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1.  Association of Cardiometabolic Genes with Arsenic Metabolism Biomarkers in American Indian Communities: The Strong Heart Family Study (SHFS) 
Background:
Metabolism of inorganic arsenic (iAs) is subject to inter-individual variability, which is explained partly by genetic determinants.
Objectives:
We investigated the association of genetic variants with arsenic species and principal components of arsenic species in the Strong Heart Family Study (SHFS).
Methods:
We examined variants previously associated with cardiometabolic traits (~ 200,000 from Illumina Cardio MetaboChip) or arsenic metabolism and toxicity (670) among 2,428 American Indian participants in the SHFS. Urine arsenic species were measured by high performance liquid chromatography–inductively coupled plasma mass spectrometry (HPLC-ICP-MS), and percent arsenic species [iAs, monomethylarsonate (MMA), and dimethylarsinate (DMA), divided by their sum × 100] were logit transformed. We created two orthogonal principal components that summarized iAs, MMA, and DMA and were also phenotypes for genetic analyses. Linear regression was performed for each phenotype, dependent on allele dosage of the variant. Models accounted for familial relatedness and were adjusted for age, sex, total arsenic levels, and population stratification. Single nucleotide polymorphism (SNP) associations were stratified by study site and were meta-analyzed. Bonferroni correction was used to account for multiple testing.
Results:
Variants at 10q24 were statistically significant for all percent arsenic species and principal components of arsenic species. The index SNP for iAs%, MMA%, and DMA% (rs12768205) and for the principal components (rs3740394, rs3740393) were located near AS3MT, whose gene product catalyzes methylation of iAs to MMA and DMA. Among the candidate arsenic variant associations, functional SNPs in AS3MT and 10q24 were most significant (p < 9.33 × 10–5).
Conclusions:
This hypothesis-driven association study supports the role of common variants in arsenic metabolism, particularly AS3MT and 10q24.
Citation:
Balakrishnan P, Vaidya D, Franceschini N, Voruganti VS, Gribble MO, Haack K, Laston S, Umans JG, Francesconi KA, Goessler W, North KE, Lee E, Yracheta J, Best LG, MacCluer JW, Kent J Jr., Cole SA, Navas-Acien A. 2017. Association of cardiometabolic genes with arsenic metabolism biomarkers in American Indian communities: the Strong Heart Family Study (SHFS). Environ Health Perspect 125:15–22; http://dx.doi.org/10.1289/EHP251
doi:10.1289/EHP251
PMCID: PMC5226702  PMID: 27352405
2.  Genetic Analysis Workshop 19: methods and strategies for analyzing human sequence and gene expression data in extended families and unrelated individuals 
BMC Proceedings  2016;10(Suppl 7):67-70.
Genetic Analysis Workshop 19 provided a platform for developing and evaluating statistical methods to analyze whole-genome sequence and gene expression data from a pedigree-based sample, as well as whole-exome sequence data from a large cohort of unrelated individuals. In this article we present an overview of the data sets, the GAW experience, and summaries of the contributions arranged into nine methodological themes.
doi:10.1186/s12919-016-0007-z
PMCID: PMC5133501  PMID: 27980613
3.  GWAS and transcriptional analysis prioritize ITPR1 and CNTN4 for a serum uric acid 3p26 QTL in Mexican Americans 
BMC Genomics  2016;17:276.
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 (h2 = 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.
doi:10.1186/s12864-016-2594-5
PMCID: PMC4818944  PMID: 27039371
Joint linkage/association approach; CNTN4; ITPR1; Family-based study
4.  Replication of the effect of SLC2A9 genetic variation on serum uric acid levels in American Indians 
Increased serum uric acid (SUA) or hyperuricemia, a risk factor for gout, renal and cardiovascular diseases, is caused by either increased production or decreased excretion of uric acid or a mix of both. The solute carrier protein 2 family, member 9 (SLC2A9) gene encodes a transporter that mediates urate flux across the renal proximal tubule. Genome-wide association studies have consistently shown the association of single-nucleotide polymorphisms in this gene with SUA in majority populations. American Indian participants of the Strong Heart Family Study, belonging to multigenerational families, have high prevalence of hyperuricemia. We conducted measured genotype analyses, based on variance components decomposition method and accounting for family relationships, to assess whether the association between SUA and SLC2A9 gene polymorphisms generalized to American Indians (n=3604) of this study. Seven polymorphisms were selected for genotyping based on their association with SUA levels in other populations. A strong association was found between SLC2A9 gene polymorphisms and SUA in all centers combined (P-values: 1.3 × 10−31–5.1 × 10−23) and also when stratified by recruitment center; P-values: 1.2 × 10−14–1.0 × 10−5. These polymorphisms were also associated with the estimated glomerular filtration rate and serum creatinine but not albumin–creatinine ratio. In summary, the association of polymorphisms in the uric acid transporter gene with SUA levels extends to a new population of American Indians.
