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1.
Am J Hum Genet ; 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32059761

RESUMO

Disease risk varies significantly between ethnic groups, however, the clinical significance and implications of these observations are poorly understood. Investigating ethnic differences within the human proteome may shed light on the impact of ancestry on disease risk. We used admixture mapping to explore the impact of genetic ancestry on 237 cardiometabolic biomarkers in 2,216 Latin Americans within the Outcomes Reduction with an Initial Glargine Intervention (ORIGIN) study. We developed a variance component model in order to determine the proportion of variance explained by inter-ancestry differences, and we applied it to the biomarker panel. Multivariable linear regression was used to identify and localize genetic loci affecting biomarker variability between ethnicities. Variance component analysis revealed that 5% of biomarkers were significantly impacted by genetic admixture (p < 0.05/237), including C-peptide, apolipoprotein-E, and intercellular adhesion molecule 1. We also identified 46 regional associations across 40 different biomarkers (p < 1.13 × 10-6). An independent analysis revealed that 34 of these 46 regions were associated at genome-wide significance (p < 5 × 10-8) with their respective biomarker in either Europeans or Latin populations. Additional analyses revealed that an admixture mapping signal associated with increased C-peptide levels was also associated with an increase in diabetes risk (odds ratio [OR] = 6.07 per SD, 95% confidence interval [CI] 1.44 to 25.56, p = 0.01) and surrogate measures of insulin resistance. Our results demonstrate the impact of ancestry on biomarker levels, suggesting that some of the observed differences in disease prevalence have a biological basis, and that reference intervals for those biomarkers should be tailored to ancestry. Specifically, our results point to a strong role of ancestry in insulin resistance and diabetes risk.

2.
Diabetes Care ; 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32019855

RESUMO

OBJECTIVE: To determine whether ACE inhibitors reduce the risk of type 2 diabetes using a Mendelian randomization (MR) approach. RESEARCH DESIGN AND METHODS: A two-sample MR analysis included 17 independent genetic variants associated with ACE serum concentration in 4,147 participants from the Outcome Reduction with Initial Glargine INtervention (ORIGIN; NCT00069784) trial, and their effects on type 2 diabetes risk were estimated from 18 studies of the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium. A genetic risk score (GRS) underpinning lower ACE concentration was then tested for association with type 2 diabetes prevalence in 341,872 participants, including 16,320 with type 2 diabetes, from the UK Biobank. MR estimates were compared after standardization for blood pressure change, with the estimate obtained from a randomized controlled trial (RCT) meta-analysis of ACE inhibitors versus placebo (n = 31,200). RESULTS: Genetically lower ACE concentrations were associated with a lower risk of type 2 diabetes (odds ratio [OR] per SD 0.92 [95% CI 0.89-0.95]; P = 1.79 × 10-7). This result was replicated in the UK Biobank (OR per SD 0.97 [0.96-0.99]; P = 8.73 × 10-4). After standardization, the ACE GRS was associated with a larger decrease in type 2 diabetes risk per 2.4-mmHg lower mean arterial pressure (MAP) compared with that obtained from an RCT meta-analysis (OR per 2.4-mmHg lower MAP 0.19 [0.07-0.51] vs. 0.76 [0.60-0.97], respectively; P = 0.007 for difference). CONCLUSIONS: These results support the causal protective effect of ACE inhibitors on type 2 diabetes risk and may guide therapeutic decision making in clinical practice.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31928076

