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1.
Nat Genet ; 53(10): 1504-1516, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34611364

RESUMO

Fine-mapping to plausible causal variation may be more effective in multi-ancestry cohorts, particularly in the MHC, which has population-specific structure. To enable such studies, we constructed a large (n = 21,546) HLA reference panel spanning five global populations based on whole-genome sequences. Despite population-specific long-range haplotypes, we demonstrated accurate imputation at G-group resolution (94.2%, 93.7%, 97.8% and 93.7% in admixed African (AA), East Asian (EAS), European (EUR) and Latino (LAT) populations). Applying HLA imputation to genome-wide association study data for HIV-1 viral load in three populations (EUR, AA and LAT), we obviated effects of previously reported associations from population-specific HIV studies and discovered a novel association at position 156 in HLA-B. We pinpointed the MHC association to three amino acid positions (97, 67 and 156) marking three consecutive pockets (C, B and D) within the HLA-B peptide-binding groove, explaining 12.9% of trait variance.

2.
Am J Hum Genet ; 108(10): 1836-1851, 2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34582791

RESUMO

Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.

3.
Hum Mol Genet ; 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34553764

RESUMO

Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing from NHLBI's Trans-Omics for Precision Medicine Initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several GWAS identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of whole genome sequencing in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits.

4.
J Community Health ; 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34383157

RESUMO

Prevention behaviors represent important public health tools to limit spread of SARS-CoV-2. Adherence with recommended public health prevention behaviors among 20000 + members of a COVID-19 syndromic surveillance cohort from the mid-Atlantic and southeastern United States was assessed via electronic survey following the 2020 Thanksgiving and winter holiday (WH) seasons. Respondents were predominantly non-Hispanic Whites (90%), female (60%), and ≥ 50 years old (59%). Non-household members (NHM) were present at 47.1% of Thanksgiving gatherings and 69.3% of WH gatherings. Women were more likely than men to gather with NHM (p < 0.0001). Attending gatherings with NHM decreased with older age (Thanksgiving: 60.0% of participants aged < 30 years to 36.3% aged ≥ 70 years [p-trend < 0.0001]; WH: 81.6% of those < 30 years to 61.0% of those ≥ 70 years [p-trend < 0.0001]). Non-Hispanic Whites were more likely to gather with NHM than were Hispanics or non-Hispanic Blacks (p < 0.0001). Mask wearing, reported by 37.3% at Thanksgiving and 41.9% during the WH, was more common among older participants, non-Hispanic Blacks, and Hispanics when gatherings included NHM. In this survey, most people did not fully adhere to recommended public health safety behaviors when attending holiday gatherings. It remains unknown to what extent failure to observe these recommendations may have contributed to the COVID-19 surges observed following Thanksgiving and the winter holidays in the United States.

5.
PLoS One ; 16(8): e0255609, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34347846

RESUMO

BACKGROUND: African ancestry individuals with comparable overall anthropometric measures to Europeans have lower abdominal adiposity. To explore the genetic underpinning of different adiposity patterns, we investigated whether genetic risk scores for well-studied adiposity phenotypes like body mass index (BMI) and waist circumference (WC) also predict other, less commonly measured adiposity measures in 2420 African American individuals from the Jackson Heart Study. METHODS: Polygenic risk scores (PRS) were calculated using GWAS-significant variants extracted from published studies mostly representing European ancestry populations for BMI, waist-hip ratio (WHR) adjusted for BMI (WHRBMIadj), waist circumference adjusted for BMI (WCBMIadj), and body fat percentage (BF%). Associations between each PRS and adiposity measures including BF%, subcutaneous adiposity tissue (SAT), visceral adiposity tissue (VAT) and VAT:SAT ratio (VSR) were examined using multivariable linear regression, with or without BMI adjustment. RESULTS: In non-BMI adjusted models, all phenotype-PRS were found to be positive predictors of BF%, SAT and VAT. WHR-PRS was a positive predictor of VSR, but BF% and BMI-PRS were negative predictors of VSR. After adjusting for BMI, WHR-PRS remained a positive predictor of BF%, VAT and VSR but not SAT. WC-PRS was a positive predictor of SAT and VAT; BF%-PRS was a positive predictor of BF% and SAT only. CONCLUSION: These analyses suggest that genetically driven increases in BF% strongly associate with subcutaneous rather than visceral adiposity and BF% is strongly associated with BMI but not central adiposity-associated genetic variants. How common genetic variants may contribute to observed differences in adiposity patterns between African and European ancestry individuals requires further study.

