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

Mary Hoekstra, Hao Yu Chen, Jian Rong, Line Dufresne, Jie Yao, Xiuqing Guo, Michael Y. Tsai, Sotirios Tsimikas, Wendy S. Post, Ramachandran S. Vasan, Jerome I. Rotter, Martin G. Larson, George Thanassoulis, James C. Engert

Research output: Contribution to journalArticlepeer-review

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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

Original languageEnglish (US)
Pages (from-to)458-464
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Volume41
Issue number1
DOIs
StatePublished - Jan 2021

Bibliographical note

Funding Information:
M. Hoekstra was supported by an award from the Canadian Institutes of Health Research (CIHR) for the duration of the study. H.Y. Chen has received grants from the McGill University Faculty of Medicine and McGill University Health Centre Foundation. J. Engert and G. Thanassoulis have received research support from the CIHR. G. Thanassoulis has received research support from the Heart and Stroke Foundation of Canada, the NHLBI (grant R01 HL128550), the Doggone Foundation, the Courtois Foundation, and the Satoko Shibata and Richard Ingram Foundation. G. Thanassoulis receives salary support from the Fonds de Recherche Santé– Québec. MESA (Multi-Ethnic Study of Atherosclerosis) and the MESA SHARe (MESA SNP Health Association Resource) project are conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420. Also supported in part by the National Center for Advancing Translational Sciences, CTSI (Clinical and Translational Science Institute of Southeastern Wisconsin) grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The funding for SHARe genotyping was provided by NHLBI contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California) and the Broad Institute of Harvard and MIT (Massachusetts Institute of Technology; Boston, MA) using the Affymetrix Genome-Wide Human SNP Array 6.0. The Framingham Heart Study acknowledges the support of contracts NO1-HC-25195, HHSN268201500001I, and 75N92019D00031 from the NHLBI and grant supplement R01 HL092577-06S1 for this research.

Funding Information:
G. Thanassoulis has participated in advisory boards for Amgen, Sanofi/Regen-eron, Ionis, HLS Therapeutics, and Servier Canada and has received research grants from Ionis and Servier for research outside the scope of this work. S. Tsimikas is a co-inventor and receives royalties from patents owned by UCSD (University of California, San Diego) on oxidation-specific antibodies and of biomarkers related to oxidized lipoproteins and is a cofounder 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

Publisher Copyright:
© 2020 American Heart Association, Inc.

Keywords

  • Atherosclerosis
  • Cardiovascular diseases
  • Genome-wide association study
  • Lipoprotein(a)
  • Risk factors

PubMed: MeSH publication types

  • Journal Article
  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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