Publications

Hyperuricemia is associated with the metabolic syndrome, gout, renal and cardiovascular disease (CVD). American Indians have high rates of CVD and 25% of individuals in the strong heart family study (SHFS) have high serum uric acid levels. The aim of this study was to investigate the genetic determinants of serum uric acid variation in American Indian participants of the SHFS. A variance component decomposition approach (implemented in SOLAR) was used to conduct univariate genetic analyses in each of three study centers and the combined sample. Serum uric acid was adjusted for age, sex, age x sex, BMI, estimated glomerular filtration rate, alcohol intake, diabetic status and medications. Overall mean +/- SD serum uric acid for all individuals was 5.14 +/- 1.5 mg/dl. Serum uric acid was found to be significantly heritable (0.46 +/- 0.03 in all centers, and 0.39 +/- 0.07, 0.51 +/- 0.05, 0.44 +/- 0.06 in Arizona, Dakotas and Oklahoma, respectively). Multipoint linkage analysis showed significant evidence of linkage for serum uric acid on chromosome 11 in the Dakotas center [logarithm of odds score (LOD) = 3.02] and in the combined sample (LOD = 3.56) and on chromosome 1 (LOD = 3.51) in the combined sample. A strong positional candidate gene in the chromosome 11 region is solute carrier family22, member 12 (SLC22A12) that encodes a major uric acid transporter URAT1. These results show a significant genetic influence and a possible role for one or more genes on chromosomes 1 and 11 on the variation in serum uric acid in American Indian populations.

BACKGROUND: Population studies have demonstrated an important role of social, behavioral, and environmental factors in blood pressure (BP) levels. Accounting for the genetic interaction of these factors may help to identify common BP susceptibility alleles.

METHODS AND RESULTS: We studied the interaction of additive genetic effects and behavioral (physical activity, smoking, alcohol use) and socioeconomic (education) factors on BP in approximately 3600 American Indian participants of the Strong Heart Family Study, using variance component models. The mean and SD of resting systolic and diastolic BPs were 123 + or - 17 and 76 + or - 11 mm Hg, respectively. We detected evidence for distinct genetic effects on diastolic BP among ever smokers compared with never smokers (P = 0.01). For alcohol intake, we observed significant genotype-by-environment interactions on diastolic (rhog = 0.10, P = 0.0003) and on systolic BPs (rhog = 0.59, P = 0.0008) among current drinkers compared with former or never drinkers. We also detected genotype-by-physical activity interactions on diastolic BP (rhog = 0.35, P = 0.0004). Finally, there was evidence for distinct genetic effects on diastolic BP among individuals with less than high school education compared with those with 12 or more years of education (rhog = 0.41, P = 0.02).

CONCLUSIONS: Our findings suggest that behavioral and socioeconomic factors can modify the genetic effects on BP phenotypes. Accounting for context dependent factors may help us to better understand the complexities of the gene effects on BP and other complex phenotypes with high levels of genetic heterogeneity.

BACKGROUND AND PURPOSE: The cerebral volume of T2-hyperintense white matter (HWM) is an important neuroimaging marker of cerebral integrity. Pathophysiology studies identified that subcortical and ependymal HWM are produced by 2 different mechanisms but shared a common risk factor: high arterial pulse pressure. Recent studies have demonstrated high heritability of the whole-brain HMW volume and reported significant and suggestive evidence of genetic linkage. We performed heritability and whole-genome linkage analysis to replicate previous reported findings and to study shared genetic variance, and possible overlap for specific loci, between subcortical and ependymal HWM volumes in a population of healthy Mexican Americans.

METHODS: The volumes of subcortical and ependymal HWM regions were measured from high-resolution (1 mm(3)), 3-dimensional fluid-attenuated inversion recovery images acquired for 459 (283 females, 176 males) active participants in the San Antonio Family Heart Study. Subjects ranged in age from 19 to 85 years of age (47.9+/-13.5 years) and were part of 49 families (9.4+/-8.5 individuals per family).

RESULTS: The volumes of whole-brain, subcortical, and ependymal HWM were highly heritable (h(2)=0.72, 0.66, and 0.73, respectively). The subcortical and ependymal HWM volumes shared 21% of genetic variability indicating significant pleiotropy. Genomewide linkage analysis showed only a suggestive bivariate linkage for subcortical and ependymal HWM volumes (log of odds=2.12) on chromosome 1 at 288 cM.

