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Genomewide association study for C-reactive protein in Indians replicates known associations of common variants

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Abstract

Elevated C-reactive protein (CRP) serves as an independent biomarker for acute and chronic inflammation, and is also associated with metabolic diseases. Genomewide loci regulating CRP level in Indian population, a high-risk group for metabolic illness, is unexplored. Therefore, we aimed to discover common polymorphisms associated with plasma CRP level in 4493 Indians of Indo-European origin using genomewide association study. Genomewide strong associations of two known intronic variants in hepatocyte nuclear factor-\(1\upalpha \) gene (HNF1A) were identified among Indian subjects. We also detected prior associations of several variants in/near metabolic and inflammatory process genes: APOC1, LEPR, CRP, HNF4A, IL6R and APOE with modest associations. This study confirms that Indians from Indo-European origin display similar core universal genetic factors for CRP levels.

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References

  • Benjamin E. J., Dupuis J., Larson M. G., Lunetta K. L., Booth S. L., Govindaraju D. R. et al. 2007 Genome-wide association with select biomarker traits in the Framingham heart study. BMC Med. Genet. 8, S11.

    Article  Google Scholar 

  • Black S., Kushner I. and Samols D. 2004 C-reactive protein. J. Biol. Chem. 279, 48487–48490.

    Article  CAS  Google Scholar 

  • Boyle A. P., Hong E. L., Hariharan M., Cheng Y., Schaub M. A., Kasowski M. et al. 2012 Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 22, 1790–1797.

    Article  CAS  Google Scholar 

  • Chambers J. C., Eda S., Bassett P., Karim Y., Thompson S. G., Gallimore J. R. et al. 2001 C-reactive protein, insulin resistance, central obesity, and coronary heart disease risk in Indian Asians from the United Kingdom compared with European whites. Circulation 104, 145–150.

    Article  CAS  Google Scholar 

  • Chandalia M., Cabo-Chan A. V., Devaraj S., Jialal I., Grundy S. M. and Abate N. 2003 Elevated plasma high-sensitivity C-reactive protein concentrations in Asian Indians living in the United States. J. Clin. Endocrinol. Metab. 88, 3773–3776.

    Article  CAS  Google Scholar 

  • Dehghan A., Dupuis J., Barbalic M., Bis J. C., Eiriksdottir G., Lu C. et al. 2011 Meta-analysis of genome-wide association studies in \(>\)80,000 subjects identifies multiple loci for C-reactive protein level. Circulation 123, 731–738.

  • Dorajoo R., Li R., Ikram M. K., Liu J., Froguel P., Lee J. et al. 2013 Are C-reactive protein associated genetic variants associated with serum levels and retinal markers of microvascular pathology in Asian populations from Singapore? PLoS One 8, e67650.

    Article  CAS  Google Scholar 

  • Elliott P., Chambers J. C., Zhang W., Clarke R., Hopewell J. C., Peden J. F. et al. 2009 Genetic loci associated with C-reactive protein levels and risk of coronary heart disease. JAMA 302, 37–48.

    Article  CAS  Google Scholar 

  • Fajans S. S., Bell G. I. and Polonsky K. S. 2001 Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N. Engl. J. Med. 345, 971–980.

    Article  CAS  Google Scholar 

  • Ford E. S., Giles W. H., Myers G. L., Rifai N., Ridker P. M. and Mannino D. M. 2003 C-reactive protein concentration distribution among US children and young adults: findings from the National Health and Nutrition Examination Survey, 1999–2000. Clin. Chem. 49, 1353–1357.

    Article  CAS  Google Scholar 

  • Giri A. K., Khan N. M., Basu A., Tandon N., Scaria V. and Bharadwaj D. 2014 Pharmacogenetic landscape of clopidogrel in north Indians suggest distinct interpopulation differences in allele frequencies. Pharmacogenomics 15, 643–653.

    Article  CAS  Google Scholar 

  • INdian DIabetes Consortium 2011 INDICO: the development of a resource for epigenomic study of Indians undergoing socioeconomic transition. Hugo J. 5, 65–69.

  • Khera A., McGuire D. K., Murphy S. A., Stanek H. G., Das S. R., Vongpatanasin W. et al. 2005 Race and gender differences in C-reactive protein levels. J. Am. Coll. Cardiol. 46, 464–469.

    Article  CAS  Google Scholar 

  • Khoo C. M., Sairazi S., Taslim S., Gardner D., Wu Y., Lee J. et al. 2011 Ethnicity modifies the relationships of insulin resistance, inflammation, and adiponectin with obesity in a multiethnic Asian population. Diabetes Care 34, 1120–1126.

