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Objective: Previous studies have reported modest associations between measures of obesity and the Trp64-Arg variant of the beta3-adrenergic receptor (ADRbeta3) and the Pro12Ala variant of the peronisome proliferator-activated receptor (PPAR)-gamma2. We hypothesized that these single gene variants may mark mutations that act through convergent pathways to produce synergistic effects on obesity.Research Design and Methods: The sample included 453 subjects from 10 large Mexican-American families participating in the population-based San Antonio Family Heart Study. The effects of each gene variant singly and jointly were estimated as fixed effects using the measured genotype approach framework. Analyses were conditioned on the pedigree structures to account for the correlations among family members. Statistical significance was evaluated by the likelihood ratio test with adjustment for age, sex and diabetes status.Results: The allele frequencies for the ADRbeta3 Trp64Arg and PPARgamma2 Pro12Ala variants were 18 and 12%, respectively. The ADRbeta3 variant was not significantly associated with any of the obesity-related traits, but subjects with the PPAR-gamma2 variant (n = 98) had significantly higher levels of lasting insulin (P = 0.03), leptin (P = 0.009), and waist circumference (P = 0.03) than those without. Subjects with the gene variants (n = 32) had significantly higher BMI, insulin, and leprtin levels than those with only the PPARgamma2 variant (n = 66) (P for interaction: 0.04, 0.02, and 0.01 for BMI, fasting insulin, and leptin, respectively).Conclusions: Our results suggest that epistatic models with genes that have modest individual effects may be useful in understanding the genetic underpinnings of typical obesity in humans. [ABSTRACT FROM AUTHOR]

Hyperinsulinemia predicts the development of type 2 diabetes, and family studies suggest that insulin levels are regulated in part by genes. We conducted a genome-wide scan to detect genes influencing variation in fasting serum insulin concentrations in 391 nondiabetic individuals from 10 large multigenerational families. Approximately 380 microsatellite markers with an average spacing of 10 cM were genotyped in all study subjects. Insulin concentrations measured by radioimmunoassay were transformed by their natural logarithms before analysis. In multipoint analysis, peak evidence for linkage occurred on chromosome 3p approximately 109 cM from pter in the region of 3p14.2-p14.1. The multipoint logarithm of odds (LOD) score was 3.07, occurring in the region flanked by markers D3S1600 and D3S1285 (P value by simulation <0.0001). In a two-point analysis, LOD scores ranged from 0.75 to 2.52 for the nine markers typed in the region spanning 88-143 cM from pter. The fasting insulin resistance index was highly correlated with fasting insulin concentrations in this sample and also provided strong evidence for linkage to this region (LOD = 2.99). There was no evidence in our genome-wide scan for linkage of insulin levels to any other chromosome. These results provide evidence that a gene-influencing variation in insulin concentrations exists on chromosome 3p. Possible candidate genes in this region include GBE1 and ACOX2, which encode enzymes involved in glycogen and fatty acid metabolism, respectively. [ABSTRACT FROM AUTHOR]

Recent estimates indicate that approximately 18% of the population in the United States can be considered obese (defined as a body mass index [BMI] > or = 30), and this rate is even higher among ethnic populations such as Mexican Americans. This figure becomes very significant given the strong evidence for obesity as a major risk factor for a variety of chronic diseases including type 2 diabetes mellitus and coronary heart disease. The search for genes involved in the expression of obesity has been one of the focal points of the San Antonio Family Heart Study (SAFHS), a large, family-based study to examine the genetics of risk for atherosclerosis in Mexican Americans. To date, our genome scanning effort has reported two quantitative trait loci (QTLs) with pronounced effects on the expression of a variety of obesity--related phenotypes (e.g., leptin levels, fat mass, and BMI) located on chromosomes 2 and 8. We are currently working to further refine these signals and to identify the genes and allelic variants involved. Here, we summarize the latest results from our ongoing efforts to identify obesity genes in the San Antonio Family Heart Study.

