Publications

Age-adjusted systolic blood pressure is higher in males than females. Genetic factors may account for this sex-specific variation. To localize sex-specific quantitative trait loci (QTL) influencing blood pressure, we conducted a genome scan of systolic blood pressure, in males and females, separately and combined, and tested for aggregate and QTL-specific genotype-by-sex interaction in American Indian participants of the Strong Heart Family Study. Blood pressure was measured 3 times and the average of the last 2 measures was used for analyses. Systolic blood pressure was adjusted for age and antihypertensive treatment within study center. We performed variance component linkage analysis in the full sample and stratified by sex among 1168 females and 726 males. Marker allele frequencies were derived using maximum likelihood estimates based on all individuals, and multipoint identity-by-descent sharing was estimated using Loki. We detected suggestive evidence of a QTL influencing systolic blood pressure on chromosome 17 at 129 cM between markers D17S784 and D17S928 (logarithm of odds [LOD] = 2.4). This signal substantially improved when accounting for QTL-specific genotype-by-sex interaction (P = 0.04), because we observed an LOD score of 3.3 for systolic blood pressure in women on chromosome 17 at 136 cM. The magnitude of the linkage signal on chromosome 17q25.3 was slightly attenuated when participants taking antihypertensive medications were excluded, although suggestive evidence for linkage was still identified (LOD = 2.8 in women). Accounting for interaction with sex improved our ability to detect QTLs and demonstrated the importance of considering genotype-by-sex interaction in our search for blood pressure genes.

BACKGROUND: Genetic and environmental contributions to childhood obesity are poorly delineated.

OBJECTIVE: The Viva la Familia Study was designed to genetically map childhood obesity and its comorbidities in the Hispanic population. The objectives of this report were to describe the study design and to summarize genetic and environmental contributions to the phenotypic variation in obesity and risk factors for metabolic diseases in Hispanic children.

DESIGN: The Viva la Familia cohort consisted of 1030 children from 319 families selected based on an overweight proband between the ages of 4 and 19 y. In-depth phenotyping to characterize the overweight children and their siblings included anthropometric and body-composition traits by dual-energy X-ray absorptiometry and assessments of diet by 24-h recalls, physical activity by accelerometry, and risk factors for metabolic diseases by standard biochemical methods. Univariate quantitative genetic analysis was used to partition phenotypic variance into additive genetic and environmental components by using the computer program SOLAR.

RESULTS: Sex, age, and environmental covariates explained 1-91% of the phenotypic variance. Heritabilities of anthropometric indexes ranged from 0.24 to 0.75. Heritability coefficients for the body-composition traits ranged from 0.18 to 0.35. Diet and physical activity presented heritabilities of 0.32 to 0.69. Risk factors for metabolic diseases were heritable with coefficients ranging from 0.25 to 0.73. Significant genetic correlations between obesity traits and risk factors for metabolic diseases substantiated pleiotropy between traits.

CONCLUSION: The Viva la Familia Study provides evidence of a strong genetic contribution to the high prevalence of obesity and its comorbidities in Hispanic children.

OBJECTIVE: Genetic components of energy homeostasis contributing to childhood obesity are poorly understood. Genome scans were performed to identify chromosomal regions contributing to physical activity and dietary intake traits in Hispanic children participating in the VIVA LA FAMILIA Study.

RESEARCH METHODS AND PROCEDURES: We report linkage findings on chromosome 18 for physical activity and dietary intake in 1030 siblings from 319 Hispanic families. Measurements entailed physical activity by accelerometry, dietary intake by two 24-hour recalls, and genetic linkage analyses using SOLAR software.

RESULTS: Significant heritabilities were seen for physical activity and dietary intake, ranging from 0.46 to 0.69, except for vigorous activity (h2 = 0.18). Percentage time in sedentary activity mapped to markers D18S1102-D18S64 on chromosome 18 [logarithm of the odds (LOD) score = 4.07], where melanocortin 4 receptor gene (MC4R) resides. Quantitative trait loci (QTLs) for total activity counts, percentage time in light or in moderate activity, and carbohydrate intake and percentage of energy intake from carbohydrates were detected in the same region (LOD = 2.28, 2.79, 2.2, 1.84, and 1.51, respectively). A novel loss of function mutation in MC4R (G55V) was detected in six obese relatives, but not in the rest of the cohort. Removal of these MC4R-deficient subjects from the analysis reduced the LOD score for sedentary activity to 3.94.

DISCUSSION: Given its role in the regulation of food intake and energy expenditure, MC4R is a strong positional candidate gene for the QTL on chromosome 18 detected for physical activity and dietary intake in Hispanic children.

