title: Pleiotropy among common genetic loci identified for cardiometabolic disorders and C-reactive protein.
abstract: 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.
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Symen
authors.initials: S
authors.lastname: Ligthart
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Paul S
authors.initials: PS
authors.lastname: de Vries
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Oscar H
authors.initials: OH
authors.lastname: Franco
authors.affiliation: Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, United States of America.
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Chasman
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Abbas
authors.initials: A
authors.lastname: Dehghan
mesh_terms: D002097:C-Reactive Protein / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D058685:Genetic Pleiotropy; D055106:Genome-Wide Association Study; D006801:Humans; D008659:Metabolic Diseases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D002097:C-Reactive Protein