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1.
Am J Hum Genet ; 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33031748

RESUMO

Variation in levels of the human metabolome reflect changes in homeostasis, providing a window into health and disease. The genetic impact on circulating metabolites in Hispanics, a population with high cardiometabolic disease burden, is largely unknown. We conducted genome-wide association analyses on 640 circulating metabolites in 3,926 Hispanic Community Health Study/Study of Latinos participants. The estimated heritability for 640 metabolites ranged between 0%-54% with a median at 2.5%. We discovered 46 variant-metabolite pairs (p value < 1.2 × 10-10, minor allele frequency ≥ 1%, proportion of variance explained [PEV] mean = 3.4%, PEVrange = 1%-22%) with generalized effects in two population-based studies and confirmed 301 known locus-metabolite associations. Half of the identified variants with generalized effect were located in genes, including five nonsynonymous variants. We identified co-localization with the expression quantitative trait loci at 105 discovered and 151 known loci-metabolites sets. rs5855544, upstream of SLC51A, was associated with higher levels of three steroid sulfates and co-localized with expression levels of SLC51A in several tissues. Mendelian randomization (MR) analysis identified several metabolites associated with coronary heart disease (CHD) and type 2 diabetes. For example, two variants located in or near CYP4F2 (rs2108622 and rs79400241, respectively), involved in vitamin E metabolism, were associated with the levels of octadecanedioate and vitamin E metabolites (gamma-CEHC and gamma-CEHC glucuronide); MR analysis showed that genetically high levels of these metabolites were associated with lower odds of CHD. Our findings document the genetic architecture of circulating metabolites in an underrepresented Hispanic/Latino community, shedding light on disease etiology.

2.
Genet Epidemiol ; 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32864785

RESUMO

Complex human diseases are affected by genetic and environmental risk factors and their interactions. Gene-environment interaction (GEI) tests for aggregate genetic variant sets have been developed in recent years. However, existing statistical methods become rate limiting for large biobank-scale sequencing studies with correlated samples. We propose efficient Mixed-model Association tests for GEne-Environment interactions (MAGEE), for testing GEI between an aggregate variant set and environmental exposures on quantitative and binary traits in large-scale sequencing studies with related individuals. Joint tests for the aggregate genetic main effects and GEI effects are also developed. A null generalized linear mixed model adjusting for covariates but without any genetic effects is fit only once in a whole genome GEI analysis, thereby vastly reducing the overall computational burden. Score tests for variant sets are performed as a combination of genetic burden and variance component tests by accounting for the genetic main effects using matrix projections. The computational complexity is dramatically reduced in a whole genome GEI analysis, which makes MAGEE scalable to hundreds of thousands of individuals. We applied MAGEE to the exome sequencing data of 41,144 related individuals from the UK Biobank, and the analysis of 18,970 protein coding genes finished within 10.4 CPU hours.

3.
Am J Kidney Dis ; 2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32979415

RESUMO

RATIONALE & OBJECTIVE: Obesity has been related to risk of chronic kidney disease (CKD). However, the associations of different measures of midlife obesity with long-term kidney function trajectories and whether they differ by sex and race is unknown. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: 13,496 participants from the ARIC study. PREDICTORS: Midlife obesity status as measured by body mass index (BMI), waist to hip ratio, and predicted percent fat at baseline. OUTCOMES: Estimated glomerular filtration rate (eGFR) calculated using serum creatinine measured at 5 study visits and end-stage kidney disease (ESKD). ANALYTICAL APPROACH: Mixed models with random intercepts and random slopes for eGFR. Cox proportional hazards models for ESKD. RESULTS: Baseline mean age was 54 years, median eGFR was 103 ml/min/1.73 m2, and median BMI was 27 kg/m2. Over 30 years of follow-up, midlife obesity measures were associated with eGFR decline in white and black women but not consistently in men. Adjusted for age, center, smoking and coronary heart disease (CHD), the differences (95% CI) in eGFR decline slope (unit: ml/min per 1.73 m2 per decade) per standard deviation higher BMI, waist to hip ratio, and predicted percent fat were 0.09 (-0.18, 0.36), -0.25 (-0.50, 0.01) and -0.14 (-0.41, 0.13) for white men, -0.91 (-1.15, -0.67), -0.82 (-1.06, -0.58) and -1.02 (-1.26, -0.78) for white women, -0.70 (-1.54, 0.14), -1.60 (-2.42, -0.78) and -1.24 (-2.08, -0.40) for black men, and -1.24 (-2.08, -0.40), -1.50 (-2.05, -0.95) and -1.43 (-2.00, -0.86) for black women. Obesity indicators were independently associated with risk of ESKD for all sex-race groups except white men. LIMITATIONS: Loss to follow-up during three decades of follow-up with five eGFR measurements. CONCLUSIONS: Obesity status is a risk factor for future decline in kidney function and development of ESKD in black and white women with less consistent associations among men.

