Evidence of How rs7575840 Influences Apolipoprotein B–Containing Lipid Particles

Abstract

Objective-Recent genome-wide association studies identified a variant rs7575840 in the apolipoprotein B (APOB) gene region as associated with low-density lipoprotein (LDL) cholesterol. However, the underlying functional mechanism of this variant, which resides 6.5 kb upstream of APOB, has remained unknown. Our objective was to investigate rs7575840 for association with refined apoB-containing lipid particles, for replication in a Mexican population, and for its underlying functional mechanism. Methods and Results-Our data show that rs7575840 is associated with serum apoB levels (Pϭ4.85ϫ10 Ϫ10 ) and apoB-containing lipid particles, very small very-low-density lipoprotein, intermediate lipoprotein, and LDL particles (Pϭ2ϫ10 Ϫ5 to 9ϫ10 Ϫ7 ) in the Finnish Metabolic Syndrome in Men study sample (nϭ7710). Fine mapping of the APOB region using 43 single-nucleotide polymorphisms replicated the association of rs7575840 with apoB in a Mexican study sample (nϭ2666, Pϭ3.33ϫ10 Ϫ5 ). Furthermore, our transcript analyses of adipose RNA samples from 175 subjects in the Finnish Metabolic Syndrome in Men study indicate that rs7575840 alters expression of APOB (Pϭ1.13ϫ10 Ϫ10 ) and a regional noncoding RNA (BU630349) (Pϭ7.86ϫ10 Ϫ6 ) in adipose tissue. Conclusion-It has been difficult to convert genome-wide association study associations into mechanistic insights. Our data show that rs7575840 is associated with serum apoB levels and apoB-containing lipid particles, as well as influencing expression of APOB and a regional transcript BU630349 in adipose tissue. We thus provide evidence how a common genome-wide significant single-nucleotide polymorphism, rs7575840, may affect serum apoB, LDL cholesterol, and total cholesterol levels. Key Words: gene expression Ⅲ adipose tissue Ⅲ apolipoprotein B Ⅲ association analysis Ⅲ Mexicans G enome-wide association studies (GWAS) have been successful in discovering single-nucleotide polymorphisms (SNPs) that affect low-density lipoprotein cholesterol (LDL-C) levels with low to moderate effect sizes. 1 However, many of the significantly associated SNPs are intergenic and belong to large linkage disequilibrium (LD) blocks, making it difficult to evaluate their functional relevance.The SNP rs7575840 has been implicated in a recent GWAS for LDL-C. 1 As rs7575840 resides in the apolipoprotein B (APOB) gene region, 6.5 kb upstream of the gene, we tested it for association with refined lipid phenotypes and proton nuclear magnetic resonance spectroscopy measurements of lipid particles in a white population sample, the Metabolic Syndrome in Men (METSIM) cohort (nϭ7710). Furthermore, to also explore the role of this GWAS variant in another population, we fine mapped the APOB region in a Mexican dyslipidemic case/control study sample and compared the regional LD between non-Mexican whites and Mexicans. The Mexican population has a 44% prevalence of hypercholesterolemia, defined by total cholesterol (TC) Ͼ200 mg/dL. 2 Other forms of dyslipidemias are highly common in this population as well. However, to...

Genetic regulation of adipose tissue transcript expression is involved in modulating serum triglyceride and HDL-cholesterol

“…Apolipoprotein B (APOB) is the main apolipoprotein of chylomicrons, very low density lipoproteins, and low density lipoproteins and is highly expressed in liver and small intestine as long (ApoB100) and short (ApoB48) isoforms, respectively, via RNA editing of the same transcript. The role of APOB in other tissues is not clear; however, Hass et al (2011) showed that a serum LDL-C associated SNP rs7575840 is a cis-eSNP for the expression of APOB mRNA in adipose tissue of European Ancestry individuals 34 . Replicating this finding, the T-allele of rs7575840 was associated with higher expression of APOB in adipose tissue of African American individuals of our AAGMEx cohort.…”

Genome-Wide Analysis of Nuclear Magnetic Resonance Metabolites Revealed Parent-of-Origin Effect on Triglycerides in Medium Very Low-Density Lipoprotein in PTPRD Gene

“…As an example, maternal allele-specific association of a common variant (rs1367117) located in the APOB gene was demonstrated in the analysis of adiposity [17] and borderline significant effect for fasting glucose and insulin levels [17]. This nonsynonymous missense variant that cause a Thr > Ile amino acid change was also observed in non-POE association with serum ApoB levels [18].…”

The Metabolic Syndrome in Men study: a resource for studies of metabolic and cardiovascular diseases

“…The METSIM study data has been helpful in generating functional information for some GWAS variants, e.g., a variant rs7575840 in the APOB gene region associated with LDL cholesterol level. Adipose tissue RNA expression analysis indicated that rs7575840 alters the expression of APOB and a regional noncoding RNA (BU630349) (76). Another study examined the functional regulatory effects of 25 noncoding variants at the GALNT2 locus associated with HDL cholesterol in the METSIM cohort.…”