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

Graves' disease (GD) and Hashimoto's thyroiditis (HT) are T-cell mediated organ-specific autoimmune disorders with a genetic predisposition. The cytotoxic T-lymphocyte antigen 4 (CTLA-4) molecule is the predominant receptor for B7 on activated T cells and represents a negative regulator for T-cell function. Since the CTLA-4-guanine at position 49 of exon 1 is associated with susceptibility to GD as well as to HT and IDDM, we investigated a recently detected cytosine/thymine substitution at position -318 within the CTLA-4 promoter region in patients with GD and HT. 125 patients with GD were significantly more often homozygous for cytosine (86% vs. 73% in controls, P=0.006) and less frequently heterozygous for cytosine and thymine (14% vs. 27%, P=0.008). In 64 patients with HT, the distribution was similar but not significant (81% homozygous for cytosine and 16% heterozygous). When correlating the promoter and the exon 1 polymorphism we found the strongest linkage between thymine (promoter) and adenine (exon 1). In conclusion, a promoter variant of the CTLA-4 gene represents an additional risk marker for GD and HT, but their predisposition is linked to the exon 1 alleles.

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