RESUMO

Background - Hypertension is a common modifiable risk factor for cardiovascular disease and mortality. Pathophysiological mechanisms leading to hypertension remain incompletely understood. Mendelian randomization (MR) allows the evaluation of the causal role of markers by minimizing the risk of biases such as reverse causation and confounding. We aimed to identify novel circulating proteins associated with blood pressure through a comprehensive screen of 227 blood biomarkers using MR. Methods - Genetic determinants of 227 biomarkers were identified in Outcome Reduction with Initial Glargine Intervention (ORIGIN; NCT00069784) participants (N=4,147) and combined with genetic effects on systolic, diastolic, mean arterial and pulse pressure (SBP, DBP, MAP and PP) from the International Consortium for Blood Pressure (ICBP; 74,064 individuals) using MR. Results were replicated in the UK Biobank (up to 319,103 individuals) and using another biomarker dataset (N=3,301). MR analyses with cardiovascular risk factors and outcomes as well as other biomarkers were performed to further evaluate the mechanisms involved. Results - Six biomarkers were associated with blood pressure using MR after adjustment for multiple hypothesis testing. Relationships between N-terminal prohormone of brain natriuretic peptide (NT-proBNP), SBP and DBP confirmed previous reports. Novel circulating proteins associated with blood pressure were also identified: urokinase-type plasminogen activator (uPA) was related to SBP; adrenomedullin (ADM) was related to SBP and PP; interleukin-16 (IL16) was related to DBP; cellular fibronectin (cFn) and insulin-like growth factor binding protein 3 (IGFBP3) were related to PP. With the exception of IL16 and DBP (p=0.58), these relationships were validated in the UK Biobank (p<0.0001). Further MR analyses with cardiovascular risk factors and outcomes showed relationships between NT-proBNP and large-artery atherosclerotic stroke, IGFBP3 and diabetes as well as cFn and body-mass index. Conclusions - We identified novel biomarkers associated with blood pressure using Mendelian randomization. These markers could prove useful for risk assessment and as potential therapeutic targets.

4.
Diabetes ; 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31974142

RESUMO

The cardiovascular benefits of fibrates have been shown to be heterogeneous and to depend on the presence of atherogenic dyslipidemia. We investigated whether genetic variability in the PPARA gene, coding for the pharmacological target of fibrates (PPAR-alpha), could be used to improve the selection of patients with type 2 diabetes who may derive cardiovascular benefit from addition of this treatment to statins. We identified a common variant at the PPARA locus (rs6008845, C/T) displaying a study-wide-significant influence on the effect of fenofibrate on major cardiovascular events (MACE) among 3,065 self-reported White subjects treated with simvastatin and randomized to fenofibrate or placebo in the Action-to-Control-Cardiovascular-Risk-in-Diabetes (ACCORD) Lipid Trial. T/T homozygotes (36% of participants) experienced a 51% MACE reduction in response to fenofibrate (HR=0.49; 95%C.I. 0.34-0.72) whereas no benefit was observed for other genotypes (p for interaction=3.7x10-4). The "rs6008845-by-fenofibrate" interaction on MACE was replicated in African-Americans from ACCORD (N=585, p=0.02) and in external cohorts (ACCORD-Blood-Pressure, ORIGIN, and TRIUMPH, total N=3059, p=0.005). Remarkably, rs6008845 T/T homozygotes experienced a cardiovascular benefit from fibrate even in the absence of atherogenic dyslipidemia. Among these individuals, but not among carriers of other genotypes, fenofibrate treatment was associated with lower circulating levels of CCL11 - a pro-inflammatory and atherogenic chemokine also known as eotaxin (p for rs6008845-by-fenofibrate interaction=0.003). The Genotype-Tissue Expression (GTEx) dataset revealed regulatory functions of rs6008845 on PPARA expression in many tissues. In summary, we have found a common PPARA regulatory variant that influences the cardiovascular effects of fenofibrate and that could be used to identify T2D patients who would derive benefit from fenofibrate treatment, in addition to those with atherogenic dyslipidemia.

6.
EBioMedicine ; 51: 102584, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31901861

RESUMO

BACKGROUND: Genetic risk factors for dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) and dengue fever (DF) are limited, in particular there are sparse data on genetic risk across diverse populations. METHODS: We conducted a genome-wide association study (GWAS) in a derivation and validation sample of 7, 460 participants of Latin American, South Asian, and South East Asian ancestries. We then developed a weighted polygenic risk score (PRS) for each participant in each of the validation cohorts of the three ancestries to predict the risk of DHF/DSS compared to DF, DHF/DSS compared to controls, and, DF compared to controls. FINDINGS: The risk of DHF/DSS was significantly increased, odds ratio [OR] 1.84 (95%CI 1.47 to 2.31) (195 SNPs), compared to DF, fourth PRS quartile versus first quartile, in the validation cohort. The risk of DHF/DSS compared to controls was increased (OR=3.94; 95% CI 2.84 to 5.45) (278 SNPs), as was the risk of DF compared to controls (OR=1.97; 95%CI 1.63 to 2.39) (251 SNPs). Risk increased in a dose-dependent manner with increase in quartiles of PRS across comparisons. Significant associations persisted for PRS built within ancestries and applied to the same or different ancestries as well as for PRS built for one outcome (DHF/DSS or DF) and applied to the other. INTERPRETATION: There is a strong genetic effect that predisposes to risk of DHF/DSS and DF. The genetic risk for DHF/DSS is higher than that for DF when compared to controls, and this effect persists across multiple ancestries.

