Biomedical subjects

Leif Groop

Publications and source records attributed to Leif Groop.

At least 19 recordsLinked to original sources

PubMed2006

Polymorphism in the MHC2TA gene is associated with features of the metabolic syndrome and cardiovascular mortality.

BACKGROUND: Recently, a -168A-->G polymorphism in the MHC class II transactivator gene (MHC2TA) was shown to be associated with increased susceptibility to myocardial infarction (MI). AIM: To confirm the association between the MHC2TA -168A-->G polymorphism and MI and to study its putative role for microalbuminuria, the metabolic syndrome (MetS) and cardiovascular mortality. MATERIALS AND METHODS: Using an allelic discrimination method we genotyped 11,064 individuals from three study populations: 1) 4,432 individuals from the Botnia type 2 diabetes (T2D) study, 2) 1,222 patients with MI and 2,345 control subjects participating in the Malmö Diet and Cancer study and comprising an MI case-control sample, and 3) 3,065 T2D patients from the Local Swedish Diabetes registry. RESULTS: No association between the -168A-->G polymorphism in MHC2TA and MI was observed. However, in the Botnia cohort the AG/GG genotypes were associated with cardiovascular mortality after MI (1.78 [1.09-2.92], p = 0.02). In addition, the AG/GG genotypes were more common in subjects with MetS (40.1% vs. 36.9%, p = 0.03) and in non-diabetic subjects with microalbuminuria (45.4% vs. 36.5%, p = 0.003) compared to control subjects. CONCLUSIONS: A polymorphism in MHC2TA was associated with cardiovascular mortality and predictors of cardiovascular mortality, microalbuminuria and MetS.

Adult↗

PubMed2006

Transferability of tag SNPs in genetic association studies in multiple populations.

A general question for linkage disequilibrium-based association studies is how power to detect an association is compromised when tag SNPs are chosen from data in one population sample and then deployed in another sample. Specifically, it is important to know how well tags picked from the HapMap DNA samples capture the variation in other samples. To address this, we collected dense data uniformly across the four HapMap population samples and eleven other population samples. We picked tag SNPs using genotype data we collected in the HapMap samples and then evaluated the effective coverage of these tags in comparison to the entire set of common variants observed in the other samples. We simulated case-control association studies in the non-HapMap samples under a disease model of modest risk, and we observed little loss in power. These results demonstrate that the HapMap DNA samples can be used to select tags for genome-wide association studies in many samples around the world.

Breast Neoplasms↗

PubMed2006

Association of the calpain-10 gene with type 2 diabetes in Europeans: results of pooled and meta-analyses.

We conducted pooled and meta-analyses of the association of the calpain-10 gene (CAPN10) polymorphisms SNP-43, Indel-19 and SNP-63 individually and as haplotypes with type 2 diabetes (T2D) in 3237 patients and 2935 controls of European ancestry. In the pooled analyses, the common SNP-43*G allele was associated with modest but statistically significant increased risk of T2D (odds ratio (OR)=1.11 (95% confidence interval (CI), 1.02-1.20), P=0.01). Two haplotype combinations were associated with increased risk of T2D (1-2-1/1-2-1, OR=1.20 (1.03-1.41), P=0.02; and 1-1-2/1-2-1, OR=1.26 (1.01-1.59), P=0.04) and one with decreased risk (1-1-1/2-2-1, OR=0.86 (0.75-0.99), P=0.03). The meta-analysis also showed a significant effect of the 1-2-1/1-2-1 haplogenotype on risk (OR=1.25 (1.05-1.50), P=0.01). However, there was evidence for heterogeneity with respect to this effect (P=0.06). The heterogeneity appeared to be due to data sets in which the cases were selected from samples used in linkage studies of T2D. Using only the population-based case-control samples removed the heterogeneity (P=0.89) and strengthened the evidence for association with T2D in both the pooled (SNP-43*G, OR=1.19 (1.07-1.32), P=0.001; 1-2-1/1-2-1 haplogenotype, OR=1.46 (1.19-1.78), P=0.0003; 1-1-2/1-2-1 haplogenotype, OR=1.52 (1.12-2.06), P=0.007; and 1-1-1/2-2-1 haplogenotype, OR=0.83 (0.70-0.99), P=0.03) and the meta-analysis (SNP-43*G, OR=1.18 (1.05-1.32), P=0.005; 1-2-1/1-2-1 haplogenotype, OR=1.68 (1.33-2.11), P=0.00001). The pooled and meta-analyses as well as the linkage disequilibrium and haplotype diversity studies suggest a role for genetic variation in CAPN10 affecting risk of T2D in Europeans.