6.
Diabetes Care ; 2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34380703

RESUMO

OBJECTIVE: We examined diabetes mellitus (DM) as a cardiovascular disease (CVD) risk equivalent based on diabetes severity and other CVD risk factors. RESEARCH DESIGN AND METHODS: We pooled 4 US cohorts (ARIC, JHS, MESA, FHS-Offspring) and classified subjects by baseline DM/CVD. CVD risks between DM+/CVD- vs. DM-/CVD+ were examined by diabetes severity and in subgroups of other CVD risk factors. We developed an algorithm to identify subjects with CVD risk equivalent diabetes by comparing the relative CVD risk of being DM+/CVD- vs. DM-/CVD+. RESULTS: The pooled cohort included 27,730 subjects (mean age of 58.5 years, 44.6% male). CVD rates per 1000 person-years were 16.5, 33.4, 43.2 and 71.4 among those with DM-/CVD-, DM+/CVD-, DM-/CVD+ and DM+/CVD+, respectively. Compared with those with DM-/CVD+, CVD risks were similar or higher for those with HbA1c ≥ 7%, diabetes duration ≥10 years, or diabetes medication use while those with less severe diabetes had lower risks. Hazard ratios (95%CI) for DM+/CVD- vs. DM-/CVD+ were 0.96(0.86-1.07), 0.97(0.88-1.07), 0.96(0.82-1.13), 1.18(0.98-1.41), 0.93(0.85-1.02) and 1.00(0.89-1.13) among women, white race, age <55 years, triglycerides ≥2.26 mmol/L, hs-CRP ≥ 2 mg/L and eGFR<60 mL/min/1.73m2, respectively. In DM+/CVD- group, 19.1% had CVD risk equivalent diabetes with a lower risk score but a higher observed CVD risk. CONCLUSION: Diabetes is a CVD risk equivalent in one-fifth of CVD-free adults living with diabetes. High HbA1c, long diabetes duration, and diabetes medication use were predictors of CVD risk equivalence. Diabetes is a CVD risk equivalent for women, white people, those of younger age, with higher triglycerides or CRP, or reduced kidney function.

7.
Science ; 373(6558): 1030-1035, 2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34385354

RESUMO

Biological mechanisms underlying human germline mutations remain largely unknown. We statistically decompose variation in the rate and spectra of mutations along the genome using volume-regularized nonnegative matrix factorization. The analysis of a sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. We provide a biological interpretation for seven of these processes. We associate one process with bulky DNA lesions that are resolved asymmetrically with respect to transcription and replication. Two processes track direction of replication fork and replication timing, respectively. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions and a mutagenic effect of long interspersed nuclear elements. We localize a mutagenic process specific to oocytes from population sequencing data. This process appears transcriptionally asymmetric.


Assuntos
Genoma Humano , Mutação em Linhagem Germinativa , Algoritmos , Ilhas de CpG , Dano ao DNA , Desmetilação do DNA , Análise Mutacional de DNA , Replicação do DNA , Variação Genética , Células Germinativas , Humanos , Elementos Nucleotídeos Longos e Dispersos , Mutagênese , Oócitos/fisiologia , Transcrição Genética
8.
Genome Med ; 13(1): 136, 2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34446064

