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1.
Am J Hum Genet ; 105(4): 706-718, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31564435

RESUMO

Hemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in individuals with diabetes. However, nonglycemic determinants, including genetic variation, may influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics, and 407 East Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-Americans, HK1 in Europeans and Hispanics, FN3K and/or FN3KRP in Europeans, and G6PD in African-Americans and Hispanics) and we identified an African-ancestry-specific low-frequency variant (rs1039215 in HBG2 and HBE1, minor allele frequency (MAF) = 0.03). The most associated G6PD variant (rs1050828-T, p.Val98Met, MAF = 12% in African-Americans, MAF = 2% in Hispanics) lowered HbA1c (-0.88% in hemizygous males, -0.34% in heterozygous females) and explained 23% of HbA1c variance in African-Americans and 4% in Hispanics. Additionally, we identified a rare distinct G6PD coding variant (rs76723693, p.Leu353Pro, MAF = 0.5%; -0.98% in hemizygous males, -0.46% in heterozygous females) and detected significant association with HbA1c when aggregating rare missense variants in G6PD. We observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 (G6PD) in the two largest TOPMed African American cohorts, and we replicated the rs76723693 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis.

2.
Mol Genet Genomic Med ; 7(10): e00788, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31407531

RESUMO

BACKGROUND: Left ventricular (LV) hypertrophy affects up to 43% of African Americans (AAs). Antihypertensive treatment reduces LV mass (LVM). However, interindividual variation in LV traits in response to antihypertensive treatments exists. We hypothesized that genetic variants may modify the association of antihypertensive treatment class with LV traits measured by echocardiography. METHODS: We evaluated the main effects of the three most common antihypertensive treatments for AAs as well as the single nucleotide polymorphism (SNP)-by-drug interaction on LVM and relative wall thickness (RWT) in 2,068 participants across five community-based cohorts. Treatments included thiazide diuretics (TDs), angiotensin converting enzyme inhibitors (ACE-Is), and dihydropyridine calcium channel blockers (dCCBs) and were compared in a pairwise manner. We performed fixed effects inverse variance weighted meta-analyses of main effects of drugs and 2.5 million SNP-by-drug interaction estimates. RESULTS: We observed that dCCBs versus TDs were associated with higher LVM after adjusting for covariates (p = 0.001). We report three SNPs at a single locus on chromosome 20 that modified the association between RWT and treatment when comparing dCCBs to ACE-Is with consistent effects across cohorts (smallest p = 4.7 × 10-8 , minor allele frequency range 0.09-0.12). This locus has been linked to LV hypertrophy in a previous study. A marginally significant locus in BICD1 (rs326641) was validated in an external population. CONCLUSIONS: Our study identified one locus having genome-wide significant SNP-by-drug interaction effect on RWT among dCCB users in comparison to ACE-I users. Upon additional validation in future studies, our findings can enhance the precision of medical approaches in hypertension treatment.

3.
Hum Mol Genet ; 2018 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-30307499

RESUMO

E-selectin mediates the rolling of circulating leukocytes during inflammatory processes. Previous genome-wide association studies (GWAS) in European and Asian individuals have identified the ABO locus associated with E-selectin levels. Using Trans-Omics for Precision Medicine (TOPMed) whole-genome sequencing (WGS) data in 2,249 African Americans (AAs) from the Jackson Heart Study (JHS), we examined genome-wide associations with soluble E-selectin levels. In addition to replicating known signals at ABO, we identified a novel association of a common loss-of-function, missense variant in FUT6 (rs17855739,p.Glu274Lys, p=9.02 x 10-24) with higher soluble E-selectin levels. This variant is considerably more common in populations of African-ancestry compared to non-African ancestry populations. We replicated the association of FUT6 p.Glu274Lys with higher soluble E-selectin in an independent population of 748 AAs from the Women's Health Initiative and identified an additional pleiotropic association with vitamin B12 levels. Despite the broad role of both selectins and fucosyltransferases in various inflammatory, immune and cancer-related processes, we were unable to identify any additional disease associations of the FUT6 p.Glu274Lys variant in an EMR-based phenome-wide association scan of over 9,000 African Americans.

