GWAS and transcriptional analysis prioritize ITPR1 and CNTN4 for a serum uric acid 3p26 QTL in Mexican Americans.

BACKGROUND: The variation in serum uric acid concentrations is under significant genetic influence. Elevated SUA concentrations have been linked to increased risk for gout, kidney stones, chronic kidney disease, and cardiovascular disease whereas reduced serum uric acid concentrations have been linked to multiple sclerosis, Parkinson's disease and Alzheimer's disease. Previously, we identified a novel locus on chromosome 3p26 affecting serum uric acid concentrations in Mexican Americans from San Antonio Family Heart Study. As a follow up, we examined genome-wide single nucleotide polymorphism data in an extended cohort of 1281 Mexican Americans from multigenerational families of the San Antonio Family Heart Study and the San Antonio Family Diabetes/Gallbladder Study. We used a linear regression-based joint linkage/association test under an additive model of allelic effect, while accounting for non-independence among family members via a kinship variance component. RESULTS: Univariate genetic analysis indicated serum uric acid concentrations to be significant heritable (h (2) = 0.50 ± 0.05, p < 4 × 10(-35)), and linkage analysis of serum uric acid concentrations confirmed our previous finding of a novel locus on 3p26 (LOD = 4.9, p < 1 × 10(-5)) in the extended sample. Additionally, we observed strong association of serum uric acid concentrations with variants in following candidate genes in the 3p26 region; inositol 1,4,5-trisphosphate receptor, type 1 (ITPR1), contactin 4 (CNTN4), decapping mRNA 1A (DCP1A); transglutaminase 4 (TGM4) and rho guanine nucleotide exchange factor (GEF) 26 (ARHGEF26) [p < 3 × 10(-7); minor allele frequencies ranged between 0.003 and 0.42] and evidence of cis-regulation for ITPR1 transcripts. CONCLUSION: Our results confirm the importance of the chromosome 3p26 locus and genetic variants in this region in the regulation of serum uric acid concentrations.

Statistical genetic analysis of serological measures of common, chronic infections in Alaska Native participants in the GOCADAN study.

This paper describes genetic investigations of seroreactivity to five common infectious pathogens in the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study. Antibody titers and seroprevalence were available for 495 to 782 (depending on the phenotype) family members at two time points, approximately 15 years apart, for Chlamydophila pneumoniae, Helicobacter pylori, cytomegalovirus (CMV), herpes simplex virus 1 (HSV-1), and herpes simplex virus 2 (HSV-2). Seroprevalence rates indicate that infections with most of these pathogens are common (≥20% for all of them, >80% for H. pylori, CMV, and HSV-1). Seropositive individuals typically remain seropositive over time, with seroreversion rates of <1% to 10% over ∼15 years. Antibody titers were significantly heritable for most pathogens, with the highest estimate being 0.61 for C. pneumoniae. Significant genome-wide linkage evidence was obtained for C. pneumoniae on chromosome 15 (logarithm of odds, LOD score of 3.13). These results demonstrate that individual host genetic differences influence antibody measures of common infections in this population, and further investigation may elucidate the underlying immunological processes and genes involved.

Genetic determinants of lipid traits in diverse populations from the population architecture using genomics and epidemiology (PAGE) study.

For the past five years, genome-wide association studies (GWAS) have identified hundreds of common variants associated with human diseases and traits, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. Approximately 95 loci associated with lipid levels have been identified primarily among populations of European ancestry. The Population Architecture using Genomics and Epidemiology (PAGE) study was established in 2008 to characterize GWAS-identified variants in diverse population-based studies. We genotyped 49 GWAS-identified SNPs associated with one or more lipid traits in at least two PAGE studies and across six racial/ethnic groups. We performed a meta-analysis testing for SNP associations with fasting HDL-C, LDL-C, and ln(TG) levels in self-identified European American (~20,000), African American (~9,000), American Indian (~6,000), Mexican American/Hispanic (~2,500), Japanese/East Asian (~690), and Pacific Islander/Native Hawaiian (~175) adults, regardless of lipid-lowering medication use. We replicated 55 of 60 (92%) SNP associations tested in European Americans at p<0.05. Despite sufficient power, we were unable to replicate ABCA1 rs4149268 and rs1883025, CETP rs1864163, and TTC39B rs471364 previously associated with HDL-C and MAFB rs6102059 previously associated with LDL-C. Based on significance (p<0.05) and consistent direction of effect, a majority of replicated genotype-phentoype associations for HDL-C, LDL-C, and ln(TG) in European Americans generalized to African Americans (48%, 61%, and 57%), American Indians (45%, 64%, and 77%), and Mexican Americans/Hispanics (57%, 56%, and 86%). Overall, 16 associations generalized across all three populations. For the associations that did not generalize, differences in effect sizes, allele frequencies, and linkage disequilibrium offer clues to the next generation of association studies for these traits.

