Pleiotropy among Common Genetic Loci Identified for Cardiometabolic Disorders and C-Reactive Protein

Pleiotropic genetic variants have independent effects on different phenotypes. C-reactive protein (CRP) is associated with several cardiometabolic phenotypes. Shared genetic backgrounds may partially underlie these associations. We conducted a genome-wide analysis to identify the shared genetic back...

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Published in:PloS one Vol. 10; no. 3; p. e0118859
Main Authors: Ligthart, Symen, de Vries, Paul S., Uitterlinden, André G., Hofman, Albert, Franco, Oscar H., Chasman, Daniel I., Dehghan, Abbas
Format: Journal Article
Language:English
Published: United States Public Library of Science 13.03.2015
Public Library of Science (PLoS)
Subjects:
Biological effects
C-reactive protein
C-Reactive Protein - metabolism
Cardiovascular disease
Cardiovascular Diseases - genetics
Cardiovascular Diseases - metabolism
Causation
Cholesterol
Consortia
Coronary vessels
Diabetes
Diabetes mellitus
Diabetes mellitus (non-insulin dependent)
Epidemiology
Fasting
Female
Gene expression
Gene loci
Genetic analysis
Genetic diversity
Genetic Loci - genetics
Genetic Pleiotropy
Genetic variance
Genetics
Genome-Wide Association Study
Genomes
Genomics
Glucose
Health risks
Hepatocyte nuclear factor 4
Humans
Hypertension
Inflammation
Insulin
Interleukin 1
Interleukin 6
Interleukin 6 receptors
Lipids
Loci
Low density lipoprotein
Meta-analysis
Metabolic Diseases - genetics
Metabolism
Mortality
Pleiotropy
Polymorphism, Single Nucleotide
Preventive medicine
Proteins
Studies
Triglycerides
Type 2 diabetes
Womens health
Working groups
Netherlands
ISSN:1932-6203, 1932-6203
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Summary:Pleiotropic genetic variants have independent effects on different phenotypes. C-reactive protein (CRP) is associated with several cardiometabolic phenotypes. Shared genetic backgrounds may partially underlie these associations. We conducted a genome-wide analysis to identify the shared genetic background of inflammation and cardiometabolic phenotypes using published genome-wide association studies (GWAS). We also evaluated whether the pleiotropic effects of such loci were biological or mediated in nature. First, we examined whether 283 common variants identified for 10 cardiometabolic phenotypes in GWAS are associated with CRP level. Second, we tested whether 18 variants identified for serum CRP are associated with 10 cardiometabolic phenotypes. We used a Bonferroni corrected p-value of 1.1×10-04 (0.05/463) as a threshold of significance. We evaluated the independent pleiotropic effect on both phenotypes using individual level data from the Women Genome Health Study. Evaluating the genetic overlap between inflammation and cardiometabolic phenotypes, we found 13 pleiotropic regions. Additional analyses showed that 6 regions (APOC1, HNF1A, IL6R, PPP1R3B, HNF4A and IL1F10) appeared to have a pleiotropic effect on CRP independent of the effects on the cardiometabolic phenotypes. These included loci where individuals carrying the risk allele for CRP encounter higher lipid levels and risk of type 2 diabetes. In addition, 5 regions (GCKR, PABPC4, BCL7B, FTO and TMEM18) had an effect on CRP largely mediated through the cardiometabolic phenotypes. In conclusion, our results show genetic pleiotropy among inflammation and cardiometabolic phenotypes. In addition to reverse causation, our data suggests that pleiotropic genetic variants partially underlie the association between CRP and cardiometabolic phenotypes.
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Membership of the CHARGE Inflammation working group is listed in the Acknowledgments.
Competing Interests: The authors have declared that no competing interests exist.
Conceived and designed the experiments: SL AD. Performed the experiments: SL AD DIC. Analyzed the data: SL AD DIC. Contributed reagents/materials/analysis tools: AH AGU OHF. Wrote the paper: SL PSdV AGU AH OHF DIC AD.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0118859