4.
PLoS One ; 13(8): e0203213, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30169531

RESUMO

BACKGROUND: In the Atherosclerosis Risk in Communities (ARIC) Study and Jackson Heart Study (JHS) cohorts, serum potassium (K) is an independent predictor of diabetes risk, particularly among African-American participants. Experimental studies show that serum K levels affects insulin secretion. The KCNJ11 gene encodes for a K channel that regulates insulin secretion and whose function is affected by serum K levels. Variants in KCNJ11 are associated with increased diabetes risk. We hypothesized that there could be a gene-by-environment interaction between KCNJ11 variation and serum K on diabetes risk. METHODS: Evaluating a combined cohort of ARIC and JHS participants, we sought to determine if KCNJ11 variants are risk factors for diabetes; and if KCNJ11 variants modify the association between serum K and diabetes risk. Among participants without diabetes at baseline, we performed multivariable logistic regression to determine the effect of serum K, KCNJ11 variants, and their interactions on the odds of incident diabetes mellitus over 8-9 years in the entire cohort and by race. RESULTS: Of 11,812 participants, 3220 (27%) participants developed diabetes. 48% and 47% had 1 or 2 diabetes risk alleles of rs5215 and rs5219, respectively. Caucasians had higher proportions of these risk alleles compared to African Americans (60% vs 17% for rs5215 and 60% vs 13% for rs5219, p<0.01). Serum K was a significant independent predictor of incident diabetes. Neither rs5215 nor rs5219 was associated with incident diabetes. In multivariable models, we found no statistically significant interactions between race and either rs5215 or rs5219 (P-values 0.493 and 0.496, respectively); nor between serum K and either rs5215 or rs5219 on odds of incident diabetes (P-values 0.534 and 0.687, respectively). CONCLUSION: In this cohort, rs5215 and rs5219 of KCNJ11 were not significant predictors of incident diabetes nor effect modifiers of the association between serum K and incident diabetes.

5.
Cardiovasc Diabetol ; 17(1): 67, 2018 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-29751802

RESUMO

BACKGROUND: Coronary artery calcified plaque (CAC) is strongly predictive of cardiovascular disease (CVD) events and mortality, both in general populations and individuals with type 2 diabetes at high risk for CVD. CAC is typically reported as an Agatston score, which is weighted for increased plaque density. However, the role of CAC density in CVD risk prediction, independently and with CAC volume, remains unclear. METHODS: We examined the role of CAC density in individuals with type 2 diabetes from the family-based Diabetes Heart Study and the African American-Diabetes Heart Study. CAC density was calculated as mass divided by volume, and associations with incident all-cause and CVD mortality [median follow-up 10.2 years European Americans (n = 902, n = 286 deceased), 5.2 years African Americans (n = 552, n = 93 deceased)] were examined using Cox proportional hazards models, independently and in models adjusted for CAC volume. RESULTS: In European Americans, CAC density, like Agatston score and volume, was consistently associated with increased risk of all-cause and CVD mortality (p ≤ 0.002) in models adjusted for age, sex, statin use, total cholesterol, HDL, systolic blood pressure, high blood pressure medication use, and current smoking. However, these associations were no longer significant when models were additionally adjusted for CAC volume. CAC density was not significantly associated with mortality, either alone or adjusted for CAC volume, in African Americans. CONCLUSIONS: CAC density is not associated with mortality independent from CAC volume in European Americans and African Americans with type 2 diabetes.