Genetic variation in selenoprotein S influences inflammatory response.

Chronic inflammation has a pathological role in many common diseases and is influenced by both genetic and environmental factors. Here we assess the role of genetic variation in selenoprotein S (SEPS1, also called SELS or SELENOS), a gene involved in stress response in the endoplasmic reticulum and inflammation control. After resequencing SEPS1, we genotyped 13 SNPs in 522 individuals from 92 families. As inflammation biomarkers, we measured plasma levels of IL-6, IL-1beta and TNF-alpha. Bayesian quantitative trait nucleotide analysis identified associations between SEPS1 polymorphisms and all three proinflammatory cytokines. One promoter variant, -105G --> A, showed strong evidence for an association with each cytokine (multivariate P = 0.0000002). Functional analysis of this polymorphism showed that the A variant significantly impaired SEPS1 expression after exposure to endoplasmic reticulum stress agents (P = 0.00006). Furthermore, suppression of SEPS1 by short interfering RNA in macrophage cells increased the release of IL-6 and TNF-alpha. To investigate further the significance of the observed associations, we genotyped -105G --> A in 419 Mexican American individuals from 23 families for replication. This analysis confirmed a significant association with both TNF-alpha (P = 0.0049) and IL-1beta (P = 0.0101). These results provide a direct mechanistic link between SEPS1 and the production of inflammatory cytokines and suggest that SEPS1 has a role in mediating inflammation.

Linkage of high-density lipoprotein-cholesterol concentrations to a locus on chromosome 9p in Mexican Americans.

High-density lipoproteins (HDLs) are anti-atherogenic lipoproteins that have a major role in transporting cholesterol from peripheral tissues to the liver, where it is removed. Epidemiologic studies have shown that low levels of high-density lipoprotein-cholesterol (HDL-C) are associated with an increased incidence of coronary heart disease and an increased mortality rate, indicating a protective role of high concentrations of HDL-C against atherogenesis and the development of coronary heart disease. HDL-C level is influenced by several genetic and nongenetic factors. Nongenetic factors include smoking, which has been shown to decrease the HDL-C level. Exercise and alcohol have been shown to increase HDL-C levels. Decreased HDL-C is often associated with other coronary heart disease risk factors such as obesity, hyperinsulinemia and insulin resistance, hypertriglyceridemia and hypertension. Although several genes have been identified for rare forms of dyslipidemia, the genes accounting for major variation in HDL-C levels have yet to be identified. Using a multipoint variance components linkage approach, we found strong evidence of linkage (lod score=3.4; P=0.00004) of a quantitative trait locus (QTL) for HDL-C level to a genetic location between markers D9S925 and D9S741 on chromosome 9p in Mexican Americans. A replication study in an independent set of Mexican American families confirmed the existence of a QTL on chromosome 9p.

Heritability of serum sodium concentration: evidence for sex- and ethnic-specific effects.

