Examination of Candidate Chromosomal Regions for Type 2 Diabetes Reveals a Susceptibility Locus on Human Chromosome 8p23.1

Abstract

In a panel of large Caucasian pedigrees, we genotyped markers in eight chromosomal regions previously reported as supporting linkage with type 2 diabetes. We previously reported significant linkage on chromosome 20q (maximum logarithm of odds score [MLS] ‫؍‬ 2.79) in this panel. In the present analysis, candidate regions on 1q, 2q, 3q, 5q, 9q, and 10q yielded little evidence for linkage; a region on 2p (MLS ‫؍‬ 1.64, P ‫؍‬ 0.01 at position 9.0 cM) gave suggestive evidence of linkage; and a region on 8p (MLS ‫؍‬ 3.67, P ‫؍‬ 2.8 ؋ 10 ؊5 , at position 7.6 cM) gave significant evidence of linkage. Conditional analyses were performed for both 2p and 8p regions and the region reported on 20q. The MLS for 2p increased from 1.64 to 1.79 (empirical P ‫؍‬ 0.142) when conditioned for heterogeneity on 20q. The case was similar for 8p, where the MLS increased from 3.67 to 4.51 (empirical P ‫؍‬ 0.023) when conditioned on families without evidence of linkage at 20q. In conclusion, our data support a type 2 diabetes susceptibility locus on chromosome 8p that appears to be independent from other susceptibility loci. Although we were able to replicate linkage in our pedigrees on chromosome 2p, we did not find evidence of linkage for regions on 1q, 2q, 3q, 5q, 9q, or 10q. Diabetes 53: 486 -491, 2004 T ype 2 diabetes is a disease characterized by hyperglycemia, insulin resistance, and impaired insulin secretion (1). Although the pathophysiology of this disease is not well understood, evidence of familial clustering indicates that genetic susceptibility plays a role in disease development (2,3). Identification of genetic susceptibility factors, however, has been difficult, and, to date, the putative genes contributing to the etiology of type 2 diabetes remain unknown.Efforts to identify the genetic factors underlying susceptibility to type 2 diabetes have used both candidate gene approaches and linkage studies (4). More than a dozen genomewide scans have been completed from which various chromosomal regions with suggestive or significant evidence of linkage with type 2 diabetes have emerged (5-23). However, despite intense efforts to clone the susceptibility genes, the identification of these genes has been unsuccessful, with the single exception of calpain-10 (CAPN10) or NIDDM1 (24).Efforts to clone type 2 diabetes susceptibility loci have been plagued by inconsistent findings. Evidence for linkage with type 2 diabetes has been reported on most autosomes (25). However, there has been little overlap among linkage results, with the notable exceptions being the findings on chromosomes 1q (8,11,15,19,23) and 20q (26 -30). Factors contributing to the failure to replicate linkage results include the presence of environmentally determined phenocopies of type 2 diabetes as well as the complex nature of the inheritance of type 2 diabetes. The latter includes genetic and allelic heterogeneity, epistasis (gene-to-gene interaction), and gene-to-environment interactions.In a recent study, we showed that the overall sibling genetic risk rati...

Examination of PPP1R3B as a candidate gene for the type 2 diabetes and MODY loci on chromosome 8p23

“…The short arm of chromosome 8 is one of the few regions in the genome for which linkage with diabetes has been consistently demonstrated in multiple populations (Wiltshire et al 2001;Busfield et al 2002;Iwasaki et al 2003;Pezzolesi et al 2004;Kim et al 2004). The strongest evidence has come from the Joslin Study on the Genetics of Type 2 Diabetes -a large panel of extended, multigenerational families characterized by transmission of type 2 diabetes consistent with an autosomal dominant pattern of inheritance.…”

“…Another region with multiple reports of linkage is the short arm of chromosome 8. In the Joslin collection of families, we observed linkage in this region with both middle-age onset type 2 diabetes (LOD = 3.62 at 7.6 cM from p-ter) and maturity-onset diabetes of the young or MODY (LOD = 3.66 in the region between 15 and 24 cM from p-ter) (Pezzolesi et al 2004;Kim et al 2004). Linkage with type 2 diabetes was also found at this location in families from Japan (peak at 15 cM) and Australia (32 cM) (Busfield et al 2002;Iwasaki et al 2003).…”

“…DNA from the diabetic probands of eight type 2 diabetic families (Pezzolesi et al 2004) and five MODY families (Kim et al 2004) that showed positive lod scores on chromosome 8p were sequenced, along with three non-diabetic individuals, to search for mutations in the PPP1R3B gene. For representative variants, allele frequencies in the probands of the 79 type 2 diabetic and 21 MODY families were compared with those in 347 unrelated controls who had a negative history for type 2 diabetes, were not currently taking any glucose-lowering medications, and had fasting glucose levels less than 6.1 mmol/l or an HbA1c value less than 6.1%.…”

Identification of a chromosome 8p locus for early-onset coronary heart disease in a French Canadian population

“…Notably, a meta-analysis of four genome scans 57 identified a peak for HDL (LOD of 2.0) at D8S1130, which had a LOD score of 3.11 in this study (Table 3). In addition, there are reports of linkage signals in this region for type II diabetes 58 and for measures of insulin response and abdominal obesity in Mexican Americans. 59 GATA4 is a transcription factor that regulates cardiacspecific genes during development.…”

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

“…This was followed by SNPs-based fine-scale linkage disequilibrium (LD) and association mapping in the candidate region, supported by replicated linkage signals in Japanese and other multiple populations. In a number of candidate regions [5][6][7][8][9][10][11] for type 2 diabetes and its related traits, we selected the overlapping region on chromosome 3p24.3-22.1. 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].…”