7.
Diabetes Care ; 43(2): 433-439, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31727687

RESUMO

OBJECTIVE: Diabetes is a major risk factor for renal function decline and failure. The availability of multiplex panels of biochemical markers provides the opportunity to identify novel biomarkers that can better predict changes in renal function than routinely available clinical markers. RESEARCH DESIGN AND METHODS: The concentration of 239 biochemical markers was measured in stored serum from participants in the biomarker substudy of Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial. Repeated-measures mixed-effects models were used to compute the annual change in eGFR (measured as mL/min/1.73 m2/year) for the 7,482 participants with a recorded baseline and follow-up eGFR. Linear regression models using forward selection were used to identify the independent biomarker determinants of the annual change in eGFR after accounting for baseline HbA1c, baseline eGFR, and routinely measured clinical risk factors. The incidence of the composite renal outcome (i.e., renal replacement therapy, renal death, renal failure, albuminuria progression, doubling of serum creatinine) and death within each fourth of change in eGFR predicted from these models was also estimated. RESULTS: During 6.2 years of median follow-up, the median annual change in eGFR was -0.18 mL/min/1.73 m2/year. Fifteen biomarkers independently predicted eGFR decline after accounting for cardiovascular risk factors, as did 12 of these plus 1 additional biomarker after accounting for renal risk factors. Every 0.1 mL/min/1.73 m2 predicted annual fall in eGFR predicted a 13% (95% CI 12, 14%) higher mortality. CONCLUSIONS: Adding up to 16 biomarkers to routinely measured clinical risk factors improves the prediction of annual change in eGFR in people with dysglycemia.

8.
J Med Genet ; 57(1): 11-17, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31391289

RESUMO

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are novel therapeutics for reducing low-density lipoprotein cholesterol (LDLc). While serious side-effects have not been observed in short-term clinical trials, there remain concerns that long-term PCSK9 inhibition may cause neurocognitive side-effects. METHODS AND RESULTS: An adult male with childhood-onset global developmental delay, cerebellar atrophy and severe hypolipidaemia underwent extensive biochemical and genetic investigations. Initial testing revealed low circulating PCSK9 levels and a common loss-of-function PCSK9 polymorphism, but these findings did not fully account for severe hypolipidaemia. Whole-exome sequencing was subsequently performed and identified two pathogenic phosphomannose mutase 2 (PMM2) variants (p.Arg141His and p.Pro69Ser) known to cause PMM2-associated congenital disorder of glycosylation (PMM2-CDG). A diagnosis of PMM2-CDG was consistent with the proband's neurological symptoms and severe hypolipidaemia. Given that PMM2-CDG is characterised by defective protein N-glycosylation and that PCSK9 is a negative regulator of LDLc, we postulated that loss of PCSK9 N-glycosylation mediates hypolipidaemia among patients with PMM2-CDG. First, in an independent cohort of patients with PMM2-CDG (N=8), we verified that circulating PCSK9 levels were significantly lower in patients than controls (p=0.0006). Second, we conducted in vitro experiments in hepatocyte-derived cells to evaluate the effects of PCSK9 N-glycosylation loss on LDL receptor (LDLR) activity. Experimental results suggest that defective PCSK9 N-glycosylation reduces the ability of circulating PCSK9 to degrade LDLR. CONCLUSION: Life-long exposure to genetically lower PCSK9 per se is unlikely to cause neurocognitive impairment. Both observational and experimental findings suggest that hypolipidaemia in PMM2-CDG may be partially mediated by loss of PCSK9 N-glycosylation and/or its regulators.

