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1.
Blood ; 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34855941

RESUMO

Chronic obstructive pulmonary disease (COPD) is associated with age and smoking, but other determinants of the disease are incompletely understood. Clonal hematopoiesis of indeterminate potential (CHIP) is a common, age-related state in which somatic mutations in clonal blood populations induce aberrant inflammatory responses. Patients with CHIP have an elevated risk for cardiovascular disease, but the association with COPD remains unclear. We analyzed whole-genome and exome sequencing data to detect CHIP in 48,835 subjects, of whom 8,444 had moderate-to-very-severe COPD, from four separate cohorts with COPD phenotyping and smoking history. We measured emphysema in murine models in which Tet2 was deleted in hematopoietic cells. In COPDGene, individuals with CHIP had a risk of moderate-to-severe and severe or very severe COPD 1.6 and 2.2 times greater than non-carriers, respectively (adjusted 95% confidence intervals [CI], 1.1 to 2.2 and 1.5 to 3.2). These findings were consistent observed in three additional cohorts and meta-analyses of all subjects. CHIP was also associated with decreased FEV1% predicted in COPDGene (mean between group difference -5.7%; adjusted 95% CI, -8.8 to -2.6), a finding replicated in additional cohorts. Smoke exposure was associated with a small but significant increased risk of having CHIP (OR 1.03 per ten pack-years, 95% CI 1.01-1.05) in the meta-analysis of all subjects. Inactivation of Tet2 in mouse hematopoietic cells exacerbated emphysema development and inflammation in cigarette smoke exposure models. Somatic mutations in blood cells are associated with the development and severity of COPD, independent of age and cumulative smoke exposure.

2.
Stroke ; : STROKEAHA120031792, 2021 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-34727735

RESUMO

BACKGROUND AND PURPOSE: Stroke is the leading cause of death and long-term disability worldwide. Previous genome-wide association studies identified 51 loci associated with stroke (mostly ischemic) and its subtypes among predominantly European populations. Using whole-genome sequencing in ancestrally diverse populations from the Trans-Omics for Precision Medicine (TOPMed) Program, we aimed to identify novel variants, especially low-frequency or ancestry-specific variants, associated with all stroke, ischemic stroke and its subtypes (large artery, cardioembolic, and small vessel), and hemorrhagic stroke and its subtypes (intracerebral and subarachnoid). METHODS: Whole-genome sequencing data were available for 6833 stroke cases and 27 116 controls, including 22 315 European, 7877 Black, 2616 Hispanic/Latino, 850 Asian, 54 Native American, and 237 other ancestry participants. In TOPMed, we performed single variant association analysis examining 40 million common variants and aggregated association analysis focusing on rare variants. We also combined TOPMed European populations with over 28 000 additional European participants from the UK BioBank genome-wide array data through meta-analysis. RESULTS: In the single variant association analysis in TOPMed, we identified one novel locus 13q33 for large artery at whole-genome-wide significance (P<5.00×10-9) and 4 novel loci at genome-wide significance (P<5.00×10-8), all of which need confirmation in independent studies. Lead variants in all 5 loci are low-frequency but are more common in non-European populations. An aggregation of synonymous rare variants within the gene C6orf26 demonstrated suggestive evidence of association for hemorrhagic stroke (P<3.11×10-6). By meta-analyzing European ancestry samples in TOPMed and UK BioBank, we replicated several previously reported stroke loci including PITX2, HDAC9, ZFHX3, and LRCH1. CONCLUSIONS: We represent the first association analysis for stroke and its subtypes using whole-genome sequencing data from ancestrally diverse populations. While our findings suggest the potential benefits of combining whole-genome sequencing data with populations of diverse genetic backgrounds to identify possible low-frequency or ancestry-specific variants, they also highlight the need to increase genome coverage and sample sizes.

