Type 1 Diabetes

Abstract

Type 1 diabetes is a common, multifactorial disease with strong familial clustering (genetic risk ratio [ S ] ϳ 15).Approximately 40% of the familial aggregation of type 1 diabetes can be attributed to allelic variation of HLA loci in the major histocompatibility complex on chromosome 6p21 (locus-specific S ϳ 3). Three other disease susceptibility loci have been clearly demonstrated based on their direct effect on risk, INS (chromosome 11p15, allelic odds ratio [OR] ϳ 1.9), CTLA4 (chromosome 2q33, allelic OR ϳ 1.2), and PTPN22 (chromosome 1p13, allelic OR ϳ 1.7). However, a large proportion of type 1 diabetes clustering remains unexplained. We report here on a combined linkage analysis of four datasets, three previously published genome scans, and one new genome scan of 254 families, which were consolidated through an international consortium for type 1 diabetes genetic studies (www.t1dgc.org) and provided a total sample of 1,435 families with 1,636 affected sibpairs. In addition to the HLA region (nominal P ‫؍‬ 2.0 ؋ 10 ؊52 ), nine non-HLA-linked regions showed some evidence of linkage to type 1 diabetes (nominal P < 0.01), including three at (or near) genome-wide significance (P < 0.05): 2q31-q33, 10p14-q11, and 16q22-q24. In addition, after taking into account the linkage at the 6p21 (HLA) region, there was evidence supporting linkage for the 6q21 region (empiric P < 10 ؊4 ). More than 80% of the genome could be excluded as harboring type 1 diabetes susceptibility genes of modest effect ( S > 1.3) that could be detected by linkage. This study represents one of the largest linkage studies ever performed for any common disease. The results demonstrate some consistency emerging for the existence of susceptibility loci on chromosomes 2q31-q33, 6q21, 10p14-q11, and 16q22-q24 but diminished support for some previously reported locations. Diabetes 54:2995-3001, 2005

Toward Further Mapping of the Association Between the IL2RA Locus and Type 1 Diabetes

“…IL2RA maps within the chromosome 10p14-q11 linkage peak identified in the largest study to date (1,435 families) with the second highest logarithm of odds score outside the HLA region (9). It is unlikely that this peak is accounted for by the relatively weak effect we detected, and it may be due to aggregate effects from additional associated loci.…”

TIM-3 polymorphisms in type 1 diabetes families

“…However, a study of Danish, European, and American families could not confirm any association, although the correlation of IL-12 alleles and expression showed a trend of a higher IL-12 secretion in the presence of the 1159C allele (Bergholdt et al 2004). Still, a genome scan finds little support of the IDDM18 locus on chromosome 5q33, with a maximum logarithm of odds (LOD) score of just below 1 (Concannon et al 2005), which may be due to the fact that susceptibility is either weak or operational in some populations only.…”

Study of the association between the CAPSL-IL7R locus and type 1 diabetes

“…The genetic predisposition to type 1 diabetes is strongly associated with the MHC region; however, some loci outside the MHC have been considered to confer disease risk. Some of these have been validated, together with MHC class II alleles [1,2], as susceptibility factors, namely the insulin gene [3,4], the CTLA4 locus [5,6] and the PTPN22 gene [7].…”