7.
PLoS Genet ; 14(3): e1007293, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29590102

RESUMO

Co-inheritance of α-thalassemia has a significant protective effect on the severity of complications of sickle cell disease (SCD), including stroke. However, little information exists on the association and interactions for the common African ancestral α-thalassemia mutation (-α3.7 deletion) and ß-globin traits (HbS trait [SCT] and HbC trait) on important clinical phenotypes such as red blood cell parameters, anemia, and chronic kidney disease (CKD). In a community-based cohort of 2,916 African Americans from the Jackson Heart Study, we confirmed the expected associations between SCT, HbC trait, and the -α3.7 deletion with lower mean corpuscular volume/mean corpuscular hemoglobin and higher red blood cell count and red cell distribution width. In addition to the recently recognized association of SCT with lower estimated glomerular filtration rate and glycated hemoglobin (HbA1c), we observed a novel association of the -α3.7 deletion with higher HbA1c levels. Co-inheritance of each additional copy of the -α3.7 deletion significantly lowered the risk of anemia and chronic kidney disease among individuals with SCT (P-interaction = 0.031 and 0.019, respectively). Furthermore, co-inheritance of a novel α-globin regulatory variant was associated with normalization of red cell parameters in individuals with the -α3.7 deletion and significantly negated the protective effect of α-thalassemia on stroke in 1,139 patients with sickle cell anemia from the Cooperative Study of Sickle Cell Disease (CSSCD) (P-interaction = 0.0049). Functional assays determined that rs11865131, located in the major alpha-globin enhancer MCS-R2, was the most likely causal variant. These findings suggest that common α- and ß-globin variants interact to influence hematologic and clinical phenotypes in African Americans, with potential implications for risk-stratification and counseling of individuals with SCD and SCT.


Assuntos
Anemia Falciforme/genética , Hemoglobina Falciforme/genética , Traço Falciforme , alfa-Globinas/genética , Adulto , Afro-Americanos , Anemia Falciforme/sangue , Anemia Falciforme/fisiopatologia , Estudos de Coortes , Variações do Número de Cópias de DNA , Eritrócitos Anormais , Taxa de Filtração Glomerular , Hemoglobina A Glicada/metabolismo , Humanos , Fenótipo , Adulto Jovem , Talassemia alfa/genética
8.
J Hum Genet ; 63(3): 327-337, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29321517

RESUMO

Homocysteine (Hcy) is a heritable biomarker for CVD, peripheral artery disease, stroke, and dementia. Little is known about genetic associations with Hcy in individuals of African ancestry. We performed a genome-wide association study for Hcy in 4927 AAs from the Jackson Heart Study (JHS), the Multi-Ethnic Study of Atherosclerosis (MESA), and the Coronary Artery Risk in Young Adults (CARDIA) study. Analyses were stratified by sex and results were meta-analyzed within and across sex. In the sex-combined meta-analysis, we observed genome-wide significant evidence (p < 5.0 × 10-8) for the NOX4 locus (lead variant rs2289125, ß = -0.15, p = 5.3 × 1011). While the NOX4 locus was previously reported as associated with Hcy in European-American populations, rs2289125 remained genome-wide significant when conditioned on the previously reported lead variants. Previously reported genome-wide significant associations at NOX4, MTR, CBS, and MMACHC were also nominally (p < 0.050) replicated in AAs. Associations at the CPS1 locus, previously reported in females only, also was replicated specifically in females in this analysis, supporting sex-specific effects for this locus. These results suggest that there may be a combination of cross-population and population-specific genetic effects, as well as differences in genetic effects between males and females, in the regulation of Hcy levels.


Assuntos
Afro-Americanos/genética , Aterosclerose/sangue , Aterosclerose/genética , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/genética , Estudo de Associação Genômica Ampla , Homocisteína/sangue , Adulto , Alelos , Aterosclerose/epidemiologia , Doença da Artéria Coronariana/epidemiologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Mississippi/epidemiologia , Polimorfismo de Nucleotídeo Único , Vigilância da População , Locos de Características Quantitativas , Característica Quantitativa Herdável , Adulto Jovem
9.
Genet Epidemiol ; 42(3): 288-302, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29226381

