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  • 1
    Language: English
    In: Diabetes care, April 2014, Vol.37(4), pp.1157-64
    Description: OBJECTIVE Given the high rates of cardiovascular disease (CVD) and associated mortality in individuals with type 2 diabetes, identifying and understanding predictors of CVD events and mortality could help inform clinical management in this high-risk group. Recent large-scale genetic studies may provide additional tools in this regard. RESEARCH DESIGN AND METHODS Genetic risk scores (GRSs) were constructed in 1,175 self-identified European American (EA) individuals comprising the family-based Diabetes Heart Study based on 1) 13 single nucleotide polymorphisms (SNPs) and 2) 30 SNPs with previously documented associations with CVD in genome-wide association studies. Associations between each GRS and a self-reported history of CVD, coronary artery calcified plaque (CAC) determined by noncontrast computed tomography scan, all-cause mortality, and CVD mortality were examined using marginal models with generalized estimating equations and Cox proportional hazards models. RESULTS The weighted 13-SNP GRS was associated with prior CVD (odds ratio [OR] 1.51 [95% CI 1.22-1.86]; P = 0.0002), CAC (β-coefficient [β] 0.22 [0.02-0.43]; P = 0.04) and CVD mortality (hazard ratio [HR] 1.35 [1.10-1.81]; P = 0.04) when adjusting for the other known CVD risk factors: age, sex, type 2 diabetes affection status, BMI, current smoking status, hypertension, and dyslipidemia. The weighted 30-SNP GRS was also associated with prior CVD (OR 1.33 [1.08-1.65]; P = 0.008), CAC (β 0.29 [0.08-0.50]; P = 0.006), all-cause mortality (HR 1.28 [1.05-1.56]; P = 0.01), and CVD mortality (HR 1.46 [1.08-1.96]; P = 0.01). CONCLUSIONS These findings support the utility of two simple GRSs in examining genetic associations for adverse outcomes in EAs with type 2 diabetes.
    Keywords: Genetic Predisposition to Disease ; Coronary Artery Disease -- Genetics ; Diabetes Mellitus, Type 2 -- Complications
    ISSN: 01495992
    E-ISSN: 1935-5548
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  • 2
    Language: English
    In: Science (New York, N.Y.), 13 August 2010, Vol.329(5993), pp.841-5
    Description: African Americans have higher rates of kidney disease than European Americans. Here, we show that, in African Americans, focal segmental glomerulosclerosis (FSGS) and hypertension-attributed end-stage kidney disease (H-ESKD) are associated with two independent sequence variants in the APOL1 gene on chromosome 22 {FSGS odds ratio = 10.5 [95% confidence interval (CI) 6.0 to 18.4]; H-ESKD odds ratio = 7.3 (95% CI 5.6 to 9.5)}. The two APOL1 variants are common in African chromosomes but absent from European chromosomes, and both reside within haplotypes that harbor signatures of positive selection. ApoL1 (apolipoprotein L-1) is a serum factor that lyses trypanosomes. In vitro assays revealed that only the kidney disease-associated ApoL1 variants lysed Trypanosoma brucei rhodesiense. We speculate that evolution of a critical survival factor in Africa may have contributed to the high rates of renal disease in African Americans.
