Genome-wide linkage of plasma adiponectin reveals a major locus on chromosome 3q distinct from the adiponectin structural gene: the IRAS family study.

Adiponectin (APM1) is an adipocyte-derived peptide that contributes to glucose, lipid, and energy homeostasis. We assessed the genetic basis of plasma adiponectin in Hispanic-American and African-American families enrolled through the Insulin Resistance Atherosclerosis Study Family Study. A 10-cM genome scan was performed in two batches: an original set (set 1) consisting of 66 families (45 Hispanic American and 21 African American) and a replication set (set 2) consisting of 66 families (45 Hispanic American and 21 African American).

Fine-mapping chromosome 20 in 230 systemic lupus erythematosus sib pair and multiplex families: evidence for genetic epistasis with chromosome 16q12.

The presence of systemic lupus erythematosus (SLE) susceptibility genes on chromosome 20 is suggested by the observation of genetic linkage in several independent SLE family collections. To further localize the genetic effects, we typed 59 microsatellites in the two best regions, as defined by genome screens. Genotypes were analyzed for statistical linkage and/or association with SLE, by use of a combination of nonparametric linkage methods, family-based tests of association (transmission/disequilibrium and pedigree disequilibrium tests), and haplotype-sharing statistics (haplotype runs test), in a set of 230 SLE pedigrees.

Genetic mapping of disposition index and acute insulin response loci on chromosome 11q. The Insulin Resistance Atherosclerosis Study (IRAS) Family Study.

Glucose homeostasis, a defining characteristic of physiological glucose metabolism, is the result of complex feedback relationships with both genetic and environmental determinants that influence insulin sensitivity and beta-cell function. Relatively little is known about the genetic basis of glucose homeostasis phenotypes or their relationship to risk of diabetes. Our group previously published a genome scan for glucose homeostasis traits in 284 African-American subjects from 21 pedigrees in the Insulin Resistance Atherosclerosis Study Family Study (IRASFS) and presented evidence for linkage to disposition index (DI) on chromosome 11q with a logarithm of odds (LOD) of 3.

Genetic mapping of a 17q chromosomal region linked to obesity phenotypes in the IRAS family study.

Objective: Obesity is widely accepted to be influenced by both environmental and genetic factors. Several recent studies have used the positional cloning approach in an attempt to discover genes contributing to obesity. In the IRAS Family Study a genomewide scan was performed on 1425 individuals of Hispanic descent (90 extended pedigree families) to identify regions of the genome linked to obesity phenotypes.

Association of protein tyrosine phosphatase-N1 polymorphisms with coronary calcified plaque in the Diabetes Heart Study.

Individuals with type 2 diabetes are at increased risk of cardiovascular disease (CVD) mortality and display increased levels of subclinical CVD. Genetic variation in PTPN1, a diabetes susceptibility gene, was investigated for a role in diabetic atherosclerosis. The PTPN1 gene encodes protein tyrosine phosphatase-1B, which is ubiquitously expressed and plays a role in the regulation of several signaling pathways.

Variants of the CD40 gene but not of the CD40L gene are associated with coronary artery calcification in the Diabetes Heart Study (DHS).

Background: CD40/CD40L signaling is known to play an important role in immune response. The proteins are expressed in a variety of cell types and ligation causes cells to produce inflammatory cytokines and cellular adhesion molecules. These processes are implicated in the development and progression of atherosclerosis.

Association analysis of genes in the renin-angiotensin system with subclinical cardiovascular disease in families with Type 2 diabetes mellitus: the Diabetes Heart Study.

Aims: Cardiovascular disease (CVD) is a major complication of Type 2 diabetes mellitus. The renin-angiotensin system (RAS) and nitric oxide production are both important regulators of vascular function and blood pressure. Genes encoding proteins involved in these pathways are candidates for a contribution to CVD in diabetic patients.

An exploration of sex-specific linkage disequilibrium on chromosome X in Caucasians from the COGA study.