4.
Epigenomics ; 12(17): 1483-1499, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32901515

RESUMO

Aim: We conducted a methylome-wide association study to examine associations between DNA methylation in whole blood and central adiposity and body fat distribution, measured as waist circumference, waist-to-hip ratio and waist-to-height ratio adjusted for body mass index, in 2684 African-American adults in the Atherosclerosis Risk in Communities study. Materials & methods: We validated significantly associated cytosine-phosphate-guanine methylation sites (CpGs) among adults using the Women's Health Initiative and Framingham Heart Study participants (combined n = 5743) and generalized associations in adolescents from The Raine Study (n = 820). Results & conclusion: We identified 11 CpGs that were robustly associated with one or more central adiposity trait in adults and two in adolescents, including CpG site associations near TXNIP, ADCY7, SREBF1 and RAP1GAP2 that had not previously been associated with obesity-related traits.

5.
Genome Med ; 12(1): 84, 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-32988399

RESUMO

BACKGROUND: Mitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. However, the mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation. METHODS: To investigate this hypothesis, we assessed the relationship between mtDNA-CN and nDNA methylation in 2507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings, we assayed an additional 2528 participants from the Cardiovascular Health Study (CHS) (N = 533) and Framingham Heart Study (FHS) (N = 1995). We further assessed the effect of experimental modification of mtDNA-CN through knockout of TFAM, a regulator of mtDNA replication, via CRISPR-Cas9. RESULTS: Thirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance (P < 5 × 10- 8). Meta-analysis across all cohorts identified six mtDNA-CN-associated CpGs at genome-wide significance (P < 5 × 10- 8). Additionally, over half of these CpGs were associated with phenotypes known to be associated with mtDNA-CN, including coronary heart disease, cardiovascular disease, and mortality. Experimental modification of mtDNA-CN demonstrated that modulation of mtDNA-CN results in changes in nDNA methylation and gene expression of specific CpGs and nearby transcripts. Strikingly, the "neuroactive ligand receptor interaction" KEGG pathway was found to be highly overrepresented in the ARIC cohort (P = 5.24 × 10- 12), as well as the TFAM knockout methylation (P = 4.41 × 10- 4) and expression (P = 4.30 × 10- 4) studies. CONCLUSIONS: These results demonstrate that changes in mtDNA-CN influence nDNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling.

6.
J Clin Endocrinol Metab ; 105(12)2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32785663

RESUMO

CONTEXT: Lower dehydroepiandrosterone-sulfate (DHEA-S) levels have been inconsistently associated with coronary heart disease (CHD) and mortality. Data are limited for heart failure (HF) and association between DHEA-S change and events. OBJECTIVE: Assess associations between low DHEA-S/DHEA-S change and incident HF hospitalization, CHD, and mortality in older adults. DESIGN: DHEA-S was measured in stored plasma from visits 4 (1996-1998) and 5 (2011-2013) of the Atherosclerosis Risk in Communities study. Follow-up for incident events: 18 years for DHEA-S level; 5.5 years for DHEA-S change. SETTING: General community. PARTICIPANTS: Individuals without prevalent cardiovascular disease (n = 8143, mean age 63 years). MAIN OUTCOME MEASURE: Associations between DHEA-S and incident HF hospitalization, CHD, or mortality; associations between 15-year change in DHEA-S (n = 3706) and cardiovascular events. RESULTS: DHEA-S below the 15th sex-specific percentile of the study population (men: 55.4 µg/dL; women: 27.4 µg/dL) was associated with increased HF hospitalization (men: hazard ratio [HR] 1.30, 95% confidence interval [CI], 1.07-1.58; women: HR 1.42, 95% CI, 1.13-1.79); DHEA-S below the 25th sex-specific percentile (men: 70.0 µg/dL; women: 37.1 µg/dL) was associated with increased death (men: HR 1.12, 95% CI, 1.01-1.25; women: HR 1.19, 95% CI, 1.03-1.37). In men, but not women, greater percentage decrease in DHEA-S was associated with increased HF hospitalization (HR 1.94, 95% CI, 1.11-3.39). Low DHEA-S and change in DHEA-S were not associated with incident CHD. CONCLUSIONS: Low DHEA-S is associated with increased risk for HF and mortality but not CHD. Further investigation is warranted to evaluate mechanisms underlying these associations.