Calpain↗

PubMed2006

Comprehensive association testing of common mitochondrial DNA variation in metabolic disease.

Many lines of evidence implicate mitochondria in phenotypic variation: (a) rare mutations in mitochondrial proteins cause metabolic, neurological, and muscular disorders; (b) alterations in oxidative phosphorylation are characteristic of type 2 diabetes, Parkinson disease, Huntington disease, and other diseases; and (c) common missense variants in the mitochondrial genome (mtDNA) have been implicated as having been subject to natural selection for adaptation to cold climates and contributing to "energy deficiency" diseases today. To test the hypothesis that common mtDNA variation influences human physiology and disease, we identified all 144 variants with frequency >1% in Europeans from >900 publicly available European mtDNA sequences and selected 64 tagging single-nucleotide polymorphisms that efficiently capture all common variation (except the hypervariable D-loop). Next, we evaluated the complete set of common mtDNA variants for association with type 2 diabetes in a sample of 3,304 diabetics and 3,304 matched nondiabetic individuals. Association of mtDNA variants with other metabolic traits (body mass index, measures of insulin secretion and action, blood pressure, and cholesterol) was also tested in subsets of this sample. We did not find a significant association of common mtDNA variants with these metabolic phenotypes. Moreover, we failed to identify any physiological effect of alleles that were previously proposed to have been adaptive for energy metabolism in human evolution. More generally, this comprehensive association-testing framework can readily be applied to other diseases for which mitochondrial dysfunction has been implicated.

Body Mass Index↗

PubMed2006

Insulin sensitivity in adults with growth hormone deficiency and effect of growth hormone treatment.

Adult growth hormone deficiency (GHD) is a multifactorial disorder in which pituitary dysfunction associated with pituitary adenomas or their treatment plays a major role. The introduction of recombinant growth hormone (GH) for the treatment of GHD has opened up new treatment avenues but has also raised concerns about possible untoward long-term metabolic effects of GH, such as the potential effect of GH on insulin sensitivity and a deterioration in glucose tolerance. Research has shown that GH induces insulin resistance by the stimulation of lipolysis and a concomitant switch from oxidation of glucose to oxidation of lipids, during both acute and chronic treatment. However, although this is a consistent effect of GH therapy, it does not mean per se that it leads to abnormal glucose tolerance and diabetes mellitus. This article discusses this and other potential long-term metabolic effects of GH, and raises a number of questions to be addressed by future research.

Adenoma↗

PubMed2006

Treatment with a thiazolidinedione increases eye protrusion in a subgroup of patients with type 2 diabetes.

OBJECTIVE: Changes in eye protrusion in patients treated with pioglitazone. DESIGN: Open-label prospective. PATIENTS: Thirty-six patients with type 2 diabetes and HbA1c >or= 6.5% were included in a study where pioglitazone was added to current therapy with metformin and sulphonylurea. MEASUREMENTS: The degree of eye protrusion before and 26 weeks after treatment with pioglitazone was measured using Krahn's exophthalmometer. RESULTS: Thirteen patients (group A) exhibited an increase of >or= 2 mm and 23 patients (group B) exhibited an increase of < 2 mm (P (between groups) = 0.036). Patients of group A vs. group B had the same BMI, HbA1c and mean doses of pioglitazone, but had lower levels (mean +/- SD) of adiponectin in microg/ml at the start (4.9 +/- 2.1) vs. (7.1 +/- 2.5), P = 0.017 and at the end of study (10.2 +/- 4) vs. (14.9 +/- 5), P = 0.007. Patients with thyroid disturbance were more frequent in group A (five vs. one), P = 0.02. In a logistic regression analysis, thyroid disturbance, low adiponectin levels and pioglitazone dose predicted a significant change in eye protrusion. CONCLUSIONS: A subgroup of patients with type 2 diabetes treated with pioglitazone responded with increased eye protrusion. This subgroup showed decreased plasma concentration of adiponectin and more frequent thyroid disturbance, and was treated with higher doses of pioglitazone. The relationship between insulin resistance, thyroid disturbance and thiazolidinedione-induced eye protrusion should be further studied.