Serum sodium concentration is the clinical index of systemic water balance. Although disordered water balance is common and morbid, little is known about genetic effects on serum sodium concentration at the population level. Prior studies addressed only participants of European descent and either failed to demonstrate significant heritability or showed only modest effect. We investigated heritability of serum sodium concentration in large cohorts reflecting a range of races/ethnicities, including the Framingham Heart Study (FHS, non-Hispanic Caucasian), the Heredity and Phenotype Intervention Heart Study (HAPI, Amish Caucasian), the Jackson Heart Study (JHS, African American), the Strong Heart Family Study (SHFS, American Indian), and the Genetics of Kidney Disease in Zuni Indians Study (GKDZI, American Indian). Serum sodium was transformed for the osmotic effect of glucose, and participants with markedly elevated glucose or reduced estimated glomerular filtration rate (eGFR) were excluded. Using a standard variance components method, incorporating covariates of age, glucose, and eGFR, we found heritability to be high in African American and American Indian populations and much more modest in non-Hispanic Caucasian populations. Estimates among females increased after stratification on sex and were suggestive among female participants in FHS (0.18 ± 0.12, P = 0.057) and male participants in JHS (0.24 ± 0.16, P = 0.067) and statistically significant among female participants in JHS (0.44 ± 0.09, P = 1 × 10 ⁻7), SHFS (0.59 ± 0.05, P = 9.4 × 10⁻46), and GKDZI (0.46 ± 0.15, P = 1.7 × 10⁻4), and male participants in HAPI (0.18 ± 0.12, P = 0.03) and SHFS (0.67 ± 0.07, P = 5.4 × 10⁻²6). Exclusion of diuretic users increased heritability among females and was significant in all cohorts where data were available. In aggregate, these data strongly support the heritability of systemic water balance and underscore sex and ethnicity-specific effects.

The association of genetic variants of type 2 diabetes with kidney function.

Type 2 diabetes is highly prevalent and is the major cause of progressive chronic kidney disease in American Indians. Genome-wide association studies identified several loci associated with diabetes but their impact on susceptibility to diabetic complications is unknown. We studied the association of 18 type 2 diabetes genome-wide association single-nucleotide polymorphisms (SNPs) with estimated glomerular filtration rate (eGFR; MDRD equation) and urine albumin-to-creatinine ratio in 6958 Strong Heart Study family and cohort participants. Center-specific residuals of eGFR and log urine albumin-to-creatinine ratio, obtained from linear regression models adjusted for age, sex, and body mass index, were regressed onto SNP dosage using variance component models in family data and linear regression in unrelated individuals. Estimates were then combined across centers. Four diabetic loci were associated with eGFR and one locus with urine albumin-to-creatinine ratio. A SNP in the WFS1 gene (rs10010131) was associated with higher eGFR in younger individuals and with increased albuminuria. SNPs in the FTO, KCNJ11, and TCF7L2 genes were associated with lower eGFR, but not albuminuria, and were not significant in prospective analyses. Our findings suggest a shared genetic risk for type 2 diabetes and its kidney complications, and a potential role for WFS1 in early-onset diabetic nephropathy in American Indian populations.

Bivariate genetic association of KIAA1797 with heart rate in American Indians: the Strong Heart Family Study.

Heart rate (HR) has been identified as a risk factor for cardiovascular disease (CVD), yet little is known regarding genetic factors influencing this phenotype. Previous research in American Indians (AIs) from the Strong Heart Family Study (SHFS) identified a significant quantitative trait locus (QTL) for HR on chromosome 9p21. Genetic association on HR was conducted in the SHFS. HR was measured from electrocardiogram (ECG) and echocardiograph (Echo) Doppler recordings. We examined 2248 single-nucleotide polymorphisms (SNPs) on chromosome 9p21 for association using a gene-centric statistical test. We replicated the aforementioned QTL [logarithm of odds (LOD) = 4.83; genome-wide P= 0.0003] on chromosome 9p21 in one SHFS population using joint linkage of ECG and Echo HR. After correcting for effective number of SNPs using a gene-centric test, six SNPs (rs7875153, rs7848524, rs4446809, rs10964759, rs1125488 and rs7853123) remained significant. We applied a novel bivariate association method, which was a joint test of association of a single locus to two traits using a standard additive genetic model. The SNP, rs7875153, provided the strongest evidence for association (P = 7.14 x 10(-6)). This SNP (rs7875153) is rare (minor allele frequency = 0.02) in AIs and is located within intron 9 of the gene KIAA1797. To support this association, we applied lymphocyte RNA expression data from the San Antonio Family Heart Study, a longitudinal study of CVD in Mexican Americans. Expression levels of KIAA1797 were significantly associated (P = 0.012) with HR. These findings in independent populations support that KIAA1797 genetic variation may be associated with HR but elucidation of a functional relationship requires additional study.

Genetic influences on serum bilirubin in American Indians: The Strong Heart Family Study.