The hepatic lipase gene (LIPC) has been implicated as a potential regulator of HDL-cholesterol concentration and HDL and LDL particle size. Studies have centered on a C to T transition in the promoter region of LIPC, 514 base pairs upstream from the transcription initiation site. We performed a genome-wide linkage screen for several lipoprotein size phenotypes and tested for association of these traits with LIPC -514C-T in 798 individuals from the San Antonio Family Heart Study. Median diameters were measured for HDL particles stained for apoA1 (A1), apoA2 (A2), unesterified cholesterol (UC), and esterified cholesterol (EC) and for LDLs stained for EC. The median diameter of all phenotypes exhibited evidence of linkage to the LIPC region of chromosome 15 (LODs of 1.78 to 3.79). Linkage was also observed for HDL-EC size on chromosome 5p (LOD = 3.50). Association with the LIPC -514C-T polymorphism was detected for HDL-A1, HDL-A2, HDL-UC, and HDL-EC median diameters (p < 0.001) but not for LDL-EC size. Linkage analyses of HDL sizes conditional on the -514C-T polymorphism reduced the LOD scores in the LIPC region only slightly, suggesting that this polymorphism does not explain the observed linkage of lipoprotein sizes to chromosome 15. These results indicate the presence of a lipoprotein size locus in the LIPC region but suggest that -514C-T is not the primary functional variant in this region, implying that additional functional mutations influencing HDL and potentially LDL size variation occur in or near LIPC.

INTRODUCTION: The hormone resistin was recently discovered in adipose tissue of mice. Functional tests suggest a role for resistin in the regulation of insulin sensitivity. However, human studies have reported controversial results on the metabolic function of this hormone.

METHODS: A 1 g omental adipose tissue biopsy was obtained from 404 adult baboons. Resistin mRNA expression was assayed by real-time, quantitative RT-PCR, and univariate and bivariate quantitative genetic analyses were performed, via the variance decomposition approach. A genome scan analysis was conducted using resistin mRNA abundance in omental adipose tissue as a quantitative phenotype.

RESULTS: A significant heritability of h2 = 0.23 (P = 0.003) was found for resistin mRNA abundance in omental adipose tissue. A genome scan detected a quantitative trait locus for resistin expression with an LOD score of 3.8, in the region between markers D19S431 and D19S714, corresponding to human chromosome 19 p13. This chromosomal region contains genes related to insulin resistance phenotypes, such as resistin, insulin receptor, angiopoietin-like 4 protein and LDL receptor.

CONCLUSIONS: Individual variation in resistin mRNA expression has a significant genetic component, and a gene or genes on chromosome 19 p13 may regulate resistin mRNA levels in baboon omental adipose tissue.

OBJECTIVE: To perform a meta-analysis of genome-wide linkage scans using body mass index (BMI) to identify genetic loci predisposing to obesity.

DATA: A total of 13 published genome scans on obesity have used BMI as their primary end point. Five of these 13 groups agreed to provide detailed results from their scans that were required for a meta-analysis. Collectively, these five studies included a total of 2814 individuals from 505 families.

METHODS: The results of the five studies were analysed using the GSMA (genome scans meta-analysis) method.

RESULTS: The analysis revealed significant evidence for linkage of the quantitative phenotype BMI to 8p (P<0.0005).

This article is a report of the design and methods of the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) Study. This longitudinal, population-based study was initiated to investigate the genetic determinants of cardiovascular disease and its risk factors. Between October 2000 and April 2004, this family study enrolled 1,214 Eskimos from several coastal villages in the Norton Sound region of Western Alaska. Examinations included a physical, laboratory determinations, and measures of subclinical disease. This study will generate a genome-wide scan for loci influencing cardiovascular disease-related traits. Relations between subclinical atherosclerosis and markers of inflammation will be examined using historic and newly drawn samples. The study will provide data on CVD prevalence, risk factors and the relative contribution of genetic and environmental determinants in Alaska Native peoples. Data from this study will contribute to the delivery of health-care and prevention of CVD in Alaska Eskimos and other populations.

CONTEXT: Because of its antiinflammatory and insulin-sensitizing properties, adiponectin may play a role in the development of cardiovascular disease and type 2 diabetes.

OBJECTIVES: The aims of these analyses were: 1) to estimate the heritability of fasting serum adiponectin; 2) to evaluate the effects of age, sex, and body composition on fasting serum adiponectin; 3) to test for associations between fasting serum adiponectin and diet, fitness, energy expenditure, and fat oxidation; and 4) to determine the relationships between fasting serum adiponectin, insulin and lipids, and blood pressure in Hispanic children.

