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

Citation
Hoekstra, M., et al. “Genome-Wide Association Study Highlights As A Novel Locus For Lipoprotein(A) Levels-Brief Report.”. Arteriosclerosis, Thrombosis, And Vascular Biology, pp. 458-464.
Center UCSD-UCLA
Author 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
Keywords atherosclerosis, cardiovascular diseases, genome-wide association study, lipoprotein(a), risk factors
Abstract

OBJECTIVE: Lp(a) (lipoprotein[a]) is an independent risk factor for cardiovascular diseases and plasma levels are primarily determined by variation at the 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 ≤5×10). In addition to validating previous associations at , , and , we identified a novel variant at the locus, encoding β2GPI (beta2-glycoprotein I). The variant rs8178824 was associated with increased Lp(a) levels (β [95% CI] [ln nmol/L], 0.064 [0.047-0.081]; =2.8×10) and demonstrated a stronger effect after adjustment for variation at the locus (β [95% CI] [ln nmol/L], 0.089 [0.076-0.10]; =3.8×10). 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]; =0.0071).

CONCLUSIONS: In a large-scale genome-wide association study of Lp(a) levels, we identified 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.

Year of Publication
2021
Journal
Arteriosclerosis, thrombosis, and vascular biology
Volume
41
Issue
1
Number of Pages
458-464
Date Published
01/2021
ISSN Number
1524-4636
DOI
10.1161/ATVBAHA.120.314965
Alternate Journal
Arterioscler Thromb Vasc Biol
PMID
33115273
PMCID
PMC7769958