doi:10.1038/ejhg.2013.264
PMCID: PMC4060115  PMID: 24301058
genetic variation; uric acid; single-nucleotide polymorphisms
5.  Heart rate is associated with markers of fatty acid desaturation: the GOCADAN study 
Objectives
To determine if heart rate (HR) is associated with desaturation indexes as HR is associated with arrhythmia and sudden death.
Study design
A community based cross-sectional study of 1214 Alaskan Inuit.
Methods
Data of FA concentrations from plasma and red blood cell membranes from those ≥35 years of age (n = 819) were compared to basal HR at the time of examination. Multiple linear regression with backward stepwise selection was employed to analyze the effect of the desaturase indexes on HR, after adjustment for relevant covariates.
Results
The Δ5 desaturase index (Δ5-DI) measured in serum has recently been associated with a protective role for cardiovascular disease. This index measured here in plasma and red blood cells showed a negative correlation with HR. The plasma stearoyl-CoA-desaturase (SCD) index, previously determined to be related to cardiovascular disease (CVD) mortality, on the other hand, was positively associated with HR, while the Δ6 desaturase index (Δ6-DI) had no significant effect on HR.
Conclusion
Endogenous FA desaturation is associated with HR and thereby, in the case of SCD, possibly with arrhythmia and sudden death, which would at least partially explain the previously observed association between cardiovascular mortality and desaturase activity.
PMCID: PMC3387544  PMID: 22456045
Inuit; diet; fatty acid metabolism; CVD risk factors
6.  Heart rate is associated with markers of fatty acid desaturation: the GOCADAN study 
International Journal of Circumpolar Health  2012;71:10.3402/ijch.v71i0.17343.
Objectives
To determine if heart rate (HR) is associated with desaturation indexes as HR is associated with arrhythmia and sudden death.
Study design
A community based cross-sectional study of 1214 Alaskan Inuit.
Methods
Data of FA concentrations from plasma and red blood cell membranes from those ≥35 years of age (n =819) were compared to basal HR at the time of examination. Multiple linear regression with backward stepwise selection was employed to analyze the effect of the desaturase indexes on HR, after adjustment for relevant covariates.
Results
The Δ5 desaturase index (Δ5-DI) measured in serum has recently been associated with a protective role for cardiovascular disease. This index measured here in plasma and red blood cells showed a negative correlation with HR. The plasma stearoyl-CoA-desaturase (SCD) index, previously determined to be related to cardiovascular disease (CVD) mortality, on the other hand, was positively associated with HR, while the Δ6 desaturase index (Δ6-DI) had no significant effect on HR.
Conclusion
Endogenous FA desaturation is associated with HR and thereby, in the case of SCD, possibly with arrhythmia and sudden death, which would at least partially explain the previously observed association between cardiovascular mortality and desaturase activity.
