Vitamin D receptor allele combinations influence genetic susceptibility to type 1 diabetes in Germans.

Abstract

inhibits lymphocyte activation and affects other elements of the immune system, such as cytokine and immunoglobulin production, as well as major histocompatibility complex (MHC) class II and cluster of differentiation (CD)-4 expression (1). In NOD mice, the development of diabetes can be prevented by administration of 1,25(OH) 2 D 3 ( 2 ) , which inhibits lymphocyte activation and restores the altered ratio of CD4/CD8 cells.Vitamin D exerts its genomic action via the nuclear vitamin D receptor (VDR), which shows an extensive polymorphism. The VDR belongs to the steroid receptor super-family and is widely expressed in many cell types, including lymphocytes, macrophages, and pancreatic -cells (3). Four major polymorphic sites have been described within the VDR gene. A polymorphic F o kI site in exon 2 results in an alternative transcription initiation site, leading to a protein variant with three additional amino acids at the amino terminus (4). Polymorphic B s mI and A p aI sites are present in intron 8, and a silent T to C substitution creates a Ta qI restriction site in exon 9. R e c e n t l y, an association of VDR alleles with type 1 diabetes in Indian Asians has been reported (5). We therefore examined the VDR locus on chromosome 12q12-14 as a candidate gene for type 1 diabetes susceptibility in German families using extended transmission disequilibrium testing (ETDT).P a i r-wise transmission distortion testing revealed a strong linkage disequilibrium between "B" and "A" (0.1514 ± 0.0145), between "B" and "T" (-0.1953 ± 0.0148), and between "A" and "T" (-0.1322 ± 0.0144). No significant linkage disequilibrium between F o kI and any of the other sites was detectable. The allele combinations "b aT " (35.3%), "B A t" (29.5%), and "b AT " (16.8%) were most frequent in the analyzed population ( Ta b l e 1 ) .Based on the linkage disequilibrium data, ETDT analysis of the 3 -haplotypes (B s mI /A p aI /Ta qI) showed a signific a n t transmission distortion ( 2 = 18.886, df = 7, P = 0.0086). These observations (Ta b l e 2) were confirmed when looking at the two-locus haplotypes that are part of the B s mI /A p aI /Ta qI

Taq I polymorphism of the vitamin D receptor and risk of severe diabetic retinopathy

“…Interestingly, at least one report associated the b allele of Bsm I, which shows strong linkage disequilibrium with T allele of Taq I site, with significantly lower serum calcitriol concentrations than control subjects [52], although other studies found the opposite effect [21]. In addition, VDR genotype combination BAt confers high risk for Type I diabetes in German people [11].…”

Genetics of type 1 diabetes mellitus

“…[220][221][222] Vitamin D has important immunomodulatory properties 223 and depletion or relative resistance may play a part in the aetiology of both T1DM and T2DM, possibly through effects on insulin secretion. 224 It has been shown that allelic variations in the vitamin D receptor (VDR) gene is a significant determinant of the amount of VDR mRNA and VDR protein expressed, 225 and may also affect plasma concentrations of 1,25(OH) 2 D 3 , and the response to oral vitamin D. 226 An association between VDR polymorphisms and T1DM has been reported in South Indian, German and Taiwanese populations, [227][228][229] although not necessarily with the same VDR polymorphisms.…”

Genetic control of autoimmunity in Type I diabetes and associated disorders

“…LRP5 is a member of the low-density lipoprotein receptor family that is expressed in cells of the mononuclear-phagocyte system, the islets of Langerhans, vitamin A-metabolising cells, and CNS neurons [131]. Vitamin D receptor polymorphisms have been associated with risk for type 1A diabetes in several populations [132,133,134,135].…”