DESIGN: Genetic and environmental factors influencing fasting serum adiponectin were investigated in a cohort of children participating in the VIVA LA FAMILIA Study in 2000-2005.

SETTING: This study was performed at the Children's Nutrition Research Center.

PARTICIPANTS: The study participants were 805 Hispanic nonoverweight and overweight children, ages 4-19 yr.

MAIN MEASURE: The main measure of the study was fasting serum adiponectin.

RESULTS: The heritability of serum adiponectin was 0.93 +/- 0.10 (P = 2.4 x 10(-40)). Adiponectin differed by age (P = 0.001), sex (P = 0.04), and weight (P = 0.001) status. Adiponectin levels declined with age, in association with changes in sex hormones and growth factors. Adiponectin was not associated with macronutrient intake, fitness, 24-h energy expenditure, or fat oxidation. Controlling for age, sex, and percent fat mass, adiponectin was inversely associated with homeostasis model of insulin resistance, triglycerides (TG)/high-density lipoprotein cholesterol (HDL-C), and systolic blood pressure (P = 0.001). Significant positive genetic correlations were detected between adiponectin and total cholesterol (rho(G) = 0.19), HDL-C (rho(G) = 0.32), low-density lipoprotein cholesterol (rho(G) = 0.24), and IGF-binding protein-1 (rho(G) = 0.39), and negative genetic correlations were detected between adiponectin and leptin (rho(G) = -0.30), TG (rho(G) = -0.21), TG/HDL-C (rho(G) = -0.33), and IGF-binding protein-3 (rho(G) = -0.32), indicating shared genetic components in their expression.

CONCLUSION: The high heritability of adiponectin and pleiotropy seen between adiponectin and leptin, growth factors, and lipids may play a role in the pathogenesis of cardiovascular disease and type 2 diabetes in overweight Hispanic children.

In previous work in non-diabetic participants of the Strong Heart Family Study, we identified three heritable principal components of nine insulin resistance (IR) phenotypes: 1) a glucose/insulin/obesity factor, 2) a blood pressure factor, and 3) a dyslipidemia factor. To localize quantitative trait loci (QTL) potentially influencing these factors, we conducted a genome scan of factor scores in Strong Heart Family Study participants. Approximately 599 men and women, >or=18 years of age, in 32 extended families at three centers (in Arizona, Oklahoma, and North and South Dakota), were examined between 1997 and 1999. We used variance components linkage analysis to identify QTLs for the IR factors. With age, sex, and study center as covariates, we detected linkage of the glucose/insulin/obesity factor to chromosome 4 (robust logarithm of the odds (LOD) = 2.2), the dyslipidemia factor to chromosome 12 (robust LOD = 2.7), and the blood pressure factor to chromosome 1 (robust LOD = 1.6). The peak linkage signals identified for these IR factors support several positive findings from other studies and occur in regions harboring interesting candidate genes. The corroboration of existing QTLs will bring us closer to the identification of the functional genes that predispose to IR.

Childhood obesity is associated with a constellation of metabolic derangements including glucose intolerance, hypertension, and dyslipidemia, referred to as metabolic syndrome. The purpose of this study was to investigate genetic and environmental factors contributing to the metabolic syndrome in Hispanic children. Metabolic syndrome, defined as having three or more metabolic risk components, was determined in 1030 Hispanic children, ages 4-19 y, from 319 families enrolled in the VIVA LA FAMILIA study. Anthropometry, body composition by dual energy x-ray absorptiometry, clinical signs, and serum biochemistries were measured using standard techniques. Risk factor analysis and quantitative genetic analysis were performed. Of the overweight children, 20%, or 28% if abnormal liver function is included in the definition, presented with the metabolic syndrome. Odds ratios for the metabolic syndrome were significantly increased by body mass index z-score and fasting serum insulin; independent effects of sex, age, puberty, and body composition were not seen. Heritabilities +/- SE for waist circumference, triglycerides (TG), HDL, systolic blood pressure (SBP), glucose, and alanine aminotransferase (ALT) were highly significant. Pleiotropy (a common set of genes affecting two traits) detected between SBP and waist circumference, SBP and glucose, HDL and waist circumference, ALT and waist circumference, and TG and ALT may underlie the clustering of the components of the metabolic syndrome. Significant heritabilities and pleiotropy seen for the components of the metabolic syndrome indicate a strong genetic contribution to the metabolic syndrome in overweight Hispanic children.