Peripheral Arterial Disease and Its Association With Arsenic Exposure and Metabolism in the Strong Heart Study.

At high levels, inorganic arsenic exposure is linked to peripheral arterial disease (PAD) and cardiovascular disease. To our knowledge, no prior study has evaluated the association between low-to-moderate arsenic exposure and incident PAD by ankle brachial index (ABI). We evaluated this relationship in the Strong Heart Study, a large population-based cohort study of American Indian communities. A total of 2,977 and 2,966 PAD-free participants who were aged 45-74 years in 1989-1991 were reexamined in 1993-1995 and 1997-1999, respectively, for incident PAD defined as either ABI <0.9 or ABI >1.4. A total of 286 and 206 incident PAD cases were identified for ABI <0.9 and ABI >1.4, respectively. The sum of inorganic and methylated urinary arsenic species (∑As) at baseline was used as a biomarker of long-term exposure. Comparing the highest tertile of ∑As with the lowest, the adjusted hazard ratios were 0.57 (95% confidence interval (CI): 0.32, 1.01) for ABI <0.9 and 2.24 (95% CI: 1.01, 4.32) for ABI >1.4. Increased arsenic methylation (as percent dimethylarsinate) was associated with a 2-fold increased risk of ABI >1.4 (hazard ratio = 2.04, 95% CI: 1.02, 3.41). Long-term low-to-moderate ∑As and increased arsenic methylation were associated with ABI >1.4 but not with ABI <0.9. Further studies are needed to clarify whether diabetes and enhanced arsenic metabolism increase susceptibility to the vasculotoxic effects of arsenic exposure.

Fatty acids linked to cardiovascular mortality are associated with risk factors.

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.

Mapping of a blood pressure QTL on chromosome 17 in American Indians of the strong heart family study.

BACKGROUND: Blood pressure (BP) is a complex trait, with a heritability of 30 to 40%. Several genome wide associated BP loci explain only a small fraction of the phenotypic variation. Family studies can provide an important tool for gene discovery by utilizing trait and genetic transmission information among relative-pairs. We have previously described a quantitative trait locus at chromosome 17q25.3 influencing systolic BP in American Indians of the Strong Heart Family Study (SHFS). This locus has been reported to associate with variation in BP traits in family studies of Europeans, African Americans and Hispanics. METHODS: To follow-up persuasive linkage findings at this locus, we performed comprehensive genotyping in the 1-LOD unit support interval region surrounding this QTL using a multi-step strategy. We first genotyped 1,334 single nucleotide polymorphisms (SNPs) in 928 individuals from families that showed evidence of linkage for BP. We then genotyped a second panel of 306 SNPs in all SHFS participants (N = 3,807) for genes that displayed the strongest evidence of association in the region, and, in a third step, included additional genotyping to better cover the genes of interest and to interrogate plausible candidate genes in the region. RESULTS: Three genes had multiple SNPs marginally associated with systolic BP (TBC1D16, HRNBP3 and AZI1). In BQTN analysis, used to estimate the posterior probability that any variant in each gene had an effect on the phenotype, AZI1 showed the most prominent findings (posterior probability of 0.66). Importantly, upon correction for multiple testing, none of our study findings could be distinguished from chance. CONCLUSION: Our findings demonstrate the difficulty of follow-up studies of linkage studies for complex traits, particularly in the context of low powered studies and rare variants underlying linkage peaks.

Generalization of associations of kidney-related genetic loci to American Indians.