3.
Diabetes Care ; 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34789503

RESUMO

OBJECTIVE: LDL cholesterol (LDLc)-lowering drugs modestly increase body weight and type 2 diabetes risk, but the extent to which the diabetogenic effect of lowering LDLc is mediated through increased BMI is unknown. RESEARCH DESIGN AND METHODS: We conducted summary-level univariable and multivariable Mendelian randomization (MR) analyses in 921,908 participants to investigate the effect of lowering LDLc on type 2 diabetes risk and the proportion of this effect mediated through BMI. We used data from 92,532 participants from 14 observational studies to replicate findings in individual-level MR analyses. RESULTS: A 1-SD decrease in genetically predicted LDLc was associated with increased type 2 diabetes odds (odds ratio [OR] 1.12 [95% CI 1.01, 1.24]) and BMI (ß = 0.07 SD units [95% CI 0.02, 0.12]) in univariable MR analyses. The multivariable MR analysis showed evidence of an indirect effect of lowering LDLc on type 2 diabetes through BMI (OR 1.04 [95% CI 1.01, 1.08]) with a proportion mediated of 38% of the total effect (P = 0.03). Total and indirect effect estimates were similar across a number of sensitivity analyses. Individual-level MR analyses confirmed the indirect effect of lowering LDLc on type 2 diabetes through BMI with an estimated proportion mediated of 8% (P = 0.04). CONCLUSIONS: These findings suggest that the diabetogenic effect attributed to lowering LDLc is partially mediated through increased BMI. Our results could help advance understanding of adipose tissue and lipids in type 2 diabetes pathophysiology and inform strategies to reduce diabetes risk among individuals taking LDLc-lowering medications.

4.
Genet Epidemiol ; 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34672390

RESUMO

Mendelian randomization (MR) is an application of instrumental variable (IV) methods to observational data in which the IV is a genetic variant. MR methods applicable to the general exponential family of distributions are currently not well characterized. We adapt a general linear model framework to the IV setting and propose a general MR method applicable to any full-rank distribution from the exponential family. Empirical bias and coverage are estimated via simulations. The proposed method is compared to several existing MR methods. Real data analyses are performed using data from the REGARDS study to estimate the potential causal effect of smoking frequency on stroke risk in African Americans. In simulations with binary variates and very weak instruments the proposed method had the lowest median [Q1 , Q3 ] bias (0.10 [-3.68 to 3.62]); compared with 2SPS (0.27 [-3.74 to 4.26]) and the Wald method (-0.69 [-1.72 to 0.35]). Low bias was observed throughout other simulation scenarios; as well as more than 90% coverage for the proposed method. In simulations with count variates, the proposed method performed comparably to 2SPS; the Wald method maintained the most consistent low bias; and 2SRI was biased towards the null. Real data analyses find no evidence for a causal effect of smoking frequency on stroke risk. The proposed MR method has low bias and acceptable coverage across a wide range of distributional scenarios and instrument strengths; and provides a more parsimonious framework for asymptotic hypothesis testing compared to existing two-stage procedures.

5.
J Am Soc Nephrol ; 2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34706968

RESUMO

BACKGROUND: Alpha globin is expressed in endothelial cells of resistance arteries, where it limits endothelial nitric oxide signaling and enhances alpha adrenergic-mediated vasoconstriction. Alpha globin gene (HBA) copy number is variable in people of African descent and other populations worldwide. Given the protective effect of nitric oxide in the kidney, we hypothesized that HBA copy number would be associated with kidney disease risk. METHODS: Community-dwelling Black Americans age ≥45 years old were enrolled in a national longitudinal cohort from 2003 through 2007. HBA copy number was measured using droplet-digital PCR. The prevalence ratio (PR) of chronic kidney disease (CKD) and the relative risk (RR) of incident reduced estimated glomerular filtration rate (eGFR) were calculated using modified Poisson multivariable regression. The hazard ratio (HR) of incident end-stage kidney disease (ESKD) was calculated using Cox proportional hazards multivariable regression. RESULTS: Among 9,908 participants, HBA copy number varied from 2 to 6. In analyses adjusted for demographic, clinical, and genetic risk factors, a one-copy increase in HBA was associated with 14% greater prevalence of CKD (PR = 1.14, 95% CI 1.07 - 1.21; p < 0.0001). While HBA copy number was not associated with incident reduced eGFR (RR = 1.06, 95% CI 0.94 - 1.19; p = 0.38), the hazard of incident ESKD was 32% higher for each additional copy of HBA (HR = 1.32, 95% CI 1.09 -1.61; p = 0.005). CONCLUSIONS: Increasing HBA copy number was associated with a greater prevalence of CKD and incidence of ESKD in a national longitudinal cohort of Black Americans.