OBJECTIVE: To identify genetic variation influencing serum bilirubin levels in American Indians, we performed genome-wide screening and association analyses in the Strong Heart Family Study. Bilirubin is an endogenous antioxidant that has demonstrated an inverse relationship with cardiovascular disease. Genetic variation within the promoter region of uridine diphosphate glucuronosyltransferase (UGT1A1) on chromosome 2q has been associated with elevated serum bilirubin levels in European populations. However, no study has investigated the UGT1A1 promoter in American Indians. METHODS: Statistical analyses were carried out with 3,484 participants aged 14 to 93 years recruited from three geographic areas in the United States; Arizona, Oklahoma, and North and South Dakota. RESULTS: Variance components linkage analysis detected a quantitative trait locus (QTL) for bilirubin on chromosome 2q in the combined centers (LOD = 6.61, P = 4.24 × 10⁻6) and in Oklahoma (LOD = 5.65, P = 4.57 24 × 10⁻5). Genetic association of the UGT1A1 promoter polymorphism was significant for all geographic locations. After adjustment using conditional linkage for UGT1A1 promoter variance, the linkage signal dropped to 1.10 in the combined sample and to 3.32 (P = 0.02) in Oklahoma, indicating this polymorphism is not completely responsible for the linkage signal in American Indians. We also detected suggestive linkage signals in the Dakotas on chromosome 10p12 (LOD = 2.18) and in the combined centers (LOD = 2.24) on chromosome 10q21. CONCLUSIONS: Replication of a serum bilirubin QTL on chromosome 2q in American Indians implicates UGT1A1 but further genotyping is warranted to identify additional causative polymorphisms. Evidence also supports a potential novel locus for bilirubin on chromosome 10.

Genetic Analysis Workshop 16: introduction to workshop summaries.

Genetic Analysis Workshop 16 (GAW16) was held on September 17-20, 2008 in St. Louis, Missouri. The focus of GAW16 was on methods and challenges in analysis of single-nucleotide polymorphism data from genome-wide scans. GAW16 attracted 221 participants from 12 countries. The 168 contributions were organized into 17 discussion groups of 6-17 papers each. Three data sets were available for analysis. Two of these were data from ongoing studies, generously provided by the investigators. The North American Rheumatoid Arthritis Consortium provided case-control data on rheumatoid arthritis, and the Framingham Heart Study (FHS) made available information on cardiovascular risk factors for participants in three generations of pedigree data. The third data set included simulated phenotypes for participants in the FHS, using actual pedigree structures and genotypes. This volume includes a paper for each of the 17 discussion groups, summarizing their main findings.

The association of the MYH9 gene and kidney outcomes in American Indians: the Strong Heart Family Study.

Chronic kidney disease (CKD) is an important public health problem in American Indian populations. Recent research has identified associations of polymorphisms in the myosin heavy chain type II isoform A (MYH9) gene with hypertensive CKD in African-Americans. Whether these associations are also present among American Indian individuals is unknown. To evaluate the role of genetic polymorphisms in the MYH9 gene on kidney disease in American Indians, we genotyped 25 SNPs in the MYH9 gene region in 1,119 comparatively unrelated individuals. Four SNPs failed, and one SNP was monomorphic We inferred haplotypes using seven SNPs within the region of the previously described E haplotype using Phase v2.1. We studied the association between 20 MYH9 SNPs with kidney function (estimated glomerular filtration rate, eGFR) and CKD (eGFR\60 ml/min/1.73 m(2) or renal replacement therapy or kidney transplant) using age-, sex- and center-adjusted models and measured genotyped within the variance component models. MYH9 SNPs were not significantly associated with kidney traits in additive or recessive genetic adjusted models. MYH9 haplotypes were also not significantly associated with kidney outcomes. In conclusion, common variants in MYH9 polymorphisms may not confer an increased risk of CKD in American Indian populations. Identification of the actual functional genetic variation responsible for the associations seen in African-Americans will likely help to clarify the lack of replication of this gene in our population of American Indians.

Heart rate is associated with red blood cell fatty acid concentration: the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study.