Objective: We conducted a whole-genome, multipoint linkage screen to localize a previously reported major locus accounting for 56% to 67% of the additive genetic effects on covariate-adjusted plasma HDL cholesterol (HDL-C) levels in Mexican Americans from the San Antonio Family Heart Study (SAFHS)., Methods and Results: After using complex segregation analysis to recover the major locus in 472 SAFHS participants from 10 genotyped families, we incorporated covariates required to detect that major locus, including plasma levels of triglycerides and apolipoprotein A-I, in a maximum-likelihood-based variance-components linkage screen. Only chromosome 16 exhibited convincing evidence for a quantitative trait locus (QTL), with a peak multipoint log of the odds (LOD)=3.73 (P=0.000034). Subsequent penetrance model-based linkage analysis, incorporating genotypes at the marker locus nearest the multipoint peak (D16S518) into the segregation model, detected linkage with the previously detected major locus (LOD=2.73, P=0.000642). Initial estimates place this QTL within a 15-cM region of chromosome 16q near the structural loci for lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP)., Conclusions: A QTL influencing plasma levels of HDL-C in Mexican Americans from San Antonio maps to a region of human chromosome 16q near LCAT and CETP.

Pulse pressure, a measure of aortic stiffness, is a strong predictor of cardiovascular mortality. To locate genes that affect pulse pressure, we performed genetic analysis on randomly ascertained families in the San Antonio Family Heart Study. Pulse pressure was defined as the difference between systolic and diastolic blood pressures. Likelihood methods were used to construct a model that had both single-locus and polygenic components for 46 families (1308 individuals). The single-locus component included sex-specific and genotype-specific effects of both age and body mass index. Using this model, we then performed 2-point linkage analysis in 10 families (440 individuals) that were among the largest of the 46 families and that had been genotyped for 399 polymorphic markers. The model that contained only the polygenic component and simple effects of the covariates showed pulse pressure heritability of 0.21. When the single-locus component was added, the sex-specific and genotype-specific effects of age and body mass index were highly significant (P<0.002). The full model accounted for 73% of the total variation of pulse pressure. Linkage analysis using this model with each marker revealed 4 markers with lod scores >1.9, which is the Lander-Kruglyak suggestive linkage standard. D21S1440 had a lod score of 2.78 with a recombination fraction (theta) of 0.02. D7S1799 had a lod score of 2.04 (theta=0.01), D8S1100 had a lod score of 1.98 (theta=0.08), and D18S844 had a lod score of 1.95 (theta=0.11). These results are highly correlated with results involving systolic blood pressure, indicating that pulse pressure may not be genetically distinct from systolic blood pressure.

Objective: To investigate whether the region of chromosome 11 (11q13) containing the genes UCP2 and UCP3 could be excluded for linkage with a variety of obesity-related phenotypes in humans., Design: Exclusion mapping using a variance component approach in extended pedigrees., Subjects: Four-hundred and fifty eight individuals (195 females, 263 males) distributed in 10 Mexican American families of probands randomly ascertained with respect to any disease state and who are participating in the San Antonio Family Heart Study. Ages range from 18 to 87 (mean age 35 y)., Measurements: Serum leptin levels, fat mass (FM), body mass index (BMI), and waist circumference., Results: We were able to exclude the chromosomal region containing UCP2/UCP3 as having an effect on this set of obesity-related phenotypes at relative effect sizes of 10% or greater (P-values<0.05)., Conclusions: These results suggest that variation in these genes is unlikely to have a substantial effect on the expression of obesity-related phenotypes in the Mexican American population.

We are performing genomic searches in randomly ascertained families to identify new quantitative trait loci (QTLs) that influence atherosclerosis and its risk factors. The genetic markers used for genomic searches are random microsatellite markers distributed throughout the human chromosomes. These markers are used for linkage analysis with variance component methods to identify QTLs for measured phenotypes related to lipid metabolism and atherosclerosis. We conducted such a genomic search in 477 participants of the San Antonio Family Heart Study. This genomic search identified QTLs on chromosomes 3 and 4 that influence LDL size class, an important risk factor of atherosclerosis. In addition to lipid risk factors, we measured a variety of gene products involved in atherogenesis in the arterial wall (such as adhesion molecules and components of hemostasis). We found QTLs for serum levels of soluble P-selectin on chromosome 15 (LOD = 3.8) and chromosome 12 (LOD = 2.6).

Peroxisome proliferator-activated receptors (PPAR) are transcription factors that regulate adipocyte differentiation and gene expression. We tested the hypothesis that the Pro12Ala variant of PPAR-gamma2 is associated with obesity and type 2 diabetes-related traits in 921 subjects from the San Antonio Family Heart Study. Subjects with at least one Ala allele (n=210) had significantly higher body mass index (P=0.015) and waist circumference (P=0.028) and significantly higher levels of serum leptin (P= 0.022) than those without the allele. Further studies will determine whether the Pro12Ala variant itself, or other genetic variation at PPAR-gamma, is responsible for this association with measures of obesity in Mexican Americans.