    Keywords: Polymorphism, Single Nucleotide ; African Americans -- Genetics ; Apolipoproteins -- Genetics ; Glomerulosclerosis, Focal Segmental -- Genetics ; Kidney Failure, Chronic -- Genetics ; Lipoproteins, HDL -- Genetics ; Trypanosoma Brucei Rhodesiense -- Metabolism
    ISSN: 00368075
    E-ISSN: 1095-9203
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  • 3
    Language: English
    In: Arthritis & Rheumatism, December 2012, Vol.64(12), pp.4060-4065
    Description: Objective The proposed pathogenesis of the cardiac manifestations of neonatal lupus (cardiac-NL) involves maternal autoantibodies to the RNPs SSA/Ro and SSB/La, enhanced by as-yet-unknown factors that likely involve dysregulation of both inflammatory and fibrotic fetal responses. This study was designed to improve the power to detect specific associations in genes with candidate biologic functions. Methods Using data from our genome-wide association study of 116 Caucasian children with cardiac-NL and 3,351 Caucasian controls, we tested for enrichment of single-nucleotide polymorphism (SNP) associations in genes with candidate biologic functions related to fibrosis, immune function, apoptosis, T cell function, cell infiltration, innate immune cell function, interferon, Toll-like receptors, and calcium channels. After linkage disequilibrium pruning and exclusion of the extended HLA region, a total of 15,103 SNPs in 3,068 genes remained. Results A highly significant enrichment of P values was observed for genes related to fibrosis (P = 2.27 10 super(-9)), apoptosis (P = 7.67 10 super(-7)), and innate immune cell (P = 2.53 10 super(-6)), immune (P = 5.01 10 super(-4)), T cell (P = 2.23 10 super(-4)), and interferon functions (P = 1.64 10 super(-3)). The most significant non-HLA associations included the sialyltransferase gene ST8SIA2 (rs1487982; odds ratio 2.20 [95% confidence interval 1.52-3.19], P = 3.37 10 super(-5)), the integrin gene ITGA1 (rs2432143; odds ratio 2.31 [95% confidence interval 1.54-3.45], P = 4.54 10 super(-5)), and the complement regulator gene CSMD1 (rs7002001; odds ratio 2.41 [95% confidence interval 1.57-3.72], P = 6.33 10 super(-5)). Conclusion This study identified novel candidate genes associated with cardiac-NL and highlights the value of studying this cohort for advancing knowledge regarding the genetic etiology of this syndrome. Identification of causal alleles is expected to provide critical insight into the molecular mechanisms responsible for linking maternal autoantibodies to cardiac scarring in these fetuses/neonates.
    Keywords: Apoptosis ; Autoimmunity ; Development & Cell Cycle;
    ISSN: 0004-3591
    E-ISSN: 1529-0131
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  • 4
    In: Circulation, 2016, Vol.134(19), pp.1444-1452
    Description: BACKGROUND:: Hypertension is a significant risk factor for intracerebral hemorrhage (ICH). Although ethnic/racial disparities related to hypertension and ICH have been reported, these previous studies were limited by a lack of Hispanics and inadequate power to analyze by ICH location. In the current study, while overcoming these prior limitations, we investigated whether there was variation by ethnicity/race of treated and untreated hypertension as risk factors for ICH. METHODS:: The ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage) is a prospective, multicenter, case-control study of ICH among whites, blacks, and Hispanics. Cases were enrolled from 42 recruitment sites. Controls matched to cases 1:1 by age (±5 years), sex, ethnicity/race, and metropolitan area were identified by random-digit dialing. Subjects were interviewed to determine history of hypertension and use of antihypertensive medications. Cases and controls within ethnic groups were compared by using conditional logistic regression. Multivariable conditional logistic regression models were computed for ICH as an overall group and separately for the location subcategories deep, lobar, and infratentorial (brainstem/cerebellar). RESULTS:: Nine hundred fifty-eight white, 880 black, and 766 Hispanic ICH patients were enrolled. For ICH cases, untreated hypertension was higher in blacks (43.6%, P〈0.0001) and Hispanics (46.9%, P〈0.0001) versus whites (32.7%). In multivariable analyses adjusted for alcohol use, anticoagulation, hypercholesterolemia, education, and medical insurance status, treated hypertension was a significant risk factor across all locations of ICH in whites (odds ratio [OR], 1.57; 95% confidence interval [CI], 1.24–1.98; P〈0.0001), blacks (OR, 3.02; 95% CI, 2.16–4.22; P〈0.0001), and Hispanics (OR, 2.50; 95% CI, 1.73–3.62; P〈0.0001). Untreated hypertension was a substantially greater risk factor for all 3 racial/ethnic groups across all locations of ICH: whites (OR, 8.79; 95% CI, 5.66–13.66; P〈0.0001), blacks (OR, 12.46; 95% CI, 8.08–19.20; P〈0.0001), and Hispanics (OR, 10.95; 95% CI, 6.58–18.23; P〈0.0001). There was an interaction between race/ethnicity and ICH risk (P〈0.0001). CONCLUSIONS:: Untreated hypertension confers a greater ICH risk in blacks and Hispanics relative to whites across all anatomic locations of ICH. Accelerated research efforts are needed to improve overall hypertension treatment rates and to monitor the impact of such efforts on racial/ethnic disparities in stroke. CLINICAL TRIAL REGISTRATION:: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01202864.
