LPA Kringle IV Type‐2 Genetic Variants Are Associated With Apolipoprotein (a) Size, Hypertension, and Nonfasting Glucose Levels

Background High plasma lipoprotein (a) (Lp[a]) levels, largely regulated by variation in the LPA gene, are a causal risk factor for atherosclerotic cardiovascular disease. LPA Kringle IV type 2 (KIV‐2) copy number (CN) inversely associates with Lp(a) levels, with Black and Hispanic individuals exhibiting higher Lp(a) levels than White individuals. These populations are underrepresented in genetic studies. We evaluated the ancestry‐specific LPA KIV‐2 variants and their associations with cardiometabolic and neurologic traits. Methods Whole‐exome sequencing data from 3817 participants in the Washington Heights Inwood Columbia Aging Project were analyzed, including 886 non‐Hispanic White individuals (23%), 1811 Caribbean Hispanic individuals (47%), and 1120 Black individuals (29%). LPA KIV‐2 CN estimation and variant calling were performed using validated pipelines. Associations with clinical outcomes were evaluated using regression models adjusted for age, sex, and population substructure. Results A total of 1421 variants were identified in the LPA KIV‐2 region, including 267 exonic variants, 35% shared across ancestry groups. LPA KIV‐2 CN correlated with 314 variants, 65.6% associated with lower KIV‐2 CN and higher Lp(a) levels. Three novel exonic variants (4785‐C/A, 727‐T/C, and 723‐A/G) positively associated with hypertension across ancestry groups. Variant 412‐C/T was associated to lower glucose levels, independently of KIV‐2 CN; 4785‐C/A was negatively associated with KIV‐CN ( P =2.3e‐159) and hypertension ( P =0.032); and in a small cohort, it was negatively associated with weighted isoform size ( P =1.5e‐4) and positively associated with Lp(a) levels ( P =0.012). Conclusions Novel LPA KIV‐2 variants are enriched in individuals with low KIV‐2 CN and are associated with hypertension and glucose levels. These findings support further investigation into Lp(a)‐mediated mechanisms underlying atherosclerotic cardiovascular disease.