doi:10.3402/ijch.v71i0.17343
PMCID: PMC3387544  PMID: 22456045
Inuit; diet; fatty acid metabolism; CVD risk factors
7.  Genetics of kidney disease and related cardiometabolic phenotypes in Zuni Indians: the Zuni Kidney Project 
The objective of this study is to identify genetic factors associated with chronic kidney disease (CKD) and related cardiometabolic phenotypes among participants of the Genetics of Kidney Disease in Zuni Indians study. The study was conducted as a community-based participatory research project in the Zuni Indians, a small endogamous tribe in rural New Mexico. We recruited 998 members from 28 extended multigenerational families, ascertained through probands with CKD who had at least one sibling with CKD. We used the Illumina Infinium Human1M-Duo version 3.0 BeadChips to type 1.1 million single nucleotide polymorphisms (SNPs). Prevalence estimates for CKD, hyperuricemia, diabetes, and hypertension were 24%, 30%, 17% and 34%, respectively. We found a significant (p < 1.58 × 10-7) association for a SNP in a novel gene for serum creatinine (PTPLAD2). We replicated significant associations for genes with serum uric acid (SLC2A9), triglyceride levels (APOA1, BUD13, ZNF259), and total cholesterol (PVRL2). We found novel suggestive associations (p < 1.58 × 10-6) for SNPs in genes with systolic (OLFML2B), and diastolic blood pressure (NFIA). We identified a series of genes associated with CKD and related cardiometabolic phenotypes among Zuni Indians, a population with a high prevalence of kidney disease. Illuminating genetic variations that modulate the risk for these disorders may ultimately provide a basis for novel preventive strategies and therapeutic interventions.
doi:10.3389/fgene.2015.00006
PMCID: PMC4311707  PMID: 25688259
single nucleotide polymorphisms; association; kidney function; serum uric acid; triglycerides
8.  Fatty acids linked to cardiovascular mortality are associated with risk factors 
International Journal of Circumpolar Health  2015;74:10.3402/ijch.v74.28055.
Background
Although saturated fatty acids (FAs) have been linked to cardiovascular mortality, it is not clear whether this outcome is attributable solely to their effects on low-density lipoprotein cholesterol (LDL-C) or whether other risk factors are also associated with FAs. The Western Alaskan Native population, with its rapidly changing lifestyles, shift in diet from unsaturated to saturated fatty acids and dramatic increase in cardiovascular disease (CVD), presents an opportunity to elucidate any associations between specific FAs and known CVD risk factors.
Objective
We tested the hypothesis that the specific FAs previously identified as related to CVD mortality are also associated with individual CVD risk factors.
Methods
In this community-based, cross-sectional study, relative proportions of FAs in plasma and red blood cell membranes were compared with CVD risk factors in a sample of 758 men and women aged ≥35 years. Linear regression analyses were used to analyze relations between specific FAs and CVD risk factors (LDL-C, high-density lipoprotein cholesterol, triglycerides, C-reactive protein, systolic blood pressure, diastolic blood pressure, heart rate, body mass index, fasting glucose and fasting insulin, 2-hour glucose and 2-hour insulin).
Results
The specific saturated FAs previously identified as related to CVD mortality, the palmitic and myristic acids, were adversely associated with most CVD risk factors, whereas unsaturated linoleic acid (18:2n-6) and the marine n-3 FAs were not associated or were beneficially associated with CVD risk factors.
Conclusions
The results suggest that CVD risk factors are more extensively affected by individual FAs than hitherto recognized, and that risk for CVD, MI and stroke can be reduced by reducing the intake of palmitate, myristic acid and simple carbohydrates and improved by greater intake of linoleic acid and marine n-3 FAs.
doi:10.3402/ijch.v74.28055
PMCID: PMC4536775  PMID: 26274054
Alaska Natives; cardiovascular risk factors; dietary fat consumption; fatty acids; fish oil consumption; Inuit; saturated fatty acids
9.  SLCO1B1 Variants and Urine Arsenic Metabolites in the Strong Heart Family Study 
Toxicological Sciences  2013;136(1):19-25.
Arsenic species patterns in urine are associated with risk for cancer and cardiovascular diseases. The organic anion transporter coded by the gene SLCO1B1 may transport arsenic species, but its association with arsenic metabolites in human urine has not yet been studied. The objective of this study is to evaluate associations of urine arsenic metabolites with variants in the candidate gene SLCO1B1 in adults from the Strong Heart Family Study. We estimated associations between % arsenic species biomarker traits and 5 single-nucleotide polymorphisms (SNPs) in the SLCO1B1 gene in 157 participants, assuming additive genetics. Linear regression models for each SNP accounted for kinships and were adjusted for sex, body mass index, and study center. The minor allele of rs1564370 was associated with lower %MMA (p = .0003) and higher %DMA (p = .0002), accounting for 8% of the variance for %MMA and 9% for %DMA. The rs1564370 minor allele homozygote frequency was 17% and the heterozygote frequency was 43%. The minor allele of rs2291075 was associated with lower %MMA (p = .0006) and higher %DMA (p = .0014), accounting for 7% of the variance for %MMA and 5% for %DMA. The frequency of rs2291075 minor allele homozygotes was 1% and of heterozygotes was 15%. Common variants in SLCO1B1 were associated with differences in arsenic metabolites in a preliminary candidate gene study. Replication of this finding in other populations and analyses with respect to disease outcomes are needed to determine whether this novel candidate gene is important for arsenic-associated disease risks.
