ABSTRACT
OBJECTIVE: A previous epidemiological study showed an association of the insulin-induced gene 2 (INSIG2) gene with BMI. Additionally, experimental investigations in animals and cell culture provided evidence that this gene might be involved in lipoprotein and free fatty acid (FFA) metabolism. Therefore, the aim of this study was to examine the association between the rs7566605 variant near the INSIG2 gene and BMI and to extend it to other quantitative measures of obesity, as well as parameters of lipoprotein and FFA metabolism. METHODS AND PROCEDURES: We genotyped rs7566605 in a group of severely obese white patients (n = 1,026) with an average BMI of 46.0 kg/m(2) and a control group (n = 818) from Utah, as well as in the Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk (SAPHIR) study from Austria, which is based on a healthy working population (n = 1,696). RESULTS: We observed no difference in the genotype frequency of rs7566605 of INSIG2 between obese subjects and population-based controls from Utah. Furthermore, we did not find evidence of an association with measures of body composition (BMI, waist, waist-to-hip ratio, percentage body fat, amount of visceral and subcutaneous abdominal adipose fat) or lipoprotein metabolism (total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, triglycerides, and FFAs) in the Utah study population or in the independent SAPHIR study. DISCUSSION: Our results do not support an association of the INSIG2 gene with the regulation of body weight or parameters related to lipoprotein metabolism.
Subject(s)
Body Mass Index , Intracellular Signaling Peptides and Proteins/genetics , Lipoproteins, HDL/metabolism , Lipoproteins, LDL/metabolism , Membrane Proteins/genetics , Obesity/genetics , Obesity/metabolism , Adult , Austria/epidemiology , Body Composition/genetics , Case-Control Studies , Computational Biology , Fatty Acids, Nonesterified/metabolism , Female , Genetic Predisposition to Disease/epidemiology , Humans , Male , Middle Aged , Obesity/epidemiology , Phenotype , Polymorphism, Genetic , Risk Factors , Triglycerides/metabolism , Utah/epidemiologyABSTRACT
Low concentrations of adiponectin, the protein product of the APM1 gene, have been reported to be associated with obesity and insulin resistance. However, contrasting results have been described on the genetic variability in APM1 and characteristics of the metabolic syndrome and adiponectin serum concentrations. In the present study, we investigated the association of the two most well-known SNPs of APM1 (+45T>G and +276G>T) and their haplotypes, with serum adiponectin concentrations, metabolic parameters and intima-media thickness of the carotid arteries in 1,745 well-phenotyped asymptomatic unrelated Caucasian subjects of the SAPHIR cohort. The common T-allele (88.5%) of SNP +45T>G and the common G-allele (70.5%) of SNP +276G>T were associated with significantly lower serum adiponectin levels (P = 0.0008 and P = 0.00005, respectively). The most frequent haplotype TG (59.0%) defined by both loci showed a strong association with lower serum adiponectin concentrations (P = 0.000000002). A clear effect per copy of the respective haplotype was observed. This association was most pronounced in lean and insulin-sensitive subjects. The two less common haplotypes TT (29.5%) and GG (11.5%) were associated with higher serum adiponectin levels in a dose-dependent association. Interestingly, no significant association between the adiponectin 45-276 haplotypes and the majority of parameters of the metabolic syndrome or intima-media thickness of the carotid arteries was found in our study. In summary, we replicated a strong association of the adiponectin 45-276 genotypes and haplotypes with adiponectin levels in healthy Caucasians. However, we could not confirm an association of this gene locus with metabolic parameters of the insulin resistance syndrome.
Subject(s)
Adiponectin/genetics , Insulin Resistance , Adult , Alleles , Blood Pressure , Carotid Arteries/metabolism , Cohort Studies , Female , Genetic Variation , Genotype , Haplotypes , Humans , Insulin/metabolism , Insulin Resistance/genetics , Lipid Metabolism , Male , Metabolic Syndrome/genetics , Middle Aged , Models, Genetic , Models, Statistical , Polymorphism, Single Nucleotide , White PeopleABSTRACT
The associations of the adiponectin (APM1) gene with parameters of the metabolic syndrome are inconsistent. We performed a systematic investigation based on fine-mapped single nucleotide polymorphisms (SNPs) highlighting the genetic architecture and their role in modulating adiponectin plasma concentrations in a particularly healthy population of 1,727 Caucasians avoiding secondary effects from disease processes. Genotyping 53 SNPs (average spacing of 0.7 kb) in the APM1 gene region in 81 Caucasians revealed a two-block linkage disequilibrium (LD) structure and enabled comprehensive tag SNP selection. We found particularly strong associations with adiponectin concentrations for 11 of the 15 tag SNPs in the 1,727 subjects (five P values <0.0001). Haplotype analysis provided a thorough differentiation of adiponectin concentrations with 9 of 17 haplotypes showing significant associations (three P values <0.0001). No significant association was found for any SNP with the parameters of the metabolic syndrome. We observed a two-block LD structure of APM1 pointing toward at least two independent association signals, one including the promoter SNPs and a second spanning the relevant exons. Our data on a large number of healthy subjects suggest a clear modulation of adiponectin concentrations by variants of APM1, which are not merely a concomitant effect in the course of type 2 diabetes or coronary artery disease.