    Keywords: Medicine ; Anatomy & Physiology;
    ISSN: 0009-7322
    E-ISSN: 15244539
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  • 5
    Language: English
    In: Diabetes care, February 2012, Vol.35(2), pp.287-92
    Description: Multiple single nucleotide polymorphisms (SNPs) associated with type 2 diabetes (T2D) susceptibility have been identified in predominantly European-derived populations. These SNPs have not been extensively investigated for individual and cumulative effects on T2D risk in African Americans. Seventeen index T2D risk variants were genotyped in 2,652 African American case subjects with T2D and 1,393 nondiabetic control subjects. Individual SNPs and cumulative risk allele loads were assessed for association with risk for T2D. Cumulative risk was assessed by counting risk alleles and evaluating the difference in cumulative risk scores between case subjects and control subjects. A second analysis weighted risk scores (ln [OR]) based on previously reported European-derived effect sizes. Frequencies of risk alleles ranged from 8.6 to 99.9%. Eleven SNPs had ORs 〉1, and 5 from ADAMTS9, WFS1, CDKAL1, JAZF1, and TCF7L2 trended or had nominally significant evidence of T2D association (P 〈 0.05). Individuals carried between 13 and 29 risk alleles. Association was observed between T2D and increase in risk allele load (unweighted OR 1.04 [95% CI 1.01-1.08], P = 0.010; weighted 1.06 [1.03-1.10], P = 8.10 × 10(-5)). When TCF7L2 SNP rs7903146 was included as a covariate, the risk score was no longer associated with T2D in either model (unweighted 1.02 [0.98-1.05], P = 0.33; weighted 1.02 [0.98-1.06], P = 0.40). The trend of increase in risk for T2D with increasing risk allele load is similar to observations in European-derived populations; however, these analyses indicate that T2D genetic risk is primarily mediated through the effect of TCF7L2 in African Americans.
    Keywords: Diabetes Mellitus, Type 2 -- Genetics ; Polymorphism, Single Nucleotide -- Genetics
    ISSN: 01495992
    E-ISSN: 1935-5548
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  • 6
    Language: English
    In: Arthritis & Rheumatism, March 2012, Vol.64(3), pp.931-939
    Description: OBJECTIVE: Neonatal lupus (NL) occurs in fetuses exposed to maternal anti-SSA/Ro and/or anti-SSB/La antibodies, although the mothers themselves may not manifest any clinical disease. A focus on transmission of risk factors for NL from maternal grandparents to mothers of children with NL may yield dividends toward understanding the aggregation of autoantibodies and genetic factors in affected families. This study was perforned to determine the role of maternal grandparents in the development of the autoimmune phenotype of mothers of children with NL.METHODS: Fifty-one mothers of children with cardiac and/or cutaneous NL, 48 maternal grandmothers, and 35 maternal grandfathers in the Research Registry for Neonatal Lupus were interrogated for clinical symptoms by questionnaire and underwent laboratory assessments, including determination of anti-SSA/Ro and anti-SSB/La antibody status (by enzyme-linked immunosorbent assay) and genotype at rs1800629 (TNFα) and rs7775397 (C6orf10) (allelic discrimination). The transmission disequilibrium test (TDT) was computed to test for nonrandom transmission from maternal grandparents to mothers of children with NL.RESULTS: The common phenotypic feature in mothers of children with NL was the autoantibody and not the clinical profile; 7 had lupus, 14 had Sjögren's syndrome, 7 had both, and 23 were asymptomatic. Mothers of children with NL were significantly enriched for the risk alleles at both TNFα and C6orf10. The grandparents of children with NL carried minimal burden for autoimmune disease or abnormal antibody production and were not enriched in the genetic risk factors. However, the TDT analysis showed significant excess transmission of the risk alleles at both TNFα (odds ratio [OR] 6.67, P = 3.93 × 10(-4) ) and C6orf10 (OR 35.0, P = 3.74 × 10(-5) ) to mothers of children with NL.CONCLUSION: Mothers of children with NL are enriched for the TNFα and C6orf10 risk alleles, which are preferentially inherited from the asymptomatic maternal grandparents. These findings support the hypothesis that the development of NL and genetic etiology are multigenerational.
