Linkage and Association Mapping of a Chromosome 1q21-q24 Type 2 Diabetes Susceptibility Locus in Northern European Caucasians

Abstract

We have identified a region on chromosome 1q21-q24 that was significantly linked to type 2 diabetes in multiplex families of Northern European ancestry and also in Pima Indians, Amish families, and families from France and England. We sought to narrow and map this locus using a combination of linkage and association approaches by typing microsatellite markers at 1.2 and 0.5 cM densities, respectively, over a region of 37 cM (23.5 Mb). We tested linkage by parametric and nonparametric approaches and association using both casecontrol and family-based methods. In the 40 multiplex families that provided the previous evidence for linkage, the highest parametric, recessive logarithm of odds (LOD) score was 5.29 at marker D1S484 (168.5 cM, 157.5 Mb) without heterogeneity. Nonparametric linkage (NPL) statistics (P ‫؍‬ 0.00009), SimWalk2 Statistic A (P ‫؍‬ 0.0002), and sib-pair analyses (maximum likelihood score ‫؍‬ 6.07) all mapped to the same location. The one LOD CI was narrowed to 156.8 -158.9 Mb. Under recessive, two-point linkage analysis, adjacent markers D1S2675 (171.5 cM, 158.9 Mb) and D1S1679 (172 cM, 159.1 Mb) showed LOD scores >3.0. Nonparametric analyses revealed a second linkage peak at 180 cM near marker D1S1158 (163.3 Mb, NPL score 3.88, P ‫؍‬ 0.0001), which was also supported by case-control (marker D1S194, 178 cM, 162.1 Mb; P ‫؍‬ 0.003) and family-based (marker ATA38A05, 179 cM, 162.5 Mb; P ‫؍‬ 0.002) association studies. We propose that the replicated linkage findings actually encompass at least two closely spaced regions, with a second susceptibility region located telomeric at 162.5-164.7 Mb. Diabetes 53:492-499, 2004 T ype 2 diabetes (MIM125853) likely encompasses a diverse set of diseases marked by elevated levels of plasma glucose. Among Caucasian populations, individuals with type 2 diabetes, individuals with the intermediate phenotype of impaired glucose tolerance, and likely individuals at risk of diabetes are all characterized by variable degrees of both decreased insulin action, particularly resistance to insulin-mediated muscle glucose uptake, and impaired insulin secretion in response to that decreased insulin action (1). Defects of both insulin action and insulin secretion among individuals with normal glucose tolerance predict later onset of diabetes (2). Despite the diverse phenotypic nature of type 2 diabetes, monozygotic and dizygotic twin studies, family studies, and marked differences in disease prevalence across populations all provide convincing evidence for an important role of genetic susceptibility loci in type 2 diabetes pathogenesis (1). Based on epidemiological data, the total sibling relative risk ( s ) has been estimated at 3-4 (3), although the number of loci that contribute to this risk is unclear.Based on these data supporting type 2 diabetes susceptibility genes, genome scans for both type 2 diabetes and type 2 diabetes-related traits have been undertaken by multiple laboratories in Caucasian, Pima Indian, AfricanAmerican, and Asian populations (1,4,5), among others. T...

Variation Within the Gene Encoding the Upstream Stimulatory Factor 1 Does Not Influence Susceptibility to Type 2 Diabetes in Samples From Populations With Replicated Evidence of Linkage to Chromosome 1q

“…To examine the impact of USF1 SNPs on insulin sensitivity (S i ), insulin secretion (AIR g ), and ␤-cell function (disposition index [DI]), we analyzed two samples. The first consisted of 124 nondiabetic members of Utah families with evidence of chromosome 1q linkage (2,5). The second sample included 181 unrelated Arkansas Caucasians with normal glucose tolerance tests, ascertained primarily for age 18 -50 years.…”

“…We used three complementary approaches to the analysis of USF1 variation: 1) a large multiethnic case-control analysis in seven 1q-linked populations, 2) family-based association analyses in an enlarged Pima dataset, and 3) analysis (2)(3)(4)(5)8,9), allowing us to exploit the increase in power when cases are selected for membership of a multiplex sibship (29). In French and Utah samples, additional cases were recruited from other sources (online appendix).…”

Transcription factor 7-like 2 polymorphisms and type 2 diabetes, glucose homeostasis traits and gene expression in US participants of European and African descent

“…Family-based analyses for type 2 diabetes, lipids and glucose homeostasis traits based on 75 g OGTTs were conducted in 673 members of 68 Utah families for which both genotypic and phenotypic data were available, as summarised in Table 1 and reported previously [25,26]. A subset of non-diabetic participants from Arkansas who had had metabolic studies also underwent fat and muscle biopsies [27], including 28 participants with impaired glucose tolerance [23].…”

Interleukin-6 Receptor Gene 48892 A/C Polymorphism Is Associated with Metabolic Syndrome in Female Taiwanese Adolescents

“…Thus, it is reasonable to hypothesize that genetic variants of the IL-6R gene are associated with obesity, T2D, and possibly MetS. The IL-6R gene is located on chromosome 1q21 (Kluck et al, 1993), a region known to be associated with T2D (Elbein et al, 1999;Das et al, 2004). In recent years, genetic variants of the IL-6R polymorphism have been identified and shown to be associated with T2D, obesity, and features of MetS in different ethnic populations (Wolford et al, 2003;Hamid et al, 2004;Wang et al, 2005;Esteve et al, 2006;Song et al, 2007;Qi et al, 2007;Zhang et al, 2009;Jiang et al, 2010).…”