    Article  Google Scholar 

  • Kocarnik J. M., Pendergrass S. A., Carty C. L., Pankow J. S., Schumacher F. R., Cheng I. et al. 2014 Multiancestral analysis of inflammation-related genetic variants and c-reactive protein in the population architecture using genomics and epidemiology study. Circ. Cardiovasc. Genet. 7, 178–188.

    Article  CAS  Google Scholar 

  • Kong M. and Lee C. 2013 Genetic associations with C-reactive protein level and white blood cell count in the KARE study. Int. J. Immunogenet. 40, 120–125.

    Article  CAS  Google Scholar 

  • Li S. P. and Goldman N. D. 1996 Regulation of human C-reactive protein gene expression by two synergistic IL-6 responsive elements. Biochemistry 35, 9060–9068.

    Article  CAS  Google Scholar 

  • Mahajan A., Tabassum R., Chavali S., Dwivedi O. P., Bharadwaj M., Tandon N. et al. 2009 High-sensitivity C- reactive protein levels and type 2 diabetes in urban North Indians. J. Clin. Endocrinol. Metab. 94, 2123–2127.

    Article  CAS  Google Scholar 

  • Mahajan A., Tabassum R., Chavali S., Dwivedi O. P., Chauhan G., Ghosh S. et al. 2011 Common variants in CRP and LEPR influence high sensitivity C-reactive protein levels in North Indians. PLoS One 6, e24645.

    Article  CAS  Google Scholar 

  • Mahajan A., Jaiswal A.,Tabassum R., Podder A., Ghosh S., Madhu S. V. et al. 2012 Elevated level of C-reactive protein as a risk factor for metabolic syndrome in Indians. Atherosclerosis 220, 275–281.

    Article  CAS  Google Scholar 

  • Montojo J., Zuberi K., Rodriguez H., Kazi F., Wright G., Donaldson S. L. et al. 2010 GeneMANIA cytoscape plugin: fast gene function predictions on the desktop. Bioinformatics 26, 2927–2928.

    Article  CAS  Google Scholar 

  • Okada Y., Takahashi A., Ohmiya H., Kumasaka N., Kamatani Y., Hosono N. et al. 2011 Genome-wide association study for C-reactive protein levels identified pleiotropic associations in the IL6 locus. Hum. Mol. Genet. 20, 1224–1231.

    Article  CAS  Google Scholar 

  • Pankow J. S., Folsom A. R., Cushman M., Borecki I. B., Hopkins P. N., Eckfeldt J. H. et al. 2001 Familial and genetic determinants of systemic markers of inflammation: the NHLBI family heart study. Atherosclerosis 154, 681–689.

    Article  CAS  Google Scholar 

  • Plomin R., Haworth C. M. and Davis O. S. 2009 Common disorders are quantitative traits. Nat. Rev. Genet. 10, 872–878.

    Article  CAS  Google Scholar 

  • Purcell S., Neale B., Todd-Brown K., Thomas L., Ferreira M. A., Bender D. et al. 2007 PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575.

    Article  CAS  Google Scholar 

  • Reiner A. P., Barber M. J., Guan Y., Ridker P. M., Lange L. A., Chasman D. I. et al. 2008 Polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1\(\alpha \) are associated with C-reactive protein. Am. J. Hum. Genet. 82, 1193–1201.

    Article  CAS  Google Scholar 

  • Reiner A. P., Beleza S., Franceschini N., Auer P. L., Robinson J. G., Kooperberg C. et al. 2012 Genome-wide association and population genetic analysis of c-reactive protein in African American and Hispanic American women. Am. J. Hum. Genet. 91, 502–512.

    Article  CAS  Google Scholar 

  • Ridker P. M., Wilson P. W. F. and Grundy S. M. 2004 Should C-reactive protein be added to metabolic syndrome and to assessment of global cardiovascular risk? Circulation 109, 2818–2825.

    Article  CAS  Google Scholar 

  • Ridker P. M., Pare G., Parker A., Zee R. Y., Danik J. S., Buring J. E. et al. 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. Am. J. Hum. Genet. 82, 1185–1192.

    Article  CAS  Google Scholar 

  • Rojo-Martinez G., Soriguer F., Colomo N., Calle A., Goday A., Bordiú E. et al. 2013 Factors determining high-sensitivity C-reactive protein values in the Spanish population. Di@bet.es study. Eur. J. Clin. Invest. 43, 1–10.