This paper explores the decay of linkage disequilibrium (LD) on the autosomes and chromosome X. The extent of marker-marker LD is important for both linkage and association studies. The analysis of the Caucasian sample from the Collaborative Study on the Genetics of Alcoholism study revealed the expected negative relationship between the magnitude of the marker-marker LD and distance (cM), with the male and female subgroups exhibiting similar patterns of LD.

Multilocus and interaction-based genome scan for alcoholism risk factors in Caucasian Americans: the COGA study.

In this paper, we applied the nonparametric linkage regression approach to the Caucasian genome scan data from the Collaborative Study on the Genetics of Alcoholism to search for regions of the genome that exhibit evidence for linkage to putative alcoholism-predisposing genes. The multipoint single-locus model identified four regions of the genome with LOD scores greater than one. These regions were on 7p near D7S1790 (LOD = 1.

A genome-wide search for quantitative trait loci contributing to variation in seasonal pollen reactivity.

Background: Asthma and atopy represent complex traits for which genetic predisposition has been demonstrated. Pollen sensitivity, whether seasonal or chronic, appears to be a major contributor to the asthmatic phenotype.

Objective: Regions of the genome contributing to skin test reactivity to 5 seasonal allergens are to be identified in a genome-wide scan.

Two-locus genome-wide linkage scan for prostate cancer susceptibility genes with an interaction effect.

Prostate cancer represents a significant worldwide public health burden. Epidemiological and genetic epidemiological studies have consistently provided data supporting the existence of inherited prostate cancer susceptibility genes. Segregation analyses of prostate cancer suggest that a multigene model may best explain familial clustering of this disease.

The relationship between C-reactive protein and subclinical cardiovascular disease in the Diabetes Heart Study (DHS).

Background: Epidemiological studies suggest that levels of C-reactive protein (CRP) predict cardiovascular disease (CVD). We have evaluated the relationship between CRP and subclinical CVD in a study cohort at high risk of CVD.

Methods: The DHS is a single-center, family-based study of the genetic and environmental components of CVD in type 2 diabetes mellitus (T2DM).

The impact of ethnicity and sex on subclinical cardiovascular disease: the Diabetes Heart Study.

Aims/hypothesis: African-Americans with type 2 diabetes and access to adequate healthcare are at lower risk of clinical coronary artery disease than are white diabetic patients. We evaluated whether ethnic differences in subclinical cardiovascular disease, coronary and carotid artery calcified plaque and carotid artery intima-medial thickness (IMT) were present in members of The Diabetes Heart Study families.

Subjects And Methods: In a bi-racial cohort of 1,180 individuals from families enriched for members with type 2 diabetes, we calculated coronary and carotid artery calcified plaque using fast-gated helical computed tomography, and measured carotid artery IMT and clinical risk factor profiles.

Association of proopiomelanocortin gene polymorphisms with obesity in the IRAS family study.

Proopiomelanocortin (POMC) has been found to be associated with rare Mendelian forms of obesity in children, and, in linkage studies, genomic regions containing the POMC locus have been linked to leptin levels, a predictor of obesity, in white, Mexican-American, and African-American families. POMC polymorphisms have not been investigated in detail for association with obesity in the general population. Five single nucleotide polymorphisms (SNPs) (G-3460C, C17T, G3473A, C3755T, and A7069G) were genotyped on 811 Hispanic individuals in the Insulin Resistance Atherosclerosis Family Study and tested for association with multiple obesity quantitative traits.

The impact of pedigree structure on heritability estimates for pulse pressure in three studies.

Objectives: Pulse pressure (PP) is a measure of large artery stiffness and has been shown to be an important predictor of cardiovascular morbidity and mortality. The aims of the present study were to investigate the heritability of PP in three studies, the Diabetes Heart Study (DHS), the Insulin Resistance Atherosclerosis Family Study (IRAS FS), and the NHLBI Family Heart Study (FHS), to estimate the residual heritability after inclusion of a common set of covariates, and to investigate the impact of pedigree structure on estimating heritability.

