Evaluation of Diverse Health Professionals' Learning Experience in a Continuing Education Activity for Quality Practices in Molecular Genetic Testing.

OBJECTIVE: This study was conducted to evaluate the responses of 3,265 health professionals who took a continuing education (CE) activity during June 2009 - April 2012 for a comprehensive set of good laboratory practice recommendations for molecular genetic testing. DESIGN: Participants completed an evaluation questionnaire as part of the CE activity. Responses were summarized to assess the participants' learning outcomes and commitment to applying the knowledge gained. PARTICIPANTS: Participants included nurses (47%), laboratory professionals (18%), physicians (14%), health educators (4%), public health professionals (2%), office staff (1%), and other health professionals (10%). RESULTS: Only 32% of all participants correctly answered all 12 open-book knowledge-check questions, ranging from 4 to 42% among the different professional groups (P<0.0001). However, over 80% of all participants expressed confidence in describing the practice recommendations, and 75% indicated the recommendations would improve the quality of their practice. Developing health education materials and local practice guidelines represented the common areas in which participants planned to use the knowledge gained (49% and 18% of all participants, respectively). CONCLUSION: Despite perceived self-efficacy in most participants, as high as 68% did not fully use the learning materials provided to answer the knowledge-check questions. These findings suggest the need for improved CE activities that motivate effective learning and address the specific needs of different health professions.

Apolipoprotein E and protection against hepatitis E viral infection in American non-Hispanic blacks.

UNLABELLED: Hepatitis E viral (HEV) infection imposes a heavy health burden worldwide and is common in the United States. Previous investigations of risks addressed environmental and host behavioral/lifestyle factors, but host genetic factors have not been examined. We assessed strength of associations between antibody to HEV (anti-HEV) immunoglobulin G seropositivity indicating past or recent HEV infection and human genetic variants among three major racial/ethnic populations in the United States, involving 2434 non-Hispanic whites, 1919 non-Hispanic blacks, and 1919 Mexican Americans from the Third National Health and Nutrition Examination Survey, 1991-1994. We studied 497 single-nucleotide polymorphisms across 190 genes (particularly those associated with lipid metabolism). The genomic control method was used to adjust for potential population stratification. Non-Hispanic blacks had the lowest seroprevalence of anti-HEV immunoglobulin G (15.3%, 95% confidence interval [CI] 12.3%-19.0%) compared with non-Hispanic whites (22.3%, 95% CI 19.1%-25.7%) and Mexican Americans (21.8%, 95% CI 19.0%-25.3%; P<0.01). Non-Hispanic blacks were the only population that showed association between anti-HEV seropositivity and functional ε3 and ε4 alleles of the apolipoprotein E (APOE) gene, encoding the apolipoprotein E protein that mediates lipoprotein metabolism. Seropositivity was significantly lower in participants carrying APOE ε4 (odds ratio=0.5, 95% CI 0.4-0.7; P=0.00004) and ε3 (odds ratio=0.6, 95% CI 0.4-0.8; P=0.001) compared to those carrying APOE ε2. No significant associations were observed between other single-nucleotide polymorphisms and anti-HEV seropositivity in non-Hispanic blacks or between any single-nucleotide polymorphisms and anti-HEV seropositivity in non-Hispanic whites or Mexican Americans. CONCLUSION: Both APOE ε3 and ε4 are significantly associated with protection against HEV infection in non-Hispanic blacks; additional studies are needed to understand the basis of protection so that preventive services can be targeted to at-risk persons.

Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data.

OBJECTIVE: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease. DESIGN: Mendelian randomisation meta-analysis of 56 epidemiological studies. PARTICIPANTS: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers. MAIN OUTCOME MEASURES: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption. RESULTS: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)). CONCLUSIONS: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.

Trends in laboratory test volumes for Medicare Part B reimbursements, 2000-2010.