9.
Age Ageing ; 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31830268

RESUMO

New trials of dementia prevention are needed to test novel strategies and agents. Large, simple, cardiovascular trials have successfully discovered treatments with moderate but worthwhile effects to prevent heart attack and stroke. The design of these trials may hold lessons for the dementia prevention. Here we outline suitable populations, interventions and outcomes for large simple trials in dementia prevention. We consider what features are needed to maximise efficiency. Populations could be selected by age, clinical or genetic risk factors or clinical presentation. Patients and their families prioritise functional and clinical outcomes over cognitive scores and levels of biomarkers. Loss of particular functions or dementia diagnoses therefore are most meaningful to participants and potential patients and can be measured in large trials. The size of the population and duration of follow-up needed for dementia prevention trials will be a major challenge and will need collaboration between many clinical investigators, funders and patient organisations.

10.
Ann Intern Med ; 2019 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-31869834

RESUMO

Background: Preliminary data suggest that preoperative N-terminal pro-B-type natriuretic peptide (NT-proBNP) may improve risk prediction in patients undergoing noncardiac surgery. Objective: To determine whether preoperative NT-proBNP has additional predictive value beyond a clinical risk score for the composite of vascular death and myocardial injury after noncardiac surgery (MINS) within 30 days after surgery. Design: Prospective cohort study. Setting: 16 hospitals in 9 countries. Patients: 10 402 patients aged 45 years or older having inpatient noncardiac surgery. Measurements: All patients had NT-proBNP levels measured before surgery and troponin T levels measured daily for up to 3 days after surgery. Results: In multivariable analyses, compared with preoperative NT-proBNP values less than 100 pg/mL (the reference group), those of 100 to less than 200 pg/mL, 200 to less than 1500 pg/mL, and 1500 pg/mL or greater were associated with adjusted hazard ratios of 2.27 (95% CI, 1.90 to 2.70), 3.63 (CI, 3.13 to 4.21), and 5.82 (CI, 4.81 to 7.05) and corresponding incidences of the primary outcome of 12.3% (226 of 1843), 20.8% (542 of 2608), and 37.5% (223 of 595), respectively. Adding NT-proBNP thresholds to clinical stratification (that is, the Revised Cardiac Risk Index [RCRI]) resulted in a net absolute reclassification improvement of 258 per 1000 patients. Preoperative NT-proBNP values were also statistically significantly associated with 30-day all-cause mortality (less than 100 pg/mL [incidence, 0.3%], 100 to less than 200 pg/mL [incidence, 0.7%], 200 to less than 1500 pg/mL [incidence, 1.4%], and 1500 pg/mL or greater [incidence, 4.0%]). Limitation: External validation of the identified NT-proBNP thresholds in other cohorts would reinforce our findings. Conclusion: Preoperative NT-proBNP is strongly associated with vascular death and MINS within 30 days after noncardiac surgery and improves cardiac risk prediction in addition to the RCRI. Primary Funding Source: Canadian Institutes of Health Research.

11.
Sci Rep ; 9(1): 17507, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31745232

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

12.
Indian Heart J ; 71(3): 184-198, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31543191

RESUMO

Malignant coronary artery disease (CAD) refers to a severe and extensive atherosclerotic process involving multiple coronary arteries in young individuals (aged <45 years in men and <50 years in women) with a low or no burden of established risk factors. Indians, in general, develop acute myocardial infarction (AMI) about 10 years earlier; AMI rates are threefold to fivefold higher in young Indians than in other populations. Although established CAD risk factors have a predictive value, they do not fully account for the excessive burden of CAD in young Indians. Lipoprotein(a) (Lp(a)) is increasingly recognized as the strongest known genetic risk factor for premature CAD, with high levels observed in Indians with malignant CAD. High Lp(a) levels confer a twofold to threefold risk of CAD-a risk similar to that of established risk factors, including diabetes. South Asians have the second highest Lp(a) levels and the highest risk of AMI from the elevated levels, more than double the risk observed in people of European descent. Approximately 25% of Indians and other South Asians have elevated Lp(a) levels (≥50 mg/dl), rendering Lp(a) a risk factor of great importance, similar to or surpassing diabetes. Lp(a) measurement is ready for clinical use and should be an essential part of all CAD research in Indians.

