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Meta-Analysis
. 2021 Jan;41(1):458-464.
doi: 10.1161/ATVBAHA.120.314965. Epub 2020 Oct 29.

Genome-Wide Association Study Highlights APOH as a Novel Locus for Lipoprotein(a) Levels-Brief Report

Mary Hoekstra  1   2 , Hao Yu Chen  1   2 , Jian Rong  3 , Line Dufresne  2 , Jie Yao  4 , Xiuqing Guo  4 , Michael Y Tsai  5 , Sotirios Tsimikas  6 , Wendy S Post  7 , Ramachandran S Vasan  3 , Jerome I Rotter  4 , Martin G Larson  3 , George Thanassoulis #  1   2 , James C Engert #  1   8   2
Affiliations
Meta-Analysis

Genome-Wide Association Study Highlights APOH as a Novel Locus for Lipoprotein(a) Levels-Brief Report

Mary Hoekstra et al. Arterioscler Thromb Vasc Biol. 2021 Jan.

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.

Keywords: atherosclerosis; cardiovascular diseases; genome-wide association study; lipoprotein(a); risk factors.

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Conflict of interest statement

Disclosures

Dr Thanassoulis has participated in advisory boards for Amgen, Sanofi/Regeneron, Ionis, HLS Therapeutics, and Servier Canada and has received research grants from Ionis and Servier for research outside the scope of this work. Dr Tsimikas is a co-inventor and receives royalties from patents owned by UCSD on oxidation-specific antibodies and of biomarkers related to oxidized lipoproteins and is a co-founder and has an equity interest in Oxitope, Inc and its affiliates (“Oxitope”) as well as in Kleanthi Diagnostics, LLC (“Kleanthi”). Although these relationships have been identified for conflict of interest management based on the overall scope of the project and its potential benefit to Oxitope and Kleanthi, the research findings included in this particular publication may not necessarily relate to the interests of Oxitope and Kleanthi. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies.

Figures

Figure 1:
Figure 1:
Log-transformed p-values for the association of 9,829,003 variants with natural log-transformed Lp(a). The plot has been cropped for better resolution, truncating only the signals at chromosome 6 (LPA region) and chromosome 19 (APOE region).
See this image and copyright information in PMC

Comment in

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