CONTEXT: Changes in reimbursements for clinical laboratory testing may help us assess the effect of various variables, such as testing recommendations, market forces, changes in testing technology, and changes in clinical or laboratory practices, and provide information that can influence health care and public health policy decisions. To date, however, there has been no report, to our knowledge, of longitudinal trends in national laboratory test use. OBJECTIVE: To evaluate Medicare Part B-reimbursed volumes of selected laboratory tests per 10,000 enrollees from 2000 through 2010. DESIGN: Laboratory test reimbursement volumes per 10,000 enrollees in Medicare Part B were obtained from the Centers for Medicare & Medicaid Services (Baltimore, Maryland). The ratio of the most recent (2010) reimbursed test volume per 10,000 Medicare enrollees, divided by the oldest data (usually 2000) during this decade, called the volume ratio, was used to measure trends in test reimbursement. Laboratory tests with a reimbursement claim frequency of at least 10 per 10,000 Medicare enrollees in 2010 were selected, provided there was more than a 50% change in test reimbursement volume during the 2000-2010 decade. We combined the reimbursed test volumes for the few tests that were listed under more than one code in the Current Procedural Terminology (American Medical Association, Chicago, Illinois). A 2-sided Poisson regression, adjusted for potential overdispersion, was used to determine P values for the trend; trends were considered significant at P < .05. RESULTS: Tests with the greatest decrease in reimbursement volumes were electrolytes, digoxin, carbamazepine, phenytoin, and lithium, with volume ratios ranging from 0.27 to 0.64 (P < .001). Tests with the greatest increase in reimbursement volumes were meprobamate, opiates, methadone, phencyclidine, amphetamines, cocaine, and vitamin D, with volume ratios ranging from 83 to 1510 (P < .001). CONCLUSIONS: Although reimbursement volumes increased for most of the selected tests, other tests exhibited statistically significant downward trends in annual reimbursement volumes. The observed changes in reimbursement volumes may be explained by disease prevalence and severity, patterns of drug use, clinical or laboratory practices, and testing recommendations and guidelines, among others. These data may be useful to policy makers, health systems researchers, laboratory directors, and industry scientists to understand, address, and anticipate trends in laboratory testing in the Medicare population.

A systematic review of cancer GWAS and candidate gene meta-analyses reveals limited overlap but similar effect sizes.

Candidate gene and genome-wide association studies (GWAS) represent two complementary approaches to uncovering genetic contributions to common diseases. We systematically reviewed the contributions of these approaches to our knowledge of genetic associations with cancer risk by analyzing the data in the Cancer Genome-wide Association and Meta Analyses database (Cancer GAMAdb). The database catalogs studies published since January 1, 2000, by study and cancer type. In all, we found that meta-analyses and pooled analyses of candidate genes reported 349 statistically significant associations and GWAS reported 269, for a total of 577 unique associations. Only 41 (7.1%) associations were reported in both candidate gene meta-analyses and GWAS, usually with similar effect sizes. When considering only noteworthy associations (defined as those with false-positive report probabilities≤0.2) and accounting for indirect overlap, we found 202 associations, with 27 of those appearing in both meta-analyses and GWAS. Our findings suggest that meta-analyses of well-conducted candidate gene studies may continue to add to our understanding of the genetic associations in the post-GWAS era.

Association between immunoglobulin GM and KM genotypes and placental malaria in HIV-1 negative and positive women in western Kenya.

Immunoglobulin (Ig) GM and KM allotypes, genetic markers of γ and κ chains, are associated with humoral immune responsiveness. Previous studies have shown the relationships between GM6-carrying haplotypes and susceptibility to malaria infection in children and adults; however, the role of the genetic markers in placental malaria (PM) infection and PM with HIV co-infection during pregnancy has not been investigated. We examined the relationship between the gene polymorphisms of Ig GM6 and KM allotypes and the risk of PM infection in pregnant women with known HIV status. DNA samples from 728 pregnant women were genotyped for GM6 and KM alleles using polymerase chain reaction-restriction fragment length polymorphism method. Individual GM6 and KM genotypes and the combined GM6 and KM genotypes were assessed in relation to PM in HIV-1 negative and positive women, respectively. There was no significant effect of individual GM6 and KM genotypes on the risk of PM infection in HIV-1 negative and positive women. However, the combination of homozygosity for GM6(+) and KM3 was associated with decreased risk of PM (adjusted OR, 0.25; 95% CI, 0.08-0.8; P = 0.019) in HIV-1 negative women while in HIV-1 positive women the combination of GM6(+/-) with either KM1-3 or KM1 was associated with increased risk of PM infection (adjusted OR, 2.10; 95% CI, 1.18-3.73; P = 0.011). Hardy-Weinberg Equilibrium (HWE) tests further showed an overall significant positive F(is) (indication of deficit in heterozygotes) for GM6 while there was no deviation for KM genotype frequency from HWE in the same population. These findings suggest that the combination of homozygous GM6(+) and KM3 may protect against PM in HIV-1 negative women while the HIV-1 positive women with heterozygous GM6(+/-) combined with KM1-3 or KM1 may be more susceptible to PM infection. The deficit in heterozygotes for GM6 further suggests that GM6 could be under selection likely by malaria infection.