RESUMO

BACKGROUND: Sleep-disordered breathing is a common disorder associated with significant morbidity. The genetic architecture of sleep-disordered breathing remains poorly understood. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, we performed the first whole-genome sequence analysis of sleep-disordered breathing. METHODS: The study sample was comprised of 7988 individuals of diverse ancestry. Common-variant and pathway analyses included an additional 13,257 individuals. We examined five complementary traits describing different aspects of sleep-disordered breathing: the apnea-hypopnea index, average oxyhemoglobin desaturation per event, average and minimum oxyhemoglobin saturation across the sleep episode, and the percentage of sleep with oxyhemoglobin saturation < 90%. We adjusted for age, sex, BMI, study, and family structure using MMSKAT and EMMAX mixed linear model approaches. Additional bioinformatics analyses were performed with MetaXcan, GIGSEA, and ReMap. RESULTS: We identified a multi-ethnic set-based rare-variant association (p = 3.48 × 10-8) on chromosome X with ARMCX3. Additional rare-variant associations include ARMCX3-AS1, MRPS33, and C16orf90. Novel common-variant loci were identified in the NRG1 and SLC45A2 regions, and previously associated loci in the IL18RAP and ATP2B4 regions were associated with novel phenotypes. Transcription factor binding site enrichment identified associations with genes implicated with respiratory and craniofacial traits. Additional analyses identified significantly associated pathways. CONCLUSIONS: We have identified the first gene-based rare-variant associations with objectively measured sleep-disordered breathing traits. Our results increase the understanding of the genetic architecture of sleep-disordered breathing and highlight associations in genes that modulate lung development, inflammation, respiratory rhythmogenesis, and HIF1A-mediated hypoxic response.

9.
Mitochondrion ; 60: 33-42, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34303007

RESUMO

We investigated the concordance of mitochondrial DNA heteroplasmic mutations (heteroplasmies) in 6745 maternal pairs of European (EA, n = 4718 pairs) and African (AA, n = 2027 pairs) Americans in whole blood. Mother-offspring pairs displayed the highest concordance rate, followed by sibling-sibling and more distantly-related maternal pairs. The allele fractions of concordant heteroplasmies exhibited high correlation (R2 = 0.8) between paired individuals. Discordant heteroplasmies were more likely to be in coding regions, be nonsynonymous or nonsynonymous-deleterious (p < 0.001). The number of deleterious heteroplasmies was significantly correlated with advancing age (20-44, 45-64, and ≥65 years, p-trend = 0.01). One standard deviation increase in heteroplasmic burden (i.e., the number of heteroplasmies carried by an individual) was associated with 0.17 to 0.26 (p < 1e - 23) standard deviation decrease in mtDNA copy number, independent of age. White blood cell count and differential count jointly explained 0.5% to 1.3% (p ≤ 0.001) variance in heteroplasmic burden. A genome-wide association and meta-analysis identified a region at 11p11.12 (top signal rs779031139, p = 2.0e - 18, minor allele frequency = 0.38) associated with the heteroplasmic burden. However, the 11p11.12 region is adjacent to a nuclear mitochondrial DNA (NUMT) corresponding to a 542 bp area of the D-loop. This region was no longer significant after excluding heteroplasmies within the 542 bp from the heteroplasmic burden. The discovery that blood mtDNA heteroplasmies were both inherited and somatic origins and that an increase in heteroplasmic burden was strongly associated with a decrease in average number of mtDNA copy number in blood are important findings to be considered in association studies of mtDNA with disease traits.

10.
Circ Genom Precis Med ; 14(4): e003300, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34319147

RESUMO

BACKGROUND: Alterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between electrocardiographic intervals and rare genetic variation at a population level are poorly understood. METHODS: Using a discovery sample of 29 000 individuals with whole-genome sequencing from Trans-Omics in Precision Medicine and replication in nearly 100 000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured electrocardiographic traits (RR, P-wave, PR, and QRS intervals and corrected QT interval). RESULTS: We found that rare variants associated with population-based electrocardiographic intervals identify established monogenic SCD genes (KCNQ1, KCNH2, and SCN5A), a controversial monogenic SCD gene (KCNE1), and novel genes (PAM and MFGE8) involved in cardiac conduction. Loss-of-function and pathogenic SCN5A variants, carried by 0.1% of individuals, were associated with a nearly 6-fold increased odds of the first-degree atrioventricular block (P=8.4×10-5). Similar variants in KCNQ1 and KCNH2 (0.2% of individuals) were associated with a 23-fold increased odds of marked corrected QT interval prolongation (P=4×10-25), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70% of carriers had normal electrocardiographic intervals. CONCLUSIONS: Our findings indicate that large-scale high-depth sequence data and electrocardiographic analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked electrocardiographic interval prolongation.

