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

Ligthart, S; de Vries, PS; Uitterlinden, AG; Hofman, A; CHARGE Inflammation working group; Franco, OH; Chasman, DI; Dehghan, A (2015) Pleiotropy among common genetic loci identified for cardiometabolic disorders and C-reactive protein. PLoS One, 10 (3). e0118859. ISSN 1932-6203 https://doi.org/10.1371/journal.pone.0118859
SGUL Authors: Jamshidi, Yalda

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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.

Item Type: Article
Additional Information: © 2015 Ligthart et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: C-Reactive Protein, Cardiovascular Diseases, Female, Genetic Loci, Genetic Pleiotropy, Genome-Wide Association Study, Humans, Metabolic Diseases, Polymorphism, Single Nucleotide, CHARGE Inflammation working group, Humans, Cardiovascular Diseases, Metabolic Diseases, C-Reactive Protein, Polymorphism, Single Nucleotide, Female, Genome-Wide Association Study, Genetic Loci, Genetic Pleiotropy, MD Multidisciplinary, General Science & Technology
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: PLoS One
ISSN: 1932-6203
Language: eng
Dates:
DateEvent
13 March 2015Published
20 January 2015Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
1 R01 AG028321NIA NIH HHSUNSPECIFIED
R01 HL043851NHLBI NIH HHSUNSPECIFIED
R01 HL076784NHLBI NIH HHSUNSPECIFIED
N01-HC 25195 1NHLBI NIH HHSUNSPECIFIED
UM1 CA182913NCI NIH HHSUNSPECIFIED
R01 CA047988NCI NIH HHSUNSPECIFIED
R01 HL080467NHLBI NIH HHSUNSPECIFIED
R01 AG028321NIA NIH HHSUNSPECIFIED
N01HC25195NHLBI NIH HHSUNSPECIFIED
R01 HL64753NHLBI NIH HHSUNSPECIFIED
916.12.154Nederlandse Organisatie voor Wetenschappelijk Onderzoekhttp://dx.doi.org/10.13039/501100003246
PubMed ID: 25768928
Web of Science ID: WOS:000351277500050
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/112979
Publisher's version: https://doi.org/10.1371/journal.pone.0118859

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