Race-ethnic differences in the association of genetic loci with HbA1c levels and mortality in U.S. adults: the third National Health and Nutrition Examination Survey (NHANES III).

BACKGROUND: Hemoglobin A1c (HbA1c) levels diagnose diabetes, predict mortality and are associated with ten single nucleotide polymorphisms (SNPs) in white individuals. Genetic associations in other race groups are not known. We tested the hypotheses that there is race-ethnic variation in 1) HbA1c-associated risk allele frequencies (RAFs) for SNPs near SPTA1, HFE, ANK1, HK1, ATP11A, FN3K, TMPRSS6, G6PC2, GCK, MTNR1B; 2) association of SNPs with HbA1c and 3) association of SNPs with mortality. METHODS: We studied 3,041 non-diabetic individuals in the NHANES (National Health and Nutrition Examination Survey) III. We stratified the analysis by race/ethnicity (NHW: non-Hispanic white; NHB: non-Hispanic black; MA: Mexican American) to calculate RAF, calculated a genotype score by adding risk SNPs, and tested associations with SNPs and the genotype score using an additive genetic model, with type 1 error = 0.05. RESULTS: RAFs varied widely and at six loci race-ethnic differences in RAF were significant (p < 0.0002), with NHB usually the most divergent. For instance, at ATP11A, the SNP RAF was 54% in NHB, 18% in MA and 14% in NHW (p < .0001). The mean genotype score differed by race-ethnicity (NHW: 10.4, NHB: 11.0, MA: 10.7, p < .0001), and was associated with increase in HbA1c in NHW (ß = 0.012 HbA1c increase per risk allele, p = 0.04) and MA (ß = 0.021, p = 0.005) but not NHB (ß = 0.007, p = 0.39). The genotype score was not associated with mortality in any group (NHW: OR (per risk allele increase in mortality) = 1.07, p = 0.09; NHB: OR = 1.04, p = 0.39; MA: OR = 1.03, p = 0.71). CONCLUSION: At many HbA1c loci in NHANES III there is substantial RAF race-ethnic heterogeneity. The combined impact of common HbA1c-associated variants on HbA1c levels varied by race-ethnicity, but did not influence mortality.

Prospective study of methylenetetrahydrofolate reductase (MTHFR) variant C677T and risk of all-cause and cardiovascular disease mortality among 6000 US adults.

BACKGROUND: The association between blood homocysteine concentration and the risk of cardiovascular disease (CVD) remains controversial, but few studies have examined the association between MTHFR C677T (a proxy for high homocysteine concentration) and death from CVD. OBJECTIVE: The objective was to examine associations of MTHFR C677T, a proxy for high homocysteine concentrations, with CVD mortality and with all-cause mortality in a national representative prospective cohort of the US adult population before the introduction of mandatory folic acid fortification of flour. DESIGN: We used Mendelian randomization to examine the association of MTHFR C677T with cause-specific mortality in 5925 participants by accessing the NHANES III (1991-1994) Linked Mortality File (through 2006). RESULTS: A comparison of homozygotes at baseline showed that individuals with a TT genotype had a 2.2-µmol/L higher homocysteine and a 1.4-ng/mL lower folate concentration, respectively, than did those with a CC genotype. The TT genotype frequency varied from 1.2% (95% CI: 0.7, 2.0) in non-Hispanic blacks and 11.6% (95% CI: 9.6, 14.0) in non-Hispanic whites to 19.4% (95% CI: 16.7, 22.3) in Mexican Americans. After adjustment for ethnic group and other CVD risk factors, the MTHFR C677T TT genotype was associated with significantly lower CVD mortality (HR: 0.69; 95% CI: 0.50, 0. 95) but had no significant effect on all-cause mortality (HR: 0.79; 95% CI: 0.59, 1.05). After stratification by period of follow-up, the inverse association of MTHFR with CVD mortality was significant only in the period after introduction of mandatory folic acid fortification. CONCLUSION: The inverse association of MTHFR with CVD mortality was unexpected and highlights the need for caution in interpretation of Mendelian randomization studies, which, like other observational studies, can be influenced by chance, bias, or confounding.

