Preventive foot-care practices among adults with diabetes in North Carolina, 1997 to 2001.

Preventive foot-care practices, such as annual foot examinations by a health-care provider, can substantially reduce the risk of lower-extremity amputations. We examined the level of preventive foot-care practices (reported rates of having at least one foot examination by a physician) among patients with diabetes mellitus in North Carolina and determined the factors associated with these practices. Of 1,245 adult respondents to the 1997 to 2001 North Carolina Behavioral Risk Factor Surveillance System, 71.

Association analysis of the plasminogen activator inhibitor-1 4G/5G polymorphism in Hispanics and African Americans: the IRAS family study.

Objective: Plasminogen activator inhibitor type-1 (PAI-1) plays a central role in fibrolysis and has recently been hypothesized to influence components of the insulin resistance syndrome. We consider whether the 4G/5G polymorphism influences components of insulin resistance and obesity solely through PAI-1 protein levels or also though a secondary pathway. In addition, we explore whether transforming growth factor (TGF-beta1), a key regulator of PAI-1 expression, modifies the influence of the PAI-1 4G/5G polymorphism on these traits.

Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE.

We genotyped 525 independent North American white individuals with systemic lupus erythematosus (SLE) for the PTPN22 R620W polymorphism and compared the results with data generated from 1,961 white control individuals. The R620W SNP was associated with SLE (genotypic P=.00009), with estimated minor (T) allele frequencies of 12.

Identification of quantitative trait loci for glucose homeostasis: the Insulin Resistance Atherosclerosis Study (IRAS) Family Study.

Genetic and environmental determinants play critical roles in insulin resistance and beta-cell function. A model of the complex feedback system for maintenance of glucose tolerance has been developed that reflects the constraint of glycemia within narrow physiologic limits. The "glucose homeostasis" model is described by insulin sensitivity (S(I)), glucose disposition (S(G)), acute insulin response to glucose (AIR(G)), and disposition index (DI).

Ordered subset analysis in genetic linkage mapping of complex traits.

Etiologic heterogeneity is a fundamental feature of complex disease etiology; genetic linkage analysis methods to map genes for complex traits that acknowledge the presence of genetic heterogeneity are likely to have greater power to identify subtle changes in complex biologic systems. We investigate the use of trait-related covariates to examine evidence for linkage in the presence of heterogeneity. Ordered-subset analysis (OSA) identifies subsets of families defined by the level of a trait-related covariate that provide maximal evidence for linkage, without requiring a priori specification of the subset.

Interaction effect of PTEN and CDKN1B chromosomal regions on prostate cancer linkage.

The tumor suppressor functions of PTEN and CDKN1B have been extensively characterized. Recent data from mouse models suggest that, for some organs, the combined action of both PTEN and CDKN1B has a stronger tumor suppressor function than each alone; for the prostate, heterozygous knockout of both genes leads to 100% penetrance for prostate cancer. To assess whether such an interaction contributes to an increased risk of prostate cancer in humans, we performed a series of epistatic PTEN and CDKN1B interaction analyses in a collection of 188 high-risk hereditary prostate cancer families.

A promoter haplotype of the immunoreceptor tyrosine-based inhibitory motif-bearing FcgammaRIIb alters receptor expression and associates with autoimmunity. I. Regulatory FCGR2B polymorphisms and their association with systemic lupus erythematosus.

FcgammaRIIb, the immunoreceptor tyrosine-based inhibitory motif-containing receptor for IgG (Mendelian Inheritance in Man no. 604590), plays an important role in maintaining the homeostasis of immune responses. We have identified 10 novel single-nucleotide polymorphisms in the promoter region of human FCGR2B gene and characterized two functionally distinct haplotypes in its proximal promoter.

Renal artery calcified plaque associations with subclinical renal and cardiovascular disease.

Background: The prognostic significance of renal artery calcified plaque (RAC) and its relationship with renal function, albuminuria, and systemic atherosclerosis are unknown.

Methods: Calcified atherosclerotic plaque was measured in the renal arteries of 96 unrelated Caucasian subjects with type 2 diabetes mellitus (DM) using four-channel multidetector-row computed tomography (MDCT4). Renal artery calcium was measured as the sum of ostial and main renal artery calcium scores.

Heritability of GFR and albuminuria in Caucasians with type 2 diabetes mellitus.

Background: Elevated urinary albumin excretion and decreased glomerular filtration rate (GFR) are risk factors for cardiovascular death and end-stage renal disease in individuals with type 2 diabetes mellitus (DM).