BACKGROUND: Consumption of omega-3 fatty acids (FAs) is associated with a reduction in deaths from coronary heart disease, arrhythmia, and sudden death. Although these FAs were originally thought to be antiatherosclerotic, recent evidence suggests that their benefits are related to reducing risk for ventricular arrhythmia and that this may be mediated by a slowed heart rate (HR). METHODS: The study was conducted in Alaskan Eskimos participating in the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) Study, a population experiencing a dietary shift from unsaturated to saturated fats. We compared HR with red blood cell (RBC) FA content in 316 men and 391 women ages 35 to 74 years. RESULTS: Multivariate linear regression analyses of individual FAs with HR as the dependent variable and specific FAs as covariates revealed negative associations between HR and docosahexaenoic acid (22:6n-3; P = .004) and eicosapentaenoic acid (20:5n-3; P = .009) and positive associations between HR and palmitoleic acid (16:1n-7; P = .021), eicosanoic acid (20:1n9; P = .007), and dihomo-gamma-linolenic acid (DGLA; 20:3n-6; P = .021). Factor analysis revealed that the omega-3 FAs were negatively associated with HR (P = .003), whereas a cluster of other, non-omega-3 unsaturated FAs (16:1, 20:1, and 20:3) was positively associated. CONCLUSIONS: Marine omega-3 FAs are associated with lower HR, whereas palmitoleic and DGLA, previously identified as associated with saturated FA consumption and directly related to cardiovascular mortality, are associated with higher HR. These relations may at least partially explain the relations between omega-3 FAs, ventricular arrhythmia, and sudden death.

Heritability of measures of kidney disease among Zuni Indians: the Zuni Kidney Project.

BACKGROUND: The long-term goal of the GKDZI (Genetics of Kidney Disease in Zuni Indians) Study is to identify genes, environmental factors, and genetic-environmental interactions that modulate susceptibility to renal disease and intermediate phenotypes. STUDY DESIGN: A community-based participatory research approach was used to recruit family members of individuals with kidney disease. SETTING & PARTICIPANTS: The study was conducted in the Zuni Indians, a small endogamous tribe located in rural New Mexico. We recruited members of extended families, ascertained through a proband with kidney disease and at least 1 sibling with kidney disease. 821 participants were recruited, comprising 7,702 relative pairs. PREDICTOR OUTCOMES & MEASUREMENTS: Urine albumin-creatinine ratio (UACR) and hematuria were determined in 3 urine samples and expressed as a true ratio. Glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease (MDRD) Study equation modified for American Indians. Probands were considered to have kidney disease if UACR was >or=0.2 in 2 or more of 3 spot urine samples or estimated GFR was decreased according to the CRIC (Chronic Renal Insufficiency Cohort) Study criteria. RESULTS: Kidney disease was identified in 192 participants (23.4%). There were significant heritabilities for estimated GFR, UACR, serum creatinine, serum urea nitrogen, and uric acid and a variety of phenotypes related to obesity, diabetes, and cardiovascular disease. There were significant genetic correlations of some kidney-related phenotypes with these other phenotypes. LIMITATIONS: Limitations include absence of renal biopsy, possible misclassification bias, lack of direct GFR measurements, and failure to include all possible environmental interactions. CONCLUSIONS: Many phenotypes related to kidney disease showed significant heritabilities in Zuni Indians, and there were significant genetic correlations with phenotypes related to obesity, diabetes, and cardiovascular disease. The study design serves as a paradigm for the conduct of research in relatively isolated, endogamous, underserved populations.

Models of population-based analyses for data collected from large extended families.

Large studies of extended families usually collect valuable phenotypic data that may have scientific value for purposes other than testing genetic hypotheses if the families were not selected in a biased manner. These purposes include assessing population-based associations of diseases with risk factors/covariates and estimating population characteristics such as disease prevalence and incidence. Relatedness among participants however, violates the traditional assumption of independent observations in these classic analyses. The commonly used adjustment method for relatedness in population-based analyses is to use marginal models, in which clusters (families) are assumed to be independent (unrelated) with a simple and identical covariance (family) structure such as those called independent, exchangeable and unstructured covariance structures. However, using these simple covariance structures may not be optimally appropriate for outcomes collected from large extended families, and may under- or over-estimate the variances of estimators and thus lead to uncertainty in inferences. Moreover, the assumption that families are unrelated with an identical family structure in a marginal model may not be satisfied for family studies with large extended families. The aim of this paper is to propose models incorporating marginal models approaches with a covariance structure for assessing population-based associations of diseases with their risk factors/covariates and estimating population characteristics for epidemiological studies while adjusting for the complicated relatedness among outcomes (continuous/categorical, normally/non-normally distributed) collected from large extended families. We also discuss theoretical issues of the proposed models and show that the proposed models and covariance structure are appropriate for and capable of achieving the aim.

