Last data update: May 20, 2024. (Total: 46824 publications since 2009)
Records 1-14 (of 14 Records) |
Query Trace: Ned RM[original query] |
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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).
Grimsby JL , Porneala BC , Vassy JL , Yang Q , Florez JC , Dupuis J , Liu T , Yesupriya A , Chang MH , Ned RM , Dowling NF , Khoury MJ , Meigs JB . BMC Med Genet 2012 13 30 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 (β = 0.012 HbA1c increase per risk allele, p = 0.04) and MA (β = 0.021, p = 0.005) but not NHB (β = 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. |
Public health action in genomics is now needed beyond newborn screening.
Bowen MS , Kolor K , Dotson WD , Ned RM , Khoury MJ . Public Health Genomics 2012 15 (6) 327-34 For decades, newborn screening was the only public health program in the US focused on reducing morbidity, mortality and disability in people affected by genetic conditions. The landscape has changed, however, as evidence-based recommendations are now available for several other genomic applications that can save lives now in the US. Many more such applications are expected to emerge in the next decade. An action plan, based on evidence, provides the impetus for a new paradigm for public health practice in genomics across the lifespan using established multilevel processes as a guide. These include policy interventions, education, clinical interventions, and surveillance. Applying what we know today in hereditary breast/ovarian cancer, Lynch syndrome and familial hypercholesterolemia has the potential to affect thousands of people in the US population every year. Enhanced partnerships between genetic and nongenetic providers of clinical medicine and public health are needed to overcome the challenges for implementing genomic medicine applications both now and in the future. |
Cascade Screening for Familial Hypercholesterolemia (FH).
Ned RM , Sijbrands EJ . PLoS Curr 2011 3 Rrn1238 Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by abnormally high concentrations of low-density lipoprotein (LDL) cholesterol in the blood, which predisposes affected persons to premature coronary heart disease (CHD) and death. FH is one of the most common inherited disorders and the most common one known to cause premature CHD in people of European descent. The vast majority of people with FH have inherited a single mutation from one parent in either the LDL receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. Despite their greatly elevated risk of coronary heart disease, most individuals with FH remain undiagnosed, untreated, or inadequately treated. Cascade screening is a mechanism for identifying people at risk for a genetic condition by a process of systematic family tracing. The National Institute for Health and Clinical Excellence in the United Kingdom recommends cascade screening of close biological relatives of people with a clinical diagnosis of FH in order to effectively identify additional FH patients. The ultimate goal of this testing is to reduce morbidity and mortality from heart disease in persons with FH through early diagnosis and effective disease management. The goal of this article is to outline the available evidence on the clinical validity and utility of cascade screening for FH, while emphasizing the availability, usefulness, and recommendation for including DNA testing (if the disease-causing mutation has been identified). |
Genetic associations with metabolic syndrome and its quantitative traits by race/ethnicity in the United States.
Vassy JL , Shrader P , Yang Q , Liu T , Yesupriya A , Chang MH , Dowling NF , Ned RM , Dupuis J , Florez JC , Khoury MJ , Meigs JB . Metab Syndr Relat Disord 2011 9 (6) 475-82 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. |
Variants in ABCB1, TGFB1, and XRCC1 genes and susceptibility to viral hepatitis A infection in Mexican Americans.
Zhang L , Yesupriya A , Hu DJ , Chang MH , Dowling NF , Ned RM , Udhayakumar V , Lindegren ML , Khudyakov Y . Hepatology 2011 55 (4) 1008-18 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 assess 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 6779 participants, including 2619 non-Hispanic whites, 2095 non-Hispanic blacks, and 2065 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 (anti-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). CONCLUSIONS: 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. (HEPATOLOGY 2011). |
The ACE I/D polymorphism in US adults: limited evidence of association with hypertension-related traits and sex-specific effects by race/ethnicity.
Ned RM , Yesupriya A , Imperatore G , Smelser DT , Moonesinghe R , Chang MH , Dowling NF . Am J Hypertens 2011 25 (2) 209-15 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.
Chang MH , Valdez R , Ned RM , Liu T , Yang Q , Yesupriya A , Dowling NF , Meigs JB , Bowen MS , Khoury MJ . Diabetes Care 2011 34 (11) 2393-9 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. |
Racial/ethnic variation in the association of lipid-related genetic variants with blood lipids in the US adult population.