7.
Nat Genet ; 52(9): 969-983, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32839606

RESUMO

Large-scale whole-genome sequencing studies have enabled the analysis of rare variants (RVs) associated with complex phenotypes. Commonly used RV association tests have limited scope to leverage variant functions. We propose STAAR (variant-set test for association using annotation information), a scalable and powerful RV association test method that effectively incorporates both variant categories and multiple complementary annotations using a dynamic weighting scheme. For the latter, we introduce 'annotation principal components', multidimensional summaries of in silico variant annotations. STAAR accounts for population structure and relatedness and is scalable for analyzing very large cohort and biobank whole-genome sequencing studies of continuous and dichotomous traits. We applied STAAR to identify RVs associated with four lipid traits in 12,316 discovery and 17,822 replication samples from the Trans-Omics for Precision Medicine Program. We discovered and replicated new RV associations, including disruptive missense RVs of NPC1L1 and an intergenic region near APOC1P1 associated with low-density lipoprotein cholesterol.

8.
JAMA Cardiol ; 2020 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-32717046

RESUMO

Importance: Cardiometabolic disease is responsible for decreased longevity and poorer cardiovascular outcomes in the modern era. Metabolite profiling provides a specific measure of global metabolic function to examine specific metabolic mechanisms and pathways of cardiometabolic disease beyond its clinical definitions. Objectives: To define a molecular basis for cardiometabolic stress and assess its association with cardiovascular prognosis. Design, Setting, and Participants: A prospective observational cohort study was conducted in a population-based setting across 2 geographically distinct centers (Boston Puerto Rican Health Study [BPRHS], an ongoing study of individuals enrolled between June 1, 2004, and October 31, 2009; and Atherosclerosis Risk in Communities [ARIC] study, whose participants were originally sampled between November 24, 1986, and February 10, 1990, and followed up through December 31, 2017). Participants in the BPRHS were 668 Puerto Rican individuals with metabolite profiling living in Massachusetts, and participants in the ARIC study were 2152 individuals with metabolite profiling and long-term follow-up for mortality and cardiovascular outcomes. Statistical analysis was performed from October 1, 2018, to March 13, 2020. Exposure: The primary exposure was metabolite profiles across both cohorts. Main Outcomes and Measures: Outcomes included associations with multisystem cardiometabolic stress and all-cause mortality and incident coronary heart disease (in the ARIC study). Results: Participants in the BPRHS (N = 668; 491 women; mean [SD] age, 57.0 [7.4] years; mean [SD] body mass index [calculated as weight in kilograms divided by height in meters squared], 32.0 [6.5]) had higher prevalent cardiometabolic risk relative to those in the ARIC study (N = 2152; 599 African American individuals; 1213 women; mean [SD] age, 54.3 [5.7] years; mean [SD] body mass index, 28.0 [5.5]). Multisystem cardiometabolic stress was defined for 668 Puerto Rican individuals in the BPRHS as a multidimensional composite of hypothalamic-adrenal axis activity, sympathetic activation, blood pressure, proatherogenic dyslipidemia, insulin resistance, visceral adiposity, and inflammation. A total of 260 metabolites associated with cardiometabolic stress were identified in the BPRHS, involving known and novel pathways of cardiometabolic disease (eg, amino acid metabolism, oxidative stress, and inflammation). A parsimonious metabolite-based score associated with cardiometabolic stress in the BPRHS was subsequently created; this score was applied to shared metabolites in the ARIC study, demonstrating significant associations with coronary heart disease and all-cause mortality after multivariable adjustment at a 30-year horizon (per SD increase in metabolomic score: hazard ratio, 1.14; 95% CI, 1.00-1.31; P = .045 for coronary heart disease; and hazard ratio, 1.15; 95% CI, 1.07-1.24; P < .001 for all-cause mortality). Conclusions and Relevance: Metabolites associated with cardiometabolic stress identified known and novel pathways of cardiometabolic disease in high-risk, community-based cohorts and were associated with coronary heart disease and survival at a 30-year time horizon. These results underscore the shared molecular pathophysiology of metabolic dysfunction, cardiovascular disease, and longevity and suggest pathways for modification to improve prognosis across all linked conditions.