RESUMO

Genetic association studies in admixed populations allow us to gain deeper understanding of the genetic architecture of human diseases and traits. However, population stratification, complicated linkage disequilibrium (LD) patterns, and the complex interplay of allelic and ancestry effects on phenotypic traits pose challenges in such analyses. These issues may lead to detecting spurious associations and/or result in reduced statistical power. Fortunately, if handled appropriately, these same challenges provide unique opportunities for gene mapping. To address these challenges and to take these opportunities, we propose a robust and powerful two-step testing procedure Local Ancestry Adjusted Allelic (LAAA) association. In the first step, LAAA robustly captures associations due to allelic effect, ancestry effect, and interaction effect, allowing detection of effect heterogeneity across ancestral populations. In the second step, LAAA identifies the source of association, namely allelic, ancestry, or the combination. By jointly modeling allele, local ancestry, and ancestry-specific allelic effects, LAAA is highly powerful in capturing the presence of interaction between ancestry and allele effect. We evaluated the validity and statistical power of LAAA through simulations over a broad spectrum of scenarios. We further illustrated its usefulness by application to the Candidate Gene Association Resource (CARe) African American participants for association with hemoglobin levels. We were able to replicate independent groups' previously identified loci that would have been missed in CARe without joint testing. Moreover, the loci, for which LAAA detected potential effect heterogeneity, were replicated among African Americans from the Women's Health Initiative study. LAAA is freely available at https://yunliweb.its.unc.edu/LAAA.


Assuntos
Afro-Americanos/genética , Alelos , Grupo com Ancestrais do Continente Europeu/genética , Pool Gênico , Estudo de Associação Genômica Ampla/métodos , Simulação por Computador , Humanos , Desequilíbrio de Ligação , Modelos Genéticos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Estatística como Assunto , Fatores de Tempo
10.
Arterioscler Thromb Vasc Biol ; 37(11): 2220-2227, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28912365

RESUMO

OBJECTIVE: Plasma levels of the fibrinogen degradation product D-dimer are higher among African Americans (AAs) compared with those of European ancestry and higher among women compared with men. Among AAs, little is known of the genetic architecture of D-dimer or the relationship of D-dimer to incident cardiovascular disease. APPROACH AND RESULTS: We measured baseline D-dimer in 4163 AAs aged 21 to 93 years from the prospective JHS (Jackson Heart Study) cohort and assessed association with incident cardiovascular disease events. In participants with whole genome sequencing data (n=2980), we evaluated common and rare genetic variants for association with D-dimer. Each standard deviation higher baseline D-dimer was associated with a 20% to 30% increased hazard for incident coronary heart disease, stroke, and all-cause mortality. Genetic variation near F3 was associated with higher D-dimer (rs2022030, ß=0.284, P=3.24×10-11). The rs2022030 effect size was nearly 3× larger among women (ß=0.373, P=9.06×10-13) than among men (ß=0.135, P=0.06; P interaction =0.009). The sex by rs2022030 interaction was replicated in an independent sample of 10 808 multiethnic men and women (P interaction =0.001). Finally, the African ancestral sickle cell variant (HBB rs334) was significantly associated with higher D-dimer in JHS (ß=0.507, P=1.41×10-14), and this association was successfully replicated in 1933 AAs (P=2.3×10-5). CONCLUSIONS: These results highlight D-dimer as an important predictor of cardiovascular disease risk in AAs and suggest that sex-specific and African ancestral genetic effects of the F3 and HBB loci contribute to the higher levels of D-dimer among women and AAs.


Assuntos
Afro-Americanos/genética , Doenças Cardiovasculares/genética , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Hemoglobinas Anormais/genética , Traço Falciforme/genética , Tromboplastina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etnologia , Doenças Cardiovasculares/mortalidade , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Epidemiologia Molecular , Fenótipo , Prognóstico , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores Sexuais , Traço Falciforme/sangue , Traço Falciforme/etnologia , Traço Falciforme/mortalidade , Fatores de Tempo , Estados Unidos/epidemiologia , Adulto Jovem
11.
Atherosclerosis ; 266: 41-47, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28950166