11.
J Am Heart Assoc ; 10(14): e020920, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34238024

RESUMO

Background Visceral adipose tissue (VAT) is associated with incident heart failure (HF) and HF with preserved ejection fraction, yet it is unknown how pericardial and abdominal adiposity affect HF and mortality risks in Black individuals. We examined the associations of pericardial adipose tissue (PAT), VAT, and subcutaneous adipose tissue (SAT) with incident HF hospitalization and all-cause mortality in a large community cohort of Black participants. Methods and Results Among the 2882 Jackson Heart Study Exam 2 participants without prevalent HF who underwent body computed tomography, we used Cox proportional hazards models to examine associations between computed tomography-derived regional adiposity and incident HF hospitalization and all-cause mortality. Fully adjusted models included demographics and cardiovascular disease risk factors. Median follow-up was 10.6 years among participants with available VAT (n=2844), SAT (n=2843), and PAT (n=1386). Fully adjusted hazard ratios (95% CIs) of distinct computed tomography-derived adiposity measures (PAT per 10 cm3, VAT or SAT per 100 cm3) were as follows: for incident HF, PAT 1.08 (95% CI, 1.02-1.14) and VAT 1.04 (95% CI, 1.01-1.08); for HF with preserved ejection fraction, PAT 1.13 (95% CI, 1.04-1.21) and VAT 1.07 (95% CI, 1.01-1.13); for mortality, PAT 1.07 (95% CI, 1.03-1.12) and VAT 1.01 (95% CI, 0.98-1.04). SAT was not associated with either outcome. Conclusions High PAT and VAT, but not SAT, were associated with incident HF and HF with preserved ejection fraction, and only PAT was associated with mortality in the fully adjusted models in a longitudinal community cohort of Black participants. Future studies may help understand whether changes in regional adiposity improves HF, particularly HF with preserved ejection fraction, risk predictions. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00005485.

12.
J Am Coll Cardiol ; 78(1): 42-52, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34210413

RESUMO

BACKGROUND: Age-related clonal hematopoiesis of indeterminate potential (CHIP), defined as clonally expanded leukemogenic sequence variations (particularly in DNMT3A, TET2, ASXL1, and JAK2) in asymptomatic individuals, is associated with cardiovascular events, including recurrent heart failure (HF). OBJECTIVES: This study sought to evaluate whether CHIP is associated with incident HF. METHODS: CHIP status was obtained from whole exome or genome sequencing of blood DNA in participants without prevalent HF or hematological malignancy from 5 cohorts. Cox proportional hazards models were performed within each cohort, adjusting for demographic and clinical risk factors, followed by fixed-effect meta-analyses. Large CHIP clones (defined as variant allele frequency >10%), HF with or without baseline coronary heart disease, and left ventricular ejection fraction were evaluated in secondary analyses. RESULTS: Of 56,597 individuals (59% women, mean age 58 years at baseline), 3,406 (6%) had CHIP, and 4,694 developed HF (8.3%) over up to 20 years of follow-up. CHIP was prospectively associated with a 25% increased risk of HF in meta-analysis (hazard ratio: 1.25; 95% confidence interval: 1.13-1.38) with consistent associations across cohorts. ASXL1, TET2, and JAK2 sequence variations were each associated with an increased risk of HF, whereas DNMT3A sequence variations were not associated with HF. Secondary analyses suggested large CHIP was associated with a greater risk of HF (hazard ratio: 1.29; 95% confidence interval: 1.15-1.44), and the associations for CHIP on HF with and without prior coronary heart disease were homogenous. ASXL1 sequence variations were associated with reduced left ventricular ejection fraction. CONCLUSIONS: CHIP, particularly sequence variations in ASXL1, TET2, and JAK2, represents a new risk factor for HF.


