Genetics
APOH, encoding beta2-glycoprotein I, emerges as a new genetic locus for Lp(a) levels, a GWAS of 293,274 UK Biobank participants (Arterioscler Thromb Vasc Biol 2021)
Original title: Genome-Wide Association Study Highlights APOH as a Novel Locus for Lipoprotein(a) Levels-Brief Report
In a genome-wide association study of 293,274 White British UK Biobank participants testing about 93 million variants, the authors identified 131 independent variants associated with Lp(a) at genome-wide significance, confirming known loci at LPA, APOE and CETP and identifying a novel variant at APOH, which encodes beta2-glycoprotein I. The APOH variant rs8178824 was associated with higher Lp(a) (beta 0.064 ln nmol/L, 95% CI 0.047-0.081, P=2.8e-13), an effect that strengthened after adjusting for LPA variation (beta 0.089, 95% CI 0.076-0.10, P=3.8e-42). This association was replicated in a meta-analysis of 5,465 European-ancestry individuals from the Framingham Offspring Study and MESA (beta 0.16 ln mg/dL, 95% CI 0.044-0.28, P=0.0071). The findings identify APOH as a novel Lp(a)-associated locus in individuals of European ancestry, warranting further study of beta2-glycoprotein I role in Lp(a) regulation and its potential as a therapeutic target.
Original abstract
Objective: Lp(a) (lipoprotein[a]) is an independent risk factor for cardiovascular diseases and plasma levels are primarily determined by variation at the LPA locus. We performed a genome-wide association study in the UK Biobank to determine whether additional loci influence Lp(a) levels. Approach and Results: We included 293 274 White British individuals in the discovery analysis. Approximately 93 095 623 variants were tested for association with natural log-transformed Lp(a) levels using linear regression models adjusted for age, sex, genotype batch, and 20 principal components of genetic ancestry. After quality control, 131 independent variants were associated at genome-wide significance (P≤5×10-8). In addition to validating previous associations at LPA, APOE, and CETP, we identified a novel variant at the APOH locus, encoding β2GPI (beta2-glycoprotein I). The APOH variant rs8178824 was associated with increased Lp(a) levels (β [95% CI] [ln nmol/L], 0.064 [0.047-0.081]; P=2.8×10-13) and demonstrated a stronger effect after adjustment for variation at the LPA locus (β [95% CI] [ln nmol/L], 0.089 [0.076-0.10]; P=3.8×10-42). This association was replicated in a meta-analysis of 5465 European-ancestry individuals from the Framingham Offspring Study and Multi-Ethnic Study of Atherosclerosis (β [95% CI] [ln mg/dL], 0.16 [0.044-0.28]; P=0.0071).
Conclusions: In a large-scale genome-wide association study of Lp(a) levels, we identified APOH as a novel locus for Lp(a) in individuals of European ancestry. Additional studies are needed to determine the precise role of β2GPI in influencing Lp(a) levels as well as its potential as a therapeutic target.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.