9.
Blood ; 2020 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-32722807

RESUMO

Fibrinogen is a key component of the coagulation cascade, and variation in its circulating levels may contribute to thrombotic diseases, such as venous thromboembolism (VTE) and ischemic stroke. Gamma prime (γ') fibrinogen is an isoform of fibrinogen that has anticoagulant properties. We applied two-sample Mendelian randomization (MR) to estimate the causal effect of total circulating fibrinogen and its isoform, γ' fibrinogen, on risk of VTE and ischemic stroke subtypes using summary statistics from genome-wide association studies. Genetic instruments for γ' fibrinogen and total fibrinogen were selected and the inverse-variance weighted MR approach was used to estimate causal effects in the main analysis, complemented by sensitivity analyses that are more robust to the inclusion of pleiotropic variants, including MR-Egger, weighted median MR, and weighted mode MR. The main inverse-variance weighted MR estimates based on a combination of 16 genetic instruments for γ' fibrinogen and 75 genetic instruments for total fibrinogen indicated a protective effect of higher γ' fibrinogen and higher total fibrinogen on VTE risk. There was also a protective effect of higher γ' fibrinogen levels on cardioembolic and large artery stroke risk. Effect estimates were consistent across sensitivity analyses. Our results provide evidence to support effects of genetically determined γ' fibrinogen on VTE and ischemic stroke risk. Further research is needed to explore mechanisms underlying these effects, and their clinical applications.

11.
J Am Heart Assoc ; 9(13): e015405, 2020 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-32573308

RESUMO

Background Circulating galectin-3 levels provide prognostic information in patients with established heart failure (HF), but the associations between galectin-3 levels and other incident cardiovascular events in asymptomatic individuals at midlife and when remeasured ≈15 years later are largely uncharacterized. Methods and Results Using multivariable Cox proportional hazards models, we identified associations between plasma galectin-3 levels (hazard ratio [HR] per 1 SD increase in natural log galectin-3) and incident coronary heart disease, ischemic stroke, HF hospitalization, and total mortality in ARIC (Atherosclerosis Risk in Communities) participants free of cardiovascular disease at ARIC visit 4 (1996-1998; n=9247) and at ARIC visit 5 (2011-2013; n=4829). Higher galectin-3 level at visit 4 (median age 62) was independently associated with incident coronary heart disease (adjusted HR, 1.30; 95% CI, 1.06-1.60), ischemic stroke (HR, 1.42; 95% CI, 1.01-2.00), HF (HR, 1.44; 95% CI, 1.17-1.76), and mortality (HR, 1.56; 95% CI, 1.35-1.80). At visit 5 (median age, 74), higher galectin-3 level was associated with incident HF (HR, 1.93; 95% CI, 1.15-3.24) and total mortality (HR, 1.70; 95% CI, 1.15-2.52), but not coronary heart disease or stoke. Individuals with the greatest increase in galectin-3 levels from visit 4 to visit 5 were also at increased risk of incident HF and total mortality. Conclusions In a large, biracial community-based cohort, galectin-3 measured at midlife and older age was associated with increased risk of cardiovascular events. An increase in galectin-3 levels over this period was also associated with increased risk.

12.
Circ Genom Precis Med ; 13(4): e002772, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32510982

RESUMO

BACKGROUND: Alcohol intake influences plasma lipid levels, and such effects may be moderated by genetic variants. We aimed to characterize the role of aggregated rare and low-frequency protein-coding variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels. METHODS: In the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, fasting plasma triglycerides and high- and low-density lipoprotein cholesterol were measured in 34 153 individuals with European ancestry from 5 discovery studies and 32 277 individuals from 6 replication studies. Rare and low-frequency functional protein-coding variants (minor allele frequency, ≤5%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction test and a joint test of genetic main and gene-environment interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least 2 drinks per week, were considered. RESULTS: We discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci (PCSK9, LPA, LPL, LIPG, ANGPTL4, APOB, APOC3, and CD300LG) remained significant after conditioning on the common index single-nucleotide polymorphism identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on triglycerides in a novel locus was significantly discovered (P=6.65×10-6 for the interaction test) and replicated at nominal significance level (P=0.013) in SMC5. CONCLUSIONS: In conclusion, this study applied new gene-based statistical approaches and suggested that rare and low-frequency genetic variants interacted with alcohol consumption on lipid levels.