13.
Curr Opin Cardiol ; 34(6): 706-713, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31436558

RESUMO

PURPOSE OF REVIEW: This review is a comprehensive update on recent discoveries on the genetics of early-onset coronary artery disease (EOCAD), and how those findings can be translated to advance its medical management. RECENT FINDINGS: To date, a total of 266 common variants of modest effect size have been reported to be associated with CAD, but many still warrant functional studies. Rare variants impacting the function of at least 10 genes are now well characterized in Mendelian EOCAD. Estimations of minor allele frequencies in multiple ancestries from large genetic databases have allowed us to estimate the prevalence of Mendelian forms of EOCAD. In fact, the prevalence of Mendelian mutations varies markedly between ancestries, ranging from 1 : 289 to 1 : 153 for familial hypercholesterolemia. Mendelian forms of EOCAD support three major biological pathways, including lipid metabolism, vascular wall integrity and function, and thrombosis. Furthermore, combining common variants of modest effect into polygenic risk scores (PRS) has shown to be effective at identifying individuals at high risk of CAD. SUMMARY: Mendelian forms of EOCAD highlight the importance of lipid metabolism, yet prevalence in many non-European populations remains to be clarified. Polygenic EOCAD affects more individuals and, in many cases, confers a higher risk of EOCAD than rare Mendelian mutations. Thus, sequencing of target genes and the derivation of PRSs can be used to identify high-risk patients, leading to more personalized therapeutic approaches.

14.
Indian Heart J ; 71(2): 99-112, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31280836

RESUMO

Lipoprotein(a) [Lp(a)] is a circulating lipoprotein, and its level is largely determined by variation in the Lp(a) gene (LPA) locus encoding apo(a). Genetic variation in the LPA gene that increases Lp(a) level also increases coronary artery disease (CAD) risk, suggesting that Lp(a) is a causal factor for CAD risk. Lp(a) is the preferential lipoprotein carrier for oxidized phospholipids (OxPL), a proatherogenic and proinflammatory biomarker. Lp(a) adversely affects endothelial function, inflammation, oxidative stress, fibrinolysis, and plaque stability, leading to accelerated atherothrombosis and premature CAD. The INTER-HEART Study has established the usefulness of Lp(a) in assessing the risk of acute myocardial infarction in ethnically diverse populations with South Asians having the highest risk and population attributable risk. The 2018 Cholesterol Clinical Practice Guideline have recognized elevated Lp(a) as an atherosclerotic cardiovascular disease risk enhancer for initiating or intensifying statin therapy.


Assuntos
Doenças Cardiovasculares/genética , Lipoproteína(a)/genética , Ásia Sudeste , Estudo de Associação Genômica Ampla , Humanos , Infarto do Miocárdio/genética , Polimorfismo de Nucleotídeo Único , Fatores de Risco
15.
Genet Epidemiol ; 43(7): 815-830, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31332826

RESUMO

Genotype-stratified variance of a quantitative trait could differ in the presence of gene-gene or gene-environment interactions. Genetic markers associated with phenotypic variance are thus considered promising candidates for follow-up interaction or joint location-scale analyses. However, as in studies of main effects, the X-chromosome is routinely excluded from "whole-genome" scans due to analytical challenges. Specifically, as males carry only one copy of the X-chromosome, the inherent sex-genotype dependency could bias the trait-genotype association, through sexual dimorphism in quantitative traits with sex-specific means or variances. Here we investigate phenotypic variance heterogeneity associated with X-chromosome single nucleotide polymorphisms (SNPs) and propose valid and powerful strategies. Among those, a generalized Levene's test has adequate power and remains robust to sexual dimorphism. An alternative approach is a sex-stratified analysis but at the cost of slightly reduced power and modeling flexibility. We applied both methods to an Estonian study of gene expression quantitative trait loci (eQTL; n = 841), and two complex trait studies of height, hip, and waist circumferences, and body mass index from Multi-Ethnic Study of Atherosclerosis (MESA; n = 2,073) and UK Biobank (UKB; n = 327,393). Consistent with previous eQTL findings on mean, we found some but no conclusive evidence for cis regulators being enriched for variance association. SNP rs2681646 is associated with variance of waist circumference (p = 9.5E-07) at X-chromosome-wide significance in UKB, with a suggestive female-specific effect in MESA (p = 0.048). Collectively, an enrichment analysis using permutated UKB (p < 0.1) and MESA (p < 0.01) datasets, suggests a possible polygenic structure for the variance of human height.