Chang MH , Ned RM , Hong Y , Yesupriya A , Yang Q , Liu T , Janssens AC , Dowling NF . Circ Cardiovasc Genet 2011 4 (5) 523-33 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 U.S. 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 U.S. 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 (LDL-C), total cholesterol (TC), triglycerides (TG), TC/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 for each of the three major racial/ethnic groups in the U.S.: non-Hispanic whites (n = 2,296), non-Hispanic blacks (n = 1,699), and Mexican Americans (n = 1,713). 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%). Genetic risk scores were strongly associated with increased lipid levels in each race/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 genetic risk score, was strongly associated with increased blood lipid measures in all major race/ethnic groups in the U.S., which may help in identifying subgroups with a high risk for an unfavorable lipid profile. |
Fecal DNA testing for Colorectal Cancer Screening: the ColoSure™ test.
Ned RM , Melillo S , Marrone M . PLoS Curr 2011 3 RRN1220 Colorectal cancer is the third most common cancer and the second leading cause of cancer-related deaths in the United States. Screening has been shown to be effective in reducing colorectal cancer incidence and mortality. Colonoscopy, sigmoidoscopy, and fecal occult blood tests are all recommended screening tests that have widespread availability. Nevertheless, many people do not receive the evidence-based recommended screening for colorectal cancer. Additional stool-based methods have been developed that offer more options for colorectal cancer screening, including a variety of fecal DNA tests. The only fecal DNA test that is currently available commercially in the United States is ColoSure(TM), which is marketed as a non-invasive test that detects an epigenetic marker (methylated vimentin) associated with colorectal cancer and pre-cancerous adenomas. We examined the published literature on the analytic validity, clinical validity, and clinical utility of ColoSure and we briefly summarized the current colorectal cancer screening guidelines regarding fecal DNA testing. We also addressed the public health implications of the test and contextual issues surrounding the integration of fecal DNA testing into current colorectal cancer screening strategies. The primary goal was to provide a basic overview of ColoSure and identify gaps in knowledge and evidence that affect the recommendation and adoption of the test in colorectal cancer screening strategies. |
Genetic variants associated with fasting blood lipids in the U.S. population: Third National Health and Nutrition Examination Survey.
Chang MH , Yesupriya A , Ned RM , Mueller PW , Dowling NF . BMC Med Genet 2010 11 62 BACKGROUND: The identification of genetic variants related to blood lipid levels within a large, population-based and nationally representative study might lead to a better understanding of the genetic contribution to serum lipid levels in the major race/ethnic groups in the U.S. population. METHODS: Using data from the second phase (1991-1994) of the Third National Health and Nutrition Examination Survey (NHANES III), we examined associations between 22 polymorphisms in 13 candidate genes and four serum lipids: high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TG). Univariate and multivariable linear regression and within-gene haplotype trend regression were used to test for genetic associations assuming an additive mode of inheritance for each of the three major race/ethnic groups in the United States (non-Hispanic white, non-Hispanic black, and Mexican American). RESULTS: Variants within APOE (rs7412, rs429358), PON1 (rs854560), ITGB3 (rs5918), and NOS3 (rs2070744) were found to be associated with one or more blood lipids in at least one race/ethnic group in crude and adjusted analyses. In non-Hispanic whites, no individual polymorphisms were associated with any lipid trait. However, the PON1 A-G haplotype was significantly associated with LDL-C and TC. In non-Hispanic blacks, APOE variant rs7412 and haplotype T-T were strongly associated with LDL-C and TC; whereas, rs5918 of ITGB3 was significantly associated with TG. Several variants and haplotypes of three genes were significantly related to lipids in Mexican Americans: PON1 in relation to HDL-C; APOE and NOS3 in relation to LDL-C; and APOE in relation to TC. CONCLUSIONS: We report the significant associations of blood lipids with variants and haplotypes in APOE, ITGB3, NOS3, and PON1 in the three main race/ethnic groups in the U.S. population using a large, nationally representative and population-based sample survey. Results from our study contribute to a growing body of literature identifying key determinants of plasma lipoprotein concentrations and could provide insight into the biological mechanisms underlying serum lipid and cholesterol concentrations. |
Gene polymorphisms in association with self-reported stroke in US adults.