No interactions between previously associated 2-hour glucose gene variants and physical activity or BMI on 2-hour glucose levels.

Gene-lifestyle interactions have been suggested to contribute to the development of type 2 diabetes. Glucose levels 2 h after a standard 75-g glucose challenge are used to diagnose diabetes and are associated with both genetic and lifestyle factors. However, whether these factors interact to determine 2-h glucose levels is unknown. We meta-analyzed single nucleotide polymorphism (SNP) × BMI and SNP × physical activity (PA) interaction regression models for five SNPs previously associated with 2-h glucose levels from up to 22 studies comprising 54,884 individuals without diabetes. PA levels were dichotomized, with individuals below the first quintile classified as inactive (20%) and the remainder as active (80%). BMI was considered a continuous trait. Inactive individuals had higher 2-h glucose levels than active individuals (ß = 0.22 mmol/L [95% CI 0.13-0.31], P = 1.63 × 10(-6)). All SNPs were associated with 2-h glucose (ß = 0.06-0.12 mmol/allele, P ≤ 1.53 × 10(-7)), but no significant interactions were found with PA (P > 0.18) or BMI (P ≥ 0.04). In this large study of gene-lifestyle interaction, we observed no interactions between genetic and lifestyle factors, both of which were associated with 2-h glucose. It is perhaps unlikely that top loci from genome-wide association studies will exhibit strong subgroup-specific effects, and may not, therefore, make the best candidates for the study of interactions.

Trends in population-based studies of human genetics in infectious diseases.

Pathogen genetics is already a mainstay of public health investigation and control efforts; now advances in technology make it possible to investigate the role of human genetic variation in the epidemiology of infectious diseases. To describe trends in this field, we analyzed articles that were published from 2001 through 2010 and indexed by the HuGE Navigator, a curated online database of PubMed abstracts in human genome epidemiology. We extracted the principal findings from all meta-analyses and genome-wide association studies (GWAS) with an infectious disease-related outcome. Finally, we compared the representation of diseases in HuGE Navigator with their contributions to morbidity worldwide. We identified 3,730 articles on infectious diseases, including 27 meta-analyses and 23 GWAS. The number published each year increased from 148 in 2001 to 543 in 2010 but remained a small fraction (about 7%) of all studies in human genome epidemiology. Most articles were by authors from developed countries, but the percentage by authors from resource-limited countries increased from 9% to 25% during the period studied. The most commonly studied diseases were HIV/AIDS, tuberculosis, hepatitis B infection, hepatitis C infection, sepsis, and malaria. As genomic research methods become more affordable and accessible, population-based research on infectious diseases will be able to examine the role of variation in human as well as pathogen genomes. This approach offers new opportunities for understanding infectious disease susceptibility, severity, treatment, control, and prevention.

Variants in ABCB1, TGFB1, and XRCC1 genes and susceptibility to viral hepatitis A infection in Mexican Americans.

