Genome-wide Association with C-Reactive Protein Levels in CLHNS: Evidence for the CRP and HNF1A Loci and their Interaction with Exposure to a Pathogenic Environment
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Recent genome-wide association studies have related several genetic loci, including C-reactive protein (CRP), hepatocyte nuclear factor 1 homeobox (HNF1A), and genetic variations in the leptin receptor (LEPR), to circulating CRP levels in populations of European ancestry. The genetic effects in other populations and across varying levels of exposure to a pathogenic environment, an important environmental factor associated with CRP, remain to be determined. We tested 2,073,674 single-nucleotide polymorphisms (SNPs) for association with plasma CRP (limited to ≤10 mg/L) in 1,709 unrelated Filipino women from the Cebu Longitudinal Health and Nutrition Survey. The strongest evidence of association was observed with variants at CRP (rs876537, P = 1.4 × 10−9) and HNF1A (rs7305618, P = 1.0 × 10−8). Among other previously reported CRP-associated loci, the apolipoprotein E ε4 haplotype was associated with decreased CRP level (P = 7.1 × 10−4), and modest association was observed with LEPR (rs1892534, P = 0.076), with direction of effects consistent with previous studies. The strongest signal at a locus not previously reported mapped to a gene desert region on chromosome 6q16.1 (rs1408282, P = 2.9 × 10−6). Finally, we observed nominal evidence of interaction with exposure to a pathogenic environment for top main effect SNPs at HNF1A (rs7305618, P = 0.031), LEPR (rs1892535, P = 0.030) and 6q16.1 (rs1408282, P = 0.046). Our findings demonstrate convincing evidence that genetic variants in CRP and HNF1A contribute to plasma CRP in Filipino women and provide the first evidence that exposure to a pathogenic environment may modify the genetic influence at the HNF1A, LEPR, and 6q16.1 loci on plasma CRP level.
KEY WORDSC-reactive protein genome-wide association Filipino women gene–environment interaction
We thank the Office of Population Studies Foundation research and data collection teams and the study participants who generously provided their time for this study.
The authors declare that they have no competing interests.
Sources of Funding
This work was supported by the National Institutes of Health grants DK078150, TW05596, HL085144, RR20649, ES10126, and DK56350.
- 3.Ridker, P.M., G. Pare, A. Parker, R.Y. Zee, J.S. Danik, J.E. Buring, D. Kwiatkowski, N.R. Cook, J.P. Miletich, and D.I. Chasman. 2008. Loci related to metabolic-syndrome pathways including LEPR, HNF1A, IL6R, and GCKR associate with plasma C-reactive protein: the Women's Genome Health Study. American Journal of Human Genetics 82: 1185–1192.PubMedCrossRefGoogle Scholar
- 4.Reiner, A.P., M.J. Barber, Y. Guan, P.M. Ridker, L.A. Lange, D.I. Chasman, J.D. Walston, G.M. Cooper, N.S. Jenny, M.J. Rieder, J.P. Durda, J.D. Smith, J. Novembre, R.P. Tracy, J.I. Rotter, M. Stephens, D.A. Nickerson, and R.M. Krauss. 2008. Polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are associated with C-reactive protein. American Journal of Human Genetics 82: 1193–1201.PubMedCrossRefGoogle Scholar
- 7.WHO. 2004. The World Health Report 2004—changing history. Geneva: World Health Organization.Google Scholar
- 8.WHO. 2006. Mortality country fact sheet 2006. Geneva: World Health Orgnization.Google Scholar
- 10.McDade, T.W., J.N. Rutherford, L. Adair, and C. Kuzawa. 2009. Population differences in associations between C-reactive protein concentration and adiposity: comparison of young adults in the Philippines and the United States. The American Journal of Clinical Nutrition 89: 1237–1245.PubMedCrossRefGoogle Scholar
