Multiancestry Genome-Wide Association Study of Aortic Stenosis Identifies Multiple Novel Loci in the Million Veteran Program

A consistent aortic stenosis phenotype was applied across all IAVGC studies (except as otherwise described in Supplementary Methods) using a previously validated definition comprised of ICD and CPT codes.

“A consistent AS phenotype was applied across all IAVGC studies (except as otherwise described in Supplementary Methods) using a previously validated definition for AS comprised of ‘International Classification of Diseases’ (ICD) and ‘Current Procedural Terminology’ codes7 (Supplementary Table 2).”

CAVS shares similar pathobiology with atherosclerotic vascular disease, involving intimal accumulation of apoB-containing particles, inflammation, and calcification.

“This is consistent with the notion that CAVS shares similar pathobiology with atherosclerotic vascular disease, involving intimal accumulation of apoB-containing particles, inflammation, and calcification17,44,45.”

Robust translational data suggest that apolipoprotein B-containing lipoproteins, including Lp(a), are causal for aortic stenosis.

“This result is concordant with robust translational data suggesting that apolipoprotein B-containing lipoproteins, including Lp(a), are causal for AS7,37,38.”

A claims-based definition for aortic stenosis was used across multiple diverse biobanks, which the authors previously validated in the MVP as having a positive predictive value of 0.78 and a negative predictive value of 0.99.

“To facilitate a uniform definition of AS across multiple diverse biobanks, we used a claims-based definition for AS which we previously validated in the MVP as having a positive predictive value of 0.78 and a negative predictive value of 0.99 (ref. 7).”

Genome-wide association studies have found associations between aortic stenosis and genetic loci harboring genes encoding the low-density lipoprotein receptor and lipoprotein(a).

“genome-wide association studies have found associations between AS and genetic loci that harbor genes encoding the low-density lipoprotein receptor and Lp(a) (lipoprotein[a]).7,8”

Aggregation of small to moderate effects across diverse genomic loci is susceptible to bias from pleiotropic effects, which may partly explain attenuation of effect sizes when controlling for Lp(a).

“However, the aggregation of small to moderate effects across diverse genomic loci is susceptible to bias because of pleiotropic effects; this may partly explain findings such as attenuation of effect sizes when controlling for Lp(a), as observed in a recent Mendelian randomization study.7”

Previous Mendelian randomization studies aggregating common genetic variants estimated that a 38.67 mg/dL (1 mmol/L) lower LDL-C was associated with 12% to 45% lower odds or hazards of AS.

“Causal effect estimates from these studies, converted to risk reductions, have ranged between 12% and 45% lower odds or hazards of AS per 38.67-mg/ dL (1-mmol/L) reduction in LDL-C.7,[9][10][11]”