Inflammation

, Volume 35, Issue 2, pp 574–583 | Cite as

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

  • Ying Wu
  • Thomas W. McDade
  • Christopher W. Kuzawa
  • Judith Borja
  • Yun Li
  • Linda S. Adair
  • Karen L. Mohlke
  • Leslie A. Lange
Article

Abstract

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 WORDS

C-reactive protein genome-wide association Filipino women gene–environment interaction 

Notes

Acknowledgments

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.

Competing Interest

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.

Supplementary material

10753_2011_9348_MOESM1_ESM.doc (1.2 mb)
ESM1(DOC 1,255 kb)

References

  1. 1.
    Hage, F.G., and A.J. Szalai. 2007. C-reactive protein gene polymorphisms, C-reactive protein blood levels, and cardiovascular disease risk. Journal of the American College of Cardiology 50: 1115–1122.PubMedCrossRefGoogle Scholar
  2. 2.
    Pankow, J.S., A.R. Folsom, M. Cushman, I.B. Borecki, P.N. Hopkins, J.H. Eckfeldt, and R.P. Tracy. 2001. Familial and genetic determinants of systemic markers of inflammation: the NHLBI Family Heart study. Atherosclerosis 154: 681–689.PubMedCrossRefGoogle Scholar
  3. 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. 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
  5. 5.
    Cordell, H.J. 2009. Genome-wide association studies: detecting gene–gene interactions that underlie human diseases. Nature Reviews. Genetics 10: 392–404.PubMedCrossRefGoogle Scholar
  6. 6.
    Moore, J.H., and S.M. Williams. 2009. Epistasis and its implications for personal genetics. American Journal of Human Genetics 85: 309–320.PubMedCrossRefGoogle Scholar
  7. 7.
    WHO. 2004. The World Health Report 2004—changing history. Geneva: World Health Organization.Google Scholar
  8. 8.
    WHO. 2006. Mortality country fact sheet 2006. Geneva: World Health Orgnization.Google Scholar
  9. 9.
    McDade, T.W., J.N. Rutherford, L. Adair, and C. Kuzawa. 2008. Adiposity and pathogen exposure to a pathogenic environment predict C-reactive protein in Filipino women. The Journal of Nutrition 138: 2442–2447.PubMedCrossRefGoogle Scholar
  10. 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. 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. 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
  13. 13.
    Li, Y., C.J. Willer, J. Ding, P. Scheet, and G.R. Abecasis. 2010. MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genetic Epidemiology 34: 816–834.PubMedCrossRefGoogle Scholar
  14. 14.
    Pruim, R.J., R.P. Welch, S. Sanna, T.M. Teslovich, P.S. Chines, T.P. Gliedt, M. Boehnke, G.R. Abecasis, and C.J. Willer. 2010. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26: 2336–2337.PubMedCrossRefGoogle Scholar
  15. 15.
    Morita, A., T. Nakayama, N. Doba, S. Hinohara, T. Mizutani, and M. Soma. 2007. Genotyping of triallelic SNPs using TaqMan PCR. Molecular and Cellular Probes 21: 171–176.PubMedCrossRefGoogle Scholar
  16. 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. 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
  18. 18.
    Judson, R., C. Brain, B. Dain, A. Windemuth, G. Ruano, and C. Reed. 2004. New and confirmatory evidence of an association between APOE genotype and baseline C-reactive protein in dyslipidemic individuals. Atherosclerosis 177: 345–351.PubMedCrossRefGoogle Scholar
  19. 19.
    Suk, H.J., P.M. Ridker, N.R. Cook, and R.Y. Zee. 2005. Relation of polymorphism within the C-reactive protein gene and plasma CRP levels. Atherosclerosis 178: 139–145.PubMedCrossRefGoogle Scholar
  20. 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. 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
  22. 22.
    Miller, D.T., R.Y. Zee, J. Suk Danik, P. Kozlowski, D.I. Chasman, R. Lazarus, N.R. Cook, P.M. Ridker, and D.J. Kwiatkowski. 2005. Association of common CRP gene variants with CRP levels and cardiovascular events. Annals of Human Genetics 69: 623–638.PubMedCrossRefGoogle Scholar
  23. 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. 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. 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
  26. 26.
    Lohmueller, K.E., C.L. Pearce, M. Pike, E.S. Lander, and J.N. Hirschhorn. 2003. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nature Genetics 33: 177–182.PubMedCrossRefGoogle Scholar
  27. 27.
    Thomas, D. 2010. Gene-environment-wide association studies: emerging approaches. Nature Reviews. Genetics 11: 259–272.PubMedCrossRefGoogle Scholar
  28. 28.
    Black, S., I. Kushner, and D. Samols. 2004. C-reactive protein. The Journal of Biological Chemistry 279: 48487–48490.PubMedCrossRefGoogle Scholar
  29. 29.
    McDade, T.W., J. Rutherford, L. Adair, and C.W. Kuzawa. 2010. Early origins of inflammation: microbial exposures in infancy predict lower levels of C-reactive protein in adulthood. Proc Biol Sci 277: 1129–1137.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Ying Wu
    • 1
  • Thomas W. McDade
    • 2
    • 3
  • Christopher W. Kuzawa
    • 2
    • 3
  • Judith Borja
    • 4
  • Yun Li
    • 1
    • 5
  • Linda S. Adair
    • 6
  • Karen L. Mohlke
    • 1
  • Leslie A. Lange
    • 1
  1. 1.Department of GeneticsUniversity of North CarolinaChapel HillUSA
  2. 2.Department of AnthropologyNorthwestern UniversityEvanstonUSA
  3. 3.Cells 2 Society: The Center for Social Disparities and Health at the Institute for Policy ResearchNorthwestern UniversityEvanstonUSA
  4. 4.USC Office of Population Studies FoundationUniversity of San CarlosCebu CityPhilippines
  5. 5.Department of BiostatisticsUniversity of North CarolinaChapel HillUSA
  6. 6.Department of NutritionUniversity of North CarolinaChapel HillUSA

Personalised recommendations