UNLABELLED: Hepatitis A vaccination has dramatically reduced the incidence of hepatitis A virus (HAV) infection, but new infections continue to occur. To identify human genetic variants conferring a risk for HAV infection among the three major racial/ethnic populations in the United States, we assessed associations between 67 genetic variants (single nucleotide polymorphisms [SNPs]) among 31 candidate genes and serologic evidence of prior HAV infection using a population-based, cross-sectional study of 6,779 participants, including 2,619 non-Hispanic whites, 2,095 non-Hispanic blacks, and 2,065 Mexican Americans enrolled in phase 2 (1991-1994) of the Third National Health and Nutrition Examination Survey. Among the three racial/ethnic groups, the number (weighted frequency) of seropositivity for antibody to HAV was 958 (24.9%), 802 (39.2%), and 1540 (71.5%), respectively. No significant associations with any of the 67 SNPs were observed among non-Hispanic whites or non-Hispanic blacks. In contrast, among Mexican Americans, variants in two genes were found to be associated with an increased risk of HAV infection: TGFB1 rs1800469 (adjusted odds ratio [OR], 1.38; 95% confidence interval [CI], 1.14-1.68; P value adjusted for false discovery rate [FDR-P] = 0.017) and XRCC1 rs1799782 (OR, 1.57; 95% CI, 1.27-1.94; FDR-P = 0.0007). A decreased risk was found with ABCB1 rs1045642 (OR, 0.79; 95% CI, 0.71-0.89; FDR-P = 0.0007). CONCLUSION: Genetic variants in ABCB1, TGFB1, and XRCC1 appear to be associated with susceptibility to HAV infection among Mexican Americans. Replication studies involving larger population samples are warranted.

The ACE I/D polymorphism in US adults: limited evidence of association with hypertension-related traits and sex-specific effects by race/ethnicity.

BACKGROUND: The insertion/deletion (I/D) variant (rs4646994) of the angiotensin I-converting enzyme (ACE) gene is one of the most studied polymorphisms in relation to blood pressure and essential hypertension in humans. The evidence to date, however, on an association of this variant with blood pressure-related outcomes has been inconclusive. METHODS: We examined 5,561 participants of the Third National Health and Nutrition Examination Survey (NHANES III), a population-based and nationally representative survey of the United States, who were ≥20 years of age and who self-identified as non-Hispanic white, non-Hispanic black, or Mexican American. Within each race/ethnicity, we assessed genetic associations of the I/D variant with systolic blood pressure (SBP), diastolic blood pressure (DBP), and hypertension, as well as genotype-sex interactions, in four genetic models (additive, dominant, recessive, and codominant). RESULTS: The frequency of the I/D variant differed significantly by race/ethnicity (P = 0.001). Among non-Hispanic blacks, the D allele was significantly associated (P < 0.05) with increased SBP in additive and dominant covariate-adjusted models and was also associated with increased DBP in dominant models when participants taking ACE inhibitors were excluded from the analyses. No other significant associations were observed in any race/ethnic group. Significant genotype-sex interactions were detected among Mexican Americans, for whom positive associations with SBP and hypertension were seen among females, but not males. CONCLUSIONS: This study gives limited support for association of the ACE I/D variant with blood pressure and for sex-specific effects among particular race/ethnic groups, though we cannot rule out the role of genetic or environmental interactions.

Influence of familial risk on diabetes risk-reducing behaviors among U.S. adults without diabetes.

OBJECTIVE: To test the association of family history of diabetes with the adoption of diabetes risk-reducing behaviors and whether this association is strengthened by physician advice or commonly known factors associated with diabetes risk. RESEARCH DESIGN AND METHODS: We used cross-sectional data from the 2005-2008 National Health and Nutrition Examination Survey (NHANES) to examine the effects of family history of diabetes on the adoption of selected risk-reducing behaviors in 8,598 adults (aged ≥20 years) without diabetes. We used multiple logistic regression to model three risk reduction behaviors (controlling or losing weight, increasing physical activity, and reducing the amount of dietary fat or calories) with family history of diabetes. RESULTS: Overall, 36.2% of U.S. adults without diabetes had a family history of diabetes. Among them, ~39.8% reported receiving advice from a physician during the past year regarding any of the three selected behaviors compared with 29.2% of participants with no family history (P < 0.01). In univariate analysis, adults with a family history of diabetes were more likely to perform these risk-reducing behaviors compared with adults without a family history. Physician advice was strongly associated with each of the behavioral changes (P < 0.01), and this did not differ by family history of diabetes. CONCLUSIONS: Familial risk for diabetes and physician advice both independently influence the adoption of diabetes risk-reducing behaviors. However, fewer than half of participants with familial risk reported receiving physician advice for adopting these behaviors.

Genetic associations with metabolic syndrome and its quantitative traits by race/ethnicity in the United States.