13.
Gut Microbes ; 11(6): 1632-1642, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32576065

RESUMO

Type 2 diabetes (T2D) is associated with reduced gut microbiome diversity, although the cause is unclear. Metabolites generated by gut microbes also appear to be causative factors in T2D. We therefore searched for serum metabolites predictive of gut microbiome diversity in 1018 females from TwinsUK with concurrent metabolomic profiling and microbiome composition. We generated a Microbial Metabolites Diversity (MMD) score of six circulating metabolites that explained over 18% of the variance in microbiome alpha diversity. Moreover, the MMD score was associated with a significantly lower odds of prevalent (OR[95%CI] = 0.22[0.07;0.70], P = .01) and incident T2D (HR[95%CI] = 0.31[0.11,0.90], P = .03). We replicated our results in 1522 individuals from the ARIC study (prevalent T2D: OR[95%CI] = 0.79[0.64,0.96], P = .02, incident T2D: HR[95%CI] = 0.87[0.79,0.95], P = .003). The MMD score mediated 28%[15%,94%] of the total effect of gut microbiome on T2D after adjusting for confounders. Metabolites predicting higher microbiome diversity included 3-phenylpropionate(hydrocinnamate), indolepropionate, cinnamoylglycine and 5-alpha-pregnan-3beta,20 alpha-diol monosulfate(2) of which indolepropionate and phenylpropionate have already been linked to lower incidence of T2D. Metabolites correlating with lower microbial diversity included glutarate and imidazole propionate, of which the latter has been implicated in insulin resistance. Our results suggest that the effect of gut microbiome diversity on T2D is largely mediated by microbial metabolites, which might be modifiable by diet.

14.
Sci Rep ; 10(1): 10018, 2020 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-32572055

RESUMO

Higher serum 6-bromotryptophan has been associated with lower risk of chronic kidney disease (CKD) progression, implicating mechanisms beyond renal clearance. We studied genetic determinants of urine 6-bromotryptophan and its association with CKD risk factors and incident end-stage kidney disease (ESKD) in 4,843 participants of the German Chronic Kidney Disease (GCKD) study. 6-bromotryptophan was measured from urine samples using mass spectrometry. Patients with higher levels of urine 6-bromotryptophan had higher baseline estimated glomerular filtration rate (eGFR, p < 0.001). A genome-wide association study of urine 6-bromotryptophan identified two significant loci possibly related to its tubular reabsorption, SLC6A19, and its production, ERO1A, which was also associated with serum 6-bromotryptophan in an independent study. The association between urine 6-bromotryptophan and time to ESKD was assessed using Cox regression. There were 216 ESKD events after four years of follow-up. Compared with patients with undetectable levels, higher 6-bromotryptophan levels were associated with lower risk of ESKD in models unadjusted and adjusted for ESKD risk factors other than eGFR (

15.
Hum Mol Genet ; 29(11): 1922-1932, 2020 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-32436959

RESUMO

Hundreds of loci have been associated with blood pressure (BP) traits from many genome-wide association studies. We identified an enrichment of these loci in aorta and tibial artery expression quantitative trait loci in our previous work in ~100 000 Genetic Epidemiology Research on Aging study participants. In the present study, we sought to fine-map known loci and identify novel genes by determining putative regulatory regions for these and other tissues relevant to BP. We constructed maps of putative cis-regulatory elements (CREs) using publicly available open chromatin data for the heart, aorta and tibial arteries, and multiple kidney cell types. Variants within these regions may be evaluated quantitatively for their tissue- or cell-type-specific regulatory impact using deltaSVM functional scores, as described in our previous work. We aggregate variants within these putative CREs within 50 Kb of the start or end of 'expressed' genes in these tissues or cell types using public expression data and use deltaSVM scores as weights in the group-wise sequence kernel association test to identify candidates. We test for association with both BP traits and expression within these tissues or cell types of interest and identify the candidates MTHFR, C10orf32, CSK, NOV, ULK4, SDCCAG8, SCAMP5, RPP25, HDGFRP3, VPS37B and PPCDC. Additionally, we examined two known QT interval genes, SCN5A and NOS1AP, in the Atherosclerosis Risk in Communities Study, as a positive control, and observed the expected heart-specific effect. Thus, our method identifies variants and genes for further functional testing using tissue- or cell-type-specific putative regulatory information.