RESUMO

BACKGROUND AND AIMS: In European descent populations, shorter leukocyte telomere length (LTL) has been associated with subclinical atherosclerosis, cardiovascular disease (CVD), and mortality, while longer LTL has been associated with greater left ventricular hypertrophy. We evaluated the relationship of LTL with subclinical cardiovascular disease indices and incident clinical events and mortality in African Americans (AAs). METHODS: Analyses were restricted to 2518 participants of the Jackson Heart Study (JHS) with LTL measured by Southern blot in baseline blood samples. RESULTS: Adjusting for established CVD risk factors, longer LTL was significantly associated with lower prevalence of coronary artery calcification (CAC) (odds ratio (OR) = 0.810) per 1 kb increase in LTL; (95% confidence interval [CI] 0.656, 0.9998), p=0.0498). Longer LTL was also associated with higher ankle brachial index (ABI) (ß = 0.023; (95% CI 0.004, 0.042), p=0.017) when comparing the highest to the lowest LTL quartile. There were no significant associations between LTL and abdominal aortic calcification, carotid intima-media thickness, or left ventricular mass. After a median follow-up of 9 years, longer LTL was associated with lower risk of incident ischemic stroke (hazard ratio (HR) 0.69 (95% CI 0.48, 0.99), p=0.044) and total mortality (HR 0.81 (95% CI 0.67, 0.97), p=0.026) in age and sex adjusted models, but these associations were no longer significant in fully adjusted models. CONCLUSIONS: Among a community-based cohort of AAs, longer LTL was nominally associated with lower odds of CAC and increased ABI, indicative of decreased prevalence of subclinical atherosclerosis and peripheral arterial disease. These findings do not offer strong support for LTL as an independent biomarker of CVD risk in AAs.


Assuntos
Afro-Americanos/genética , Doenças Cardiovasculares/etnologia , Doenças Cardiovasculares/genética , Leucócitos/química , Homeostase do Telômero , Telômero/genética , Idoso , Doenças Assintomáticas , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/mortalidade , Feminino , Marcadores Genéticos , Humanos , Incidência , Modelos Lineares , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Mississippi/epidemiologia , Razão de Chances , Prevalência , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco
12.
Heart Rhythm ; 14(11): 1675-1684, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28610988

RESUMO

BACKGROUND: Although time-domain measures of heart rate variability (HRV) are used to estimate cardiac autonomic tone and disease risk in multiethnic populations, the genetic epidemiology of HRV in Hispanics/Latinos has not been characterized. OBJECTIVE: The purpose of this study was to conduct a genome-wide association study of heart rate (HR) and its variability in the Hispanic Community Health Study/Study of Latinos, Multi-Ethnic Study of Atherosclerosis, and Women's Health Initiative Hispanic SNP-Health Association Resource project (n = 13,767). METHODS: We estimated HR (bpm), standard deviation of normal-to-normal interbeat intervals (SDNN, ms), and root mean squared difference in successive, normal-to-normal interbeat intervals (RMSSD, ms) from resting, standard 12-lead ECGs. We estimated associations between each phenotype and 17 million genotyped or imputed single nucleotide polymorphisms (SNPs), accounting for relatedness and adjusting for age, sex, study site, and ancestry. Cohort-specific estimates were combined using fixed-effects, inverse-variance meta-analysis. We investigated replication for select SNPs exceeding genome-wide (P <5 × 10-8) or suggestive (P <10-6) significance thresholds. RESULTS: Two genome-wide significant SNPs replicated in a European ancestry cohort, 1 one for RMSSD (rs4963772; chromosome 12) and another for SDNN (rs12982903; chromosome 19). A suggestive SNP for HR (rs236352; chromosome 6) replicated in an African-American cohort. Functional annotation of replicated SNPs in cardiac and neuronal tissues identified potentially causal variants and mechanisms. CONCLUSION: This first genome-wide association study of HRV and HR in Hispanics/Latinos underscores the potential for even modestly sized samples of non-European ancestry to inform the genetic epidemiology of complex traits.