Assuntos
Hematopoiese Clonal/genética , Proteínas de Ligação a DNA/genética , Insuficiência Cardíaca , Janus Quinase 2/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Disfunção Ventricular Esquerda , Idoso , Correlação de Dados , Demografia , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Modelos de Riscos Proporcionais , Fatores de Risco , Volume Sistólico , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/genética , Sequenciamento Completo do Exoma/métodos
13.
Genome Biol ; 22(1): 194, 2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34187551

RESUMO

BACKGROUND: Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. RESULTS: Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. CONCLUSION: This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

14.
JACC Heart Fail ; 9(7): 484-493, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34119468

RESUMO

OBJECTIVES: This study sought to evaluate the independent associations and interactions between high-sensitivity cardiac troponin I (hs-cTnI) and physical activity (PA) with risk of heart failure (HF) subtypes, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF). BACKGROUND: Black adults are at high risk for developing HF. Physical inactivity and subclinical myocardial injury, as assessed by hs-cTnI concentration, are independent risk factors for HF. METHODS: Black adults from the Jackson Heart Study without prevalent HF who had hs-cTnI concentration and self-reported PA assessed at baseline were included. Adjusted Cox models were used to evaluate the independent and joint associations and interaction between hs-cTnI concentrations and PA with risk of HFpEF and HFrEF. RESULTS: Among 3,959 participants, 25.1% had subclinical myocardial injury (hs-cTnI ≥4 and ≥6 ng/l in women and men, respectively), and 48.2% were inactive (moderate-to-vigorous PA = 0 min/week). Over 12.0 years of follow-up, 163 and 150 participants had an incident HFpEF and HFrEF event, respectively. In adjusted analysis, higher hs-cTnI concentration (per 1-U log increase) was associated with higher risk of HFpEF (hazard ratio [HR]: 1.47; 95% confidence interval [CI]: 1.25 to 1.72]) and HFrEF (HR: 1.57; 95% CI: 1.35 to 1.83]). In contrast, higher PA (per 1-U log increase) was associated with a lower risk of HFpEF (HR: 0.93; 95% CI: 0.88 to 0.99]) but not HFrEF. There was a significant interaction between hs-cTnI and PA for risk of HFpEF (p interaction = 0.04) such that inactive participants with subclinical myocardial injury were at higher risk of HFpEF but active participants were not. CONCLUSIONS: Among Black adults with subclinical myocardial injury, higher levels of PA were associated with attenuated risk of HFpEF.

15.
Am J Hypertens ; 2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34166486

RESUMO

BACKGROUND: Little is known on the association of plasma adiponectin with blood pressure (BP) changes in African Americans (AAs). We evaluated the associations between plasma adiponectin and BP progression among AAs. METHODS: We analyzed data from 1184 participants without hypertension at baseline (2000-2004) with ≥1 follow-up visits in the Jackson Heart Study. We used robust Poisson regression to generate risk ratios (RR) for BP progression (an increase by ≥1 BP stage) and incident hypertension. RESULTS: Over a median of 7 years, 71 % progressed to higher BP stage and 65% developed hypertension. We found evidence of interaction by sex (P-interaction=0.088). Compared to those in the lowest quartile (Q1), male participants in the highest adiponectin quartile (Q4) had reduced risks of BP progression (Risk Ratio [RR] 0.76 [95% CI 0.60-0.96]) and incident hypertension (RR 0.74 [95% CI 0.56-0.97]). After accounting for body mass index, this relation persisted among obese men (RR for the highest (vs. lowest) adiponectin quartile: 0.59 (95% CI 0.36-0.97) for incident hypertension, and 0.69 (95% CI 0.45-1.06) for BP progression). Among women, adiponectin was not associated with BP outcomes (RR [95% CI] for Q4 vs Q1: 1.03 [0.86-1.23], and 1.01[0.83-1.23] for BP progression and incident hypertension respectively). Our findings were consistent across both the ACC/AHA and JNC-7 BP categories. CONCLUSIONS: In a large, community-based sample of African Americans, higher adiponectin concentrations were associated with lower risks of BP progression and incident hypertension in men, but no significant association was observed in women.