16.
Kidney Int ; 98(3): 708-716, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32454124

RESUMO

Blood pressure and kidney function have a bidirectional relation. Hypertension has long been considered as a risk factor for kidney function decline. However, whether intensive blood pressure control could promote kidney health has been uncertain. The kidney is known to have a major role in affecting blood pressure through sodium extraction and regulating electrolyte balance. This bidirectional relation makes causal inference between these two traits difficult. Therefore, to examine the causal relations between these two traits, we performed two-sample Mendelian randomization analyses using summary statistics of large-scale genome-wide association studies. We selected genetic instruments more likely to be specific for kidney function using meta-analyses of complementary kidney function biomarkers (glomerular filtration rate estimated from serum creatinine [eGFRcr], and blood urea nitrogen from the CKDGen Consortium). Systolic and diastolic blood pressure summary statistics were from the International Consortium for Blood Pressure and UK Biobank. Significant evidence supported the causal effects of higher kidney function on lower blood pressure. Based on the mode-based Mendelian randomization method, the effect estimates for one standard deviation (SD) higher in log-transformed eGFRcr was -0.17 SD unit (95 % confidence interval: -0.09 to -0.24) in systolic blood pressure and -0.15 SD unit (95% confidence interval: -0.07 to -0.22) in diastolic blood pressure. In contrast, the causal effects of blood pressure on kidney function were not statistically significant. Thus, our results support causal effects of higher kidney function on lower blood pressure and suggest preventing kidney function decline can reduce the public health burden of hypertension.

17.
Am J Clin Nutr ; 112(1): 57-65, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32469399

RESUMO

BACKGROUND: Genetic or pharmacological inhibition of de novo sphingolipid synthases prevented diabetes in animal studies. OBJECTIVES: We sought to evaluate prospective associations of serum sphingolipids with incident diabetes in a population-based cohort. METHODS: We included 2010 participants of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) aged 18-74 y who were free of diabetes and other major chronic diseases at baseline (2008-2011). Metabolomic profiling of fasting serum was performed using a global, untargeted approach. A total of 43 sphingolipids were quantified and, considering subclasses and chemical structures of individual species, 6 sphingolipid scores were constructed. Diabetes status was assessed using standard procedures including blood tests. Multivariable survey Poisson regressions were applied to estimate RR and 95% CI of incident diabetes associated with individual sphingolipids or sphingolipid scores. RESULTS: There were 224 incident cases of diabetes identified during, on average, 6 y of follow-up. After adjustment for socioeconomic and lifestyle factors, a ceramide score (RR Q4 versus Q1 = 2.40; 95% CI: 1.24, 4.65; P-trend = 0.003) and a score of sphingomyelins with fully saturated sphingoid-fatty acid pairs (RR Q4 versus Q1 = 3.15; 95% CI: 1.75, 5.67; P-trend <0.001) both were positively associated with risk of diabetes, whereas scores of glycosylceramides, lactosylceramides, or other unsaturated sphingomyelins (even if having an SFA base) were not associated with risk of diabetes. After additional adjustment for numerous traditional risk factors (especially triglycerides), both associations were attenuated and only the saturated-sphingomyelin score remained associated with risk of diabetes (RR Q4 versus Q1 = 1.98; 95% CI: 1.09, 3.59; P-trend = 0.031). CONCLUSIONS: Our findings suggest that a cluster of saturated sphingomyelins may be associated with elevated risk of diabetes beyond traditional risk factors, which needs to be verified in other population studies. This study was registered at clinicaltrials.gov as NCT02060344.


Assuntos
Diabetes Mellitus/sangue , Diabetes Mellitus/etnologia , Esfingolipídeos/sangue , Adolescente , Adulto , Idoso , Diabetes Mellitus/epidemiologia , Feminino , Hispano-Americanos/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Estados Unidos/epidemiologia , Estados Unidos/etnologia , Adulto Jovem
18.
FASEB J ; 34(6): 7941-7957, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32293069

