Genetic variation within IL18 is associated with insulin levels, insulin resistance and postprandial measures

• Published in: Nutrition, metabolism, and cardiovascular diseases Vol. 21; no. 7; pp. 476 - 484
• Main Authors: Smart, M.C, Dedoussis, G, Yiannakouris, N, Grisoni, M.L, Dror, G.K, Yannakoulia, M, Papoutsakis, C, Louizou, E, Mantzoros, C.S, Melistas, L, Kontogianni, M.D, Cooper, J.A, Humphries, S.E, Talmud, P.J
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2011; Elsevier
• Subjects: Adolescent; Adult; adults; Aged; atherosclerosis; Cardiovascular; Child; childhood obesity; energy; Europe; Female; Gene Frequency; genes; Genetic Association Studies; Genetic Predisposition to Disease; Genetic variants; genetic variation; glucose; Greece; Haplotypes; homeostasis; Humans; insulin; Insulin - blood; Insulin resistance; Insulin Resistance - genetics; Interleukin 18; Interleukin-18 - genetics; Male; men; metabolic syndrome; Metabolic Syndrome - blood; Metabolic Syndrome - genetics; Middle Aged; noninsulin-dependent diabetes mellitus; nutrition-genotype interaction; Obesity; Obesity - blood; Obesity - genetics; Polymorphism, Single Nucleotide; Postprandial Period; progeny; single nucleotide polymorphism; Single nucleotide polymorphisms; triacylglycerols; Triglycerides - blood; women; women's health; Young Adult; single nucleotide polymorphism; Gene-Diet Attica Investigation on childhood obesity; Catanzaro Metabolic Risk; AUC; GrOW; UTR; Hardy–Weinberg equilibrium; QUICKI; HWE; Single nucleotide polymorphisms; MI; linkage disequilibrium; myocardial infarct; Obesity; GENDAI; T2D; IR; untranslated region; IIPGA; Interleukin 18; CVD; MAF; OFTT; tagging single nucleotide polymorphisms; IL-18; tSNPs; Haplotypes; Greek Obese Women; oral glucose tolerance test; EARSII; Innate Immunity PGA; SNP; FDR; Genetic variants; European Atherosclerosis Research case control Study; false discovery rate; homeostasis model assessment; cardiovascular disease; CI; CATAMERI; oral fat tolerance test; area under the curve; quantitative insulin sensitivity check index; type 2 diabetes; minor allele frequency; LD; Insulin resistance; coronary heart disease; HOMA; confidence intervals; OGTT; CHD
• ISSN: 0939-4753; 1590-3729
• DOI: 10.1016/j.numecd.2009.12.004

Abstract Background and aims IL-18 expression is up-regulated in atherosclerotic plaques, and higher levels are seen in obese and Type 2 Diabetic individuals. More recently, a possible role for IL-18 in glucose and energy homeostasis has been suggested. Methods and results We investigated variation within the IL18 gene and its association with measures of obesity and the metabolic syndrome. Five IL18 tagging single nucleotide polymorphisms (rs1946519, rs2043055, rs549908, rs360729, rs3882891) were selected and genotyped in the Gene-Diet Attica Investigation on childhood obesity (GENDAI) (age range 10–14 yrs); in young European men in the second European Atherosclerosis Research offspring Study (EARSII), an offspring study (age range 18–28 yrs) and in a group of healthy women from the Greek Obese Women study (GrOW) (age range 18–74 yrs). Six common haplotypes were observed. In GrOW, Hap6 (Frequency-2.6%) was associated with higher insulin levels ( p < 0.0001), estimates of HOMA-Insulin Resistance ( p < 0.0001) and HOMA-β-cell ( p < 0.0001) compared to the common haplotype Hap1 (Frequency-33.2%). In EARSII, rs2043055 was associated with peak and area under the curve triglycerides ( p = 0.001 and p = 0.002, respectively) after an oral fat tolerance test in ‘cases’ but not ‘controls’. None of the haplotypes were associated with measures of body fatness in any of the studies. Conclusion Association of IL18 variation with insulin levels and estimates of insulin resistance were only observed in our adult study, suggesting that the effects of IL-18 are only associated with increasing age. Taken together with the association of IL18 variants with post-prandial measures, this provides support for IL-18 as a metabolic factor.