Assuntos
Afro-Americanos , Arritmias Cardíacas/genética , Sistema Nervoso Autônomo/fisiopatologia , Estudo de Associação Genômica Ampla/métodos , Frequência Cardíaca/genética , Hispano-Americanos , Polimorfismo de Nucleotídeo Único , Arritmias Cardíacas/etnologia , Eletrocardiografia , Genótipo , Humanos , Fenótipo , Estados Unidos/epidemiologia
13.
Hum Mol Genet ; 26(10): 1966-1978, 2017 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-28334935

RESUMO

Genetic variants contribute to normal variation of iron-related traits and may also cause clinical syndromes of iron deficiency or excess. Iron overload and deficiency can adversely affect human health. For example, elevated iron storage is associated with increased diabetes risk, although mechanisms are still being investigated. We conducted the first genome-wide association study of serum iron, total iron binding capacity (TIBC), transferrin saturation, and ferritin in a Hispanic/Latino cohort, the Hispanic Community Health Study/Study of Latinos (>12 000 participants) and also assessed the generalization of previously known loci to this population. We then evaluated whether iron-associated variants were associated with diabetes and glycemic traits. We found evidence for a novel association between TIBC and a variant near the gene for protein phosphatase 1, regulatory subunit 3B (PPP1R3B; rs4841132, ß = -0.116, P = 7.44 × 10-8). The effect strengthened when iron deficient individuals were excluded (ß = -0.121, P = 4.78 × 10-9). Ten of sixteen variants previously associated with iron traits generalized to HCHS/SOL, including variants at the transferrin (TF), hemochromatosis (HFE), fatty acid desaturase 2 (FADS2)/myelin regulatory factor (MYRF), transmembrane protease, serine 6 (TMPRSS6), transferrin receptor (TFR2), N-acetyltransferase 2 (arylamine N-acetyltransferase) (NAT2), ABO blood group (ABO), and GRB2 associated binding protein 3 (GAB3) loci. In examining iron variant associations with glucose homeostasis, an iron-raising variant of TMPRSS6 was associated with lower HbA1c levels (P = 8.66 × 10-10). This association was attenuated upon adjustment for iron measures. In contrast, the iron-raising allele of PPP1R3B was associated with higher levels of fasting glucose (P = 7.70 × 10-7) and fasting insulin (P = 4.79 × 10-6), but these associations were not attenuated upon adjustment for TIBC-so iron is not likely a mediator. These results provide new genetic information on iron traits and their connection with glucose homeostasis.


Assuntos
Glucose/genética , Glucose/metabolismo , Ferro/metabolismo , Adulto , Anemia Ferropriva/sangue , Antígenos CD , Glicemia/metabolismo , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Jejum , Feminino , Ferritinas/análise , Ferritinas/sangue , Ferritinas/metabolismo , Estudos de Associação Genética/métodos , Variação Genética/genética , Estudo de Associação Genômica Ampla , Genômica , Hemocromatose/genética , Hispano-Americanos/genética , Hospitais Comunitários/métodos , Humanos , Insulina/metabolismo , Ferro/sangue , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Receptores da Transferrina/genética , Fatores de Risco , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Transferrina/análise , Transferrina/metabolismo
14.
Diabetes Care ; 39(12): 2225-2231, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27703028

RESUMO

OBJECTIVE: Dementia is a debilitating illness with a disproportionate burden in patients with type 2 diabetes (T2D). Among the contributors, genetic variation at the apolipoprotein E locus (APOE) is posited to convey a strong effect. This study compared and contrasted the association of APOE with cognitive performance and cerebral structure in the setting of T2D. RESEARCH DESIGN AND METHODS: European Americans from the Diabetes Heart Study (DHS) MIND (n = 754) and African Americans from the African American (AA)-DHS MIND (n = 517) were examined. The cognitive battery assessed executive function, memory, and global cognition, and brain MRI was performed. RESULTS: In European Americans and African Americans, the APOE E4 risk haplotype group was associated with poorer performance on the modified Mini-Mental Status Examination (P < 0.017), a measure of global cognition. In contrast to the literature, the APOE E2 haplotype group, which was overrepresented in these participants with T2D, was associated with poorer Rey Auditory Verbal Learning Test performance (P < 0.032). Nominal associations between APOE haplotype groups and MRI-determined cerebral structure were observed. CONCLUSIONS: Compared with APOE E3 carriers, E2 and E4 carriers performed worse in the cognitive domains of memory and global cognition. Identification of genetic contributors remains critical to understanding new pathways to prevent and treat dementia in the setting of T2D.