BACKGROUND: Elevated insulin resistance (IR), triglycerides (TG), body mass index (BMI), and waist circumference (WC) are features of the metabolic syndrome. Although several single-nucleotide polymorphisms (SNPs) associated with these traits have been reported, no study has reported their risk allele frequencies and effect sizes among the major U.S. race/ethnic groups in a nationally representative sample. METHODS: We compared the risk allele frequencies of eight SNPs previously associated with IR, TG, BMI, or WC by race/ethnicity (non-Hispanic white, non-Hispanic black, Mexican American) in 3,030 participants of the National Health and Nutrition Examination Study III (NHANES III). In regression models predicting IR, TG, BMI, WC, and metabolic syndrome, we tested whether the SNP effect sizes on these traits varied by race/ethnicity. RESULTS: Risk allele frequencies varied by race/ethnicity for all eight loci (P<0.0001). The directionality of effects of the variants on IR, TG, WC, and BMI was generally consistent with previous observations and did not differ by race/ethnicity (P>0.001), although our study had low power for this test. No SNP predicted metabolic syndrome in any of the three groups (P>0.05). CONCLUSIONS: The significance of racial/ethnic differences in risk allele frequencies merits consideration if genetic discoveries are to have clinical and public health applicability.

Racial/ethnic variation in the association of lipid-related genetic variants with blood lipids in the US adult population.

BACKGROUND: Genome-wide association studies (GWAS) have identified a number of single-nucleotide polymorphisms (SNPs) associated with serum lipid level in populations of European descent. The individual and the cumulative effect of these SNPs on blood lipids are largely unclear for the US population. METHODS AND RESULTS: Using data from the second phase (1991-1994) of the Third National Health and Nutrition Examination Survey (NHANES III), a nationally representative survey of the US population, we examined associations of 57 GWAS-identified or well-established lipid-related genetic loci with plasma concentrations of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, total cholesterol, triglycerides, total cholesterol/HDL-C ratio, and non-HDL-C. We used multivariable linear regression to examine single SNP associations and the cumulative effect of multiple SNPs (using a genetic risk score [GRS]) on blood lipid levels. Analyses were conducted in adults from each of the 3 major racial/ethnic groups in the United States: non-Hispanic whites (n=2296), non-Hispanic blacks (n=1699), and Mexican Americans (n=1713). Allele frequencies for all SNPs varied significantly by race/ethnicity, except rs3764261 in CETP. Individual SNPs had very small effects on lipid levels, effects that were generally consistent in direction across racial/ethnic groups. More GWAS-validated SNPs were replicated in non-Hispanic whites (<67%) than in non-Hispanic blacks (<44%) or Mexican Americans (<44%). GRSs were strongly associated with increased lipid levels in each racial/ethnic group. The combination of all SNPs into a weighted GRS explained no more than 11% of the total variance in blood lipid levels. CONCLUSIONS: Our findings show that the combined association of SNPs, based on a GRS, was strongly associated with increased blood lipid measures in all major race/ethnic groups in the United States, which may help in identifying subgroups with a high risk for an unfavorable lipid profile.

GWAS Integrator: a bioinformatics tool to explore human genetic associations reported in published genome-wide association studies.

Genome-wide association studies (GWAS) have successfully identified numerous genetic loci that are associated with phenotypic traits and diseases. GWAS Integrator is a bioinformatics tool that integrates information on these associations from the National Human Genome Research institute (NHGRI) Catalog, SNAP (SNP Annotation and Proxy Search), and the Human Genome Epidemiology (HuGE) Navigator literature database. This tool includes robust search and data mining functionalities that can be used to quickly identify relevant associations from GWAS, as well as proxy single-nucleotide polymorphisms (SNPs) and potential candidate genes. Query-based University of California Santa Cruz (UCSC) Genome Browser custom tracks are generated dynamically on the basis of users' selected GWAS hits or candidate genes from HuGE Navigator literature database (http://www.hugenavigator.net/HuGENavigator/gWAHitStartPage.do). The GWAS Integrator may help enhance inference on potential genetic associations identified from GWAS studies.

Inflammation gene variants and susceptibility to albuminuria in the U.S. population: analysis in the Third National Health and Nutrition Examination Survey (NHANES III), 1991-1994.