BACKGROUND AND OBJECTIVES: CKD disproportionally affects American Indians, who similar to other populations, show genetic susceptibility to kidney outcomes. Recent studies have identified several loci associated with kidney traits, but their relevance in American Indians is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study used data from a large, family-based genetic study of American Indians (the Strong Heart Family Study), which includes 94 multigenerational families enrolled from communities located in Oklahoma, the Dakotas, and Arizona. Individuals were recruited from the Strong Heart Study, a population-based study of cardiovascular disease in American Indians. This study selected 25 single nucleotide polymorphisms in 23 loci identified from recently published kidney-related genome-wide association studies in individuals of European ancestry to evaluate their associations with kidney function (estimated GFR; individuals 18 years or older, up to 3282 individuals) and albuminuria (urinary albumin to creatinine ratio; n=3552) in the Strong Heart Family Study. This study also examined the association of single nucleotide polymorphisms in the APOL1 region with estimated GFR in 1121 Strong Heart Family Study participants. GFR was estimated using the abbreviated Modification of Diet in Renal Disease Equation. Additive genetic models adjusted for age and sex were used. RESULTS: This study identified significant associations of single nucleotide polymorphisms with estimated GFR in or nearby PRKAG2, SLC6A13, UBE2Q2, PIP5K1B, and WDR72 (P<2.1 × 10(-3) to account for multiple testing). Single nucleotide polymorphisms in these loci explained 2.2% of the estimated GFR total variance and 2.9% of its heritability. An intronic variant of BCAS3 was significantly associated with urinary albumin to creatinine ratio. APOL1 single nucleotide polymorphisms were not associated with estimated GFR in a single variant test or haplotype analyses, and the at-risk variants identified in individuals with African ancestry were not detected in DNA sequencing of American Indians. CONCLUSION: This study extends the genetic associations of loci affecting kidney function to American Indians, a population at high risk of kidney disease, and provides additional support for a potential biologic relevance of these loci across ancestries.

Cadmium exposure and incident peripheral arterial disease.

BACKGROUND: Cadmium has been associated with peripheral arterial disease (PAD) in cross-sectional studies, but prospective evidence is lacking. Our goal was to evaluate the association of urine cadmium concentrations with incident PAD in a large population-based cohort. METHODS AND RESULTS: A prospective cohort study was performed with 2864 adult American Indians 45 to 74 years of age from Arizona, Oklahoma, and North and South Dakota who participated in the Strong Heart Study from 1989 to 1991 and were followed through 2 follow-up examination visits in 1993 to 1995 and 1997 to 1999. Participants were free of PAD, defined as an ankle brachial index <0.9 or >1.4 at baseline, and had complete baseline information on urine cadmium, potential confounders, and ankle brachial index determinations in the follow-up examinations. Urine cadmium was measured using inductively coupled plasma mass spectrometry and corrected for urinary dilution by normalization to urine creatinine. Multivariable-adjusted hazard ratios were computed using Cox-proportional hazards models for interval-censored data. A total of 470 cases of incident PAD, defined as an ankle brachial index <0.9 or >1.4, were identified. After adjustment for cardiovascular disease risk factors including smoking status and pack-years, the hazard ratio comparing the 80th to the 20th percentile of urine cadmium concentrations was 1.41 (1.05-1.81). The hazard ratio comparing the highest to the lowest tertile was 1.96 (1.32-2.81). The association persisted after excluding participants with ankle brachial index >1.4 only as well as in subgroups defined by sex and smoking status. CONCLUSIONS: Urine cadmium, a biomarker of long-term cadmium exposure, was independently associated with incident PAD, providing further support for cadmium as a cardiovascular disease risk factor.

Genome-wide linkage analysis of carotid artery lumen diameter: the strong heart family study.

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 3300 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 diameters 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 were 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.

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.

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 Δ(5) desaturase index (Δ(5)-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 Δ(6) desaturase index (Δ(6)-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.

Sex-specific associations of nutrition with hypertension and systolic blood pressure in Alaska Natives findings from the GOCADAN study.

OBJECTIVES: To examine sex-specific associations of nutritional factors with prevalent hypertension (HTN) and systolic blood pressure (SBP) in Alaska Natives. Diet is known to affect SBP, a major risk factor for cardiovascular disease. STUDY DESIGN: Cross-sectional analysis of participants without diabetes in the Genetics of Coronary Artery Disease in Alaska Natives study. METHODS: Macronutrients such as fat, carbohydrate and protein and micronutrients such as sodium were investigated. HTN was defined as SBP≥140 mmHg, diastolic blood pressure≥90 mmHg and/or taking anti-HTN medication. Analyses were stratified by sex and covariates included age, body mass index (BMI), energy intake, smoking and physical activity. RESULTS: Mean age was 42 years for men (n=456) and women (n=602). Men with HTN (n=106) compared to men without HTN consumed a higher proportion of calories from total (p=0.01), saturated (p<0.01) and trans fatty acid (p=0.03) fats. Women with HTN (n=99) compared to women without HTN consumed more total (p=0.03) and monounsaturated (p=0.04) fat, higher protein (p=0.02) and lower total (p<0.01) and simple (p<0.01) carbohydrates. After covariate adjustment, men not on anti-HTN medications (n=407) had significantly higher average SBP with increasing quartiles of trans fatty acid intake (p for linear trend=0.01) and sodium intake (p for linear trend=0.02). For women not on anti-HTN medications (n=528), after covariate adjustment, average SBP decreased with increasing quartiles of omega 3 fatty acid intake (p for linear trend <0.01). CONCLUSIONS: Prospective evaluation of the sex-specific associations of nutritional factors with HTN and SBP on outcomes is needed along with novel interventions to lower the risk of cardiovascular disease.

