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Objective: Recently independent studies, including genome-wide scans, have shown that variation in the fat mass and obesity associated gene (FTO) were significantly associated with obesity in populations of European origin., Design and Methods: In this study we examined the association between rs9939609 FTO variant and obesity related parameters in a population based-study of 732 unrelated individuals (46.9% males and 53.1% females; ages 35-74 years) from the province of Segovia in Central Spain (Castille)., Results: The AA genotype was significantly more frequent in obese individuals (defined as body mass index >or= 30 kg/m(2), n = 207; 80 males and 127 females) than in non-obese (19.9%vs. 13.7%, P = 0.026). In addition to increased obesity, AA homozygous individuals had higher waist circumference than individuals with AT heterozygous and TT homozygous genotypes. The minor A-allele of rs9939609 was associated with an increased odds ratio (OR) for obesity [OR 1.51, 95% confidence interval (CI) 1.10-2.12] as compared to the TT genotype. This difference was also statistically significant even after the adjustment for sex and age (OR 1.46, 95% CI 1.02-2.07)., Conclusions: Our results support the association of FTO gene variants with obesity, including parameters of visceral (abdominal) obesity, in an adult general population from Spain. Overall we confirm the previously reported association studies between variants in FTO gene and the risk of obesity.

Background: The metabolic syndrome (MS), a cluster of several metabolic disorders, is increasingly being recognized as a risk factor for cardiovascular disease. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), originally described as a plasma cell allo-antigen and named plasma cell membrane glycoprotein (PC-1), is an inhibitor of insulin-induced activation of the insulin receptor. The single nucleotide polymorphism (SNP) K121Q in the ENPP1 gene has been studied in relation to obesity, insulin resistance and other features of MS in several populations with conflicting results. We therefore investigate the role of the K121Q SNP in the ENPP1 gene in MS in Caucasians from the province of Segovia in Central Spain (Castille)., Design and Methods: We recruited 794 unrelated persons (46.5% males and 53.5% females), ages 35-74 years from a cross-sectional population-based epidemiological survey in the province of Segovia in Central Spain (Castille). Obesity-related anthropometric measurements included BMI, waist circumference, blood pressure and lipid profile. MS was defined by International Diabetes Federation (IDF) guidelines. K121Q PC-1 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)., Results: The 121Q allele was associated with an increased BMI and waist circumference among subjects fulfilling the criteria for MS. These differences remained statistically significant even after the adjustment for sex, age and degree of glucose tolerance (beta = 1.347, P = 0.017 and beta = 2.824, P = 0.046; for BMI and waist circumference, respectively). Moreover, among type 2 diabetic patients those carrying the 121Q allele had higher BMI and higher leptin levels than subjects carrying the K121K genotype., Conclusions: Our results suggest that the ENPP1121Q allele might contribute to the genetic susceptibility to abdominal obesity among subjects with MS.

ObjectiveProinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology.Research design and methodsWe have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates.ResultsNine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets.ConclusionsWe have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

To determine whether the Pro12A1a polymorphism of the PPARγ2 gene was associated with increased risk for the development of insulin resistance and other features of the metabolic syndrome in a representative sample of Spanish population and its interaction with the TNF-α-308 G/A polymorphism, we genotyped 783 unrelated subjects recruited from a cross-sectional population-based epidemiological survey in Segovia, Spain (The Segovia Study Group). Anthropometric parameters: BMI, waist to hip ratio (WHR). OGTT, fasting and 2 hrs glucose; serum insulin, adiponectin levels (RIA); lipid profile. Plasma PAI-1 and plasma soluble TNF-αreceptor 2 (sTNFR2) levels by ELISA. Insulin resistance was assessed by HOMA-IR. Categories of glucose tolerance (ADA Clinical Practice Recommendations 2006) MS was defined according to the 2005 IDF criteria. Pro12A1a PPARγand -308G/A TNF-α genotypes determined by PCR-RFLP. PPARγ genotype distribution: Pro12Pro 87.2%, Pro12A1a 12.4%, A1a12A1a: 0.4%. Impaired glucose tolerance (IGT) was higher in Pro 12Pro homozygous compared to carriers of the A1a12 allele (16.8% vs 8.1%, p=027) even after adjustment for sex, age, BMI, WHR and insulin resistance (OR: 2.5, CI 95% 1.04-6.25, p=0.049) in a logistic regression model. Plasma levels of sTNFR2 were positively correlated with BMI, and waist circumference among type 2 diabetic subjects. Interestingly diabetic subjects carrying the -308A allele had higher sTNFR2 levels,. WHR, insulin 2 hours PAI levels,and lower adiponectin concentrations as compared with G-308G homozygous. A gene-gene interaction was detected. Subjects simultaneously having the Ala12 allele of the PPARγ2 gene and the -308A allele of the TNF-α gene had higher waist to hip ratio than those carrying only either one of these gene polymorphisms alone (P<0.001), independently of sex, age, and glucose tolerance status. Our findings indicate a gene-gene interaction between the PPARγPro12Ala polymorphism and the TNF-α-308Apolymorphism, which may result in higher risk for abdominal obesity, but not for type 2 diabetes. [ABSTRACT FROM AUTHOR]