Cardiovascular disease prevalence and its relation to risk factors in Alaska Eskimos.

BACKGROUND AND AIMS: Although Eskimos were thought to be protected from cardiovascular disease (CVD), state health data show a large proportion of deaths from CVD, despite traditional lifestyles and high omega-3 fatty acid intake. This article explores CVD prevalence and its relation to risk factors in Alaska Eskimos. METHODS AND RESULTS: A population-based cohort of 499 Alaska Eskimos > age 45 from the Norton Sound region was examined in 2000-2004 for CVD and associated risk factors as part of the Genetics of Coronary Artery Disease in Alaska Natives study. CVD and atherosclerosis were evaluated and adjudicated using standardized methods. Average age was 58 years; diabetes prevalence was low and high-density lipoprotein cholesterol (HDL-C) concentrations were high, but a large proportion smoked and had high pathogen burden. CVD was higher in men (12.6%) than in women (5.3%) (prevalence ratio 2.4, CI 1.3-4.4). Rates of stroke (6.1% in men, 1.8% in women) were similar to those for coronary heart disease (CHD) (6.1% men, 2.5% women). MI prevalence was low in both genders (1.9% and 0.7%). CVD was higher in men and in those >60 years. Hypertension, diabetes, high LDL-C, high apoB, and low HDL-C were all strong correlates (<.002) and albuminuria and CRP were also correlated with CVD (p<.05) after adjustment for age and gender. Carotid atherosclerosis was correlated with CVD (p=.0079) independent of other risk factors. CONCLUSION: These data show high CHD and stroke prevalence in Alaska Eskimos, despite low average LDL-C and high HDL-C. Hypertension and high LDL-C were independent correlates; identifying these risk factors early and treating to target is recommended.

Linkage analysis of albuminuria.

American Indians have a higher prevalence of albuminuria than the general population, likely resulting from a combination of environmental and genetic risk factors. To localize gene regions influencing variation in urinary albumin-to-creatinine ratio, we performed a linkage analysis and explored gene-by-diabetes, -hypertension, and -obesity interactions in a large cohort of American Indian families. We recruited >3600 individuals from 13 American Indian tribes from three centers (Arizona, North and South Dakota, and Oklahoma). We performed multipoint variance component linkage analysis in each center as well as in the entire cohort after controlling for center effects. We used two modeling strategies: Model 1 incorporated age, gender, and interaction terms; model 2 also controlled for diabetes, BP, body mass index, HDL, LDL, triglycerides, and smoking status. We evaluated interactions with diabetes, hypertension, and obesity using additive, interaction-specific linkage and stratified analyses. Loci suggestive for linkage to urinary albumin-to-creatinine ratio included 1q, 6p, 9q, 18q, and 20p. Gene-by-diabetes interaction was present with a quantitative trait locus specific to the diabetic stratum in the Dakotas isolated on 18q21.2 to 21.3 using model 1 (logarithm of odds = 3.3). Gene-by-hypertension interaction was present with quantitative trait loci specific to the hypertensive stratum in the Dakotas on 7q21.11 using model 1 (logarithm of odds = 3.4) and 10q25.1 using model 2 (logarithm of odds = 3.3). These loci replicate findings from multiple other genome scans of kidney disease phenotypes with distinct populations and are worthy of further study.

Associations of diet soda and non-caloric artificial sweetener use with markers of glucose and insulin homeostasis and incident diabetes: the Strong Heart Family Study.

