Pleiotropic Effects of APOB Variants on Lipid Profiles, Metabolic Syndrome, and the Risk of Diabetes Mellitus

Abstract

Apolipoprotein B (ApoB) plays a crucial role in lipid and lipoprotein metabolism. The effects of APOB locus variants on lipid profiles, metabolic syndrome, and the risk of diabetes mellitus (DM) in Asian populations are unclear. We included 1478 Taiwan Biobank participants with whole-genome sequence (WGS) data and 115,088 TWB participants with Axiom genome-wide CHB array data and subjected them to genotype–phenotype analyses using APOB locus variants. Five APOB nonsynonymous mutations, including Asian-specific rs144467873 and rs13306194 variants, were selected from participants with the WGS data. Using a combination of regional association studies, a linkage disequilibrium map, and multivariate analysis, we revealed that the APOB locus variants rs144467873, rs13306194, and rs1367117 were independently associated with total, low-density lipoprotein (LDL), and non-high-density lipoprotein (non-HDL) cholesterol levels; rs1318006 was associated with HDL cholesterol levels; rs13306194 and rs35131127 were associated with serum triglyceride levels; rs144467873, rs13306194, rs56213756, and rs679899 were associated with remnant cholesterol levels; and rs144467873 and rs4665709 were associated with metabolic syndrome. Mendelian randomization (MR) analyses conducted using weighted genetic risk scores from three or two LDL-cholesterol-level-associated APOB variants revealed significant association with prevalent DM (p = 0.0029 and 8.2 × 10−5, respectively), which became insignificant after adjustment for LDL-C levels. In conclusion, these results indicate that common and rare APOB variants are independently associated with various lipid levels and metabolic syndrome in Taiwanese individuals. MR analyses supported APOB variants associated with the risk of DM through their associations with LDL cholesterol levels.

A Genome-Wide Association Study of Metabolic Syndrome in the Taiwanese Population

“…Similar to our population, several studies within Taiwan have explored the genetic underpinnings of MetS [ 61 , 62 , 63 ]. One investigation, analyzing nine genes: APOA5 , APOC1 , BRAP , BUD13 , CETP , LIPA , LPL , PLCG1 , and ZPR1 , examined their association with MetS.…”

“…Another study delved into APOB variants, revealing their independent relationships with various lipid levels and MetS traits. Notably, specific APOB variants impacted diabetes risk through low-density lipoprotein cholesterol levels [ 62 ]. In addition, an exploration of TGF-β pathway genes ( SMAD2 and TGFBR2 ) found significant associations with MetS and its traits, emphasizing gene–gene interactions affecting MetS risk [ 63 ].…”

Population-enriched innate immune variants may identify candidate gene targets at the intersection of cancer and cardio-metabolic disease

“…The Arg3638Gln variant (2-21005955-C-T, rs1801701), which is present in no more than 10% of any population, was associated with survival outcomes in non-small cell lung cancer (NSCLC) patients ( 236 ). Additionally, two nonsynonymous variants unique to the Asian population, namely 2-21006289-G-A (rs144467873, MAF = 0.001253 and 0.0003594 in East and South Asians, respectively, but < 0.00008 for all other populations (gnomAD v2.1.1) and 2-21029662-G-A (rs13306194, MAF = 0.1343 in East Asians, MAF < 0.007 in all other populations) were evaluated for their association with lipid profiles, metabolic syndrome and risk of diabetes in a large Taiwan Biobank study ( 237 ). Both variants were independently associated with total, LDL, and non-HDL cholesterol levels, whereas rs144467873 (Arg3527Trp) was associated with elevated lipid levels and metabolic syndrome, while rs13306194 (Arg532Trp) was linked with serum triglyceride levels.…”

Current Data and New Insights into the Genetic Factors of Atherogenic Dyslipidemia Associated with Metabolic Syndrome

“…Later, two GWASs analyzed in the Caucasian population identified two other allelic variants involved in MetS: rs673548, identified by Lind et al [25] and rs1367117, identified by Guindo-Martínez et al [26]. Jang et al [27] identified two new APOB allelic variants (rs4665709 and rs144467873) in MetS patients from Taiwan [27].…”