Assuntos
Cromossomos Humanos X/genética , Heterogeneidade Genética , Herança Multifatorial/genética , Locos de Características Quantitativas/genética , Simulação por Computador , Feminino , Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Fenótipo , Caracteres Sexuais , Circunferência da Cintura
16.
Circulation ; 140(10): 819-830, 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31208196

RESUMO

BACKGROUND: Novel, effective, and safe drugs are warranted for treatment of ischemic stroke. Circulating protein biomarkers with causal genetic evidence represent promising drug targets, but no systematic screen of the proteome has been performed. METHODS: First, using Mendelian randomization (MR) analyses, we assessed 653 circulating proteins as possible causal mediators for 3 different subtypes of ischemic stroke: large artery atherosclerosis, cardioembolic stroke, and small artery occlusion. Second, we used MR to assess whether identified biomarkers also affect risk for intracranial bleeding, specifically intracerebral and subarachnoid hemorrhages. Third, we expanded this analysis to 679 diseases to test a broad spectrum of side effects associated with hypothetical therapeutic agents for ischemic stroke that target the identified biomarkers. For all MR analyses, summary-level data from genome-wide association studies (GWAS) were used to ascertain genetic effects on circulating biomarker levels versus disease risk. Biomarker effects were derived by meta-analysis of 5 GWAS (N≤20 509). Disease effects were derived from large GWAS analyses, including MEGASTROKE (N≤322 150) and UK Biobank (N≤408 961) studies. RESULTS: Several biomarkers emerged as causal mediators for ischemic stroke. Causal mediators for cardioembolic stroke included histo-blood group ABO system transferase, coagulation factor XI, scavenger receptor class A5 (SCARA5), and tumor necrosis factor-like weak inducer of apoptosis (TNFSF12). Causal mediators for large artery atherosclerosis included ABO, cluster of differentiation 40, apolipoprotein(a), and matrix metalloproteinase-12. SCARA5 (odds ratio [OR]=0.78; 95% CI, 0.70-0.88; P=1.46×10-5) and TNFSF12 (OR=0.86; 95% CI, 0.81-0.91; P=7.69×10-7) represent novel protective mediators of cardioembolic stroke. TNFSF12 also increased the risk of subarachnoid (OR=1.53; 95% CI, 1.31-1.78; P=3.32×10-8) and intracerebral (OR=1.34; 95% CI, 1.14-1.58; P=4.05×10-4) hemorrhages, whereas SCARA5 decreased the risk of subarachnoid hemorrhage (OR=0.61; 95% CI, 0.47-0.81; P=5.20×10-4). Multiple side effects beyond stroke were identified for 6 of 7 biomarkers, most (75%) of which were beneficial. No adverse side effects were found for coagulation factor XI, apolipoprotein(a), and SCARA5. CONCLUSIONS: Through a systematic MR screen of the circulating proteome, causal roles for 5 established and 2 novel biomarkers for ischemic stroke were identified. Side-effect profiles were characterized to help inform drug target prioritization. In particular, SCARA5 represents a promising target for treatment of cardioembolic stroke, with no predicted adverse side effects.

17.
Diabetes Care ; 42(9): 1800-1808, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31235487

RESUMO

OBJECTIVE: Observations of a metabolically unhealthy normal weight phenotype suggest that a lack of favorable adiposity contributes to an increased risk of type 2 diabetes. We aimed to identify causal blood biomarkers linking favorable adiposity with type 2 diabetes risk for use in cardiometabolic risk assessments. RESEARCH DESIGN AND METHODS: A weighted polygenic risk score (PRS) underpinning metabolically favorable adiposity was validated in the UK Biobank (n = 341,872) and the Outcome Reduction With Initial Glargine Intervention (ORIGIN Trial) (n = 8,197) and tested for association with 238 blood biomarkers. Associated biomarkers were investigated for causation with type 2 diabetes risk using Mendelian randomization and for its performance in predictive models for incident major adverse cardiovascular events (MACE). RESULTS: Of the 238 biomarkers tested, only insulin-like growth factor-binding protein (IGFBP)-3 concentration was associated with the PRS, where a 1 unit increase in PRS predicted a 0.28-SD decrease in IGFBP-3 blood levels (P < 0.05/238). Higher IGFBP-3 levels causally increased type 2 diabetes risk (odds ratio 1.26 per 1 SD genetically determined IGFBP-3 level [95% CI 1.11-1.43]) and predicted a higher incidence of MACE (hazard ratio 1.13 per 1 SD IGFBP-3 concentration [95% CI 1.07-1.20]). Adding IGFBP-3 concentrations to the standard clinical assessment of metabolic health enhanced the prediction of incident MACE, with a net reclassification improvement of 11.5% in normal weight individuals (P = 0.004). CONCLUSIONS: We identified IGFBP-3 as a novel biomarker linking a lack of favorable adiposity with type 2 diabetes risk and a predictive marker for incident cardiovascular events. Using IGFBP-3 blood concentrations may improve the risk assessment of cardiometabolic diseases.

