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

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.

Figure 1

Linkage disequilibrium between the five IL18 tagging single nucleotide polymorphisms in the Gene-Diet Attica Investigation on childhood obesity (GENDAI), European Atherosclerosis Research case control Study (EARSII) and the Greek Obese Women (GrOW). Single nucleotide polymorphism order; −9731 G > T (rs1946519), −5848 T > C (rs2043055), +4860 A > C (rs549908), +8855 T > A (rs360729), +11015 T > G (rs3882891). Colour represents D' - D'.95-1; - D'.80-.94; - D' –.75-.79. Values represent r².