CONCLUSIONS: We replicated previous findings of high heritability for the whole-brain HWM volume. We also showed that subcortical and ependymal volume shared a significant portion of genetic variability and the bivarate linkage analysis produced a suggestive linkage near the locus previously identified in a study of whole-brain HWM volume and arterial pulse pressure.

gamma Glutamyl transferase (GGT) and albumin (ALB) are two markers of liver function. These two proteins have been associated with non-alcoholic fatty liver disease and cardiovascular disease. The objectives of this study were to explore the genetic factors that influence variation in the plasma levels of GGT and ALB and to evaluate their genetic correlations with cardiovascular risk factors. Baboons from the Southwest National Primate Research Center at the Southwest Foundation for Biomedical Research, San Antonio, TX, were used as an animal model. The baboons were fed a standard monkey chow diet ad libitum. Fasting plasma concentrations of GGT, ALB, triglycerides, total cholesterol and LDL cholesterol were measured in 350 pedigreed adult baboons by standard assay procedures. A maximum likelihood-based variance decomposition approach implemented in the computer program SOLAR was used to conduct genetic analyses. The heritabilities of GGT (h(2) = 0.55; P < 0.0001) and ALB (h(2) = 0.42; P < 0.01) were significant. No statistically significant associations were found between GGT and the cardiovascular-related phenotypes. Genetic correlations between ALB and total cholesterol, LDL cholesterol and triglycerides were significant. A QTL (LOD = 2.8) for GGT plasma levels was identified on the baboon homologue of human chromosome 22 between markers D22S304 and D22S280. A QTL (LOD = 2.3) near marker D10S1432 was detected on the baboon homologue of human chromosome 10 for ALB. These results imply that variations in the plasma levels of GGT and ALB are under significant genetic regulation and that a common genetic component influences ALB and cardiovascular risk factor phenotypes.

BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1) is an inflammatory chemokine known to induce adipocyte dedifferentiation and insulin resistance. Inflammation, insulin resistance, and obesity have been implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD).

METHODS: Fasting plasma from 43 baboons were assayed for MCP-1, insulin, glucose, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Adipocyte number and volume were measured via biopsies of omental adipose tissue. The homeostatic model assessment method (HOMA) was used to estimate systemic insulin resistance.

RESULTS: Sex and age adjusted correlations were significant for MCP-1 with adipocyte number (r = -0.42; P = 0.01), adipocyte volume (r = 0.38; P = 0.02), HOMA (r = 0.45; P = 0.004), ALT (r = 0.46; P = 0.03) and AST (r = 0.45; P = 0.03).

CONCLUSIONS: These results suggest that MCP-1 is related with adipocyte dedifferentiation and systemic insulin resistance, thereby potentially contributing to the development of NAFLD.

BACKGROUND: Pulse pressure, a measure of central arterial stiffness and a predictor of cardiovascular mortality, has known genetic components.

METHODS: To localize the genetic effects of pulse pressure, we conducted a genome-wide linkage analysis of 1,892 American-Indian participants of the Strong Heart Family Study (SHFS). Blood pressure was measured three times and the average of the last two measures was used for analyses. Pulse pressure, the difference between systolic blood pressure (SBP) and diastolic blood pressure (DBP), was log-transformed and adjusted for the effects of age and sex within each study center. Variance component linkage analyses were performed using marker allele frequencies derived from all individuals and multipoint identity-by-descent matrices calculated in Loki.

RESULTS: We identified a quantitative-trait locus influencing pulse pressure on chromosome 7 at 37 cM (marker D7S493, LOD = 3.3) and suggestive evidence of linkage on chromosome 19 at 92 cM (marker D19S888, LOD = 1.8).

CONCLUSIONS: The signal on 7p15.3 overlaps positive findings for pulse pressure among Utah population samples, suggesting that this region may harbor gene variants for blood pressure related traits.

Baboons show significant variation in body weight and composition, coupled with insulin resistance and phenotypes associated with the metabolic syndrome. An omental adipose tissue biopsy and a fasting blood sample were collected from 40 unrelated adult baboons from the colony at Southwest Foundation for Biomedical Research in San Antonio, TX. Serum was separated for analyses of circulating levels of glucose, insulin, adiponectin, resistin, interleukin 6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1 or CCL-2). Adipose tissue biopsies were analyzed for cell volume and number. Total RNA was isolated from adipose tissue and adiponectin, resistin, delta-resistin, MCP-1 and IL-6 mRNA abundance were measured using real time, quantitative RT-PCR. Partial correlation coefficients were calculated among adipokine expression, fat tissue cell volume, and circulating levels of proteins. Cell volume was significantly correlated with expression of MCP-1 (r=0.44, p<0.05) and IL-6 mRNA (r=0.47, p<0.01). A step wise regression analysis was conducted with adipose tissue cell volume as dependent variable. The model identified IL-6 mRNA levels in adipose tissue as the only predictor. These observations support the role of IL-6 as a possible paracrine regulator in adipose tissue.