18.
Nat Rev Genet ; 20(8): 467-484, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31068683

RESUMO

Genome-wide association studies (GWAS) involve testing genetic variants across the genomes of many individuals to identify genotype-phenotype associations. GWAS have revolutionized the field of complex disease genetics over the past decade, providing numerous compelling associations for human complex traits and diseases. Despite clear successes in identifying novel disease susceptibility genes and biological pathways and in translating these findings into clinical care, GWAS have not been without controversy. Prominent criticisms include concerns that GWAS will eventually implicate the entire genome in disease predisposition and that most association signals reflect variants and genes with no direct biological relevance to disease. In this Review, we comprehensively assess the benefits and limitations of GWAS in human populations and discuss the relevance of performing more GWAS.


Assuntos
Estudos de Associação Genética/métodos , Estudo de Associação Genômica Ampla/métodos , Animais , Predisposição Genética para Doença/genética , Variação Genética/genética , Genoma/genética , Genótipo , Humanos , Fenótipo
19.
Circulation ; 139(12): 1472-1482, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30667276

RESUMO

BACKGROUND: Lipoprotein(a) [Lp(a)] levels predict the risk of myocardial infarction (MI) in populations of European ancestry; however, few data are available for other ethnic groups. Furthermore, differences in isoform size distribution and the associated Lp(a) concentrations have not fully been characterized between ethnic groups. METHODS: We studied 6086 cases of first MI and 6857 controls from the INTERHEART study that were stratified by ethnicity and adjusted for age and sex. A total of 775 Africans, 4443 Chinese, 1352 Arabs, 1856 Europeans, 1469 Latin Americans, 1829 South Asians, and 1221 Southeast Asians were included in the study. Lp(a) concentration was measured in each participant using an assay that was insensitive to isoform size, with isoform size being assessed by Western blot in a subset of 4219 participants. RESULTS: Variations in Lp(a) concentrations and isoform size distributions were observed between populations, with Africans having the highest Lp(a) concentration (median=27.2 mg/dL) and smallest isoform size (median=24 kringle IV repeats). Chinese samples had the lowest concentration (median=7.8 mg/dL) and largest isoform sizes (median=28). Overall, high Lp(a) concentrations (>50 mg/dL) were associated with an increased risk of MI (odds ratio, 1.48; 95% CI, 1.32-1.67; P<0.001). The association was independent of established MI risk factors, including diabetes mellitus, smoking, high blood pressure, and apolipoprotein B and A ratio. An inverse association was observed between isoform size and Lp(a) concentration, which was consistent across ethnic groups. Larger isoforms tended to be associated with a lower risk of MI, but this relationship was not present after adjustment for concentration. Consistent with variations in Lp(a) concentration across populations, the population-attributable risk of high Lp(a) for MI varied from 0% in Africans to 9.5% in South Asians. CONCLUSIONS: Lp(a) concentration and isoform size varied markedly between ethnic groups. Higher Lp(a) concentrations were associated with an increased risk of MI and carried an especially high population burden in South Asians and Latin Americans. Isoform size was inversely associated with Lp(a) concentration, but did not significantly contribute to risk.


Assuntos
Lipoproteína(a)/sangue , Infarto do Miocárdio/diagnóstico , Adulto , Idoso , Apolipoproteínas A/análise , Apolipoproteínas B/análise , Pressão Sanguínea , Estudos de Casos e Controles , Complicações do Diabetes/diagnóstico , Grupos Étnicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/etnologia , Razão de Chances , Isoformas de Proteínas/sangue , Fatores de Risco , Fumar
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