    Keywords: Medicine;
    ISSN: 0004-3591
    E-ISSN: 1529-0131
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  • 7
    Language: English
    In: The Journal of Allergy and Clinical Immunology, February 2018, Vol.141(2), pp.632-637.e5
    Description: Although eosinophilic esophagitis (EoE) is associated with certain gene variants, the rapidly increasing incidence of EoE suggests that environmental factors contribute to disease development. We tested for gene-environment interaction between EoE-predisposing polymorphisms (within , , , , and ) and implicated early-life factors (antibiotic use in infancy, cesarean delivery, breast-feeding, neonatal intensive care unit [NICU] admission, and absence of pets in the home). We conducted a case-control study using hospital-based cases (n = 127) and control subjects representative of the hospital catchment area (n = 121). We computed case-only interaction tests and in secondary analyses evaluated the combined and independent effects of genotype and environmental factors on the risk of EoE. Case-only analyses identified interactions between rs6736278 and breast-feeding (  = .02) and rs17815905 and NICU admission (  = .02) but not with any of the factors examined. Case-control analyses suggested that disease risk might be modifiable in subjects with certain gene variants. In particular, breast-feeding in those with the susceptibility gene variant at rs6736278 reduced the risk of EoE (adjusted odds ratio, 0.08; 95% CI, 0.01-0.59). Admission to the NICU in those without the susceptibility gene variant at rs17815905 significantly increased the risk of having disease (adjusted odds ratio, 4.83; 95% CI, 1.49-15.66). The interplay of gene and ) and early-life environment factors (breast-feeding and NICU admission) might contribute to EoE susceptibility.
    Keywords: Early-Life Factors ; Eosinophilic Esophagitis ; Gene-Environment Interaction ; Exposures ; Medicine
    ISSN: 0091-6749
    E-ISSN: 1097-6825
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  • 8
    In: British Journal of Nutrition, 2012, Vol.107(4), pp.547-555
    Description: Over the past 50 years, increases in dietary n -6 PUFA, such as linoleic acid, have been hypothesised to cause or exacerbate chronic inflammatory diseases. The present study examines an individual's innate capacity to synthesise n -6 long-chain PUFA (LC-PUFA) with respect to the fatty acid desaturase ( FADS ) locus in Americans of African and European descent with diabetes or the metabolic syndrome. Compared with European Americans (EAm), African Americans (AfAm) exhibited markedly higher serum levels of arachidonic acid (AA) (EAm 7·9 ( sd 2·1), AfAm 9·8 ( sd 1·9) % of total fatty acids; P  〈 2·29 × 10 − 9 ) and the AA: n -6-precursor fatty acid ratio, which estimates FADS1 activity (EAm 5·4 ( sd 2·2), AfAm 6·9 ( sd 2·2); P  = 1·44 × 10 − 5 ). In all, seven SNP mapping to the FADS locus revealed strong association with AA, EPA and dihomo-γ-linolenic acid (DGLA) in the EAm. Importantly, EAm homozygous for the minor allele (T) had significantly lower AA levels (TT 6·3 ( sd 1·0); GG 8·5 ( sd 2·1); P  = 3·0 × 10 − 5 ) and AA:DGLA ratios (TT 3·4 ( sd 0·8), GG 6·5 ( sd 2·3); P  = 2·2 × 10 − 7 ) but higher DGLA levels (TT 1·9 ( sd 0·4), GG 1·4 ( sd 0·4); P  = 3·3 × 10 − 7 ) compared with those homozygous for the major allele (GG). Allele frequency patterns suggest that the GG genotype at rs174537 (associated with higher circulating levels of AA) is much higher in AfAm (0·81) compared with EAm (0·46). Similarly, marked differences in rs174537 genotypic frequencies were observed in HapMap populations. These data suggest that there are probably important differences in the capacity of different populations to synthesise LC-PUFA. These differences may provide a genetic mechanism contributing to health disparities between populations of African and European descent.