16.
Nat Commun ; 12(1): 3505, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34108472

RESUMO

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.


Assuntos
Diabetes Mellitus Tipo 2/genética , Dislipidemias/genética , Predisposição Genética para Doença/genética , Adulto , Variação Biológica da População , Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dislipidemias/metabolismo , Exoma/genética , Genótipo , Humanos , Herança Multifatorial , Penetrância , Medição de Risco
17.
J Hypertens ; 39(11): 2200-2209, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34173799

RESUMO

OBJECTIVE: There is a paucity of data on the relations of insulin resistance with incident blood pressure (BP) changes among Blacks. We investigated the associations of insulin resistance and metabolic syndrome (MetS) with BP progression in a community-based sample of African Americans. METHODS: We analyzed 1064 participants without hypertension at baseline (2000-2004) who attended at least one follow-up visit in 2005-2008 or 2009-2013. Four insulin resistance indices [fasting insulin, insulin-to-glucose ratio (IGR), homeostasis model assessment of insulin resistance (HOMA-IR), and quantitative insulin sensitivity check index (QUICKI)] and MetS (excluding hypertension in the definition) were assessed at baseline. Robust Poisson regression was used to generate risk ratios (RRs) and 95% confidence intervals (CI) for BP progression and incident hypertension. RESULTS: Over a median of 7 years, 69.6% progressed to a higher BP category and 62.7% developed hypertension. After multivariable adjustment, participants in the highest quartile of HOMA-IR had higher risks of BP progression [RR 1.25 (95% CI 1.09-1.43), Ptrend = 0.004] and hypertension [RR 1.35 (95% CI 1.16-1.58), Ptrend < 0.001] compared with those in the lowest quartile. A similar positive association of insulin resistance with BP outcomes was noted with insulin resistance assessed using IGR, fasting insulin, and QUICKI. MetS was associated with increased risks of BP progression [RR 1.15 (95% CI 1.02-1.30), P = 0.02] and incident hypertension [RR 1.23 [95% CI 1.08-1.41], P = 0.002]. These associations were present across baseline BP categories. CONCLUSION: Our findings support the notion that higher insulin resistance levels are associated with greater risks of BP progression and incident hypertension among Blacks.

18.
Clin Epigenetics ; 13(1): 121, 2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34078457

RESUMO

BACKGROUND: The difference between an individual's chronological and DNA methylation predicted age (DNAmAge), termed DNAmAge acceleration (DNAmAA), can capture life-long environmental exposures and age-related physiological changes reflected in methylation status. Several studies have linked DNAmAA to morbidity and mortality, yet its relationship with kidney function has not been assessed. We evaluated the associations between seven DNAm aging and lifespan predictors (as well as GrimAge components) and five kidney traits (estimated glomerular filtration rate [eGFR], urine albumin-to-creatinine ratio [uACR], serum urate, microalbuminuria and chronic kidney disease [CKD]) in up to 9688 European, African American and Hispanic/Latino individuals from seven population-based studies. RESULTS: We identified 23 significant associations in our large trans-ethnic meta-analysis (p < 1.43E-03 and consistent direction of effect across studies). Age acceleration measured by the Extrinsic and PhenoAge estimators, as well as Zhang's 10-CpG epigenetic mortality risk score (MRS), were associated with all parameters of poor kidney health (lower eGFR, prevalent CKD, higher uACR, microalbuminuria and higher serum urate). Six of these associations were independently observed in European and African American populations. MRS in particular was consistently associated with eGFR (ß = - 0.12, 95% CI = [- 0.16, - 0.08] change in log-transformed eGFR per unit increase in MRS, p = 4.39E-08), prevalent CKD (odds ratio (OR) = 1.78 [1.47, 2.16], p = 2.71E-09) and higher serum urate levels (ß = 0.12 [0.07, 0.16], p = 2.08E-06). The "first-generation" clocks (Hannum, Horvath) and GrimAge showed different patterns of association with the kidney traits. Three of the DNAm-estimated components of GrimAge, namely adrenomedullin, plasminogen-activation inhibition 1 and pack years, were positively associated with higher uACR, serum urate and microalbuminuria. CONCLUSION: DNAmAge acceleration and DNAm mortality predictors estimated in whole blood were associated with multiple kidney traits, including eGFR and CKD, in this multi-ethnic study. Epigenetic biomarkers which reflect the systemic effects of age-related mechanisms such as immunosenescence, inflammaging and oxidative stress may have important mechanistic or prognostic roles in kidney disease. Our study highlights new findings linking kidney disease to biological aging, and opportunities warranting future investigation into DNA methylation biomarkers for prognostic or risk stratification in kidney disease.

