George Thanassoulis1,2, James C Engert1,3,2, Mary Hoekstra1,2, Hao Yu Chen1,2, Jian Rong4, Line Dufresne2, Jie Yao5, Xiuqing Guo5, Michael Y Tsai6, Sotirios Tsimikas7, Wendy S Post8, Ramachandran S Vasan4, Jerome I Rotter5, Martin G Larson4. 1. Division of Experimental Medicine (M.H., H.Y.C., G.T., J.C.E.), McGill University, Montreal, Quebec. 2. Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Montreal, Quebec, Canada (M.H., H.Y.C., L.D., G.T., J.C.E.). 3. Department of Human Genetics (J.C.E.), McGill University, Montreal, Quebec. 4. Boston University's and NHLBI's Framingham Heart Study, MA (J.R., R.S.V., M.G.L.). 5. The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance (J.Y., X.G., J.I.R.). 6. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis (M.Y.T.). 7. Division of Cardiovascular Medicine, Sulpizio Cardiovascular Center, University of California San Diego, La Jolla (S.T.). 8. Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (W.S.P.).
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.
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.
Entities:
Keywords:
atherosclerosis; cardiovascular diseases; genome-wide association study; lipoprotein(a); risk factors
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