doi:10.1093/toxsci/kft181
PMCID: PMC3829571  PMID: 23970802
American Indians; arsenic metabolism; arsenic species; SLCO1B1; OATPC; Strong Heart Study.
10.  Statistical genetic analysis of serological measures of common, chronic infections in Alaska Native participants in the GOCADAN study 
Genetic epidemiology  2013;37(7):751-757.
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 (LOD 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.
doi:10.1002/gepi.21745
PMCID: PMC3969261  PMID: 23798484
Chlamydophila pneumoniae; Helicobacter pylori; cytomegalovirus; herpes simplex virus-1; herpes simplex virus-2; antibodies; heritability; linkage; Inupiaq
11.  Genome-wide Linkage Analysis of Carotid Artery Lumen Diameter: The Strong Heart Family Study 
International journal of cardiology  2013;168(4):3902-3908.
Background
A significant proportion of the variability in carotid artery lumen diameter is attributable to genetic factors.
Methods
Carotid ultrasonography and genotyping were performed in the 3,300 American Indian participants in the Strong Heart Family Study (SHFS) to identify chromosomal regions harboring novel genes associated with inter-individual variation in carotid artery lumen diameter. Genome-wide linkage analysis was conducted using standard variance component linkage methods, implemented in SOLAR, based on multipoint identity-by-descent matrices.
Results
Genome-wide linkage analysis revealed a significant evidence for linkage for a locus for left carotid artery diastolic and systolic lumen diameter in Arizona SHFS participants on chromosome 7 at 120 cM (lod=4.85 and 3.77, respectively, after sex and age adjustment, and lod=3.12 and 2.72, respectively, after adjustment for sex, age, height, weight, systolic and diastolic blood pressure, diabetes mellitus and current smoking). Other regions with suggestive evidence of linkage for left carotid artery diastolic and systolic lumen diameter was found on chromosome 12 at 153 cM (lod=2.20 and 2.60, respectively, after sex and age adjustment, and lod=2.44 and 2.16, respectively, after full covariate adjustment) in Oklahoma SHFS participants; suggestive linkage for right carotid artery diastolic and systolic lumen diameter was found on chromosome 9 at 154 cM (lod=2.72 and 3.19, respectively after sex and age adjustment, and lod=2.36 and 2.21, respectively, after full covariate adjustment) in Oklahoma SHFS participants.
Conclusion
We found significant evidence for loci influencing carotid artery lumen diameter on chromosome 7q and suggestive linkage on chromosomes 12q and 9q.
doi:10.1016/j.ijcard.2013.06.048
PMCID: PMC4028022  PMID: 23871337
genetics; carotid artery; ultrasonography; linkage analysis; variance components
12.  Models of population-based analyses for data collected from large extended families 
European journal of epidemiology  2010;25(12):855-865.
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.
doi:10.1007/s10654-010-9512-y
PMCID: PMC4167007  PMID: 20882324
Correlated outcomes; Marginal models; Family study; Large and inter-related extended families
14.  Genetic Analysis Workshop 18: Methods and strategies for analyzing human sequence and phenotype data in members of extended pedigrees 
BMC Proceedings  2014;8(Suppl 1):S1.
