Differential Effects of ABCG5/G8 Gene Region Variants on Lipid Profile, Blood Pressure Status, and Gallstone Disease History in Taiwan

Abstract

ABCG5 and ABCG8 are two key adenosine triphosphate-binding cassette (ABC) proteins that regulate whole-body sterol trafficking. This study aimed to elucidate the association between ABCG5/G8 gene region variants and lipid profile, cardiometabolic traits, and gallstone disease history in Taiwan. A total of 1494 Taiwan Biobank participants with whole-genome sequencing data and 117,679 participants with Axiom Genome-Wide CHB Array data were enrolled for analysis. Using genotype-phenotype and stepwise linear regression analyses, we found independent associations of four Asian-specific ABCG5 variants, rs119480069, rs199984328, rs560839317, and rs748096191, with total, low-density lipoprotein (LDL), and non-high-density lipoprotein (HDL) cholesterol levels (all p ≤ 0.0002). Four other variants, which were in nearly complete linkage disequilibrium, exhibited genome-wide significant associations with gallstone disease history, and the ABCG8 rs11887534 variant showed a trend of superiority for gallstone disease history in a nested logistic regression model (p = 0.074). Through regional association analysis of various other cardiometabolic traits, two variants of the PLEKHH2, approximately 50 kb from the ABCG5/G8 region, exhibited significant associations with blood pressure status (p < 10^-6). In conclusion, differential effects of ABCG5/G8 region variants were noted for lipid profile, blood pressure status, and gallstone disease history in Taiwan. These results indicate the crucial role of individualized assessment of ABCG5/G8 variants for different cardiometabolic phenotypes.

Keywords: ABCG5; ABCG8; differential effect; gallstone disease; genetic variants; lipid profile.

Figure 1

Study flowchart of inclusion and exclusion criteria used to screen Taiwan Biobank project participants. The number of participants analyzed were shown in each box.

Figure 2

Regional association analysis of ABCG5 and ABCG8 region variants, (A) total cholesterol level, (B) LDL cholesterol level, (C) Non-HDL cholesterol level, and (D) gallstone disease history in Taiwan Biobank participants who had Axiom Genome-Wide CHB Array data. The lead SNPs with genome-wide significance were rs75832441 for total, LDL, and non-HDL cholesterol levels and rs115445558 for history of gallstone disease.

Figure 3

Linkage disequilibrium (LD) map of PLEKHH2, ABCG5, and ABCG8 region single-nucleotide polymorphisms (SNPs). Color of the SNPs represent the associated phenotypes, such as red for lipid profile, orange for gallstone disease history, and blue for mean and diastolic blood pressure.