    Keywords: Human And Clinical Nutrition; Snp; Fatty Acid Desaturase; Arachidonic Acid Synthesis
    ISSN: 0007-1145
    E-ISSN: 1475-2662
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  • 9
    In: Neurology, 2017, Vol.88(21), pp.2043-2051
    Description: OBJECTIVE:: To analyze the dose–risk relationship for alcohol consumption and intracerebral hemorrhage (ICH) in the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study. METHODS:: ERICH is a multicenter, prospective, case-control study, designed to recruit 1,000 non-Hispanic white patients, 1,000 non-Hispanic black patients, and 1,000 Hispanic patients with ICH. Cases were matched 1:1 to ICH-free controls by age, sex, race/ethnicity, and geographic area. Comprehensive interviews included questions regarding alcohol consumption. Patterns of alcohol consumption were categorized as none, rare (〈1 drink per month), moderate (≥1 drink per month and ≤2 drinks per day), intermediate (〉2 drinks per day and 〈5 drinks per day), and heavy (≥5 drinks per day). ICH risk was calculated using the no-alcohol use category as the reference group. RESULTS:: Multivariable analyses demonstrated an ordinal trend for alcohol consumption: rare (odds ratio [OR] 0.57, p 〈 0.0001), moderate (OR 0.65, p 〈 0.0001), intermediate (OR 0.82, p = 0.2666), and heavy alcohol consumption (OR 1.77, p = 0.0003). Subgroup analyses demonstrated an association of rare and moderate alcohol consumption with decreased risk of both lobar and nonlobar ICH. Heavy alcohol consumption demonstrated a strong association with increased nonlobar ICH risk (OR 2.04, p = 0.0003). Heavy alcohol consumption was associated with significant increase in nonlobar ICH risk in black (OR 2.34, p = 0.0140) and Hispanic participants (OR 12.32, p 〈 0.0001). A similar association was not found in white participants. CONCLUSIONS:: This study demonstrated potential protective effects of rare and moderate alcohol consumption on ICH risk. Heavy alcohol consumption was associated with increased ICH risk. Race/ethnicity was a significant factor in alcohol-associated ICH risk; heavy alcohol consumption in black and Hispanic participants poses significant nonlobar ICH risk.
    Keywords: Medicine;
    ISSN: 0028-3878
    E-ISSN: 1526632X
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  • 10
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 10 January 2012, Vol.109(2), pp.E59-67
    Description: Systemic lupus erythematosus (SLE), the prototypic systemic autoimmune disease, is a debilitating multisystem autoimmune disorder characterized by chronic inflammation and extensive immune dysregulation in multiple organ systems, resulting in significant morbidity and mortality. Here, we present a multidisciplinary approach resulting in the identification of neutrophil cytosolic factor 2 (NCF2) as an important risk factor for SLE and the detailed characterization of its causal variant. We show that NCF2 is strongly associated with increased SLE risk in two independent populations: childhood-onset SLE and adult-onset SLE. The association between NCF2 and SLE can be attributed to a single nonsynonymous coding mutation in exon 12, the effect of which is the substitution of histidine-389 with glutamine (H389Q) in the PB1 domain of the NCF2 protein, with glutamine being the risk allele. Computational modeling suggests that the NCF2 H389Q mutation reduces the binding efficiency of NCF2 with the guanine nucleotide exchange factor Vav1. The model predicts that NCF2/H389 residue interacts with Vav1 residues E509, N510, E556, and G559 in the ZF domain of Vav1. Furthermore, replacing H389 with Q results in 1.5 kcal/mol weaker binding. To examine the effect of the NCF2 H389Q mutation on NADPH oxidase function, site-specific mutations at the 389 position in NCF2 were tested. Results show that an H389Q mutation causes a twofold decrease in reactive oxygen species production induced by the activation of the Vav-dependent Fcγ receptor-elicited NADPH oxidase activity. Our study completes the chain of evidence from genetic association to specific molecular function.
    Keywords: Genetic Variation ; Models, Molecular ; Genetic Predisposition to Disease -- Genetics ; Lupus Erythematosus, Systemic -- Genetics ; Multiprotein Complexes -- Genetics ; Nadph Oxidases -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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