6.
J Endocr Soc ; 5(11): bvab139, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34568709

RESUMO

Context: Dyslipidemia is highly prevalent in youth with type 2 diabetes (T2D), yet the pathogenic components of dyslipidemia in youth with T2D are poorly understood. Objective: To evaluate the genetic determinants of lipid traits in youth with T2D through a genome-wide association study. Design Participants and Main Outcome Measures: We genotyped 206 928 variants and imputed 17 642 824 variants in 1076 youth (mean age 15.0 ± 2.48 years) with T2D from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) and SEARCH for Diabetes in Youth (SEARCH) studies as part of the Progress in Diabetes Genetics in Youth (ProDiGY) consortium. We performed association testing for triglyceride and low-density lipoprotein cholesterol and high-density lipoprotein cholesterol (HDL-c) concentrations adjusted for the genetic relationship matrix within each substudy followed by meta-analyses for each trait. Results: We identified a novel association between a deletion on chromosome 3 (3:67817380_AT/A_Deletion:RP11-81N13.1) and triglyceride levels at genome-wide level of significance (P = 2.3 × 10-8) with each risk allele increasing triglycerides by 20%. We also identified a genome-wide significant signal at rs247617 (P = 5.1 × 10-9) between HERFUD1 and CETP associated with HDL-c, with carriers of 1 copy of the risk allele having twice higher HDL-c. Conclusions: Our genetic analyses of lipid traits in youth with T2D have identified 1 novel and 1 previously known locus. Additional studies are needed to further characterize the genetic architecture of dyslipidemia in youth with T2D.

7.
Am J Hum Genet ; 108(10): 1836-1851, 2021 10 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.


Assuntos
Asma/epidemiologia , Biomarcadores/metabolismo , Dermatite Atópica/epidemiologia , Leucócitos/patologia , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Locos de Características Quantitativas , Asma/genética , Asma/metabolismo , Asma/patologia , Dermatite Atópica/genética , Dermatite Atópica/metabolismo , Dermatite Atópica/patologia , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , National Heart, Lung, and Blood Institute (U.S.) , Fenótipo , Prognóstico , Proteoma/análise , Proteoma/metabolismo , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Reino Unido/epidemiologia , Estados Unidos/epidemiologia , Sequenciamento Completo do Genoma
8.
J Am Heart Assoc ; 10(18): e020809, 2021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34514816

RESUMO

Background Individual blood cell count abnormalities have been associated with cardiovascular disease and increased mortality. In this study, we defined a "cytopenia phenotype," reflecting bone marrow hypoproliferation, to determine if peripheral blood cytopenia is associated with increased cardiovascular disease and mortality risk. Methods and Results Study participants were derived from a biracial observational cohort study, REGARDS (Reasons for Geographic and Racial Differences in Stroke), that enrolled 30 239 Black and White participants aged ≥45 years between 2003 and 2007. Median follow up was ≈9 years. The current study included 19 864 participants from REGARDS study (37.9% men, 40% Black participants) who have complete blood count available at study enrollment. We defined a cytopenia phenotype based on age-, sex-, and race-adjusted lowest fifth percentile of blood counts. Multivariable Cox proportional hazards models estimated the hazard ratios (HR) and 95% CI of cytopenia for mortality and incident cardiovascular disease in adjusted models. Mean age of the study participants was 64 years (SD:9.7). The prevalence of cytopenia was 1.9% (n=378). Cytopenia was associated with increased risk of all-cause mortality (HR, 1.73; 95% CI, 1.34-2.22) and cardiovascular disease mortality (HR, 1.56; 95% CI, 1.11-2.29). Cytopenia was associated with stroke risk in Black but not White participants (HR, 1.96 versus 0.86; P-interaction for race=0.08) and was not associated with coronary heart disease risk. Conclusions We defined a cytopenia phenotype with clinical implications for mortality and stroke risk in a large biracial and geographically diverse population. Whether generated through somatic mutations or decreased organ function, cytopenia was associated with mortality risk and was a race-specific risk factor for stroke.

