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

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.