RESUMO

Acute renal depletion of sorting nexin 1 (SNX1) in mice results in blunted natriuretic response and hypertension due to impaired dopamine D5 receptor (D5 R) activity. We elucidated the molecular mechanisms for these phenotypes in Snx1-/- mice. These mice had increased renal expressions of angiotensin II type 1 receptor (AT1 R), NADPH oxidase (NOX) subunits, D5 R, and NaCl cotransporter. Basal reactive oxygen species (ROS), NOX activity, and blood pressure (BP) were also higher in Snx1-/- mice, which were normalized by apocynin, a drug that prevents NOX assembly. Renal proximal tubule (RPT) cells from hypertensive (HT) Euro-American males had deficient SNX1 activity, impaired D5 R endocytosis, and increased ROS compared with cells from normotensive (NT) Euro-American males. siRNA-mediated depletion of SNX1 in RPT cells from NT subjects led to a blunting of D5 R agonist-induced increase in cAMP production and decrease in Na+ transport, effects that were normalized by over-expression of SNX1. Among HT African-Americans, three of the 12 single nucleotide polymorphisms interrogated for the SNX1 gene were associated with a decrease in systolic BP in response to hydrochlorothiazide (HCTZ). The results illustrate a new paradigm for the development of hypertension and imply that the trafficking protein SNX1 may be a crucial determinant for hypertension and response to antihypertensive therapy.

19.
Artigo em Inglês | MEDLINE | ID: mdl-32233023

RESUMO

BACKGROUND: Wolff-Parkinson-White (WPW) syndrome is a relatively common arrhythmia affecting ~1-3/1,000 individuals. Mutations in PRKAG2 have been described in rare patients in association with cardiomyopathy. However, the genetic basis of WPW in individuals with a structurally normal heart remains poorly understood. Sudden death due to atrial fibrillation (AF) can also occur in these individuals. Several studies have indicated that despite ablation of an accessory pathway, the risk of AF remains high in patients compared to general population. METHODS: We applied exome sequencing in 305 subjects, including 65 trios, 80 singletons, and 6 multiple affected families. We used de novo analysis, candidate gene approach, and burden testing to explore the genetic contributions to WPW. RESULTS: A heterozygous deleterious variant in PRKAG2 was identified in one subject, accounting for 0.6% (1/151) of the genetic basis of WPW in this study. Another individual with WPW and left ventricular hypertrophy carried a known pathogenic variant in MYH7. We found rare de novo variants in genes associated with arrhythmia and cardiomyopathy (ANK2, NEBL, PITX2, and PRDM16) in this cohort. There was an increased burden of rare deleterious variants (MAF ≤ 0.005) with CADD score ≥ 25 in genes linked to AF in cases compared to controls (P = .0023). CONCLUSIONS: Our findings show an increased burden of rare deleterious variants in genes linked to AF in WPW syndrome, suggesting that genetic factors that determine the development of accessory pathways may be linked to an increased susceptibility of atrial muscle to AF in a subset of patients.

20.
Ann Clin Transl Neurol ; 7(5): 610-627, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32286009

RESUMO

OBJECTIVE: Defects in ion channels and neurotransmitter receptors are implicated in developmental and epileptic encephalopathy (DEE). Metabotropic glutamate receptor 7 (mGluR7), encoded by GRM7, is a presynaptic G-protein-coupled glutamate receptor critical for synaptic transmission. We previously proposed GRM7 as a candidate disease gene in two families with neurodevelopmental disorders (NDDs). One additional family has been published since. Here, we describe three additional families with GRM7 biallelic variants and deeply characterize the associated clinical neurological and electrophysiological phenotype and molecular data in 11 affected individuals from six unrelated families. METHODS: Exome sequencing and family-based rare variant analyses on a cohort of 220 consanguineous families with NDDs revealed three families with GRM7 biallelic variants; three additional families were identified through literature search and collaboration with a clinical molecular laboratory. RESULTS: We compared the observed clinical features and variants of 11 affected individuals from the six unrelated families. Identified novel deleterious variants included two homozygous missense variants (c.2671G>A:p.Glu891Lys and c.1973G>A:p.Arg685Gln) and one homozygous stop-gain variant (c.1975C>T:p.Arg659Ter). Developmental delay, neonatal- or infantile-onset epilepsy, and microcephaly were universal. Three individuals had hypothalamic-pituitary-axis dysfunction without pituitary structural abnormality. Neuroimaging showed cerebral atrophy and hypomyelination in a majority of cases. Two siblings demonstrated progressive loss of myelination by 2 years in both and an acquired microcephaly pattern in one. Five individuals died in early or late childhood. CONCLUSION: Detailed clinical characterization of 11 individuals from six unrelated families demonstrates that rare biallelic GRM7 pathogenic variants can cause DEEs, microcephaly, hypomyelination, and cerebral atrophy.

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