Association of variation in the interleukin-1 gene family with diabetes and glucose homeostasis.
OBJECTIVE
Proinflammatory cytokine IL-1beta is capable of decreasing insulin-induced glucose transport. Therefore, we hypothesized that genetic variation in the IL-1 gene family is associated with measures of glucose homeostasis and diabetes.


METHODS
Fifteen haplotype-tagging single-nucleotide polymorphisms in the IL-1alpha, IL-1beta, and IL-1 receptor antagonist genes were determined in a Finnish population survey (n = 6771). Glucose and insulin concentrations were measured, and indices of insulin resistance and beta-cell function were calculated using the homeostasis model assessment. Two-hour oral glucose tolerance tests were carried out on a subsample of 1390 participants. Associations with prevalent diabetes were tested for replication in a sample of European myocardial infarction survivors (n = 972).


RESULTS
The minor allele of the IL-1beta rs1143634(G-->A) was associated with higher blood glucose than the major allele: 5.37, 5.41, and 5.48 mmol/liter for the GG, AG, and AA genotypes, respectively (multivariate adjusted P for trend <0.0001; Bonferroni corrected P = 0.00096). The 2-h glucose was also higher (6.45 and 7.20 mmol/liter for the GG vs. AA; P = 0.003, Bonferroni corrected P = 0.045). The haplotype ACG of rs1143634, rs3917356, and rs16944 associated with higher glucose, higher homeostasis model assessment for insulin resistance index, higher 2-h insulin, and prevalent diabetes (adjusted rate ratio = 1.54; 95% confidence interval = 1.03-2.30; P = 0.037). The association with prevalent diabetes was replicated among European myocardial infarction survivors (rate ratio = 2.09; 95% confidence interval = 1.17-3.76; P = 0.013).


CONCLUSIONS
These results suggest that genetic variation in the IL-1 gene family is associated with measures of glucose homeostasis and prevalent diabetes.
Luotola
Kari
K
Department of Medicine, Helsinki University Central Hospital, Helsinki 00290, Finland. kari.luotola@helsinki.fi
Pääkkönen
Rauni
R
Alanne
Mervi
M
Lanki
Timo
T
Moilanen
Leena
L
Surakka
Ida
I
Pietilä
Arto
A
Kähönen
Mika
M
Nieminen
Markku S
MS
Kesäniemi
Y Antero
YA
Peters
Annette
A
Jula
Antti
A
Perola
Markus
M
Salomaa
Veikko
V
D003920:Diabetes Mellitus / Q000235:genetics*; D014644:Genetic Variation; D005838:Genotype; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000502:physiology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics; D007375:Interleukin-1 / Q000235:genetics*; D053582:Interleukin-1alpha / Q000235:genetics; D053583:Interleukin-1beta / Q000235:genetics; D008264:Macrophages / Q000502:physiology; D005810:Multigene Family; D020641:Polymorphism, Single Nucleotide; D017472:Receptors, Interleukin-1 / Q000235:genetics
C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D017472:Receptors, Interleukin-1; D005947:Glucose