Background: The familial aggregation of coronary heart disease can be in large part accounted for by a clustering of cardiovascular disease risk factors. To elucidate the determinants of cardiovascular disease, many epidemiological studies have focused on the behavioral and lifestyle determinants of these risk factors, whereas others have examined whether specific candidate genes influence quantitative variation in these phenotypes., Methods and Results: Among Mexican Americans from San Antonio (Tex), we quantified the relative contributions of both genetic and environmental influences to a large panel of cardiovascular risk factors, including serum levels of lipids, lipoproteins, glucose, hormones, adiposity, and blood pressure. Members of 42 extended families were studied, including 1236 first-, second-, and third-degree relatives of randomly ascertained probands and their spouses. In addition to the phenotypic assessments, information was obtained regarding usual dietary and physical activity patterns, medication use, smoking habits, alcohol consumption, and other lifestyle behaviors and medical factors. Maximum likelihood methods were used to partition the variance of each phenotype into components attributable to the measured covariates, additive genetic effects (heritability), household effects, and an unmeasured environmental residual. For the lipid and lipoprotein phenotypes, age, gender, and other environmental covariates accounted in general for < 15% of the total phenotypic variance, whereas genes accounted for 30% to 45% of the phenotypic variation. Similarly, genes accounted for 15% to 30% of the phenotypic variation in measures of glucose, hormones, adiposity, and blood pressure., Conclusions: These results highlight the importance of considering genetic factors in studies of risk factors for cardiovascular disease.

We investigated the effects of apolipoprotein (apo) B signal peptide length polymorphisms on low density lipoprotein cholesterol (LDL-C), apo B, and post-challenge (2 h) glucose levels in 686 Mexican Americans from 34 families. The most common allele encoded an apo B signal peptide of 27 amino acids (ins; SP-27), the next most frequent allele encoded a 24 amino acid signal peptide (del; SP-24), and the rarest allele encoded a 29 amino acid signal peptide (ins; SP-29) that has been found only in Mexican Americans. Homozygotes for the SP-24 allele had significantly higher mean levels of apo B. LDL-C, and 2-h glucose than SP-27 homozygotes, and SP-27/SP-24 heterozygotes had intermediate levels (P = 0.01 for apo B, P < 0.001 for LDL-C, and P = 0.04 for 2-h glucose). Heterozygotes for the SP-29 allele had higher apo B and LDL-C levels compared to homozygotes for the SP-27 or SP-24 alleles. Apo B signal peptide length polymorphism accounted for 4.2%, 3.5%, and 3.0% of the residual variation in LDL-C, apo B, and 2-h glucose levels, respectively, among the Mexican American families.

Increased adiposity has repeatedly been identified as a major risk factor for a variety of chronic diseases. However, the question still remains whether the amount of adipose tissue itself is genetically mediated. To address this question, a segregation analysis, using maximum likelihood techniques as implemented in the computer program Pedigree Analysis Package (PAP), was performed on fat mass (kilograms of body fat) in a large sample of extended Mexican American families residing in San Antonio, TX. The only model not rejected was a Mendelian mixed model for fat mass, incorporating genotype x sex interaction. In males the major gene accounted for 37% of the total variance compared with 43% in females. In both sexes homozygous recessive individuals have a fat mass more than double that of individuals of the other two genotypes. It was possible to reject linkage of the anonymous major gene for fat mass with several candidate loci for obesity. However, tentative evidence of linkage was detected with markers on both chromosomes 2 and 11, thereby providing hypotheses for future testing.

Objectives: This study was undertaken to evaluate (1) the applicability of previously reported regression equations for gestational age assessment to our patient population in Pittsburgh and (2) whether the addition of radius length or its substitution for one of the other fetal measurements could improve the prediction of gestational age., Study Design: Five fetal parameters--biparietal diameter, head circumference, abdominal circumference, femur length, and radius length--were measured in a prospective cross-sectional study of gestational age assessment in 265 pregnant women between 13 and 43 weeks' gestation., Results: The regression equation derived for each fetal parameter was found to be quite similar to previously published reports. Although the coefficient of determination was only minimally affected, the variability improved with the institutionally derived regression equation., Conclusion: The incorporation of several fetal measurements into a composite assessment of gestational age generally enhances the accuracy of the prediction. The addition of a second long bone to a gestational age assessment does not significantly improve results.