Adiponectin↗

PubMed2006

Common variants in the ENPP1 gene are not reproducibly associated with diabetes or obesity.

The common missense single nucleotide polymorphism (SNP) K121Q in the ectoenzyme nucleotide pyrophosphate phosphodiesterase (ENPP1) gene has recently been associated with type 2 diabetes in Italian, U.S., and South-Asian populations. A three-SNP haplotype, including K121Q, has also been associated with obesity and type 2 diabetes in French and Austrian populations. We set out to confirm these findings in several large samples. We genotyped the haplotype K121Q (rs1044498), rs1799774, and rs7754561 in 8,676 individuals of European ancestry with and without type 2 diabetes, in 1,900 obese and 930 lean individuals of European ancestry from the U.S. and Poland, and in 1,101 African-American individuals. Neither the K121Q missense polymorphism nor the putative risk haplotype were significantly associated with type 2 diabetes or BMI. Two SNPs showed suggestive evidence of association in a meta-analysis of our European ancestry samples. These SNPs were rs7754561 with type 2 diabetes (odds ratio for the G-allele, 0.85 [95% CI 0.78-0.92], P = 0.00003) and rs1799774 with BMI (homozygotes of the delT-allele, 0.6 [0.42-0.88], P = 0.007). However, these findings are not supported by other studies. We did not observe a reproducible association between these three ENPP1 variants and BMI or type 2 diabetes.

Asian People↗

PubMed2006

IL6 gene promoter polymorphisms and type 2 diabetes: joint analysis of individual participants' data from 21 studies.

Several lines of evidence indicate a causal role of the cytokine interleukin (IL)-6 in the development of type 2 diabetes in humans. Two common polymorphisms in the promoter of the IL-6 encoding gene IL6, -174G>C (rs1800795) and -573G>C (rs1800796), have been investigated for association with type 2 diabetes in numerous studies but with results that have been largely equivocal. To clarify the relationship between the two IL6 variants and type 2 diabetes, we analyzed individual data on >20,000 participants from 21 published and unpublished studies. Collected data represent eight different countries, making this the largest association analysis for type 2 diabetes reported to date. The GC and CC genotypes of IL6 -174G>C were associated with a decreased risk of type 2 diabetes (odds ratio 0.91, P = 0.037), corresponding to a risk modification of nearly 9%. No evidence for association was found between IL6 -573G>C and type 2 diabetes. The observed association of the IL6 -174 C-allele with a reduced risk of type 2 diabetes provides further evidence for the hypothesis that immune mediators are causally related to type 2 diabetes; however, because the association is borderline significant, additional data are still needed to confirm this finding.

Case-Control Studies↗

PubMed2006

The Krüppel-like factor 11 (KLF11) Q62R polymorphism is not associated with type 2 diabetes in 8,676 people.

Krüppel-like factor 11 is a pancreatic transcription factor whose activity induces the insulin gene. A common glutamine-to-arginine change at codon 62 (Q62R) in its gene KLF11 has been recently associated with type 2 diabetes in two independent samples. Q62R and two other rare missense variants (A347S and T220M) were also shown to affect the function of KLF11 in vitro, and insulin levels were lower in carriers of the minor allele at Q62R. We therefore examined their impact on common type 2 diabetes in several family-based and case-control samples of northern-European ancestry, totaling 8,676 individuals. We did not detect the rare A347S and T220M variants in our samples. With respect to Q62R, despite >99% power to detect an association of the previously published magnitude, Q62R was not associated with type 2 diabetes (pooled odds ratio 0.97 [95% CI 0.88-1.08], P = 0.63). In a subset of normoglycemic individuals, we did not observe significant differences in various insulin traits according to genotype at KLF11 Q62R. We conclude that the KLF11 A347S and T220M mutations do not contribute to increased risk of diabetes in European-derived populations and that the Q62R polymorphism has, at best, a minor effect on diabetes risk.