Genetic Analysis Workshop 18 provided a platform for developing and evaluating statistical methods to analyze whole-genome sequence data from a pedigree-based sample. In this article we present an overview of the data sets and the contributions that analyzed these data. The family data, donated by the Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Ethnic Samples Consortium, included sequence-level genotypes based on sequencing and imputation, genome-wide association genotypes from prior genotyping arrays, and phenotypes from longitudinal assessments. The contributions from individual research groups were extensively discussed before, during, and after the workshop in theme-based discussion groups before being submitted for publication.
doi:10.1186/1753-6561-8-S1-S1
PMCID: PMC4143625  PMID: 25519310
16.  Genetic Architecture of Carotid Artery Intima-Media Thickness in Mexican Americans 
Circulation. Cardiovascular genetics  2013;6(2):10.1161/CIRCGENETICS.113.000079.
Background
Intima-media thickness (IMT) of the common and internal carotid arteries is an established surrogate for atherosclerosis and predicts risk of stroke and myocardial infarction. Often IMT is measured as the average of these two arteries, yet they are believed to result from separate biological mechanisms. The aim of this study was to conduct a family-based genome-wide association study (GWAS) for IMT to identify polymorphisms influencing IMT and to determine if distinct carotid artery segments are influenced by different genetic components.
Methods and Results
IMT for the common and internal carotid arteries was determined through B-mode ultrasound in 772 Mexican Americans from the San Antonio Family Heart Study. A GWAS utilizing 931,219 single nucleotide polymorphisms (SNPs) was undertaken with six internal and common carotid artery IMT phenotypes utilizing an additive measured genotype model. The most robust association detected was for two SNPs (rs16983261, rs6113474, p=1.60e−7) in complete linkage disequilibrium on chromosome 20p11 for the internal carotid artery near wall, next to the gene PAX1. We also replicated previously reported GWAS regions on chromosomes 19q13 and 7q22. We found no overlapping associations between internal and common carotid artery phenotypes at p<5.0e0−6. The genetic correlation between the two carotid IMT arterial segments was 0.51.
Conclusions
This study represents the first large scale GWAS of carotid IMT in a non-European population and identified several novel loci. We do not detect any shared GWAS signals between common and internal carotid arterial segments but the moderate genetic correlation implies both common and unique genetic components.
doi:10.1161/CIRCGENETICS.113.000079
PMCID: PMC3865281  PMID: 23487405
intima-media thickness; carotid artery; GWAS; Hispanics
18.  Genome-wide association analysis confirms and extends the association of SLC2A9 with serum uric acid levels to Mexican Americans 
Frontiers in Genetics  2013;4:279.
Increased serum uric acid (SUA) is a risk factor for gout and renal and cardiovascular disease (CVD). The purpose of this study was to identify genetic factors that affect the variation in SUA in 632 Mexican Americans participants of the San Antonio Family Heart Study (SAFHS). A genome-wide association (GWA) analysis was performed using the Illumina Human Hap 550K single nucleotide polymorphism (SNP) microarray. We used a linear regression-based association test under an additive model of allelic effect, while accounting for non-independence among family members via a kinship variance component. All analyses were performed in the software package SOLAR. SNPs rs6832439, rs13131257, and rs737267 in solute carrier protein 2 family, member 9 (SLC2A9) were associated with SUA at genome-wide significance (p < 1.3 × 10−7). The minor alleles of these SNPs had frequencies of 36.2, 36.2, and 38.2%, respectively, and were associated with decreasing SUA levels. All of these SNPs were located in introns 3–7 of SLC2A9, the location of the previously reported associations in European populations. When analyzed for association with cardiovascular-renal disease risk factors, conditional on SLC2A9 SNPs strongly associated with SUA, significant associations were found for SLC2A9 SNPs with BMI, body weight, and waist circumference (p < 1.4 × 10−3) and suggestive associations with albumin-creatinine ratio and total antioxidant status (TAS). The SLC2A9 gene encodes an urate transporter that has considerable influence on variation in SUA. In addition to the primary association locus, suggestive evidence (p < 1.9 × 10−6) for joint linkage/association (JLA) was found at a previously-reported urate quantitative trait locus (Logarithm of odds score = 3.6) on 3p26.3. In summary, our GWAS extends and confirms the association of SLC2A9 with SUA for the first time in a Mexican American cohort and also shows for the first time its association with cardiovascular-renal disease risk factors.
doi:10.3389/fgene.2013.00279
PMCID: PMC3863993  PMID: 24379826
variance components decomposition approach; joint linkage/association analysis; kinship; hyperuricemia
19.  QTL mapping of leukocyte telomere length in American Indians: The Strong Heart Family Study 
Aging (Albany NY)  2013;5(9):704-716.