Assuntos
Apolipoproteínas E/genética , Encéfalo/patologia , Transtornos Cognitivos/genética , Cognição/fisiologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/psicologia , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Transtornos Cognitivos/complicações , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Feminino , Estudos de Associação Genética , Genótipo , Heterozigoto , Humanos , Imagem por Ressonância Magnética , Masculino , Memória/fisiologia , Pessoa de Meia-Idade , Testes Neuropsicológicos
15.
Am J Hum Genet ; 99(1): 8-21, 2016 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-27346685

RESUMO

Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.


Assuntos
Eritrócitos/citologia , Eritropoese/genética , Exoma/genética , Pleiotropia Genética , Variação Genética/genética , Genótipo , Afro-Americanos/genética , Desequilíbrio Alélico , Índices de Eritrócitos , Eritrócitos/metabolismo , Frequência do Gene , Hematócrito , Hemoglobinas/genética , Humanos , Locos de Características Quantitativas/genética
16.
Am J Hum Genet ; 99(1): 40-55, 2016 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-27346686

RESUMO

Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.


Assuntos
Plaquetas/metabolismo , Exoma/genética , Variação Genética/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Volume Plaquetário Médio , Contagem de Plaquetas
17.
Am J Hum Genet ; 99(1): 22-39, 2016 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-27346689

RESUMO

White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of âˆ¼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.


Assuntos
Exoma/genética , Loci Gênicos/genética , Pleiotropia Genética , Estudo de Associação Genômica Ampla , Doenças do Sistema Imunitário/genética , Leucócitos/citologia , Contagem de Células Sanguíneas , Humanos , Controle de Qualidade
18.
Brain Behav ; 6(4): e00446, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-27066308

RESUMO

BACKGROUND: There is an established association between type 2 diabetes and accelerated cognitive decline. The exact mechanism linking type 2 diabetes and reduced cognitive function is less clear. The monoamine system, which is extensively involved in cognition, can be altered by type 2 diabetes status. Thus, this study hypothesized that sequence variants in genes linked to dopamine metabolism and associated pathways are associated with cognitive function as assessed by the Digit Symbol Substitution Task, the Modified Mini-Mental State Examination, the Stroop Task, the Rey Auditory-Verbal Learning Task, and the Controlled Oral Word Association Task for Phonemic and Semantic Fluency in the Diabetes Heart Study, a type 2 diabetes-enriched familial cohort (n = 893). METHODS: To determine the effects of candidate variants on cognitive performance, genetic association analyses were performed on the well-documented variable number tandem repeat located in the 3' untranslated region of the dopamine transporter, as well as on single-nucleotide polymorphisms covering genes in the dopaminergic pathway, the insulin signaling pathway, and the convergence of both. Next, polymorphisms in loci of interest with strong evidence for involvement in dopamine processing were extracted from genetic datasets available in a subset of the cohort (n = 572) derived from Affymetrix(®) Genome-Wide Human SNP Array 5.0 and 1000 Genomes imputation from this array. RESULTS: The candidate gene analysis revealed one variant from the DOPA decarboxylase gene, rs10499695, to be associated with poorer performance on a subset of Rey Auditory-Verbal Learning Task measuring retroactive interference (P = 0.001, ß = -0.45). Secondary analysis of genome-wide and imputed data uncovered another DOPA decarboxylase variant, rs62445903, also associated with retroactive interference (P = 7.21 × 10(-7), ß = 0.3). These data suggest a role for dopaminergic genes, specifically a gene involved in regulation of dopamine synthesis, in cognitive performance in type 2 diabetes.