19.
Circ Genom Precis Med ; 14(3): e003191, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34019435

RESUMO

BACKGROUND: Increased left ventricular (LV) mass is associated with adverse cardiovascular events including heart failure (HF). Both increased LV mass and HF disproportionately affect Black individuals. To understand the underlying mechanisms, we undertook a proteomic screen in a Black cohort and compared the findings to results from a White cohort. METHODS: We measured 1305 plasma proteins using the SomaScan platform in 1772 Black participants (mean age, 56 years; 62% women) in JHS (Jackson Heart Study) with LV mass assessed by 2-dimensional echocardiography. Incident HF was assessed in 1600 participants. We then compared protein associations in JHS to those observed in White participants from FHS (Framingham Heart Study; mean age, 54 years; 56% women). RESULTS: In JHS, there were 110 proteins associated with LV mass and 13 proteins associated with incident HF hospitalization with false discovery rate <5% after multivariable adjustment. Several proteins showed expected associations with both LV mass and HF, including NT-proBNP (N-terminal pro-B-type natriuretic peptide; ß=0.04; P=2×10-8; hazard ratio, 1.48; P=0.0001). The strongest association with LV mass was novel: LKHA4 (leukotriene-A4 hydrolase; ß=0.05; P=5×10-15). This association was confirmed on an alternate proteomics platform and further supported by related metabolomic data. Fractalkine/CX3CL1 (C-X3-C Motif Chemokine Ligand 1) showed a novel association with incident HF (hazard ratio, 1.32; P=0.0002). While established biomarkers such as cystatin C and NT-proBNP showed consistent associations in Black and White individuals, LKHA4 and fractalkine were significantly different between the two groups. CONCLUSIONS: We identified several novel biological pathways specific to Black adults hypothesized to contribute to the pathophysiologic cascade of LV hypertrophy and incident HF including LKHA4 and fractalkine.

20.
Genome Med ; 13(1): 74, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33931109

RESUMO

BACKGROUND: DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach. METHODS: The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear mixed models adjusting for age, sex, smoking, and study-specific and technical variables. Summary results were meta-analyzed within and across ethnicities. Findings were assessed using integrative epigenomics methods and pathway analyses. RESULTS: We identified 93 DMPs associated with eGFR at an FDR of 0.05 and replicated 13 and 1 DMPs across independent samples in trans-ethnic and African American meta-analyses, respectively. The study also validated 6 previously published DMPs. Identified DMPs showed significant overlap enrichment with DNase I hypersensitive sites in kidney tissue, sites associated with the expression of proximal genes, and transcription factor motifs and pathways associated with kidney tissue and kidney development. CONCLUSIONS: We uncovered trans-ethnic and ethnic-specific DMPs associated with eGFR, including DMPs enriched in regulatory elements in kidney tissue and pathways related to kidney development. These findings shed light on epigenetic mechanisms associated with kidney function, bridging the gap between population-specific eGFR-associated DNAm and tissue-specific regulatory context.

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