The Finland–United States Investigation of Non–Insulin-Dependent Diabetes Mellitus Genetics (FUSION) Study. II. An Autosomal Genome Scan for Diabetes-Related Quantitative-Trait Loci

Abstract

Type 2 diabetes mellitus is a complex disorder encompassing multiple metabolic defects. We report results from an autosomal genome scan for type 2 diabetes-related quantitative traits in 580 Finnish families ascertained for an affected sibling pair and analyzed by the variance components-based quantitative-trait locus (QTL) linkage approach. We analyzed diabetic and nondiabetic subjects separately, because of the possible impact of disease on the traits of interest. In diabetic individuals, our strongest results were observed on chromosomes 3 (fasting Cpeptide/glucose: maximum LOD score [MLS] p 3.13 at 53.0 cM) and 13 (body-mass index: MLS p 3.28 at 5.0 cM). In nondiabetic individuals, the strongest results were observed on chromosomes 10 (acute insulin response: MLS p 3.11 at 21.0 cM), 13 (2-h insulin: MLS p 2.86 at 65.5 cM), and 17 (fasting insulin/glucose ratio: MLS p 3.20 at 9.0 cM). In several cases, there was evidence for overlapping signals between diabetic and nondiabetic individuals; therefore we performed joint analyses. In these joint analyses, we observed strong signals for chromosomes 3 (body-mass index: MLS p 3.43 at 59.5 cM), 17 (empirical insulin-resistance index: MLS p 3.61 at 0.0 cM), and 19 (empirical insulin-resistance index: MLS p 2.80 at 74.5 cM). Integrating genome-scan results from the companion article by Ghosh et al., we identify several regions that may harbor susceptibility genes for type 2 diabetes in the Finnish population.

A genome scan for loci linked to quantitative insulin traits in persons without diabetes: the Framingham Offspring Study

“…In a QTL analysis in the same population, however, this region has not been replicated [6]. Other reported findings of linkage between insulin traits and loci on chromosome 11 mostly refer to 11p, like sur1 at 11p15.1 at 20-26 cM pter and refer clearly to a different chromosomal region [42].…”

“…In most studies however, the families and participants were collected through an index patient with Type 2 diabetes, and the study cohorts were known to have a higher risk for developing Type 2 diabetes, such as Pima Indians, Mexican Americans and Australian Aborigines. in unaffected individuals three genome scans carried out from such higher risk populations resulted in several candidate regions on chromosome 3 [4,5], chromosome 4 [4], chromosome 9 [4], chromosome 10 [6], chromosome 13 [6], chromosome 17 [6] and chromosome 22 [4]. However, probably due to the complex nature of the disease, failure of replication of postulated genes and false-positive discovery of new loci remains a major concern.…”

Human Population Genetics: Lessons from Finland

“…The spectrum of diseases is already wide, including type 2 diabetes (9,50,90), multiple sclerosis (34), asthma (38a, 39), myocardial infarction (67), familial combined hyperlipidemia (65), hypertension (70), obesity (63), schizophrenia (8,15), psoriasis (1), and systemic lupus (32). Several other projects are in progress.…”

Upstream stimulatory factor 1 associated with familial combined hyperlipidemia, LDL cholesterol, and triglycerides

“…FCHL criteria require elevation in both serum total cholesterol and triglycerides within the family, with at least two affected first-degree relatives (Goldstein et al 1973). A candidate chromosomal region at 1q21-23 was originally identified by linkage in Finnish families (Pajukanta et al 1998) and subsequently replicated by several groups studying FCHL (Coon et al 2000;Pei et al 2000;Allayee et al 2002), and by groups studying type 2 diabetes mellitus (Hanson et al 1998;Elbein et al 1999;Vionnet et al 2000;Watanabe et al 2000;Wiltshire et al 2001;Hsueh et al 2003). Two recent reports strongly suggest these linkage findings may be explained by alterations in the gene for upstream stimulatory factor 1 (USF1; Pajukanta et al 2004;Putt et al 2004).…”