Assuntos
Descarboxilases de Aminoácido-L-Aromático/genética , Disfunção Cognitiva/genética , Diabetes Mellitus Tipo 2/genética , Dopamina/genética , Estudo de Associação Genômica Ampla , Transdução de Sinais/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/etiologia , Estudos de Coortes , Diabetes Mellitus Tipo 2/complicações , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Repetições Minissatélites , Linhagem , Polimorfismo de Nucleotídeo Único
19.
Gene ; 584(2): 173-9, 2016 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-26915486

RESUMO

Advanced glycation end-products (AGEs) are a diverse group of molecules produced by the non-enzymatic addition of glucose to proteins, lipids, and nucleic acids. AGE levels have been associated with hyperglycemia and diabetic complications, especially in animal models, but less clearly in human studies. We measured total serum AGEs using an enzyme linked immunosorbant assay (ELISA) in 506 subjects from 246 families in the Diabetes Heart Study (DHS)/DHS MIND Study (n=399 type 2 diabetes (T2D)-affected). Single nucleotide polymorphisms (SNPs) in several candidate genes, including known AGE receptors, were tested for their influence on circulating AGE levels. The genetic analysis was expanded to include an exploratory genome-wide association study (GWAS) and exome chip analysis of AGEs (≈440,000 SNPs). AGEs were found to be highly heritable (h(2)=0.628, p=8.96 × 10(-10)). While no SNPs from candidate genes were significantly associated after Bonferroni correction, rs1035798 in the gene AGER was the most significantly associated (p=0.007). Additionally, rs7198427, in MT1A, showed a nominally significant p-value (p=0.0099). No SNPs from the GWAS or exome studies were identified after correction for multiple comparisons; however, rs17054480 in the PALLD2 gene on chromosome 4 showed the strongest association (p=7.77 × 10(-7)). Five SNPs at two loci (ISCA2/NPC2 and FBXO33) had p-values of less than 2.0 × 10(-5) and three additional SNPs (rs716326 in MACROD2, and rs6795197 and rs6765857 in ZBTB38) showed a nominal association with p-values of less than 1.0 × 10(-5).These findings provide a foundation for further investigation into the genetic component of circulating AGEs.


Assuntos
Produtos Finais de Glicação Avançada/genética , Idoso , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
20.
J Diabetes Complications ; 30(2): 262-8, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26739237

RESUMO

AIMS: Human studies of links between advanced glycation end-products (AGEs) and disease phenotypes are less common than studies of animal and cell models. Here, we examined the association of total AGEs with diabetes risk factors in a predominately type 2 diabetes (T2D) affected cohort. METHODS: AGEs were measured using an enzyme linked immunosorbant assay in 816 individuals from the DHS Mind Study (n=709 T2D affected), and association analyses were completed. RESULTS: Total AGEs were associated with estimated glomerular filtration rate (p=0.0054; ß=-0.1291) and coronary artery calcification (p=0.0352; ß=1.1489) in the entire cohort. No significant associations were observed when individuals with T2D were analyzed separately. In individuals without T2D, increased circulating AGEs were associated with increased BMI (p=0.02, ß=0.138), low density lipoproteins (p=0.046, ß=17.07) and triglycerides (p=0.0004, ß=0.125), and decreased carotid artery calcification (p=0.0004, ß=-1.2632) and estimated glomerular filtration rate (p=0.0018, ß=-0.1405). Strong trends were also observed for an association between AGEs and poorer cognitive performance on the digit symbol substitution test (p=0.046, ß=-6.64) and decreased grey matter volume (p=0.037, ß=-14.87). CONCLUSIONS: AGEs may play an important role in a number of phenotypes and diseases, although not necessarily in interindividual variation in people with T2D. Further evaluation of specific AGE molecules may shed more light on these relationships.


Assuntos
Cognição/fisiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/psicologia , Produtos Finais de Glicação Avançada/análise , Idoso , Estudos de Coortes , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/diagnóstico por imagem , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/diagnóstico por imagem , Feminino , Neuroimagem Funcional , Produtos Finais de Glicação Avançada/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos
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