Genomewide Search for Type 2 Diabetes Susceptibility Genes in Four American Populations

Abstract

Type 2 diabetes is a serious, genetically influenced disease for which no fully effective treatments are available. Identification of biochemical or regulatory pathways involved in the disease syndrome could lead to innovative therapeutic interventions. One way to identify such pathways is the genetic analysis of families with multiple affected members where disease predisposing genes are likely to be segregating. We undertook a genomewide screen (389-395 microsatellite markers) in samples of 835 white, 591 Mexican American, 229 black, and 128 Japanese American individuals collected as part of the American Diabetes Association's GENNID study. Multipoint nonparametric linkage analyses were performed with diabetes, and diabetes or impaired glucose homeostasis (IH). Linkage to diabetes or IH was detected near markers D5S1404 (map position 77 cM, LOD = 2.80), D12S853 (map position 82 cM, LOD = 2.81) and GATA172D05 (X-chromosome map position 130 cM, LOD = 2.99) in whites, near marker D3S2432 (map position 51 cM, LOD = 3.91) in Mexican Americans, and near marker D10S1412 (map position 14 cM, LOD = 2.39) in African Americans mainly collected in phase 1 of the study. Further analyses showed evidence for interactions between the chromosome 5 locus and region on chromosome 12 containing the MODY 3 gene (map position 132 cM) and between the X-chromosome locus and region near D12S853 (map position 82 cM) in whites. Although these results were not replicated in samples collected in phase 2 of the GENNID study, the region on chromosome 12 was replicated in samples from whites described by Bektas et al. (1999).

Studies of the relationship between the ENPP1 K121Q polymorphism and type 2 diabetes, insulin resistance and obesity in 7,333 Danish white subjects

“…The involvement of PC-1 in insulin-resistant states is further supported by recent studies revealing evidence for linkage between the chromosomal region 6q22-q23 of the gene encoding PC-1 (ENPP1) and insulin resistance [9], obesity [10,11] and type 2 diabetes [12][13][14][15]. Furthermore, the minor Q allele of a K121Q variant (rs1044498) of ENPP1 has been shown to influence PC-1 protein function by inhibiting insulin receptor function and insulin signalling more effectively than the major K allele [16,17].…”

Haplotypic analysis of Wellcome Trust Case Control Consortium data

“…The third associated region (chromosome 12q15 with T2D) has been implicated in two linkage scans of type 2 diabetes (Bektas et al 2001;Ehm et al 2000). Localized haplotype cluster analysis provided improved evidence for association (p = 1.88 × 10 -7 ) to 12q15 compared to single marker tests (genotyped SNP minimum p = 1.5 × 10 -6 ; imputed SNP minimum p = 7.0 × 10 -7 ).…”

Genetic association of single nucleotide polymorphisms in endonuclease G-like 1 gene with type 2 diabetes in a Japanese population

“…In this study, we selected a target region on chromosome 3p24.3-22.1 that corresponds to 20.4 Mb based on replicated linkage for type 2 diabetes or its related traits [6,[12][13][14][15][16]. We adopted a two-step association test using 1,762 Japanese subjects to reduce the time and cost of genotyping.…”

“…This candidate region, supported by replicated linkage signals including significant evidence of linkage with lod >3.6 [14], is expected to contain susceptibility gene(s). Studying this region, we focused on 44-70 cM in a Japanese population, assessing it here, in Japanese persons, by means of an association test.…”

“…This region showed nominal significance in linkage (maximum logarithm of the odds [lod] score=1.58) for type 2 diabetes in a Japanese population [12]. In Japanese people, it was reported to substantially overlap with that in Mexican Americans [6,13] and with that reported in the American Diabetes Association's Genetics of NIDDM study in Mexican Americans [14]. These results in Mexican Americans were replicated in Pima Indians [15] and Finnish families [16] (Electronic supplementary material [ESM] Table 1).…”