Ancestry specific distribution of LPA Kringle IV-Type-2 genetic variants highlight associations to apo(a) copy number, glucose, and hypertension

Abstract

BackgroundHigh Lp(a) levels contribute to atherosclerotic cardiovascular disease and are tightly regulated by theLPAgene. Lp(a) levels have an inverse correlation withLPAKringle IV Type-2 (KIV-2) copy number (CN). Black (B) and Hispanic (H) individuals exhibit higher levels of Lp(a), and rates of CVD compared to non-Hispanic Whites (NHW). Therefore, we investigated genetic variations in theLPAKIV-2 region across three ancestries and their associations with metabolic risk factors.MethodsUsing published pipelines, we analyzed a multi-ethnic whole exome dataset comprising 3,817 participants from the Washington Heights and Inwood Columbia Aging Project (WHICAP): 886 [NHW (23%), 1,811 Caribbean (C) H (47%), and 1,120 B individuals (29%). Rare and common variants (alternative allele carrier frequency, CF < 0.01 or > 0.99 and 0.01 < CF < 0.99, respectively) were identified and KIV-2 CN estimated. The associations of variants and CN with history of heart disease, hypertension (HTN), stroke, lipid levels and clinical diagnosis of Alzheimer’s disease (AD) was assessed. A small pilot provided in-silico validation of study findings.ResultsWe report 1421 variants in theLPAKIV-2 repeat region, comprising 267 exonic and 1154 intronic variants. 61.4% of the exonic variants have not been previously described. Three novel exonic variants significantly increase the risk of HTN across all ethnic groups: 4785-C/A (frequency = 78%, odds ratio [OR] = 1.45, p = 0.032), 727-T/C (frequency = 96%, OR = 2.11, p = 0.032), and 723-A/G (frequency = 96%, OR = 1.97, p = 0.038). Additionally, six intronic variants showed associations with HTN: 166-G/A, 387-G/C, 402-G/A, 4527-A/T, 4541-G/A, and 4653-A/T. One intronic variant, 412-C/T, was associated with decreased blood glucose levels (frequency = 72%, β = −14.52, p = 0.02).Three of the associations were not affected after adjusting forLPAKIV-2 CN: 412-C/T (β = −14.2, p = 0.03), 166-G/A (OR = 1.41, p = 0.05), and 387-G/C (OR = 1.40, p = 0.05). KIV CN itself was significantly associated with 314 variants and was negatively correlated with plasma total cholesterol levels.ConclusionsIn three ancestry groups, we identify novel rare and commonLPAKIV-2 region variants. We report new associations of variants with HTN and Glucose levels. These results underscore the genetic complexity of theLPAKIV-2 region in influencing cardiovascular and metabolic health, suggesting potential genetic regulation of pathways that can be studied for research and therapeutic interventions.Clinical PerspectiveLp(a) levels are mostly controlled by theLPAgene and are higher in Blacks and Hispanics.Novel LPAKIV-2 variants found in three ancestry groups, including data on Caribbean Hispanics, show strong positive associations to hypertension and negative associations to glucose levels.Further characterization of these variants and identifying links to disease can help precision medicine efforts to understand disease mechanisms in all populations.