A Genome-Wide Scan for Loci Linked to Plasma Levels of Glucose and HbA1c in a Community-Based Sample of Caucasian Pedigrees

Abstract

Elevated blood glucose levels are the hallmark of type 2 diabetes as well as a powerful risk factor for development of the disease. We conducted a genome-wide search for diabetes-related genes, using measures of glycemia as quantitative traits in 330 pedigrees from the Framingham Heart Study. Of 3,799 attendees at the 5th Offspring Study exam cycle (1991-1995), 1,461, 1,251, and 771 men (49%) and women provided information on levels of 20-year mean fasting glucose, current fasting glucose, and HbA 1c , respectively, and 1,308 contributed genotype data (using 401 microsatellite markers with an average spacing of 10 cM). Levels of glycemic traits were adjusted for age, cigarette smoking, alcohol and estrogen use, physical activity, and BMI. We ranked standardized residuals from these models, created normalized deviates from the ranks, and used the variance component model implemented in SOLAR (Sequential Oligogenic Linkage Analysis Routines) to evaluate linkage to normalized deviates as quantitative traits. We found peak evidence for linkage to 20-year mean fasting glucose levels on chromosome 1 at ϳ247 cM from p-telomere (pter) (multipoint logarithm of odds [LOD] 2.33) and on chromosome 10 at ϳ86 cM from pter (multipoint LOD 2.07); to current fasting glucose levels on chromosome 1 at ϳ218 cM from pter (multipoint LOD 1.80) and on chromosome 10 at ϳ96 cM from pter (multipoint LOD 2.15); and to HbA 1c levels on chromosome 1 at ϳ187 cM (multipoint LOD 2.81). This analysis of unselected European Caucasian pedigrees suggests localization of quantitative trait loci influencing glucose homeostasis on chromosomes 1q and 10q. Findings at ϳ187-218 cM on chromosome 1 appear to replicate linkage reported in previous studies of other populations, pointing to this large chromosomal region as worthy of more detailed scrutiny in the search for type 2 diabetes susceptibility genes. Diabetes 51: 833-840, 2002

Genome-wide scans for heritability of fasting serum insulin and glucose concentrations in hypertensive families

“…The heritability of fasting serum insulin and glucose concentrations remained highly significant even after controlling for the effects of significant covariates. The marked heritability of fasting serum glucose and insulin concentrations appears consistent with other reports in Framingham [6,7], Amish [8], and HERITAGE families [9]. Additionally, the genome scans in AAs and EAs provided suggestive evidence that genes regulating fasting serum insulin concentrations and insulin sensitivity (HOMA) were present on chromosomes 19, 7, 5, 4 and 2, and genes regulating fasting glucose concentration were present on chromosomes 2, 5, 9, 13 and 18.…”

“…These difficulties are encountered in all cross-sectional studies. The overlapping regions of linkage observed for the diabetes-related phenotypes in Pima [23] and Finnish [26] families, and the Framingham Offspring [6] and Heart Studies [25], support the existence of genes affecting fasting serum insulin concentrations on chromosomes 19 and 5 and fasting serum glucose on chromosome 13.…”

“…On chromosome 19, linkage was detected at 18 cM for fasting insulin in Pima Indians (LOD 1.33) [23], and for type 2 diabetes and glucose intolerance in young-onset French families at 36 cM (LOD 1.26) [24]. Linkage with fasting glucose, and combined fasting and non-fasting glucose, was detected on chromosome 5 at 0 cM in the Framingham Offspring Study (LOD 1.09) [6], and Framingham Heart Study (LOD 1.65) [25]. The HyperGEN fasting serum glucose scan loci on chromosome 13 are near reported loci for related phenotypes in 580 Finnish families from the FUSION Study [26], i.e., 2-h insulin (LOD 2.86 at 65 cM) and insulin secretion (insulin/ glucose) (LOD 1.37 at 62 cM), and loci for type 2 diabetes in AAs with earlier age at diagnosis (p<0.006 at 76 cM) [27] and Japanese families (LOD 0.94, 79 cM) [28].…”

“…In non-hypertensive populations, an adjusted h 2 value of 0.34 for fasting serum glucose [6] and 0.46 for fasting serum insulin concentrations [7] were reported in the Framingham Offspring Study. Similar high familial correlations for these prediabetic measures were reported in Amish families [8], the HERITAGE FAMILY study [9], and Caucasian twins [3].…”

Heritability of fasting glucose levels in a young genetically isolated population

“…In the Finnish population, where the heritability of fasting glucose was estimated to be 8.4% after correction for ascertainment, elevated fasting glucose was suggestively linked to chromosome 3 [19]. In another population of European Caucasian descent, the heritability of fasting glucose was 34%, but only suggestive linkage to chromosome 10q and weak linkage to 1q were found [20]. Given a heritability estimate of at least 25% for FPG, further linkage studies in the ERF population could well find genes that affect FPG levels and possibly play a role in outbred populations.…”