Methods: To determine the extent of familial aggregation of GFR and urine albumin-creatinine ratio (ACR), we calculated heritability (h2) estimates by using a variance component approach.

Results: Among 662 participants with DM from 310 families (422 DM-concordant sibling pairs), 51.

Race-specific relationships between coronary and carotid artery calcification and carotid intimal medial thickness.

Background And Purpose: Calcified arterial plaque has been proposed as a subclinical marker of atherosclerosis. We compared it to a well-validated surrogate--carotid intimal medial thickness (IMT).

Methods: Calcified arterial plaque was measured in 2 vascular beds (coronary and carotid) by computed tomography, and common carotid artery IMT was measured by B-mode ultrasonography, in 438 participants.

Linkage of the metabolic syndrome to 1q23-q31 in Hispanic families: the Insulin Resistance Atherosclerosis Study Family Study.

The metabolic syndrome is characterized by central obesity, dyslipidemia, elevated blood pressure, and hyperglycemia. The Insulin Resistance Atherosclerosis Study (IRAS) Family Study recruited extended pedigrees of Hispanic descent from San Antonio, TX (SA) and San Luis Valley, CO (SLV). Thirty-five of these pedigrees (27 SA and 8 SLV) had at least 2 individuals with metabolic syndrome (216 affected individuals and 563 affected relative pairs).

Power for genetic association studies with random allele frequencies and genotype distributions.

One of the first and most important steps in planning a genetic association study is the accurate estimation of the statistical power under a proposed study design and sample size. In association studies for candidate genes or in fine-mapping applications, allele and genotype frequencies are often assumed to be known when, in fact, they are unknown (i.e.

A genome-wide scan for type 2 diabetes in African-American families reveals evidence for a locus on chromosome 6q.

African Americans are at increased risk of type 2 diabetes and many diabetes complications. We have carried out a genome-wide scan for African American type 2 diabetes using 638 affected sibling pairs (ASPs) from 247 families ascertained through impaired renal function to identify type 2 diabetes loci in this high-risk population. Of the 638 ASPs, 210 were concordant for diabetes with impaired renal function.

Exploring pleiotropy using principal components.

A standard multivariate principal components (PCs) method was utilized to identify clusters of variables that may be controlled by a common gene or genes (pleiotropy). Heritability estimates were obtained and linkage analyses performed on six individual traits (total cholesterol (Chol), high and low density lipoproteins, triglycerides (TG), body mass index (BMI), and systolic blood pressure (SBP)) and on each PC to compare our ability to identify major gene effects. Using the simulated data from Genetic Analysis Workshop 13 (Cohort 1 and 2 data for year 11), the quantitative traits were first adjusted for age, sex, and smoking (cigarettes per day).

Age-stratified heritability estimation in the Framingham Heart Study families.

The Framingham Heart Study provides a unique source of longitudinal family data related to CVD risk factors. Age-stratified heritability estimates were obtained over three age groups (31-49 years, 50-60 years, and 61-79 years), reflecting the longitudinal nature of the data, for four quantitative traits. Age-adjusted heritability estimates were obtained at a single common time point for the same four quantitative traits.

Age-stratified QTL genome scan analyses for anthropometric measures.

With the availability of longitudinal data, age-specific (stratified) or age-adjusted genetic analyses have the potential to localize different putative trait influencing loci. If age does not influence the locus-specific penetrance function within the range examined, age-stratified analyses will tend to yield comparable results for an individual trait. However, age-stratified results should vary across age strata when the locus-specific penetrance function is age dependent.

Measurement of trabecular bone mineral density in the thoracic spine using cardiac gated quantitative computed tomography.

Objectives: To develop a method and evaluate the performance of thoracic bone mineral density (BMD) measurement using cardiac gated quantitative computed tomography (QCT).

Methods: A total of 762 participants (57% female) with a mean age of 61 years had a CT examination of the heart using prospective cardiac gating. A subset of 443 participants had replicate CT examinations of the heart.

A genome-wide search for allergic response (atopy) genes in three ethnic groups: Collaborative Study on the Genetics of Asthma.

Atopy is an IgE-mediated condition known to aggregate in families and is a major risk factor for asthma. As part of the Collaborative Study on the Genetics of Asthma (CSGA), a genome-wide scan for atopy, defined by skin sensitivity to one or more common environmental allergens, was conducted in 287 CSGA families (115 African American, 138 Caucasian and 34 Hispanic). Using a nonparametric genetic analysis approach, two regions were observed in the sample of all families that yielded multipoint lod scores >1.