9.
PLoS One ; 16(8): e0255411, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34411107

RESUMO

Human modification of water and nutrient flows has resulted in widespread degradation of aquatic ecosystems. The resulting global water crisis causes millions of deaths and trillions of USD in economic damages annually. Semiarid regions have been disproportionately affected because of high relative water demand and pollution. Many proven water management strategies are not fully implemented, partially because of a lack of public engagement with freshwater ecosystems. In this context, we organized a large citizen science initiative to quantify nutrient status and cultivate connection in the semiarid watershed of Utah Lake (USA). Working with community members, we collected samples from ~200 locations throughout the 7,640 km2 watershed on a single day in the spring, summer, and fall of 2018. We calculated ecohydrological metrics for nutrients, major ions, and carbon. For most solutes, concentration and leverage (influence on flux) were highest in lowland reaches draining directly to the lake, coincident with urban and agricultural sources. Solute sources were relatively persistent through time for most parameters despite substantial hydrological variation. Carbon, nitrogen, and phosphorus species showed critical source area behavior, with 10-17% of the sites accounting for most of the flux. Unlike temperate watersheds, where spatial variability often decreases with watershed size, longitudinal variability showed an hourglass shape: high variability among headwaters, low variability in mid-order reaches, and high variability in tailwaters. This unexpected pattern was attributable to the distribution of human activity and hydrological complexity associated with return flows, losing river reaches, and diversions in the tailwaters. We conclude that participatory science has great potential to reveal ecohydrological patterns and rehabilitate individual and community relationships with local ecosystems. In this way, such projects represent an opportunity to both understand and improve water quality in diverse socioecological contexts.


Assuntos
Ciência do Cidadão , Ecossistema , Rios , Nitrogênio , Fósforo , Qualidade da Água
10.
PLoS One ; 16(8): e0255337, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34432807

RESUMO

Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of mortality in the United States; however, COPD has heterogeneous clinical phenotypes. This is the first large scale attempt which uses transcriptomics, proteomics, and metabolomics (multi-omics) to determine whether there are molecularly defined clusters with distinct clinical phenotypes that may underlie the clinical heterogeneity. Subjects included 3,278 subjects from the COPDGene cohort with at least one of the following profiles: whole blood transcriptomes (2,650 subjects); plasma proteomes (1,013 subjects); and plasma metabolomes (1,136 subjects). 489 subjects had all three contemporaneous -omics profiles. Autoencoder embeddings were performed individually for each -omics dataset. Embeddings underwent subspace clustering using MineClus, either individually by -omics or combined, followed by recursive feature selection based on Support Vector Machines. Clusters were tested for associations with clinical variables. Optimal single -omics clustering typically resulted in two clusters. Although there was overlap for individual -omics cluster membership, each -omics cluster tended to be defined by unique molecular pathways. For example, prominent molecular features of the metabolome-based clustering included sphingomyelin, while key molecular features of the transcriptome-based clusters were related to immune and bacterial responses. We also found that when we integrated the -omics data at a later stage, we identified subtypes that varied based on age, severity of disease, in addition to diffusing capacity of the lungs for carbon monoxide, and precent on atrial fibrillation. In contrast, when we integrated the -omics data at an earlier stage by treating all data sets equally, there were no clinical differences between subtypes. Similar to clinical clustering, which has revealed multiple heterogenous clinical phenotypes, we show that transcriptomics, proteomics, and metabolomics tend to define clusters of COPD patients with different clinical characteristics. Thus, integrating these different -omics data sets affords additional insight into the molecular nature of COPD and its heterogeneity.


Assuntos
Perfilação da Expressão Gênica/métodos , Metabolômica/métodos , Proteômica/métodos , Doença Pulmonar Obstrutiva Crônica/classificação , Fatores Etários , Idoso , Análise por Conglomerados , Bases de Dados Factuais , Feminino , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/genética , Máquina de Vetores de Suporte
11.
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.


Assuntos
Adiposidade/genética , Afro-Americanos/estatística & dados numéricos , Estudo de Associação Genômica Ampla/métodos , Gordura Intra-Abdominal/patologia , Obesidade/fisiopatologia , Gordura Subcutânea/patologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores de Risco , Fatores Sexuais , Circunferência da Cintura
12.
Pediatr Rep ; 13(2): 279-288, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34205853

