indicating a genetic etiological role for vitamin D deficiency in type 1 diabetes.

CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo

“…The former is consistent with liver being the major site of 25-hydroxylation, but its abundance in testis awaits further investigation to decipher the physiological relevance, although it has been linked to male reproduction, testicular cancer, and other testiculopathic conditions (33)(34)(35). Cyp2r1 polymorphisms have been implicated in the variation of circulating 25(OH)D 3 concentrations (36)(37)(38) and as risk factors in type 1 diabetes and multiple sclerosis in humans (39)(40)(41)(42).…”

The role of vitamin D3 in the regulation of the mineral metabolism in experimental type 1 diabetes

“…В частности, дефицит витамина D 3 и нарушение образования его гормонально активных форм снижает абсорбцию ионизированного кальция в тонком кишечнике, повышает уровень паратгормона и через снижение уровня кальцитонина ведёт к усилению резорбции костной ткани и остеопорозу. Гормонально активная форма витамина D 3 (1,25 [11,12].…”

ANKRD55 and DHCR7 are novel multiple sclerosis risk loci

“…This was either due to the very-low published ORs for the association of SNPs in the vitamin D pathway genes CYP2R1 and DHCR7 with T1D, or to the low risk allele frequency of the PXK SNP. 6,14 Notwithstanding, we identified a moderately significant association of DHCR7 rs12785878 with MS in the full cohort (OR ¼ 1.10; 95% confidence interval (CI) ¼ 1.02 --1.19; P CMH ¼ 0.009) ( Table 2). The only other, though much stronger, association found was that with the ANKRD55 SNP rs6859219 (OR ¼ 1.26; 95% CI ¼ 1.16 --1.38; P CMH ¼ 1.9 Â 10 À7 ).…”

“…12,13 CYP2R1 rs10741657 and DHCR7 rs12785878 were found to be associated with T1D, a condition associated with vitamin D deficiency. 14,15 Given the welldocumented candidacy of vitamin D as key factor in the pathogenesis of MS, both the SNPs were included in the present association study. 16 An intronic SNP in IL2RA, rs12722489, emerged from the first GWAS in MS as one of the first ever non-HLA MS risk polymorphisms to be identified.…”