- 11.Adair, L. S., B. M. Popkin, J. S. Akin, D. K. Guilkey, S. Gultiano, J. Borja, L. Perez, C. W. Kuzawa, T. McDade, and M. J. Hindin (2011) Cohort profile: the Cebu Longitudinal Health and Nutrition Survey. Int J Epidemiol (in press).Google Scholar
- 12.Lange, L.A., D.C. Croteau-Chonka, A.F. Marvelle, L. Qin, K.J. Gaulton, C.W. Kuzawa, T.W. McDade, Y. Wang, Y. Li, S. Levy, J.B. Borja, E.M. Lange, L.S. Adair, and K.L. Mohlke. 2010. Genome-wide association study of homocysteine levels in Filipinos provides evidence for CPS1 in women and a stronger MTHFR effect in young adults. Human Molecular Genetics 19: 2050–2058.PubMedCrossRefGoogle Scholar
- 16.Szalai, A.J., J. Wu, E.M. Lange, M.A. McCrory, C.D. Langefeld, A. Williams, S.O. Zakharkin, V. George, D.B. Allison, G.S. Cooper, F. Xie, Z. Fan, J.C. Edberg, and R.P. Kimberly. 2005. Single-nucleotide polymorphisms in the C-reactive protein (CRP) gene promoter that affect transcription factor binding, alter transcriptional activity, and associate with differences in baseline serum CRP level. Journal of Molecular Medicine 83: 440–447.PubMedCrossRefGoogle Scholar
- 17.Kathiresan, S., M.G. Larson, R.S. Vasan, C.Y. Guo, P. Gona, J.F. Keaney Jr., P.W. Wilson, C. Newton-Cheh, S.L. Musone, A.L. Camargo, J.A. Drake, D. Levy, C.J. O'Donnell, J.N. Hirschhorn, and E.J. Benjamin. 2006. Contribution of clinical correlates and 13 C-reactive protein gene polymorphisms to interindividual variability in serum C-reactive protein level. Circulation 113: 1415–1423.PubMedCrossRefGoogle Scholar
- 20.Kovacs, A., F. Green, L.O. Hansson, P. Lundman, A. Samnegard, S. Boquist, C.G. Ericsson, H. Watkins, A. Hamsten, and P. Tornvall. 2005. A novel common single nucleotide polymorphism in the promoter region of the C-reactive protein gene associated with the plasma concentration of C-reactive protein. Atherosclerosis 178: 193–198.PubMedCrossRefGoogle Scholar
- 21.Brull, D. J., N. Serrano, F. Zito, L. Jones, H. E. Montgomery, A. Rumley, P. Sharma, G. D. Lowe, M. J. World, S. E. Humphries, and A. D. Hingorani. 2003. Human CRP gene polymorphism influences CRP levels: implications for the prediction and pathogenesis of coronary heart disease. Arteriosclerosis, Thrombosis, and Vascular Biology 23: 2063–2069.CrossRefGoogle Scholar
- 23.Lange, L.A., C.S. Carlson, L.A. Hindorff, E.M. Lange, J. Walston, J.P. Durda, M. Cushman, J.C. Bis, D. Zeng, D. Lin, L.H. Kuller, D.A. Nickerson, B.M. Psaty, R.P. Tracy, and A.P. Reiner. 2006. Association of polymorphisms in the CRP gene with circulating C-reactive protein levels and cardiovascular events. JAMA 296: 2703–2711.PubMedCrossRefGoogle Scholar
- 24.Nishikawa, T., K. Hagihara, S. Serada, T. Isobe, A. Matsumura, J. Song, T. Tanaka, I. Kawase, T. Naka, and K. Yoshizaki. 2008. Transcriptional complex formation of c-Fos, STAT3, and hepatocyte NF-1 alpha is essential for cytokine-driven C-reactive protein gene expression. Journal of Immunology 180: 3492–3501.Google Scholar
- 25.Reiner, A.P., M.D. Gross, C.S. Carlson, S.J. Bielinski, L.A. Lange, M. Fornage, N.S. Jenny, J. Walston, R.P. Tracy, O.D. Williams, D.R. Jacobs Jr., and D.A. Nickerson. 2009. Common coding variants of the HNF1A gene are associated with multiple cardiovascular risk phenotypes in community-based samples of younger and older European-American adults: the Coronary Artery Risk Development in Young Adults Study and The Cardiovascular Health Study. Circ Cardiovasc Genet 2: 244–254.PubMedCrossRefGoogle Scholar