RESUMO

To examine whether BMI-associated genetic risk variants modify the association of intrauterine diabetes exposure with childhood BMI z-scores, we assessed the interaction between 95 BMI-associated genetic variants and in utero exposure to maternal diabetes among 459 children in the Exploring Perinatal Outcomes among Children historical prospective cohort study (n = 86 exposed; 373 unexposed) in relation to age- and sex-standardized childhood BMI z-scores (mean age = 10.3 years, standard deviation = 1.5 years). For the genetic variants showing a nominally significant interaction, we assessed the relationship in an additional 621 children in Project Viva, which is an independent longitudinal cohort study, and used meta-analysis to combine the results for the two studies. Seven of the ninety-five genetic variants tested exhibited a nominally significant interaction with in utero exposure to maternal diabetes in relation to the offspring BMI z-score in EPOCH. Five of the seven variants exhibited a consistent direction of interaction effect across both EPOCH and Project Viva. While none achieved statistical significance in the meta-analysis after accounting for multiple testing, three variants exhibited a nominally significant interaction with in utero exposure to maternal diabetes in relation to offspring BMI z-score: rs10733682 near LMX1B (interaction ß = 0.39; standard error (SE) = 0.17), rs17001654 near SCARB2 (ß = 0.53; SE = 0.22), and rs16951275 near MAP2K5 (ß = 0.37; SE = 0.17). BMI-associated genetic variants may enhance the association between exposure to in utero diabetes and higher childhood BMI, but larger studies of in utero exposures are necessary to confirm the observed nominally significant relationships.

13.
Diabetes Care ; 44(9): 2018-2024, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34257098

RESUMO

OBJECTIVE: The metabolic phenotype of youth-onset type 2 diabetes (T2D) differs from that of adult-onset T2D, but little is known about genetic contributions. We aimed to evaluate the association between a T2D genetic risk score (GRS) and traits related to glucose-insulin homeostasis among healthy youth. RESEARCH DESIGN AND METHODS: We used data from 356 youth (mean age 16.7 years; 50% female) in the Exploring Perinatal Outcomes Among Children (EPOCH) cohort to calculate a standardized weighted GRS based on 271 single nucleotide polymorphisms associated with T2D in adults. We used linear regression to assess associations of the GRS with log-transformed fasting glucose, 2-h glucose, HOMA of insulin resistance (HOMA-IR), oral disposition index, and insulinogenic index adjusted for age, sex, BMI z score, in utero exposure to maternal diabetes, and genetic principal components. We also evaluated effect modification by BMI z score, in utero exposure to maternal diabetes, and ethnicity. RESULTS: Higher weighted GRS was associated with lower oral disposition index (ß = -0.11; 95% CI -0.19, -0.02) and insulinogenic index (ß = -0.08; 95% CI -0.17, -0.001), but not with fasting glucose (ß = 0.01; 95% CI -0.01, 0.02), 2-h glucose (ß = 0.03; 95% CI -0.0004, 0.06), or HOMA-IR (ß = 0.02; 95% CI -0.04, 0.07). BMI z score and in utero exposure to maternal diabetes increased the effect of the GRS on glucose levels. CONCLUSIONS: Our results suggest that T2D genetic risk factors established in adults are relevant to glucose-insulin homeostasis in youth and that maintaining a healthy weight may be particularly important for youth with high genetic risk of T2D.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Adolescente , Glicemia , Criança , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Glucose , Homeostase , Humanos , Insulina , Resistência à Insulina/genética , Masculino , Fenótipo , Gravidez , Fatores de Risco
14.
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.

