Genome-wide associated loci influencing interleukin (IL)-10, IL-1Ra, and IL-6 levels in African Americans.
Interleukins (ILs) are key mediators of the immune response and inflammatory process. Plasma levels of IL-10, IL-1Ra, and IL-6 are associated with metabolic conditions, show large inter-individual variations, and are under strong genetic control. Therefore, elucidation of the genetic variants that influence levels of these ILs provides useful insights into mechanisms of immune response and pathogenesis of diseases. We conducted a genome-wide association study (GWAS) of IL-10, IL-1Ra, and IL-6 levels in 707 non-diabetic African Americans using 5,396,780 imputed and directly genotyped single nucleotide polymorphisms (SNPs) with adjustment for gender, age, and body mass index. IL-10 levels showed genome-wide significant associations (p  < 5 × 10(-8)) with eight SNPs, the most significant of which was rs5743185 in the PMS1 gene (p = 2.30 × 10(-10)). We tested replication of SNPs that showed genome-wide significance in 425 non-diabetic individuals from West Africa, and successfully replicated rs17365948 in the YWHAZ gene (p = 0.02). IL-1Ra levels showed suggestive associations with two SNPs in the ASB3 gene (p = 2.55 × 10(-7)), ten SNPs in the IL-1 gene family (IL1F5, IL1F8, IL1F10, and IL1Ra, p = 1.04 × 10(-6) to 1.75 × 10(-6)), and 23 SNPs near the IL1A gene (p = 1.22 × 10(-6) to 1.63 × 10(-6)). We also successfully replicated rs4251961 (p = 0.009); this SNP was reported to be associated with IL-1Ra levels in a candidate gene study of Europeans. IL-6 levels showed genome-wide significant association with one SNP (RP11-314E23.1; chr6:133397598; p = 8.63 × 10(-9)). To our knowledge, this is the first GWAS on IL-10, IL-1Ra, and IL-6 levels. Follow-up of these findings may provide valuable insight into the pathobiology of IL actions and dysregulations in inflammation and human diseases.
Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. ayeleft@mail.nih.gov
Fasil
F
Tekola Ayele
Ayo
A
Doumatey
Hanxia
H
Huang
Jie
J
Zhou
Bashira
B
Charles
Michael
M
Erdos
Jokotade
J
Adeleye
Williams
W
Balogun
Olufemi
O
Fasanmade
Thomas
T
Johnson
Johnnie
J
Oli
Godfrey
G
Okafor
Albert
A
Amoah
Benjamin A
BA
Eghan
Kofi
K
Agyenim-Boateng
Joseph
J
Acheampong
Clement A
CA
Adebamowo
Alan
A
Herbert
Norman
N
Gerry
Michael
M
Christman
Guanjie
G
Chen
Daniel
D
Shriner
Adebowale
A
Adeyemo
Charles N
CN
Rotimi
D048948:14-3-3 Proteins / Q000235:genetics; D000328:Adult; D001741:Black or African American / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D055261:Immunogenetic Phenomena; D053590:Interleukin 1 Receptor Antagonist Protein / Q000097:blood* / Q000235:genetics*; D007375:Interleukin-1 / Q000235:genetics; D016753:Interleukin-10 / Q000097:blood* / Q000235:genetics*; D015850:Interleukin-6 / Q000097:blood* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D005810:Multigene Family; D000070956:MutL Proteins; D009363:Neoplasm Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics
D048948:14-3-3 Proteins; C502210:ASB3 protein, human; C508609:IL10 protein, human; C507763:IL1RN protein, human; C508600:IL6 protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D009363:Neoplasm Proteins; C088996:PMS1 protein, human; D050826:Suppressor of Cytokine Signaling Proteins; C572235:YWHAZ protein, human; D016753:Interleukin-10; D000070956:MutL Proteins