TY - JOUR
T1 - Multiancestral analysis of inflammation-related genetic variants and c-reactive protein in the population architecture using genomics and epidemiology study
AU - Kocarnik, Jonathan M.
AU - Pendergrass, Sarah A.
AU - Carty, Cara L.
AU - Pankow, James S.
AU - Schumacher, Fredrick R.
AU - Cheng, Iona
AU - Durda, Peter
AU - Ambite, Josè Luis
AU - Deelman, Ewa
AU - Cook, Nancy R.
AU - Liu, Simin
AU - Wactawski-Wende, Jean
AU - Hutter, Carolyn
AU - Brown-Gentry, Kristin
AU - Wilson, Sarah
AU - Best, Lyle G.
AU - Pankratz, Nathan
AU - Hong, Ching Ping
AU - Cole, Shelley A.
AU - Voruganti, V. Saroja
AU - Buz̃kovà, Petra
AU - Jorgensen, Neal W.
AU - Jenny, Nancy S.
AU - Wilkens, Lynne R.
AU - Haiman, Christopher A.
AU - Kolonel, Laurence N.
AU - Croix, Andrea La
AU - North, Kari
AU - Jackson, Rebecca
AU - Marchand, Loic Le
AU - Hindorff, Lucia A.
AU - Crawford, Dana C.
AU - Gross, Myron
AU - Peters, Ulrike
PY - 2014/4
Y1 - 2014/4
N2 - Background-C-reactive protein (CRP) is a biomarker of inflammation. Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) associated with CRP concentrations and inflammation-related traits such as cardiovascular disease, type 2 diabetes mellitus, and obesity. We aimed to replicate previous CRP-SNP associations, assess whether these associations generalize to additional race/ethnicity groups, and evaluate inflammationrelated SNPs for a potentially pleiotropic association with CRP. Methods and Results-We selected and analyzed 16 CRP-associated and 250 inflammation-related GWAS SNPs among 40 473 African American, American Indian, Asian/Pacific Islander, European American, and Hispanic participants from 7 studies collaborating in the Population Architecture using Genomics and Epidemiology (PAGE) study. Fixed-effect metaanalyses combined study-specific race/ethnicity-stratified linear regression estimates to evaluate the association between each SNP and high- sensitivity CRP. Overall, 18 SNPs in 8 loci were significantly associated with CRP (Bonferronicorrected P>3.1×10-3 for replication, P>2.0×10-4 for pleiotropy): Seven of these were specific to European Americans, while 9 additionally generalized to African Americans (1), Hispanics (5), or both (3); 1 SNP was seen only in African Americans and Hispanics. Two SNPs in the CELSR2/PSRC1/SORT1 locus showed a potentially novel association with CRP: rs599839 (P=2.0×10-6) and rs646776 (P=3.1×10-5). Conclusions-We replicated 16 SNP-CRP associations, 10 of which generalized to African Americans and/or Hispanics. We also identified potentially novel pleiotropic associations with CRP for two SNPs previously associated with coronary artery disease and/or low-density lipoprotein-cholesterol. These findings demonstrate the benefit of evaluating genotype- phenotype associations in multiple race/ethnicity groups and looking for pleiotropic relationships among SNPs previously associated with related phenotypes.
AB - Background-C-reactive protein (CRP) is a biomarker of inflammation. Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) associated with CRP concentrations and inflammation-related traits such as cardiovascular disease, type 2 diabetes mellitus, and obesity. We aimed to replicate previous CRP-SNP associations, assess whether these associations generalize to additional race/ethnicity groups, and evaluate inflammationrelated SNPs for a potentially pleiotropic association with CRP. Methods and Results-We selected and analyzed 16 CRP-associated and 250 inflammation-related GWAS SNPs among 40 473 African American, American Indian, Asian/Pacific Islander, European American, and Hispanic participants from 7 studies collaborating in the Population Architecture using Genomics and Epidemiology (PAGE) study. Fixed-effect metaanalyses combined study-specific race/ethnicity-stratified linear regression estimates to evaluate the association between each SNP and high- sensitivity CRP. Overall, 18 SNPs in 8 loci were significantly associated with CRP (Bonferronicorrected P>3.1×10-3 for replication, P>2.0×10-4 for pleiotropy): Seven of these were specific to European Americans, while 9 additionally generalized to African Americans (1), Hispanics (5), or both (3); 1 SNP was seen only in African Americans and Hispanics. Two SNPs in the CELSR2/PSRC1/SORT1 locus showed a potentially novel association with CRP: rs599839 (P=2.0×10-6) and rs646776 (P=3.1×10-5). Conclusions-We replicated 16 SNP-CRP associations, 10 of which generalized to African Americans and/or Hispanics. We also identified potentially novel pleiotropic associations with CRP for two SNPs previously associated with coronary artery disease and/or low-density lipoprotein-cholesterol. These findings demonstrate the benefit of evaluating genotype- phenotype associations in multiple race/ethnicity groups and looking for pleiotropic relationships among SNPs previously associated with related phenotypes.
KW - C-reactive protein
KW - Continental population groups
KW - Ethnic groups
KW - Genetic pleiotropy
KW - Inflammation
KW - Molecular epidemiology
KW - Polymorphism
KW - Single nucleotide
UR - http://www.scopus.com/inward/record.url?scp=84903601289&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84903601289&partnerID=8YFLogxK
U2 - 10.1161/CIRCGENETICS.113.000173
DO - 10.1161/CIRCGENETICS.113.000173
M3 - Article
C2 - 24622110
AN - SCOPUS:84903601289
SN - 1942-325X
VL - 7
SP - 178
EP - 188
JO - Circulation: Cardiovascular Genetics
JF - Circulation: Cardiovascular Genetics
IS - 2
ER -