BACKGROUND/OBJECTIVES: Non-caloric artificial sweeteners (NAS) are marketed as healthier alternatives to sugar, but the relationship between consumption of NAS and development of diabetes is unclear. This study assessed the associations of diet soda and NAS consumption with (1) early markers of insulin and glucose homeostasis (cross-sectionally) and (2) incident diabetes (over an average of 8 years of follow-up) among American Indians, a population with high rates of obesity. SUBJECTS/METHODS: The study population included Strong Heart Family Study participants without cardiovascular disease or diabetes who participated in the 2007-2009 study exam (n = 1359). Diet soda and NAS consumption were assessed using a Block food frequency questionnaire and supplemental NAS questionnaire at the study exam. Fasting plasma glucose and insulin were measured during the study exam after a 12-h overnight fast. Participants were followed for incident diabetes through December 2017 using a single phone interview and medical record review; diabetes was identified by self-report and confirmed by documentation in medical records. Associations of diet soda and NAS consumption with fasting insulin, glucose, and incident diabetes were assessed using generalized estimating equations (fasting insulin and glucose analyses) and parametric survival models with Weibull distributions (incident diabetes analyses). RESULTS: Just under half of participants reported regularly consuming diet soda (40%) or using NAS to sweeten their beverages (41%). During an average 8 years of follow-up, we identified 98 cases of incident diabetes. After correction for multiple comparisons, there were no statistically significant associations of reported diet soda and NAS consumption with fasting insulin, fasting glucose, or incident diabetes. CONCLUSIONS: Although reported consumption of diet soda and NAS were high, neither were associated with diabetes risk.

Genetics of variation in serum uric acid and cardiovascular risk factors in Mexican Americans.

BACKGROUND: Elevated serum uric acid is associated with several cardiovascular disease (CVD) risk factors such as hypertension, inflammation, endothelial dysfunction, insulin resistance, dyslipidemia, and obesity. However, the role of uric acid as an independent risk factor for CVD is not yet clear. OBJECTIVE: The aim of the study was to localize quantitative trait loci regulating variation in serum uric acid and also establish the relationship between serum uric acid and other CVD risk factors in Mexican Americans (n = 848; men = 310, women = 538) participating in the San Antonio Family Heart Study. METHODS: Quantitative genetic analysis was conducted using variance components decomposition method, implemented in the software program SOLAR. RESULTS: Mean +/- SD of serum uric acid was 5.35 +/- 1.38 mg/dl. Univariate genetic analysis showed serum uric acid and other CVD risk markers to be significantly heritable (P < 0.005). Bivariate analysis showed significant correlation of serum uric acid with body mass index, waist circumference, waist/hip ratio, total body fat, plasma insulin, serum triglycerides, high-density lipoprotein cholesterol, C-reactive protein, and granulocyte macrophage-colony stimulating factor (P < 0.05). A genome-wide scan for detecting quantitative trait loci regulating serum uric acid variation showed a significant logarithm of odds (LOD) score of 4.72 (empirical LOD score = 4.62; P < 0.00001) on chromosome 3p26. One LOD support interval contains 25 genes, of which an interesting candidate gene is chemokine receptor 2. SUMMARY: There is a significant genetic component in the variation in serum uric acid and evidence of pleiotropy between serum uric acid and other cardiovascular risk factors.

Genetic influence on variation in serum uric acid in American Indians: the strong heart family study.

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.

Genetic and other factors determining mannose-binding lectin levels in American Indians: the Strong Heart Study.

BACKGROUND: Mannose-binding lectin (MBL) forms an integral part of the innate immune system. Persistent, subclinical infections and chronic inflammatory states are hypothesized to contribute to the pathogenesis of atherosclerosis. MBL gene (MBL2) variants with between 12 to 25% allele frequency in Caucasian and other populations, result in markedly reduced expression of functional protein. Prospective epidemiologic studies, including a nested, case-control study from the present population, have demonstrated the ability of MBL2 genotypes to predict complications of atherosclerosis,. The genetic control of MBL2 expression is complex and genetic background effects in specific populations are largely unknown. METHODS: The Strong Heart Study is a longitudinal, cohort study of cardiovascular disease among American Indians. A subset of individuals genotyped for the above mentioned case-control study were selected for analysis of circulating MBL levels by double sandwich ELISA method. Mean MBL levels were compared between genotypic groups and multivariate regression was used to determine other independent factors influencing MBL2 expression. RESULTS: Our results confirm the effects of variant structural (B, C, and D) and promoter (H and Y) alleles that have been seen in other populations. In addition, MBL levels were found to be positively associated with male gender and hemoglobin A1c levels, but inversely related to triglyceride levels. Correlation was not found between MBL and other markers of inflammation. CONCLUSION: New data is presented concerning the effects of known genetic variants on MBL levels in an American Indian population, as well as the relationship of MBL2 expression to clinical and environmental factors, including inflammatory markers.