| Title: | Genome-Wide Association Study Highlights APOH as a Novel Locus for Lipoprotein(a) Levels - Brief Report |
| Journal: | Arteriosclerosis Thrombosis and Vascular Biology |
| Published: | 29 Oct 2020 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/33115273/ |
| DOI: | https://doi.org/10.1161/atvbaha.120.314965 |
| URL: | https://www.ahajournals.org/doi/pdf/10.1161/ATVBAHA.120.314965 |
Publication 5026
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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).</p>
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.</p>
17 Keywords
- Aged
- Aged, 80 and over
- Biomarkers
- Cardiovascular Diseases
- Female
- Genetic Loci
- Genetic Predisposition to Disease
- Genetic Variation
- Genome-Wide Association Study
- Heart Disease Risk Factors
- Humans
- Lipoprotein(a)
- Male
- Middle Aged
- Phenotype
- Risk Assessment
- beta 2-Glycoprotein I
14 Authors
- 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
Enabling scientific discoveries that improve human health