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Pleiotropy among common genetic loci identified for cardiometabolic disorders and C-reactive protein.

TitlePleiotropy among common genetic loci identified for cardiometabolic disorders and C-reactive protein.
Publication TypeJournal Article
Year of Publication2015
AuthorsLigthart S, de Vries PS, Uitterlinden AG, Hofman A, Franco OH, Chasman DI
Secondary AuthorsDehghan A
Corporate AuthorsCHARGE Inflammation working group
JournalPLoS One
Date Published2015
KeywordsC-Reactive Protein, Cardiovascular Diseases, Female, Genetic Loci, Genetic Pleiotropy, Genome-Wide Association Study, Humans, Metabolic Diseases, Polymorphism, Single Nucleotide

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.

Alternate JournalPLoS One
PubMed ID25768928
PubMed Central IDPMC4358943
Grant List1 R01 AG028321 / AG / NIA NIH HHS / United States
N01-HC 25195 1 / HC / NHLBI NIH HHS / United States
UM1 CA182913 / CA / NCI NIH HHS / United States
R01 HL64753 / HL / NHLBI NIH HHS / United States
R01 HL076784 / HL / NHLBI NIH HHS / United States