A QTL for genotype by sex interaction for anthropometric measurements in Alaskan Eskimos (GOCADAN Study) on chromosome 19q12-13.

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 G×S 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 (logarithm of odds (lod) = 3.5), %BF (lod = 1.7), BMI (lod = 2.4), waist/height ratio (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 the 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.

Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study.

The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10(-8)) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10(-8)). The top IBC association for SBP was rs2012318 (P= 6.4 × 10(-6)) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10(-6)) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.

Combined admixture mapping and association analysis identifies a novel blood pressure genetic locus on 5p13: contributions from the CARe consortium.

Admixture mapping based on recently admixed populations is a powerful method to detect disease variants with substantial allele frequency differences in ancestral populations. We performed admixture mapping analysis for systolic blood pressure (SBP) and diastolic blood pressure (DBP), followed by trait-marker association analysis, in 6303 unrelated African-American participants of the Candidate Gene Association Resource (CARe) consortium. We identified five genomic regions (P< 0.001) harboring genetic variants contributing to inter-individual BP variation. In follow-up association analyses, correcting for all tests performed in this study, three loci were significantly associated with SBP and one significantly associated with DBP (P< 10(-5)). Further analyses suggested that six independent single-nucleotide polymorphisms (SNPs) contributed to the phenotypic variation observed in the admixture mapping analysis. These six SNPs were examined for replication in multiple, large, independent studies of African-Americans [Women's Health Initiative (WHI), Maywood, Genetic Epidemiology Network of Arteriopathy (GENOA) and Howard University Family Study (HUFS)] as well as one native African sample (Nigerian study), with a total replication sample size of 11 882. Meta-analysis of the replication set identified a novel variant (rs7726475) on chromosome 5 between the SUB1 and NPR3 genes, as being associated with SBP and DBP (P< 0.0015 for both); in meta-analyses combining the CARe samples with the replication data, we observed P-values of 4.45 × 10(-7) for SBP and 7.52 × 10(-7) for DBP for rs7726475 that were significant after accounting for all the tests performed. Our study highlights that admixture mapping analysis can help identify genetic variants missed by genome-wide association studies because of drastically reduced number of tests in the whole genome.

Comment on "Multidimensional results reporting to participants in genomic studies: getting it right".

Bookman et al. write to correct the impression given in the Commentary by Kohane and Taylor that the recommendations of the National Heart, Lung, and Blood Institute (NHLBI) Working Group "Reporting Genetic Results in Research Studies" included advice to return genetic information to research subjects only in cases where there is a proven or preventative intervention for the identified disorder. In fact, the report does recommend that genetic information be returned to subjects when there is an intervention available, but it does not recommend against giving this kind of information to subjects if there is no available intervention.

Fasting plasma glucose and hemoglobin A1c in identifying and predicting diabetes: the strong heart study.