    Article  CAS  Google Scholar 

  • Shen R., Fan J. B., Campbell D., Chang W., Chen J., Doucet D. et al. 2005 High-throughput SNP genotyping on universal bead arrays. Mutat. Res. 573, 70–82.

    Article  CAS  Google Scholar 

  • Tabassum R., Mahajan A., Chauhan G., Dwivedi O. P., Dubey H., Sharma V. et al. 2011 No association of TNFRSF1B variants with type 2 diabetes in Indians of Indo-European origin. BMC Med. Genet. 12, 110.

    Article  CAS  Google Scholar 

  • Tabassum R., Chauhan G., Dwivedi O. P., Mahajan A., Jaiswal A., Kaur I. et al. 2013 Genome-wide association study for type 2 diabetes in Indians identifies a new susceptibility locus at 2q21. Diabetes 62, 977–986.

    Article  CAS  Google Scholar 

  • Turner S. D. 2014 qqman: an R package for visualizing GWAS results using Q–Q and Manhattan plots. BioRxiv.

  • Ward L. D. and Kellis M. 2012 HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 40, D930–D934.

    Article  CAS  Google Scholar 

  • Welter D., MacArthur J., Morales J., Burdett T., Hall P., Junkins H. et al. 2014 The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res. 42, D1001–D1006.

    Article  CAS  Google Scholar 

  • Wessel J., Moratorio G., Rao F., Mahata M., Zhang L., Greene W. et al. 2007 C-reactive protein, an ‘intermediate phenotype’ for inflammation: human twin studies reveal heritability, association with blood pressure and the metabolic syndrome, and the influence of common polymorphism at catecholaminergic/beta-adrenergic pathway loci. J. Hypertens. 25, 329–343.

    Article  CAS  Google Scholar 

  • Willer C. J., Li Y. and Abecasis G. R. 2010 METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191.

    Article  CAS  Google Scholar 

  • Wu Y., McDade T. W., Kuzawa C. W., Borja J., Li Y., Adair L. S. et al. 2012 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. Inflammation 35, 574–583.

    Article  CAS  Google Scholar 

  • Yang J., Lee S. H., Goddard M. E. and Visscher P. M. 2011 GCTA: a tool for genome-wide complex trait analysis. Am. J. Hum. Genet. 88, 76–82.

    Article  CAS  Google Scholar 

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Acknowledgements

The authors are thankful to all the study participants and the members of INdian DIabetes COnsortium (INDICO) for their support in generation of data. This study was supported by grants provided by the Council of Scientific and Industrial Research (CSIR), Government of India through Centre for Cardiovascular and Metabolic Disease Research (CARDIOMED) project (Grant no. BSC0122-(13)). This study was also partially funded by the Department of Science and Technology, Government of India through PURSE II CDST/SR/PURSE PHASE II/11. GP and AKG acknowledge University Grants Commission (UGC), Government of India for Senior Research Fellowship.

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Authors and Affiliations

  1. Genomics and Molecular Medicine Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi , 110 020, India

    Gauri Prasad & Anil K. Giri

  2. Academy of Scientific and Innovative Research, CSIR-Institute of Genomics and Integrative Biology Campus, New Delhi, 110 020, India

    Gauri Prasad, Anil K. Giri & Dwaipayan Bharadwaj

  3. National Institute of Biomedical Genomics, Netaji Subhas Sanatorium (Tuberculosis Hospital), Kalyani, West Bengal, 741 251, India

    Analabha Basu

  4. Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi,  110 029, India

    Nikhil Tandon

  5. Systems Genomics Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi,  110 067, India

    Dwaipayan Bharadwaj

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  1. Gauri Prasad
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  2. Anil K. Giri
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  5. Dwaipayan Bharadwaj
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Indico Consortium

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Correspondence to Nikhil Tandon or Dwaipayan Bharadwaj.

Additional information

Corresponding editor: H. A. Ranganath.

Members of the INDICO consortium are listed in the supplementary material.

DB designed the study and overall management of the project. GP, AKG and INDICO collected samples and conducted the experiments. GP and AKG analysed and interpreted data. GP drafted the manuscript. DB and AB critically revised the manuscript and checked statistical procedures. DB and NT approved the final version of the manuscript. All authors read and approved the final manuscript.

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Prasad, G., Giri, A.K., Indico Consortium. et al. Genomewide association study for C-reactive protein in Indians replicates known associations of common variants. J Genet 98, 20 (2019). https://doi.org/10.1007/s12041-019-1065-6

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  • DOI: https://doi.org/10.1007/s12041-019-1065-6

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