Amino Acid Substitution↗

PubMed2006

Variation in the adiponutrin gene influences its expression and associates with obesity.

Adiponutrin is one of three recently identified adipocyte lipases. Surprisingly, these proteins also retain transacylase activity, a hitherto unknown pathway of triacylglycerol synthesis in the adipocytes. This may enable them to participate in both anabolic and catabolic processes. The adiponutrin gene (ADPN) is downregulated by fasting and upregulated by refeeding, suggesting a role in lipogenesis. Experiments in human adipocytes confirmed that the gene is upregulated in response to insulin in a glucose-dependent fashion. Obese subjects had increased levels of subcutaneous and visceral abdominal adipose tissue ADPN mRNA. Visceral ADPN mRNA expression was correlated to measures of insulin sensitivity (fasting insulin and homeostasis model assessment). We also studied genetic variation in ADPN and its relation to obesity, lipolysis, and mRNA expression. Two ADPN polymorphisms showed association with obesity. Carriers of the obesity-associated variants showed a lesser increase in the levels of adipose tissue ADPN mRNA and an increased basal lipolysis. Our results suggest that obese subjects that are insulin resistant and/or carriers of the obesity-associated ADPN alleles fail to upregulate the gene and that upregulation of adiponutrin may be an appropriate response to orchestrate energy excess.

Adult↗

PubMed2006

Haplotype structures and large-scale association testing of the 5' AMP-activated protein kinase genes PRKAA2, PRKAB1, and PRKAB2 [corrected] with type 2 diabetes.

AMP-activated protein kinase (AMPK) is a key molecular regulator of cellular metabolism, and its activity is induced by both metformin and thiazolidinedione antidiabetic medications. It has therefore been proposed both as a putative agent in the pathophysiology of type 2 diabetes and as a valid target for therapeutic intervention. Thus, the genes that encode the various AMPK subunits are intriguing candidates for the inherited basis of type 2 diabetes. We therefore set out to test for the association of common variants in the genes that encode three selected AMPK subunits with type 2 diabetes and related phenotypes. Of the seven genes that encode AMPK isoforms, we initially chose PRKAA2, PRKAB1, and PRKAB2 because of their higher prior probability of association with type 2 diabetes, based on previous reports of genetic linkage, functional molecular studies, expression patterns, and pharmacological evidence. We determined their haplotype structure, selected a subset of tag single nucleotide polymorphisms that comprehensively capture the extent of common genetic variation in these genes, and genotyped them in family-based and case/control samples comprising 4,206 individuals. Analysis of single-marker and multi-marker tests revealed no association with type 2 diabetes, fasting plasma glucose, or insulin sensitivity. Several nominal associations of variants in PRKAA2 and PRKAB1 with BMI appear to be consistent with statistical noise.

AMP-Activated Protein Kinases↗

PubMed2006

High-density haplotype structure and association testing of the insulin-degrading enzyme (IDE) gene with type 2 diabetes in 4,206 people.

The insulin-degrading enzyme is responsible for the intracellular proteolysis of insulin. Its gene IDE is located on chromosome 10, in an area with suggestive linkage to type 2 diabetes and related phenotypes. Due to the impact of genetic variants of this gene in rodents and the function of its protein product, it has been proposed as a candidate gene for type 2 diabetes. Various groups have explored the role of the common genetic variation of IDE on insulin resistance and reported associations of various single nucleotide polymorphisms (SNPs) and haplotypes on both type 2 diabetes and glycemic traits. We sought to characterize the haplotype structure of IDE in detail and replicate the association of common variants with type 2 diabetes, fasting insulin, fasting glucose, and insulin resistance. We assessed linkage disequilibrium, selected single-marker and multimarker tags, and genotyped these markers in several case-control and family-based samples totalling 4,206 Caucasian individuals. We observed no statistically significant evidence of association between single-marker or multimarker tests in IDE and type 2 diabetes. Nominally significant differences in quantitative traits are consistent with statistical noise. We conclude that common genetic variation at IDE is unlikely to confer clinically significant risk of type 2 diabetes in Caucasians.