OBJECTIVE: To compare fasting plasma glucose (FPG) and HbA(1c) in identifying and predicting type 2 diabetes in a population with high rates of diabetes. RESEARCH DESIGN AND METHODS: Diabetes was defined as an FPG level ≥ 126 mg/dL or an HbA(1c) level ≥ 6.5%. Data collected from the baseline and second exams (1989-1995) of the Strong Heart Study were used. RESULTS For cases of diabetes identified by FPG ≥ 126 mg/dL, using HbA(1c) ≥ 6.5% at the initial and 4-year follow-up diabetes screenings (or in identifying incident cases in 4 years) among undiagnosed participants left 46% and 59% of cases of diabetes undetected, respectively, whereas for cases identified by HbA(1c) ≥ 6.5%, using FPG ≥ 126 mg/dL left 11% and 59% unidentified, respectively. Age, waist circumference, urinary albumin-to-creatinine ratio, and baseline FPG and HbA(1c) levels were common significant risk factors for incident diabetes defined by either FPG or HbA(1c); triglyceride levels were significant for diabetes defined by HbA(1c) alone, and blood pressure and sibling history of diabetes were significant for diabetes defined by FPG alone. Using both the baseline FPG and HbA(1c) in diabetes prediction identified more people at risk than using either measure alone. CONCLUSIONS Among undiagnosed participants, using HbA(1c) alone in initial diabetes screening identifies fewer cases of diabetes than FPG, and using either FPG or HbA(1c) alone cannot effectively identify diabetes in a 4-year periodic successive diabetes screening or incident cases of diabetes in 4 years. Using both criteria may identify more people at risk. The proposed models using the commonly available clinical measures can be applied to assessing the risk of incident diabetes using either criterion.

Prevalence of diabetes and impaired fasting glucose in Chinese adults, China National Nutrition and Health Survey, 2002.

INTRODUCTION: As a result of rapid economic development in China, the lifestyles and dietary habits of its people have been changing, and the rates of obesity, diabetes, and other chronic conditions have increased substantially. We report the prevalence of type 2 diabetes and impaired fasting glucose (IFG) and the association between diabetes and overweight and obesity in Chinese adults. We also compare the results with those from the US National Health and Nutrition Examination Survey, 1999-2002. METHODS: Data were from adults aged 20 years or older who participated in the China National Nutrition and Health Survey, 2002 (n = 47,729). Diabetes and IFG were defined by the American Diabetes Association 2009 criteria. We assessed the prevalence of diabetes, IFG, and overweight and obesity by sex, age, region of residence, and ethnicity. RESULTS: The prevalence of diabetes and IFG in Chinese adults was 2.7% and 4.9%, respectively. The prevalence of diabetes increased with age and body mass index. Men and women had a similar prevalence of diabetes, but men had a significantly higher prevalence of IFG. The prevalence of diabetes among Chinese who lived in urban areas was 2 to 3 times higher than the prevalence among those who lived in rural areas (3.9% for urban areas and 6.1% for large cities vs 1.9% for rural areas), and the prevalence of IFG was 1.5 to 2 times higher (6.1% and 8.1% vs 4.2%, respectively). The prevalence of diabetes among Chinese women and young (20-39 y) and middle-aged (40-59 y) adults who lived in large cities was similar to the prevalence of diabetes in the US population. CONCLUSION: The prevalence of diabetes and IFG was much higher in urban than rural areas, particularly in the large cities of China. Prevention must be emphasized among adults to reduce the future social and economic burden of diabetes in China.

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.

Ethical and practical guidelines for reporting genetic research results to study participants: updated guidelines from a National Heart, Lung, and Blood Institute working group.

In January 2009, the National Heart, Lung, and Blood Institute convened a 28-member multidisciplinary Working Group to update the recommendations of a 2004 National Heart, Lung, and Blood Institute Working Group focused on Guidelines to the Return of Genetic Research Results. Changes in the genetic and societal landscape over the intervening 5 years raise multiple questions and challenges. The group noted the complex issues arising from the fact that technological and bioinformatic progress has made it possible to obtain considerable information on individuals that would not have been possible a decade ago. Although unable to reach consensus on a number of issues, the working group produced 5 recommendations. The working group offers 2 recommendations addressing the criteria necessary to determine when genetic results should and may be returned to study participants, respectively. In addition, it suggests that a time limit be established to limit the duration of obligation of investigators to return genetic research results. The group recommends the creation of a central body, or bodies, to provide guidance on when genetic research results are associated with sufficient risk and have established clinical utility to justify their return to study participants. The final recommendation urges investigators to engage the broader community when dealing with identifiable communities to advise them on the return of aggregate and individual research results. Creation of an entity charged to provide guidance to institutional review boards, investigators, research institutions, and research sponsors would provide rigorous review of available data, promote standardization of study policies regarding return of genetic research results, and enable investigators and study participants to clarify and share expectations for the handling of this increasingly valuable information with appropriate respect for the rights and needs of participants.