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

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(-ß-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.

The Val81 missense mutation of the melanocortin 3 receptor gene, but not the 1908c/T nucleotide polymorphism in lamin A/C gene, is associated with hyperleptinemia and hyperinsulinemia in obese Greek caucasians.

Obesity-related phenotypes have been linked to human chromosomes 1q21 and 20q13, regions where the lamin A/C gene (LMNA) and the melanocortin 3 receptor gene (MC3R) map, respectively. Recently, a common single nucleotide polymorphism (SNP) in LMNA (1908C/T) was associated with plasma leptin and obesity indices in aboriginal Canadians, but these associations have not yet been explored in other populations. In contrast, no significant associations of MC3R variants with obesity have been detected, although a significant association with hyperinsulinemia has been reported in Caucasian populations. We investigated the associations between the LMNA 1908C/T variant and the 241G/A variant of the MC3R gene (Val81Ile missense mutation) and body composition, as well as plasma leptin and insulin levels, in two samples of unrelated healthy Greek subjects. A group of 112 young nonobese subjects, and a group of 116 adult women with a body mass index (BMI) ranging from 23.2 to 47.7 kg/m2 were studied cross-sectionally. We found no significant association of the LMNA 1908C/T and a borderline significant association of MC3R 241G/A SNPs with body composition variables, in the entire study sample. However, unlike the LMNA 1908C/T genetic variation, the MC3R 241G/A genetic variation was significantly associated with hyperleptinemia and huperinsulinemia in obese subjects, and there was evidence of interaction between this polymorphism and fat mass or BMI in predicting hyperinsulinemia. Our results suggest that the LMNA 1908C-->T substitution and the Val81Ile mutation of the MC3R gene are unlikely to be major predictors of body composition in Greek Caucasians, but the latter genetic variation may predispose obese subjects to develop insulin and leptin resistance. Future studies are needed to confirm these data and assess whether individuals carrying this mutation are more resistant to weight-reducing and insulin-sensitizing treatments.

The Q223R polymorphism of the leptin receptor gene is significantly associated with obesity and predicts a small percentage of body weight and body composition variability.

Genetic variation at the leptin receptor gene locus may play an important role in the pathophysiology of human obesity, a leptin-resistant state. Previous studies exploring potential associations between leptin receptor gene polymorphisms and obesity have reported conflicting results. The aim of this study was to evaluate a genetically homogeneous population for associations between body composition variables and three common leptin receptor gene polymorphisms (K109R, Q223R, and K656N) that have potential functional significance as well as to assess the contributions of these polymorphisms to the variability of obesity. One hundred and eighteen consecutively enrolled subjects (62 women: mean age, 17.5 +/- 1.6 yr; body mass index range, 16.2-30.1; 56 men: mean age, 17.8 +/- 1.8 yr; body mass index range, 15.4-35.9) were genotyped for the three polymorphisms, and their body mass index, sum of 4 skinfolds, fat-free mass, percent fat mass, serum leptin levels, caloric intake, fat intake, and exercise patterns were determined. Allele frequencies were estimated by the gene-counting method, and genotype distributions between 89 normal weight (body mass index, < or =25 kg/m(2)) and 29 overweight-obese (body mass index, >25 kg/m(2)) subjects were compared using chi(2) test (using codominant, dominant, and recessive models). Analysis of covariance was also performed to evaluate associations between the polymorphisms and body composition variables after controlling for potential confounders. For the Q223R polymorphism, there was a higher prevalence of the R223 allele in the homozygous form among overweight-obese subjects vs. normal weight subjects (20.7% vs. 4.5%; P = 0.01). Furthermore, simple and multiple regression analyses revealed that the R223 allele in the homozygous form is a significant predictor of both body mass index (P = 0.015) and percent fat mass (P = 0.02) even after adjusting for age and gender and explains 4.5% of the variance in percent fat mass and 5% of the variance in body mass index. There was no significant difference in allele frequencies or genotype distributions for the K109R or K656N polymorphisms. These findings support the hypothesis that the Q223R polymorphism (but not the K109R or K656N polymorphism) of the leptin receptor gene is associated with obesity and predicts a small percentage of body weight and body composition variability in a genetically homogeneous population.