Telomeres play a central role in cellular senescence and are associated with a variety of age-related disorders such as dementia, Alzheimer's disease and atherosclerosis. Telomere length varies greatly among individuals of the same age, and is heritable. Here we performed a genome-wide linkage scan to identify quantitative trait loci (QTL) influencing leukocyte telomere length (LTL) measured by quantitative PCR in 3,665 American Indians (aged 14 – 93 years) from 94 large, multi-generational families. All participants were recruited by the Strong Heart Family Study (SHFS), a prospective study to identify genetic factors for cardiovascular disease and its risk factors in American Indians residing in Oklahoma, Arizona and Dakota. LTL heritability was estimated to be between 51% and 62%, suggesting a strong genetic predisposition to interindividual variation of LTL in this population. Significant QTLs were localized to chromosome 13 (Logarithm of odds score (LOD) = 3.9) at 13q12.11, to 18q22.2 (LOD = 3.2) and to 3p14.1 (LOD = 3.0) for Oklahoma. This is the first study to identify susceptibility loci influencing leukocyte telomere variation in American Indians, a minority group suffering from a disproportionately high rate of type 2 diabetes and other age-related disorders.
PMCID: PMC3808702  PMID: 24036517
leukocyte telomere length; genome-wide linkage scan; quantitative trait loci; American Indians
20.  Heritability and Preliminary Genome-Wide Linkage Analysis of Arsenic Metabolites in Urine 
Environmental Health Perspectives  2013;121(3):345-351.
Background: Arsenic (III) methyltransferase (AS3MT) has been related to urine arsenic metabolites in association studies. Other genes might also play roles in arsenic metabolism and excretion.
Objective: We evaluated genetic determinants of urine arsenic metabolites in American Indian adults from the Strong Heart Study (SHS).
Methods: We evaluated heritability of urine arsenic metabolites [percent inorganic arsenic (%iAs), percent monomethylarsonate (%MMA), and percent dimethylarsinate (%DMA)] in 2,907 SHS participants with urine arsenic measurements and at least one relative within the cohort. We conducted a preliminary linkage analysis in a subset of 487 participants with available genotypes on approximately 400 short tandem repeat markers using a general pedigree variance component approach for localizing quantitative trait loci (QTL).
Results: The medians (interquartile ranges) for %iAs, %MMA, and %DMA were 7.7% (5.4–10.7%), 13.6% (10.5–17.1%), and 78.4% (72.5–83.1%), respectively. The estimated heritability was 53% for %iAs, 50% for %MMA, and 59% for %DMA. After adjustment for sex, age, smoking, body mass index, alcohol consumption, region, and total urine arsenic concentrations, LOD [logarithm (to the base of 10) of the odds] scores indicated suggestive evidence for genetic linkage with QTLs influencing urine arsenic metabolites on chromosomes 5 (LOD = 2.03 for %iAs), 9 (LOD = 2.05 for %iAs and 2.10 for %MMA), and 11 (LOD = 1.94 for %iAs). A peak for %DMA on chromosome 10 within 2 Mb of AS3MT had an LOD of 1.80.
Conclusions: This population-based family study in American Indian communities supports a genetic contribution to variation in the distribution of arsenic metabolites in urine and, potentially, the involvement of genes other than AS3MT.
doi:10.1289/ehp.1205305
PMCID: PMC3621197  PMID: 23322787
American Indians; arsenic metabolism; arsenic species; determinants; heritability; linkage scan; Strong Heart Study
21.  A QTL for genotype by sex interaction for anthropometric measurements in Alaskan Eskimos (GOCADAN study) on chromosome 19q12-13 
Obesity (Silver Spring, Md.)  2011;19(9):1840-1846.
