Dataset Information

Global genetic diversity of human apolipoproteins and effects on cardiovascular disease risk.

ABSTRACT: Abnormal plasma apolipoprotein levels are consistently implicated in CVD risk. Although 30% to 60% of their interindividual variability is genetic, common genetic variants explain only 10% to 20% of these differences. Rare genetic variants may be major sources of the missing heritability, yet quantitative evaluations of their contribution to phenotypic variability are lacking. Here, we analyzed whole-genome and whole-exome sequencing data from 138,632 individuals across seven major human populations to present a systematic overview of genetic apolipoprotein variability. We provide population-specific frequencies of 38 clinically important apolipoprotein alleles and identify further 6,875 genetic variants, 33% of which are novel and 98.7% of which are rare with minor allele frequencies <1%. We predicted the functional impact of rare variants and found that their relative importance differed drastically between genes and among ethnicities. Importantly, we validated the clinical relevance of multiple variants with predicted effects by leveraging association data from the CARDIoGRAM (Coronary Artery Disease Genomewide Replication and Meta-analysis) and Global Lipids Genetics consortia. Overall, we provide a consolidated overview of population-specific apolipoprotein genetics as a valuable data resource for scientists and clinicians, estimate the importance of rare genetic variants for the missing heritability of apolipoprotein-associated disease traits, and pinpoint multiple novel apolipoprotein variants with putative population-specific impacts on serum lipid levels.

SUBMITTER: Zhou Y

PROVIDER: S-EPMC6168301 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Global genetic diversity of human apolipoproteins and effects on cardiovascular disease risk.

Zhou Yitian Y Mägi Reedik R Milani Lili L Lauschke Volker M VM

Journal of lipid research 20180803 10

Abnormal plasma apolipoprotein levels are consistently implicated in CVD risk. Although 30% to 60% of their interindividual variability is genetic, common genetic variants explain only 10% to 20% of these differences. Rare genetic variants may be major sources of the missing heritability, yet quantitative evaluations of their contribution to phenotypic variability are lacking. Here, we analyzed whole-genome and whole-exome sequencing data from 138,632 individuals across seven major human populat ...[more]

PMID: 30076208

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Project description:To identify, critically appraise and summarise existing systematic reviews on the impact of global cardiovascular risk assessment in the primary prevention of cardiovascular disease (CVD) in adults.Systematic review of systematic reviews published between January 2005 and October 2016 in The Cochrane Library, EMBASE, MEDLINE or CINAHL databases, and post hoc analysis of primary trials.Systematic reviews of interventions involving global cardiovascular risk assessment relative to no formal risk assessment in adults with no history of CVD. The primary outcomes of interest were CVD-related morbidity and mortality and all-cause mortality; secondary outcomes were systolic blood pressure (SBP), cholesterol and smoking.We identified six systematic reviews of variable but generally of low quality (mean Assessing the Methodological Quality of Systematic Reviews 4.2/11, range 0/11 to 7/11). No studies identified by the systematic reviews reported CVD-related morbidity or mortality or all-cause mortality. Meta-analysis of reported randomised controlled trials (RCTs) showed small reductions in SBP (mean difference (MD) -2.22?mm?Hg (95% CI -3.49 to -0.95); I2=66%; n=9; GRADE: very low), total cholesterol (MD -0.11?mmol/L (95% CI -0.20 to -0.02); I2=72%; n=5; GRADE: very low), low-density lipoprotein cholesterol (MD -0.15?mmol/L (95% CI -0.26 to -0.05), I2=47%; n=4; GRADE: very low) and smoking cessation (RR 1.62 (95% CI 1.08 to 2.43); I2=17%; n=7; GRADE: low). The median follow-up time of reported RCTs was 12?months (range 2-36?months).The quality of existing systematic reviews was generally poor and there is currently no evidence reported in these reviews that the prospective use of global cardiovascular risk assessment translates to reductions in CVD morbidity or mortality. There are reductions in SBP, cholesterol and smoking but they may not be clinically significant given their small effect size and short duration. Resources need to be directed to conduct high-quality systematic reviews focusing on hard patient outcomes, and likely further primary RCTs.CRD42015019821.

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Dataset Information

Global genetic diversity of human apolipoproteins and effects on cardiovascular disease risk.

Publications

Global genetic diversity of human apolipoproteins and effects on cardiovascular disease risk.

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