Methods And Results: DHS is primarily a sibling pair nuclear family study design, while both IRAS FS and FHS have large pedigrees.

Association of genes of lipid metabolism with measures of subclinical cardiovascular disease in the Diabetes Heart Study.

Background: Dyslipidaemia is a well known risk factor for cardiovascular disease (CVD). Lipid metabolism is affected by a range of genes and proteins. This study investigated whether some of these genes are associated with measures of subclinical CVD.

Association of the mu-opioid receptor gene with type 2 diabetes mellitus in an African American population.

African Americans (AA) are at increased risk for developing type 2 diabetes mellitus (T2DM) relative to European Americans. We previously detected linkage of T2DM to 6q24-q27 (LOD 2.26) at 163.

Loci contributing to adult height and body mass index in African American families ascertained for type 2 diabetes.

Height and body mass index (BMI) have high heritability in most studies. High BMI and reduced height are well-recognized as important risk factors for a number of cardiovascular diseases. We investigated these phenotypes in African American families originally ascertained for studies of linkage with type 2 diabetes using self-reported height and weight.

P-selectin gene haplotype associations with albuminuria in the Diabetes Heart Study.

Background: Adhesion molecules, such as P-selectin, play a pivotal role in leukocyte adhesion to the endothelium during inflammation. We investigated the relationship between P-selectin gene polymorphisms and albuminuria in 565 European American siblings (84% with type 2 diabetes) from 227 families participating in the Diabetes Heart Study (DHS).

Methods: Three common missense P-selectin polymorphisms (S290N, N562D, and T715P) were genotyped.

Progress towards understanding the genetic pathogenesis of systemic lupus erythematosus.

In order to better understand the genetic factors that initiate systemic lupus erythematosus (SLE), we are using both linkage and association approaches to identify susceptibility genes for the disease. Association studies have recently identified three HLA Class II haplotypes as well as a functional missense polymorphism in protein tyrosine phosphatase (PTP) PTPN22 as important risk alleles for SLE. Here, we will review these data, and explain how these findings contribute to an understanding of the genetic architecture of human SLE.

Relationship between albuminuria and cardiovascular disease in Type 2 diabetes.

Impaired renal function and albuminuria, common among people with type 2 diabetes, are strong predictors of atherosclerotic cardiovascular events. However, the relationships among albuminuria and measures of calcified atherosclerotic plaque are unknown. Coronary and carotid artery calcified plaque were measured using fast-gated helical computed tomography, and B-mode ultrasonography measured common carotid artery intima-medial thickness (IMT) in 588 white participants with type 2 diabetes from 325 families ascertained for the presence of multiple siblings with type 2 diabetes.

Genetic analysis of adiponectin and obesity in Hispanic families: the IRAS Family Study.

Adiponectin, coded for by the APM1 gene, is a novel adipocyte-derived hormone implicated in energy homeostasis and obesity. Several genetic studies have observed evidence of association between APM1 gene polymorphisms and features of the metabolic syndrome, such as insulin resistance and obesity. As part of a comprehensive genetic analysis of the APM1 gene, we have screened 96 unrelated individuals for polymorphisms in the promoter, coding regions, and 3'untranslated region (UTR).

Heritability of body composition measured by DXA in the diabetes heart study.

Objective: The purpose of this study was to investigate the heritability of body composition measured by DXA in the Diabetes Heart Study (DHS).

Research Methods And Procedures: Participants were 292 women and 262 men (age, 38 to 86 years; BMI, 17 to 57 kg/m(2)) from 244 families. There were 492 white and 49 African-American sibling pairs.

Genetic analysis of HNF4A polymorphisms in Caucasian-American type 2 diabetes.

Hepatocyte nuclear factor 4alpha (HNF4A), the gene for the maturity-onset diabetes of the young type 1 monogenic form of type 2 diabetes, is within the type 2 diabetes-linked region on chromosome 20q12-q13.1 and, consequently, is a positional candidate gene for type 2 diabetes in the general population. Previous studies have identified only a few rare coding mutations.