Genome-wide association study identifies variants at the IL18-BCO2 locus associated with interleukin-18 levels.
OBJECTIVE
Interleukin-18 (IL-18) is a proinflammatory cytokine involved in the processes of innate and acquired immunities and associated with cardiovascular disease and type 2 diabetes. We sought to identify the common genetic variants associated with IL-18 levels.


RESULTS
We performed a 2-stage genome-wide association study among women of European ancestry from the Nurses' Health Study (NHS) and Women's Genome Health Study (WGHS). IL-18 levels were measured by ELISA. In the discovery stage (NHS, n=1523), 7 single-nucleotide polymorphisms (SNPs) at the IL18-BCO2 locus were associated with IL-18 concentrations at the 1 x 10(-5) significance level. The strongest association was found for SNP rs2115763 in the BCO2 gene (P=6.31 x 10(-8)). In silico replication in WGHS (435 women) confirmed these findings. The combined analysis of the 2 studies indicated that SNPs rs2115763, rs1834481, and rs7106524 reached a genome-wide significance level (P<5 x 10(-8)). Forward selection analysis indicated that SNPs rs2115763 and rs1834481 were independently associated with IL-18 levels (P=0.0002 and 0.0006, respectively). The 2 SNPs together explained 2.9% of variation of plasma IL-18 levels.


CONCLUSIONS
This study identified several novel variants at the IL18-BCO2 locus associated with IL-18 levels.
He
Meian
M
Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA.
Cornelis
Marilyn C
MC
Kraft
Peter
P
van Dam
Rob M
RM
Sun
Qi
Q
Laurie
Cathy C
CC
Mirel
Daniel B
DB
Chasman
Daniel I
DI
Ridker
Paul M
PM
Hunter
David J
DJ
Hu
Frank B
FB
Qi
Lu
L
D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood*; D020382:Interleukin-18 / Q000097:blood* / Q000235:genetics*; D016014:Linear Models; D015810:Linkage Disequilibrium; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
D015415:Biomarkers; D018836:Inflammation Mediators; D020382:Interleukin-18