Genome- and exome-wide association study of serum lipoprotein (a) in the Jackson Heart Study

Abstract

Lipoprotein (a) (Lp(a)) is an independent risk factor for cardiovascular disease. Lp(a) levels in African Americans (AAs) are much higher compared with that in European Americans. We conducted a genome- and an exome-wide association study of Lp(a) among 2895 AAs participating in the Jackson Heart Study. We observed that local ancestry at 6q25.3 was an important risk factor for Lp(a) in AAs, and that multiple single-nucleotide polymorphisms (SNPs) at the well-established LPA locus were significantly associated with Lp(a) (P<5 × 10(-8)) after adjusting for the local ancestry at 6q25.3. Interestingly, before adjusting for local ancestry, we observed significant (P<5 × 10(-8)) associations for hundreds of SNPs spanning ~10 Mb region on 6q surrounding the LPA gene, whereas after adjusting for local ancestry, the region containing significantly associated SNPs got much narrower and was centered over the LPA gene (<1 Mb). We observed a single nonsynonymous SNP in APOE significantly associated with Lp(a) (P<5 × 10(-8)). A high burden of coding variants in LPA and APOE were also associated with higher Lp(a) levels. Our study provides evidence that ancestry-specific causal risk variant(s) resides in or near LPA and that most of the observed associations outside this narrower region are spurious associations.

Structure, function, and genetics of lipoprotein (a)

“…In lipoprotein lipase deficiency (232) and abetalipoproteinemia (233), Lp(a) levels are decreased. A recent GWAS in African Americans identified the APOE gene locus to be associated with Lp(a) concentrations (234). This finding will require confirmation in different populations and functional elucidation.…”

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study

“…12,13 Two common LPA single-nucleotide polymorphisms (SNPs), rs10455872 (intronic non-coding) and rs3798220 (missense variant Ile4399Met in the apolipoprotein(a) protease-like domain), explain much of the variation in lipoprotein(a) concentrations, and are linked to the risk of incident myocardial infarction. 14,15 …”

PCSK9 in context: A contemporary review of an important biological target for the prevention and treatment of atherosclerotic cardiovascular disease

“…Oxidized phospholipids, preferentially carried by Lp(a) compared with LDL, may contribute to the particle's role in arterial inflammation and progression of atherosclerosis . The direct and probably causal relationship of Lp(a) with cardiovascular risk is strongly suggested by genome‐wide association and Mendelian randomization studies . Elevated Lp(a) is associated with greater cardiovascular risk in people with established ASCVD already on statins, and may attenuate the effect of statins on LDL cholesterol by an unknown mechanism …”

“…39 The direct and probably causal relationship of Lp(a) with cardiovascular risk is strongly suggested by genome-wide association and Mendelian randomization studies. 40,41 Elevated Lp(a) is associated with greater cardiovascular risk in people with established ASCVD already on statins, 42,43 and may attenuate the effect of statins on LDL cholesterol by an unknown mechanism. 44 Whether pharmacologically lowering Lp(a) reduces cardiovascular risk has not so far been demonstrated because no specific Lp(a)lowering agent is currently available.…”

“…In the multiple-dose group that received 300 mg inclisiran monthly for 2 doses, LDL cholesterol was reduced by 45.5% on day 84 in patients taking a statin, and by 30.9% in patients not taking a statin, when compared with placebo. Remarkably, LDL cholesterol remained reduced by40.3% compared with baseline in patients taking a statin, and by 47.2% in patients not taking a statin, at 196 days after the first of…”