No abstract

Cardiovascular disease (CVD) is a major contributor to morbidity and mortality in type 2 diabetes, but the relationship between CVD and type 2 diabetes is not well understood. The Diabetes Heart Study is a study of type 2 diabetes-enriched families extensively phenotyped for measures of CVD, type 2 diabetes, and metabolic syndrome. A total of 977 Caucasian subjects from 358 pedigrees (575 type 2 diabetic relative pairs) with at least two individuals with type 2 diabetes and, where possible, unaffected siblings were included in a genome scan. Qualitative traits evaluated in this analysis are with or without the presence of coronary calcified plaque (CCP) and with or without carotid calcified plaque (CarCP) measured by electrocardiogram-gated helical computed tomography. In addition, prevalent CVD was measured using two definitions: CVD1, based on self-reported history of clinical CVD (393 subjects), and CVD2, defined as CVD1 and/or CCP >400 (606 subjects). These discrete traits (type 2 diabetes, metabolic syndrome, CVD1, CVD2, CCP, and CarCP) frequently coincide in the same individuals with concordance ranging from 42.9 to 99%. Multipoint nonparametric linkage analysis revealed evidence for coincident mapping of each trait (type 2 diabetes, metabolic syndrome, CVD1, CVD2, CCP, and CarCP) to three different genomic regions: a broad region on chromosome 3 (70 -160 cM; logarithm of odds [LOD] scores ranging between 1.15 and 2.71), chromosome 4q31 (peak LOD 146 cM; LOD scores ranging between 0.90 and 2.41), and on chromosome 14p (peak LOD 23 cM; LOD scores ranging between 1.43 and 2.31). Ordered subset analysis (OSA) suggests that the linked chromosome 3 region consists of at least two separate loci on 3p and 3q. In addition, OSA based on lipid measures and other traits identify family subsets with significantly stronger evidence of linkage (e.g., CVD2 on chromosome 3 at 87 cM subsetting on low HDL with an initial LOD of 2.19 is maximized to an LOD of 7.04 in a subset of 25% of the families and CVD2 on chromosome 14 at 22 cM subsetting on high triglycerides with an initial LOD of 1.99 maximized to an LOD of 4.90 in 44% of the families). When subjects are defined as affected by the presence of each trait (type 2 diabetes, metabolic syndrome, CVD1, and CCP), significant evidence for linkage to the 3p locus is observed with a peak LOD of 4.13 at 87 cM. While the correlated nature of the traits makes it unclear whether these loci represent distinct type 2 diabetes, metabolic syndrome, or CVD loci or single loci with pleiotropic effects, the coincident linkage suggests that identification of the underlying genes may help clarify the relationship of diabetes, metabolic syndrome, and CVD.

SummaryA genome-wide linkage scan of 357 European American (EA) and 72 African American (AA) pedigrees multiplex for type 2 diabetes mellitus (T2DM) was performed with multipoint nonparametric QTL linkage analysis. Four subclinical measures of cardiovascular disease (CVD): coronary artery (CCP), carotid artery (CarCP), and abdominal aortic calcified plaque (AACP) and carotid artery intima-media thickness (IMT) were mapped. Analyses were adjusted for age, gender, body mass index, and (if appropriate) ethnicity and diabetes status.Evidence for linkage was observed in EA T2DM subjects to CarCP near 16p13 (LOD=4.39 at 8.4 cM; P = 0.00001). When all EA subjects were included, the LOD score was 2.52, suggesting an amplification of the linkage by diabetes. Linkage analysis of a principal components measure of vascular calcium (LOD = 3.85 at 9.3 cM on 16p in EA T2DM subjects) and bivariate analysis of CarCP X IMT (LOD = 3.77 at 9.3 cM on 16p in EA T2DM subjects) were consistent with this linkage. In addition, evidence for linkage was observed with CCP near D15S1515 (LOD = 2.34) in EAs. Additional loci on chromosomes 1, 2, 7, 10, 13, and 21 had LODs > 2.0. The identification of trait-determining polymorphisms underlying these linkages will help delineate risk factors for CVD in T2DM and the general population.