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Hum Mol Genet. 2018 Aug 15;27(16):2940-2953. doi: 10.1093/hmg/ddy211.

Discovery, fine-mapping, and conditional analyses of genetic variants associated with C-reactive protein in multiethnic populations using the Metabochip in the Population Architecture using Genomics and Epidemiology (PAGE) study.

Author information

1
Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
2
Institute of Translational Health Sciences, University of Washington, Seattle, WA, USA.
3
Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, TX, USA.
4
Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
5
PATH, Seattle, WA, USA.
6
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
7
Department of Epidemiology, University of San Diego, San Diego, CA, USA.
8
Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
9
Division of Epidemiology, Human Genetics & Environmental Sciences, The University of Texas, Houston, TX, USA.
10
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
11
Division of Epidemiology & Community Health, University of Minnesota, Minneapolis, MN, USA.
12
Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.
13
Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
14
Division of Health Promotion and Behavioral Science, San Diego State University, San Diego, CA, USA.
15
Institute for Minority Health Research, University of Illinois College of Medicine, Chicago, IL, USA.
16
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
17
Division of Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
18
Department of Biostatistics, University of Washington, Seattle, WA, USA.
19
Missouri Breaks Industries Research, Inc., Eagle Butte, SD, USA.
20
Information Sciences Institute, University of Southern California, Marina del Rey, CA, USA.
21
Department of Epidemiology & Biostatistics, University of California San Francisco, San Francisco, CA, USA.
22
Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
23
Division of Genomic Medicine, NHGRI, NIH, Bethesda, MD, USA.
24
Human Genetics Center, School of Public Health, The University of Texas Health Science Center, Houston, TX, USA.
25
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
26
University of Hawaii Cancer Center, Honolulu, HI, USA.

Abstract

C-reactive protein (CRP) is a circulating biomarker indicative of systemic inflammation. We aimed to evaluate genetic associations with CRP levels among non-European-ancestry populations through discovery, fine-mapping and conditional analyses. A total of 30 503 non-European-ancestry participants from 6 studies participating in the Population Architecture using Genomics and Epidemiology study had serum high-sensitivity CRP measurements and ∼200 000 single nucleotide polymorphisms (SNPs) genotyped on the Metabochip. We evaluated the association between each SNP and log-transformed CRP levels using multivariate linear regression, with additive genetic models adjusted for age, sex, the first four principal components of genetic ancestry, and study-specific factors. Differential linkage disequilibrium patterns between race/ethnicity groups were used to fine-map regions associated with CRP levels. Conditional analyses evaluated for multiple independent signals within genetic regions. One hundred and sixty-three unique variants in 12 loci in overall or race/ethnicity-stratified Metabochip-wide scans reached a Bonferroni-corrected P-value <2.5E-7. Three loci have no (HACL1, OLFML2B) or only limited (PLA2G6) previous associations with CRP levels. Six loci had different top hits in race/ethnicity-specific versus overall analyses. Fine-mapping refined the signal in six loci, particularly in HNF1A. Conditional analyses provided evidence for secondary signals in LEPR, IL1RN and HNF1A, and for multiple independent signals in CRP and APOE. We identified novel variants and loci associated with CRP levels, generalized known CRP associations to a multiethnic study population, refined association signals at several loci and found evidence for multiple independent signals at several well-known loci. This study demonstrates the benefit of conducting inclusive genetic association studies in large multiethnic populations.

PMID:
29878111
PMCID:
PMC6077792
[Available on 2019-08-15]
DOI:
10.1093/hmg/ddy211

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Publication type

Grant support

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