15.
Circ Genom Precis Med ; 14(4): e003258, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34241534

RESUMO

BACKGROUND: Coronary artery calcification (CAC) and carotid artery intima-media thickness (cIMT) are measures of subclinical atherosclerosis in asymptomatic individuals and strong risk factors for cardiovascular disease. Type 2 diabetes (T2D) is an independent cardiovascular disease risk factor that accelerates atherosclerosis. METHODS: We performed meta-analyses of genome-wide association studies in up to 2500 T2D individuals of European ancestry (EA) and 1590 T2D individuals of African ancestry with or without exclusion of prevalent cardiovascular disease, for CAC measured by cardiac computed tomography, and 3608 individuals of EA and 838 individuals of African ancestry with T2D for cIMT measured by ultrasonography within the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium. RESULTS: We replicated 2 loci (rs9369640 and rs9349379 near PHACTR1 and rs10757278 near CDKN2B) for CAC and one locus for cIMT (rs7412 and rs445925 near APOE-APOC1) that were previously reported in the general EA populations. We identified one novel CAC locus (rs8000449 near CSNK1A1L/LINC00547/POSTN at 13q13.3) at P=2.0×10-8 in EA. No additional loci were identified with the meta-analyses of EA and African ancestry. The expression quantitative trait loci analysis with nearby expressed genes derived from arterial wall and metabolic tissues from the Genotype-Tissue Expression project pinpoints POSTN, encoding a matricellular protein involved in bone formation and bone matrix organization, as the potential candidate gene at this locus. In addition, we found significant associations (P<3.1×10-4) for 3 previously reported coronary artery disease loci for these subclinical atherosclerotic phenotypes (rs2891168 near CDKN2B-AS1 and rs11170820 near FLJ12825 for CAC, and rs7412 near APOE for cIMT). CONCLUSIONS: Our results provide potential biological mechanisms that could link CAC and cIMT to increased cardiovascular disease risk in individuals with T2D.

16.
Clin Epigenetics ; 13(1): 121, 2021 06 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.

17.
J Pediatr ; 237: 50-58.e3, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34171361

RESUMO

OBJECTIVE: To examine associations of dietary changes from childhood to adolescence with adolescent hepatic fat and whether the PNPLA3 rs738409 risk allele, a strong genetic risk factor for hepatic fat, modifies associations. STUDY DESIGN: Data were from 358 participants in the Exploring Perinatal Outcomes among CHildren (EPOCH) study, a longitudinal cohort in Colorado. Diet was assessed by food frequency questionnaire in childhood (approximately 10 years of age) and adolescence (approximately 16 years of age) and converted to nutrient densities. Hepatic fat was assessed in adolescence by magnetic resonance imaging. Linear regression was used to test associations of dietary changes from childhood to adolescence with adolescent hepatic fat. RESULTS: Increases in fiber, vegetable protein, and polyunsaturated fat intake from childhood to adolescence were associated with lower adolescent hepatic fat, and increases in animal protein were associated with higher hepatic fat (ß per 5-unit increase on log-hepatic fat: -0.12 [95% CI, -0.21 to -0.02] for ▵fiber; -0.26 [95% CI, -0.45 to -0.07] for ▵vegetable protein; -0.18 [95% CI, -0.35 to -0.02] for ▵polyunsaturated fat; 0.13 [95% CI, 0.04-0.22] for ▵animal protein). There was evidence of effect modification by PNPLA3 variant, whereby inverse associations of ▵fiber and ▵vegetable protein and positive associations of ▵saturated fat with adolescent hepatic fat were stronger in risk allele carriers. Most conclusions were similar after adjusting for obesity in adolescence, but associations of ▵saturated fat with hepatic fat were attenuated toward the null. CONCLUSIONS: Our results suggest that nutrient intake changes between childhood and adolescence, particularly decreases in fiber and vegetable protein and increases in saturated fat intake, interact with the PNPLA3 variant to predict higher hepatic fat in adolescence, and may be targets for reducing hepatic fat in high-risk youth.


Assuntos
Dieta/efeitos adversos , Fígado Gorduroso/etiologia , Adolescente , Comportamento do Adolescente , Criança , Comportamento Infantil , Dieta/psicologia , Inquéritos sobre Dietas , Fígado Gorduroso/diagnóstico por imagem , Fígado Gorduroso/genética , Fígado Gorduroso/psicologia , Feminino , Interação Gene-Ambiente , Marcadores Genéticos , Predisposição Genética para Doença , Comportamentos Relacionados com a Saúde , Humanos , Modelos Lineares , Lipase/genética , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Proteínas de Membrana/genética , Estudos Prospectivos , Fatores de Risco , Autorrelato
19.
Genome Med ; 13(1): 74, 2021 04 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.

20.
Nat Commun ; 12(1): 2182, 2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33846329

RESUMO

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10-72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10-4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10-5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.


Assuntos
Fatores de Risco Cardiometabólico , Cromossomos Humanos X/genética , Lipídeos/sangue , Proteínas do Olho/metabolismo , Feminino , Regulação da Expressão Gênica , Estudos de Associação Genética , Loci Gênicos , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Fenômica , Polimorfismo de Nucleotídeo Único/genética , Tela Subcutânea/metabolismo , Sequenciamento Completo do Genoma
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