Abstract
Genetic variation at the ABCG5/G8 locus has been associated with markers of cholesterol homeostasis. As data originate from small-scale studies, we performed a meta-analysis to study these associations in a large dataset. We first investigated associations between five common ABCG5/G8 polymorphisms (p.Q604E, p.D19H, p.Y54C, p.T400K, and p.A632V) and plasma sterol levels in 245 hypercholesterolaemic individuals. No significant associations were found. Subsequently, our data were pooled into a meta-analysis that comprised 3,364 subjects from 16 studies (weighted mean age, 46.7 ± 10.5 years; BMI, 23.9 ± 3.5 kg/m(2)). Presence of the minor 632V allele correlated with reduced LDL-C concentrations (n = 367) compared with homozygosity for the 632A variant [n = 614; -0.11 mmol/l (95% CI, range: -0.20 to -0.02 mmol/l); P = 0.01]. The remaining polymorphisms were not associated with plasma lipid levels. Carriers of the 19H allele exhibited lower campesterol/TC (n = 83; P < 0.001), sitosterol/TC (P < 0.00001), and cholestanol/TC (P < 0.00001), and increased lathosterol/TC ratios (P = 0.001) compared with homozygous 19D allele carriers (n = 591). The ABCG8 632V variant was associated with a clinically irrelevant LDL-C reduction, whereas the 19H allele correlated with decreased cholesterol absorption and increased synthesis without affecting the lipid profile. Hence, associations between frequently studied missense ABCG5/G8 polymorphisms and markers of cholesterol homeostasis are modest at best.
Highlights
Genetic variation at the ABCG5/G8 locus has been associated with markers of cholesterol homeostasis
We evaluated associations of five frequently tested missense polymorphisms in ABCG5/G8 and plasma cholesterol and non-cholesterol sterol levels in 245 mildly hypercholesterolaemic subjects, as a replication dataset for results found in a comparable cohort [13]
The p.T400K polymorphism showed similar trends with borderline significance, whereas the remaining three polymorphisms were not associated with baseline non-cholesterol sterol levels. This meta-analysis is the first to evaluate associations between frequently studied missense ABCG5/G8 variants and plasma cholesterol and non-cholesterol levels in a large dataset, which consists of 3,364 individuals from 16 studies
Summary
Genetic variation at the ABCG5/G8 locus has been associated with markers of cholesterol homeostasis. We evaluated associations of five frequently tested missense polymorphisms in ABCG5/G8 and plasma cholesterol and non-cholesterol sterol levels in 245 mildly hypercholesterolaemic subjects, as a replication dataset for results found in a comparable cohort [13]. To obtain a large cohort for replication of signals observed in studies with limited subjects (reviewed in Ref. 15), we performed a systematic review and meta-analysis, in which we quantitatively assessed associations between five common ABCG5/ G8 polymorphisms and plasma cholesterol and non-cholesterol sterol levels.
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