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Association of exome sequences with plasma C-reactive protein levels in >9000 participants.

Publication ,  Journal Article
Schick, UM; Auer, PL; Bis, JC; Lin, H; Wei, P; Pankratz, N; Lange, LA; Brody, J; Stitziel, NO; Kim, DS; Carlson, CS; Fornage, M; Haessler, J ...
Published in: Hum Mol Genet
January 15, 2015

C-reactive protein (CRP) concentration is a heritable systemic marker of inflammation that is associated with cardiovascular disease risk. Genome-wide association studies have identified CRP-associated common variants associated in ∼25 genes. Our aims were to apply exome sequencing to (1) assess whether the candidate loci contain rare coding variants associated with CRP levels and (2) perform an exome-wide search for rare variants in novel genes associated with CRP levels. We exome-sequenced 6050 European-Americans (EAs) and 3109 African-Americans (AAs) from the NHLBI-ESP and the CHARGE consortia, and performed association tests of sequence data with measured CRP levels. In single-variant tests across candidate loci, a novel rare (minor allele frequency = 0.16%) CRP-coding variant (rs77832441-A; p.Thr59Met) was associated with 53% lower mean CRP levels (P = 2.9 × 10(-6)). We replicated the association of rs77832441 in an exome array analysis of 11 414 EAs (P = 3.0 × 10(-15)). Despite a strong effect on CRP levels, rs77832441 was not associated with inflammation-related phenotypes including coronary heart disease. We also found evidence for an AA-specific association of APOE-ε2 rs7214 with higher CRP levels. At the exome-wide significance level (P < 5.0 × 10(-8)), we confirmed associations for reported common variants of HNF1A, CRP, IL6R and TOMM40-APOE. In gene-based tests, a burden of rare/lower frequency variation in CRP in EAs (P ≤ 6.8 × 10(-4)) and in retinoic acid receptor-related orphan receptor α (RORA) in AAs (P = 1.7 × 10(-3)) were associated with CRP levels at the candidate gene level (P < 2.0 × 10(-3)). This inquiry did not elucidate novel genes, but instead demonstrated that variants distributed across the allele frequency spectrum within candidate genes contribute to CRP levels.

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Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

January 15, 2015

Volume

24

Issue

2

Start / End Page

559 / 571

Location

England

Related Subject Headings

  • White People
  • Risk Factors
  • Receptors, Interleukin-6
  • Polymorphism, Single Nucleotide
  • Plasma
  • Male
  • Humans
  • Hepatocyte Nuclear Factor 1-alpha
  • Genome-Wide Association Study
  • Genetics & Heredity
 

Citation

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Schick, U. M., Auer, P. L., Bis, J. C., Lin, H., Wei, P., Pankratz, N., … National Heart, Lung, and Blood Institute GO Exome Sequencing Project, . (2015). Association of exome sequences with plasma C-reactive protein levels in >9000 participants. Hum Mol Genet, 24(2), 559–571. https://doi.org/10.1093/hmg/ddu450
Schick, Ursula M., Paul L. Auer, Joshua C. Bis, Honghuang Lin, Peng Wei, Nathan Pankratz, Leslie A. Lange, et al. “Association of exome sequences with plasma C-reactive protein levels in >9000 participants.Hum Mol Genet 24, no. 2 (January 15, 2015): 559–71. https://doi.org/10.1093/hmg/ddu450.
Schick UM, Auer PL, Bis JC, Lin H, Wei P, Pankratz N, et al. Association of exome sequences with plasma C-reactive protein levels in >9000 participants. Hum Mol Genet. 2015 Jan 15;24(2):559–71.
Schick, Ursula M., et al. “Association of exome sequences with plasma C-reactive protein levels in >9000 participants.Hum Mol Genet, vol. 24, no. 2, Jan. 2015, pp. 559–71. Pubmed, doi:10.1093/hmg/ddu450.
Schick UM, Auer PL, Bis JC, Lin H, Wei P, Pankratz N, Lange LA, Brody J, Stitziel NO, Kim DS, Carlson CS, Fornage M, Haessler J, Hsu L, Jackson RD, Kooperberg C, Leal SM, Psaty BM, Boerwinkle E, Tracy R, Ardissino D, Shah S, Willer C, Loos R, Melander O, Mcpherson R, Hovingh K, Reilly M, Watkins H, Girelli D, Fontanillas P, Chasman DI, Gabriel SB, Gibbs R, Nickerson DA, Kathiresan S, Peters U, Dupuis J, Wilson JG, Rich SS, Morrison AC, Benjamin EJ, Gross MD, Reiner AP, Cohorts for Heart and Aging Research in Genomic Epidemiology, National Heart, Lung, and Blood Institute GO Exome Sequencing Project. Association of exome sequences with plasma C-reactive protein levels in >9000 participants. Hum Mol Genet. 2015 Jan 15;24(2):559–571.
Journal cover image

Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

January 15, 2015

Volume

24

Issue

2

Start / End Page

559 / 571

Location

England

Related Subject Headings

  • White People
  • Risk Factors
  • Receptors, Interleukin-6
  • Polymorphism, Single Nucleotide
  • Plasma
  • Male
  • Humans
  • Hepatocyte Nuclear Factor 1-alpha
  • Genome-Wide Association Study
  • Genetics & Heredity