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.

APOB gene polymorphisms may affect the risk of minor or minimal bleeding complications in patients on warfarin maintaining therapeutic INR

“…Moreover, c.293C>T has been suggested to affect activation of APOB and LDL during cholesterol transport [25]. A previous study showed that c.293C>T and c.1853C>T were associated with LDL and total cholesterol levels [26]. Specifically, it was revealed that polymorphism of c.293C>T increased LDL concentration, whereas that of c.1853C>T decreased LDL concentration [27].…”

Association of ApoE Gene Polymorphisms With Cardio-cerebrovascular Complications in Type 2 Diabetes Mellitus in the Chinese Population

“…The comparison results between the case group and the control group showed that although the ε3 allele frequency was the highest in both groups, the ε2 and ε4 allele frequency was signi cantly different, which showed that the ε4 allele frequency in the case group was signi cantly higher than that in the control group, suggesting that ε4 allele might be a risk factor for cardio-cerebrovascular diseases. ApoE is one of the important parameters for the occurrence of cardiovascular diseases [28]. Studies have suggested that ApoE ε4 allele is an independent risk factor for T2DM and coronary heart disease [29], but the correlation between ApoE and cerebral infarction is controversial.…”

Association of ApoE Gene Polymorphisms With Cardio-cerebrovascular Complications in Type 2 Diabetes Mellitus in the Chinese Population

“…The case group was divided into two types: coronary heart disease and cerebral infarction. ApoE is one of the important parameters for the occurrence of cardiovascular diseases [23]. Studies have suggested that ApoE E4 allele is an independent risk factor for T2DM and coronary heart disease [24], but the correlation between ApoE and cerebral infarction is controversial.…”