Fan AZ , Fang J , Yesupriya A , Chang MH , Kilmer G , House M , Hayes D , Ned RM , Dowling NF , Mokdad AH . Appl Clin Genet 2010 3 23-8 PURPOSE: Epidemiologic studies suggest that several gene variants increase the risk of stroke, and population-based studies help provide further evidence. We identified polymorphisms associated with the prevalence of self-reported stroke in US populations using a representative sample. METHODS: Our sample comprised US adults in the Third National Health and Nutrition Examination (NHANES III) DNA bank. We examined nine candidate gene variants within ACE, F2, F5, ITGA2, MTHFR, and NOS3 for associations with self-reported stroke. We used multivariate regression and Cox proportional hazards models to test the association between these variants and history of stroke. RESULTS: In regression models, the rs4646994 variant of ACE (I/I and I/D genotypes) was associated with higher prevalence adjusted prevalence odds ratio [APOR] = 2.66 [1.28, 5.55] and 2.23 [1.30, 3.85], respectively) compared with the D/D genotype. The heterozygous genotype of MTHFR rs1801131 (A/C) was associated with lower prevalence of stroke (APOR = 0.48 [0.25, 0.92]) compared with A/A and C/C genotypes. For rs2070744 of NOS3, both the C/T genotype (APOR = 1.91 [1.12, 3.27]) and C/C genotype (APOR = 3.31 [1.66, 6.60]) were associated with higher prevalence of stroke compared with the T/T genotype. CONCLUSION: Our findings suggest an association between the prevalence of self-reported stroke and polymorphisms in ACE, MTHFR, and NOS3 in a population-based sample. |
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.
Ned RM , Yesupriya A , Imperatore G , Smelser DT , Moonesinghe R , Chang MH , Dowling NF . BMC Med Genet 2010 11 155 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. |
Genetic testing for CYP450 polymorphisms to predict response to clopidogrel: current evidence and test availability. Application: pharmacogenomics.
Ned RM . PLoS Curr 2010 2 The anti-platelet agent clopidogrel bisulfate (sold under the trade name Plavix in the United States) is a widely prescribed medication for the prevention of blood clots in patients with acute coronary syndrome, in those who have suffered other cardiovascular disease-related events such as ischemic stroke, and in patients who are undergoing percutaneous coronary intervention. Response to clopidogrel varies substantially due to genetic and acquired factors. Patients who experience recurrent cardiovascular ischemic or thrombotic events while taking clopidogrel are typically described as non-responsive or resistant. The drug's oxidation is mainly dependent on the cytochrome P450 enzyme 2C19 (CYP2C19). Patients with certain genetic variants in CYP2C19 have been found to have lower levels of the active metabolite, less platelet inhibition, and greater risk of major adverse cardiovascular events such as heart attack, stroke, and death. Testing for CYP2C19 polymorphisms may identify patients who will not respond adequately to the standard clopidogrel regimen and who should, consequently, be given an alternate treatment strategy. This article outlines the evidence concerning pharmacogenetic testing for clopidogrel response, including data on clinical validity and clinical utility, and summarizes the currently available tests marketed for this purpose. |
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.
Yang Q , Liu T , Shrader P , Yesupriya A , Chang MH , Dowling NF , Ned RM , Dupuis J , Florez JC , Khoury MJ , Meigs JB . Diabetes Care 2010 33 (11) 2370-7 OBJECTIVE: To estimate allele frequencies, marginal and combined effects of novel fasting glucose (FG)-associated SNPs on FG levels and on risk of impaired fasting glucose (IFG) among non-Hispanic white, non-Hispanic black and Mexican American. RESEARCH DESIGN AND METHODS: DNA samples from 3024 adult fasting participants in 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-assessed beta-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 the 16 SNPs, was associated with a 0.022 mmol/L (95% confidence interval [CI] 0.009, 0.035), 0.036 mmol/L (95% CI 0.019, 0.052), and 0.033 mmol/L (95% CI 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 (CI 1.07, 5.37), and 2.39 for Mexican American (95% CI 1.37, 4.14) when we compared the highest to 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. |
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