To detect and localize the effects of genes influencing variation in adiponectin mRNA and protein levels, we conducted statistical genetic analyses of circulating concentrations of adiponectin and adiponectin (ADIPOQ) mRNA expression in omental adipose tissue in adult, pedigreed baboons (Papio anubis). An omental adipose tissue biopsy and blood sample were collected from 427 baboons from the colony at the Southwest Foundation for Biomedical Research, San Antonio, TX. Total RNA was isolated from adipose tissue and adiponectin mRNA levels were assayed by real-time, quantitative reverse transcriptase-PCR. Adiponectin, insulin, glucose, cholesterol, high-density lipoproteins and triglycerides were measured in fasting serum. Quantitative genetic analyses were conducted for adiponectin mRNA and serum protein using a maximum likelihood-based variance decomposition approach. A genome-wide linkage analysis was conducted using adiponectin mRNA and protein levels as phenotypes. Significant heritability was estimated for ADIPOQ mRNA levels (h2=0.19+/-0.07, P=0.01) and protein levels (h2=0.28+/-0.14, P=0.003). Genetic correlations were found between adiponectin protein and body weight (rho(G)=-0.51, P=0.03), cell volume (rho(G)=-0.73, P=0.04), serum triglycerides (rho(G)=-0.67, P=0.03), and between adiponectin mRNA and glucose (rho(G)=0.93, P<0.01). A logarithm of odds score of 2.9 was found for ADIPOQ mRNA levels on baboon chromosome 4p, which is orthologous to human 6p21. There is a significant genetic component affecting variation in the analyzed traits, and common genes may be influencing adiponectin expression, adipocyte volume, body weight and circulating triglycerides. The region on 6p21 has been linked to diabetes-related phenotypes in human studies.

Insulin resistance is a major biochemical defect underlying the pathogenesis of cardiovascular disease (CVD). Mexican-Americans are known to have an unfavorable cardiovascular profile. Thus, the aim of this study was to investigate the genetic effect on variation in HOMA-IR and to evaluate its genetic correlations with other phenotypes related to risk of CVD in Mexican-Americans. The homeostatic model assessment method (HOMA-IR) is one of several approaches that are used to measure insulin resistance and was used here to generate a quantitative phenotype for genetic analysis. For 644 adults who had participated in the San Antonio Family Heart Study (SAFHS), estimates of genetic contribution were computed using a variance components method implemented in SOLAR. Traits that exhibited significant heritabilities were body mass index (BMI) (h (2) = 0.43), waist circumference (h (2) = 0.48), systolic blood pressure (h (2) = 0.30), diastolic blood pressure (h (2) = 0.21), pulse pressure (h (2) = 0.32), triglycerides (h (2) = 0.51), LDL cholesterol (h (2) = 0.31), HDL cholesterol (h (2) = 0.24), C-reactive protein (h (2) = 0.17), and HOMA-IR (h (2) = 0.33). A genome-wide scan for HOMA-IR revealed significant evidence of linkage on chromosome 12q24 (close to PAH (phenylalanine hydroxylase), LOD = 3.01, p < 0.001). Bivariate analyses demonstrated significant genetic correlations (p < 0.05) of HOMA-IR with BMI (rho (G) = 0.36), waist circumference (rho (G) = 0.47), pulse pressure (rho (G) = 0.39), and HDL cholesterol (rho (G) = -0.18). Identification of significant linkage for HOMA-IR on chromosome 12q replicates previous family-based studies reporting linkage of phenotypes associated with type 2 diabetes in the same chromosomal region. Significant genetic correlations between HOMA-IR and phenotypes related to CVD risk factors suggest that a common set of gene(s) influence the regulation of these phenotypes.

BACKGROUND: Ghrelin is an orexigenic hormone that is produced primarily in the stomach, and stimulates food intake via its receptors situated in the hypothalamus.

OBJECTIVE: The purpose of this study was to characterize baboon ghrelin cDNA and investigate the genetic influence on the variation in plasma ghrelin levels in baboons.

METHODS AND PROCEDURES: The sample consisted of 376 baboons (263 females, 113 males) from a pedigreed colony at the Southwest Foundation for Biomedical Research, San Antonio, Texas. Ghrelin cDNA was cloned by reverse-transcription polymerase chain reaction (RT-PCR) and sequenced. Real-time RT-PCR was performed to quantify mRNA from the collected tissues. Genetic contribution to plasma ghrelin was estimated using a variance components method implemented in SOLAR.

RESULTS: The baboon coding region and predicted amino acid sequence for ghrelin showed 97 and 96% sequence identity with humans, respectively. Maximum expression of ghrelin mRNA was detected in hypothalamus and stomach. Mean +/- s.e. plasma levels of ghrelin were 3,406 +/- 99 pg/ml. A significant heritability was observed for plasma ghrelin (h(2)= 0.25, P < 0.001). A genome-wide scan revealed the evidence of suggestive linkage for a locus affecting plasma ghrelin on chromosome 9q22 (between markers D9S910 and D9S261, logarithm of the odds (LOD) score = 2.3). Significant genetic correlations (P < 0.001) among ghrelin, body weight, and leptin were observed.

DISCUSSION: These results indicate a significant genetic component in the variation of plasma ghrelin in baboons and reveal a high degree of similarity between baboon and human ghrelin with respect to its cDNA and its correlation with other obesity traits.