BACKGROUND: Albuminuria, a common marker of kidney damage, serves as an important predictive factor for the progression of kidney disease and for the development of cardiovascular disease. While the underlying etiology is unclear, chronic, low-grade inflammation is a suspected key factor. Genetic variants within genes involved in inflammatory processes may, therefore, contribute to the development of albuminuria. METHODS: We evaluated 60 polymorphisms within 27 inflammatory response genes in participants from the second phase (1991-1994) of the Third National Health and Nutrition Examination Survey (NHANES III), a population-based and nationally representative survey of the United States. Albuminuria was evaluated as logarithm-transformed albumin-to-creatinine ratio (ACR), as ACR ≥ 30 mg/g, and as ACR above sex-specific thresholds. Multivariable linear regression and haplotype trend analyses were conducted to test for genetic associations in 5321 participants aged 20 years or older. Differences in allele and genotype distributions among non-Hispanic whites, non-Hispanic blacks, and Mexican Americans were tested in additive and codominant genetic models. RESULTS: Variants in several genes were found to be marginally associated (uncorrected P value < 0.05) with log(ACR) in at least one race/ethnic group, but none remained significant in crude or fully-adjusted models when correcting for the false-discovery rate (FDR). In analyses of sex-specific albuminuria, IL1B (rs1143623) among Mexican Americans remained significantly associated with increased odds, while IL1B (rs1143623), CRP (rs1800947) and NOS3 (rs2070744) were significantly associated with ACR ≥ 30 mg/g in this population (additive models, FDR-P < 0.05). In contrast, no variants were found to be associated with albuminuria among non-Hispanic blacks after adjustment for multiple testing. The only variant among non-Hispanic whites significantly associated with any outcome was TNF rs1800750, which failed the test for Hardy-Weinberg proportions in this population. Haplotypes within MBL2, CRP, ADRB2, IL4R, NOS3, and VDR were significantly associated (FDR-P < 0.05) with log(ACR) or albuminuria in at least one race/ethnic group. CONCLUSIONS: Our findings suggest a small role for genetic variation within inflammation-related genes to the susceptibility to albuminuria. Additional studies are needed to further assess whether genetic variation in these, and untested, inflammation genes alter the susceptibility to kidney damage.

Racial/ethnic differences in association of fasting glucose-associated genomic loci with fasting glucose, HOMA-B, and impaired fasting glucose in the U.S. adult population.

OBJECTIVE: To estimate allele frequencies and the marginal and combined effects of novel fasting glucose (FG)-associated single nucleotide polymorphisms (SNPs) on FG levels and on risk of impaired FG (IFG) among non-Hispanic white, non-Hispanic black, and Mexican Americans. RESEARCH DESIGN AND METHODS: DNA samples from 3,024 adult fasting participants in the National Health and Nutrition Examination Survey (NHANES) III (1991-1994) were genotyped for 16 novel FG-associated SNPs in multiple genes. We determined the allele frequencies and influence of these SNPs alone and in a weighted genetic risk score on FG, homeostasis model assessment of ß-cell function (HOMA-B), and IFG by race/ethnicity, while adjusting for age and sex. RESULTS: All allele frequencies varied significantly by race/ethnicity. A weighted genetic risk score, based on 16 SNPs, was associated with a 0.022 mmol/l (95% CI 0.009-0.035), 0.036 mmol/l (0.019-0.052), and 0.033 mmol/l (0.020-0.046) increase in FG levels per risk allele among non-Hispanic whites, non-Hispanic blacks, and Mexican Americans, respectively. Adjusted odds ratios for IFG were 1.78 for non-Hispanic whites (95% CI 1.00-3.17), 2.40 for non-Hispanic blacks (1.07-5.37), and 2.39 for Mexican Americans (1.37-4.14) when we compared the highest with the lowest quintiles of genetic risk score (P=0.365 for testing heterogeneity of effect across race/ethnicity). CONCLUSIONS: We conclude that allele frequencies of 16 novel FG-associated SNPs vary significantly by race/ethnicity, but the influence of these SNPs on FG levels, HOMA-B, and IFG were generally consistent across all racial/ethnic groups.