| Application: | 41025, Pleiotropic effects of cardiometabolic genetic markers and their interaction with diet and fatty acids in cardiovascular diseases. |
| Title: | Genome-Wide Association Study Highlights APOHas a Novel Locus for Lipoprotein(a) Levels - Brief Report |
| Size: | 238619 B |
| Archived: | 28 Sep 2021 |
| Stability: | Complete |
| Personal: | No individual-level data |
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Notes
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 293274 White British individuals in the discovery analysis. Approximately 93095623 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 2GPI (beta2-glycoprotein I). The APOH variant rs8178824 was associated with increased Lp(a) levels ( [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 ( [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 ( [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 n
Application 41025
Pleiotropic effects of cardiometabolic genetic markers and their interaction with diet and fatty acids in cardiovascular diseases.
DNA variation and environmental factors contribute to multiple cardiovascular diseases. The genetic variation is found in multiple genes that are in turn involved in various processes leading to diseases. For example, many variants that are known to increase cholesterol, have been shown to also influence cardiovascular diseases. Furthermore, the risk for individuals with certain genetic variants may be even greater if they have an unhealthy lifestyle. Because many disease processes remain to be discovered, we aim to both identify new interactions as well as combine genetic variants, into a "Genetic Risk Score" or GRS that allows us to quantify an individual's total genetic risk. In addition, we will study the genetic causes of various risk factors and identify specific cellular processes that contribute to specific cardiovascular diseases. For example, we will study the contribution of diet and fatty acids to cardiovascular risk factors and diseases. We believe that a combined genetic and risk factor analysis will uncover novel causes of disease and contribute to our understanding of the risk factors for multiple cardiovascular diseases. This increased understanding of risk factors and the discovery of new cellular processes could help to develop novel treatment strategies for diseases having a common etiology.
| Lead investigator: | Dr James Engert |
| Lead institution: | Research Institute McGill University Health Centre |
Enabling scientific discoveries that improve human health