Variation in anthropometric measurements due to sexual dimorphism can be the result of genotype by sex interactions (G×S). The purpose of this study was to examine the sex-specific genetic architecture in anthropometric measurements in Alaskan Eskimos from the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study. Maximum likelihood based variance components decomposition methods, implemented in SOLAR, were used for GxS analyses. Anthropometric measurements included BMI, waist circumference (WC), waist/height ratio, percent body fat (%BF) and subscapular and triceps skinfolds. Except for WC, mean values of all phenotypes were significantly different in men and women (p < 0.05). All anthropometric measures were significantly heritable (p< 0.001). In a preliminary analysis not allowing for G×S interaction, evidence of linkage was detected between markers D19S414 and D19S220 on chromosome 19 for WC (LOD = 3.5), %BF (LOD = 1.7), BMI (LOD = 2.4), WHtR (LOD = 2.5), subscapular (LOD = 2.1) and triceps skinfolds (LOD = 1.9). In subsequent analyses which allowed for G×S interaction, linkage was again found between these traits and the same two markers on chromosome 19 with significantly improved LOD scores for: WC (LOD = 4.5), %BF (LOD = 3.8), BMI (LOD = 3.5), waist/height ratio (LOD = 3.2), subscapular (LOD = 3.0) and triceps skinfolds (LOD = 2.9). These results support evidence of a G×S interaction in the expression of genetic effects resulting in sexual dimorphism in anthropometric phenotypes and identify the chromosome 19q12-13 region as important for adiposity-related traits in Alaskan Eskimos.
doi:10.1038/oby.2011.78
PMCID: PMC3525327  PMID: 21527897
Abdominal obesity; Adiposity; Body composition; Linkage
22.  The 27-bp repeat polymorphism in intron 4 (27 bp-VNTR) of endothelial nitric oxide synthase (eNOS) gene is associated with albumin to creatinine ratio in Mexican Americans 
Molecular and cellular biochemistry  2009;331(1-2):201-205.
The T-786C, Glu298Asp, and 27 bp variable number of tandem repeats (27 bp-VNTR-a/b) polymorphsims of the endothelial nitric oxide synthase (eNOS) gene are thought to alter nitric oxide production and contribute to the development of vascular and renal disease risk. The objective of this study is to investigate whether these three polymorphisms examined previously by others are associated with cardiovascular and renal disease risk in Mexican Americans. Study participants (N = 848; 21 families) were genotyped for T-786C, Glu298Asp, and 27 bp-VNTR-a/b polymorphisms by PCR followed by restriction digestion. Association analyses were performed by a measured genotype approach implemented in the program SOLAR. Of the phenotypes (type 2 diabetes, hypertension, body mass index, waist circumference, total cholesterol, high density lipoprotein cholesterol, triglycerides, systolic and diastolic blood pressure, albumin to creatinine ratio (ACR), and estimated glomerular filtration rate) examined for association, the 27 bp-VNTR-a/b variant exhibited statistically significant association with ACR (P = 0.047) after accounting for the trait specific covariate effects. In addition, the promoter variant (T-786C) showed a significant association with triglycerides (P = 0.034) after accounting for covariate influences. In conclusion, the present study adds evidence to the role of eNOS candidate gene polymorphisms in modulating the risk factors related to cardiovascular-renal disease in Mexican Americans although the magnitude of the genetic effect is small.
doi:10.1007/s11010-009-0159-5
PMCID: PMC3428139  PMID: 19468830
eNOS; Genetic polymorphisms; Association analyses; ACR; Triglycerides; Mexican Americans
23.  Variants in CPT1A, FADS1, and FADS2 are Associated with Higher Levels of Estimated Plasma and Erythrocyte Delta-5 Desaturases in Alaskan Eskimos 
The delta-5 and delta-6 desaturases (D5D and D6D), encoded by fatty acid desaturase 1 (FADS1) and 2 (FADS2) genes, respectively, are rate-limiting enzymes in the metabolism of ω-3 and ω-6 fatty acids. The objective of this study was to identify genes influencing variation in estimated D5D and D6D activities in plasma and erythrocytes in Alaskan Eskimos (n = 761) participating in the genetics of coronary artery disease in Alaska Natives (GOCADAN) study. Desaturase activity was estimated by product: precursor ratio of polyunsaturated fatty acids. We found evidence of linkage for estimated erythrocyte D5D (eD5D) on chromosome 11q12-q13 (logarithm of odds score = 3.5). The confidence interval contains candidate genes FADS1, FADS2, 7-dehydrocholesterol reductase (DHCR7), and carnitine palmitoyl transferase 1A, liver (CPT1A). Measured genotype analysis found association between CPT1A, FADS1, and FADS2 single-nucleotide polymorphisms (SNPs) and estimated eD5D activity (p-values between 10−28 and 10−5). A Bayesian quantitative trait nucleotide analysis showed that rs3019594 in CPT1A, rs174541 in FADS1, and rs174568 in FADS2 had posterior probabilities > 0.8, thereby demonstrating significant statistical support for a functional effect on eD5D activity. Highly significant associations of FADS1, FADS2, and CPT1A transcripts with their respective SNPs (p-values between 10−75 and 10−7) in Mexican Americans of the San Antonio Family Heart Study corroborated our results. These findings strongly suggest a functional role for FADS1, FADS2, and CPT1A SNPs in the variation in eD5D activity.