Insulin sensitivity, insulin secretion, and abdominal fat: the Insulin Resistance Atherosclerosis Study (IRAS) Family Study.

The relationship between insulin sensitivity and overall obesity is well established. However, there remains debate as to which of the fat depots, visceral abdominal tissue (VAT) or subcutaneous abdominal tissue (SAT), is of greater importance. Also, the relationship between fat distribution and insulin secretion is largely unknown.

Pleiotropy and heterogeneity in the expression of atherogenic lipoproteins: the IRAS Family Study.

Objective: Dyslipidemia is an important determinant of coronary disease. Phenotypic correlations between atherogenic lipids are well established, but the contribution of common genetic influences is less clear.

Methods: This study investigates the pair-wise genetic (rhog) and environmental (rhoe) correlations between apoB, LDL-C, HDL-C, and triglyceride (Tg) from Hispanic and African American families of the IRAS Family Study.

Nucleotide variation, haplotype structure, and association with end-stage renal disease of the human interleukin-1 gene cluster.

A dense gene-based SNP map was constructed across a 360-kb region containing the interleukin-1 gene cluster (IL1A, IL1B, and IL1RN), focusing on IL1RN. In total, 95 polymorphisms were confirmed or identified primarily by direct sequencing. Polymorphisms were precisely mapped to completed BAC and genomic sequences spanning this region.

Genetic epidemiology of insulin resistance and visceral adiposity. The IRAS Family Study design and methods.

Purpose: Insulin resistance and visceral adiposity are associated with increased risk of type 2 diabetes. In this report, we describe the methods of the IRAS Family Study, which was designed to identify the genetic and environmental risk factors for insulin resistance and visceral adiposity.

Methods: Families from two ethnic groups (African American and Hispanic) have been recruited from three clinical sites.

Association of an IL-1A 3'UTR polymorphism with end-stage renal disease and IL-1 alpha expression.

Background: We evaluated polymorphisms in the interleukin-1 alpha 3'-untranslated region (IL-1A 3'[UTR]) for association with type 2 diabetes-associated (DM) and nondiabetic-associated (non-DM) end-stage renal disease (ESRD) in two ethnic groups.

Methods: IL-1A 3'UTR polymorphisms were identified by alignment of overlapping human expressed sequence tags (ESTs). Sequence ambiguities were experimentally confirmed and variants genotyped to test for association with ESRD in 75 unrelated Caucasians with DM ESRD, 95 unrelated Caucasian controls and, in a parallel study, 92 unrelated African Americans with type 2 DM ESRD, 95 unrelated African Americans with non-DM ESRD, and 86 unrelated African American controls.

Genetic linkage and association of Fcgamma receptor IIIA (CD16A) on chromosome 1q23 with human systemic lupus erythematosus.

Objective: Although low-affinity alleles of human Fcgamma receptor types IIA and IIIA (FcgammaRIIA and FcgammaRIIIA, respectively) polymorphisms have been associated with systemic lupus erythematosus (SLE) in case-control studies, the relative contribution of these genes to SLE susceptibility has not been resolved.

Methods: We analyzed the distribution of alleles of FcgammaRIIA, FcgammaRIIIA, and FcgammaRIIIB in 126 multiplex-SLE pedigrees and FcgammaRIIA and FcgammaRIIIA in a case-control replication study, using allele-specific polymerase chain reaction and direct sequencing of genomic DNA. Statistical tests of association were performed to detect evidence of linkage between the single nucleotide polymorphisms and SLE.

Nephropathy in siblings of African Americans with overt type 2 diabetic nephropathy.

Background: The prevalence of abnormal proteinuria and elevated serum creatinine (sCr) concentrations in diabetic sibs of African Americans (AAs) with overt type 2 diabetic nephropathy (DN) or end-stage renal disease (ESRD) is unknown.

Methods: We measured urine albumin-creatinine (UAC) ratio, sCr, and hemoglobin A1c (HbA1c) in 211 sibs from 66 families (66 unrelated index cases with overt type 2 DN/ESRD, 132 of their diabetic sibs, and 13 of their nondiabetic sibs). Overt DN was defined as a UAC ratio of 1,000 mg/g or greater or ESRD attributed to diabetes.