Genetic variation of the interleukin-1 family and nongenetic factors determining the interleukin-1 receptor antagonist phenotypes.
The natural anti-inflammatory protein interleukin-1 receptor antagonist (IL-1Ra) inhibits the activity of IL-1 and is associated with vascular injury and metabolic disorders. We analyzed genetic and nongenetic determinants of the IL-1Ra phenotype. Fifteen haplotype-tagging single nucleotide polymorphisms (SNPs) in the IL-1α (IL1A), IL-1β (IL1B), and IL-1 receptor antagonist (IL-1RN) genes were determined in the Health 2000 survey (n = 6771) and European myocardial infarction (MI) survivors (n = 972). Three SNPs were genotyped in the FINRISK97 (FR97) study (n = 7222). We found 3 IL1RN variants that were associated with the IL-1Ra phenotype in the study populations and remained significant after Bonferroni correction with increasing significance in meta-analysis (P values for rs3213448,rs315952, rs315949, respectively: 5.5 x 10(-11), 1.5 x 10(-11), and 4.0 x 10(-14)). Minor allele of the rare IL1B variant rs1143642 was associated with decreased IL-1Ra levels in the Health 2000 and FR97 populations, and the association strengthened in the meta-analysis (P = 9.4 x 10(-7)). The proportion of variance explained by the IL1RN variant was larger in MI survivors (5.0%) than in the unselected population (0.5%). Body mass index was the strongest nongenetic predictor of the IL-1Ra phenotype, explaining 11.8% of the variance in Health 2000, 18.1% in FR97, and 25% in MI survivors. In conclusion, 3 IL1RN SNPs and 1 IL1B variant were determining IL-1Ra phenotype independently of body mass index and other metabolic phenotypes. The proportion of phenotypic variation in IL-1Ra explained by the genetic variants was, however, modest compared with the proportion explained by the body mass index.
Luotola
Kari
K
Department of Medicine, HUCH-Helsinki University Central Hospital, Box 340 HUS, FI-00029 Helsinki, Finland. kari.luotola@helsinki.fi
Pietilä
Arto
A
Alanne
Mervi
M
Lanki
Timo
T
Loo
Britt-Marie
BM
Jula
Antti
A
Perola
Markus
M
Peters
Annette
A
Zeller
Tanja
T
Blankenberg
Stefan
S
Salomaa
Veikko
V
D000328:Adult; D000368:Aged; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation / Q000502:physiology; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics*; D007375:Interleukin-1 / Q000235:genetics*; D008137:Longitudinal Studies; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D005810:Multigene Family / Q000235:genetics; D009203:Myocardial Infarction / Q000145:classification / Q000453:epidemiology / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D017741:Survivors / Q000706:statistics & numerical data
C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1