doi:10.3389/fgene.2012.00086
PMCID: PMC3371589  PMID: 22701466
essential fatty acids; single-nucleotide polymorphisms; bayesian quantitative trait nucleotide analysis
24.  Novel Associations of Nonstructural Loci with Paraoxonase Activity 
Journal of Lipids  2012;2012:189681.
The high-density-lipoprotein-(HDL-) associated esterase paraoxonase 1 (PON1) is a likely contributor to the antioxidant and antiatherosclerotic capabilities of HDL. Two nonsynonymous mutations in the structural gene, PON1, have been associated with variation in activity levels, but substantial interindividual differences remain unexplained and are greatest for substrates other than the eponymous paraoxon. PON1 activity levels were measured for three substrates—organophosphate paraoxon, arylester phenyl acetate, and lactone dihydrocoumarin—in 767 Mexican American individuals from San Antonio, Texas. Genetic influences on activity levels for each substrate were evaluated by association with approximately one million single nucleotide polymorphism (SNPs) while conditioning on PON1 genotypes. Significant associations were detected at five loci including regions on chromosomes 4 and 17 known to be associated with atherosclerosis and lipoprotein regulation and loci on chromosome 3 that regulate ubiquitous transcription factors. These loci explain 7.8% of variation in PON1 activity with lactone as a substrate, 5.6% with the arylester, and 3.0% with paraoxon. In light of the potential importance of PON1 in preventing cardiovascular disease/events, these novel loci merit further investigation.
doi:10.1155/2012/189681
PMCID: PMC3345224  PMID: 22577559
25.  Individual saturated fatty acids are associated with different components of insulin resistance and glucose metabolism: the GOCADAN study 
Objectives
Type 2 diabetes and the consumption of saturated fatty acids (FAs) are on the rise among Alaska Inuits. This analysis, based on a cross-sectional study, explores the possible associations of saturated FA content in red blood cells (RBCs) and parameters of glucose metabolism in a sample of Alaska Natives.
Study design and methods
The sample included 343 women and 282 men aged 35–74. Statistical analyses explored the associations of selected RBC (myristic, palmitic and stearic acids) FAs with fasting glucose (plasma), fasting insulin (plasma), 2h glucose (2-hour glucose tolerance test), 2h insulin and homeostasis model assessment (HOMA) index. The models included sex and glucose metabolism status as fixed factors and age, body mass index (BMI), waist circumference, physical activity (METS) and FA content in RBCs as covariates. Measures of insulin, glucose and HOMA index were used as dependent variables.
Results
Myristic acid was positively associated with fasting insulin (β=0.47, p<0.001), 2h insulin (β=0.53, p=0.02) and HOMA index (β=0.455, p<0.001). Palmitic acid was associated with 2h glucose (β=2.3×10-2, p<0.001) and 2h insulin (β=5.6×10-2, p=0.002) and stearic acid was associated with fasting glucose (β=4.8×10-3, p=0.006).
Conclusions
These results strongly support the hypothesis that saturated fatty acids are associated with insulin resistance and glucose intolerance and that saturated fatty acids are significant risk factors for type 2 diabetes.
PMCID: PMC3307791  PMID: 20719107
myristic acid; palmitic acid; stearic acid; Inuit; Alaska Natives; diabetes; saturated fat

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