Diabetes Mellitus, Type 2↗

PubMed2006

Analysis of the interleukin-1 and interleukin-6 polymorphisms in patients with chronic periodontitis. A pilot study.

The aim of this study was to analyse whether the interleukin-1 (IL-1) and IL-6 gene polymorphisms were associated with the susceptibility of chronic periodontitis. Genomic DNA was obtained from 20 patients with chronic periodontitis and 31 periodontally healthy subjects. All subjects were of North European heritage. The test subjects were kept in a maintenance program after periodontal treatment but yet showing signs of recurrent disease. Genotyping of the IL-1alpha [+4845C>T], IL-1beta [-3954C>T] and IL-6 [-174G>C] polymorphisms was carried out using an allelic discrimination Assay-by-Design method on ABI PRISM 7900 Sequence Detection System. All genotypes were analyzed using the GeneMapper 2.0 software. A similar distribution of Single Nucleotide Polymorphism (SNP) was seen in both groups. Analysis by logistic regression including gender, IL-1alpha [+4845C>T], IL-1beta [-3954C>T], IL-6 [-174G>C] genotypes, the composite IL-1 genotype, the combination of the composite IL-1 genotype and the IL-6 -174G>C genotype and adjusting for smoking did not result in any statistically significant difference. SNPs in IL-1alpha [+4845C>T], IL-1beta [-3954C>T] and IL-6 [-174G>C] do not seem to increase the susceptibility to chronic periodontitis in this group of subjects.

Adult↗

PubMed2005

Complex relationship between blood pressure and mortality in type 2 diabetic patients: a follow-up of the Botnia Study.

The presence of hypertension aggravates the high cardiovascular risk in type 2 diabetic patients. Pulse pressure is a marker of arterial stiffness and constitutes a risk factor for cardiovascular mortality. This study examines the relationship between different blood pressure indices and mortality in a cohort of type 2 diabetic patients. A total of 1294 type 2 diabetic patients with a median age of 69.1 years participated in the Botnia Study from 1990 to 1997. In 2004, after a median follow-up of 9.5 years, data on mortality was collected from the national population registry and hospital records. Systolic and diastolic blood pressure correlated negatively with mortality after adjustment for other risk factors. The association between low systolic and diastolic blood pressure and mortality was pronounced in patients with previous cardiovascular disease. A U-shaped association between pulse pressure and mortality was observed in elderly patients. These observations could be linked to arterial stiffness and heart failure. Low blood pressure in high-risk patients is likely to be a marker of poor health rather than the cause of mortality. The results suggest that the role of blood pressure as a risk marker in elderly type 2 diabetic patients with cardiovascular disease needs to be reevaluated.

Age Factors↗

PubMed2005

Genetic and nongenetic determinants of skeletal muscle glucose transporter 4 messenger ribonucleic acid levels and insulin action in twins.

CONTEXT: Insulin-stimulated glucose uptake in skeletal muscle is mediated through translocation of the insulin-sensitive glucose transporter 4 (GLUT4)-containing vesicles to the plasma membrane. Thus, skeletal muscle GLUT4 content plays an important role in whole-body insulin sensitivity. OBJECTIVES: The objectives of this study were 1) to examine the relative impact of genetic vs. environmental factors on skeletal muscle GLUT4 mRNA expression using biometric modeling, and 2) to identify factors influencing the expression of GLUT4 and insulin-stimulated whole-body metabolism. DESIGN: We measured GLUT4 mRNA expression in biopsies from young and elderly monozygotic (MZ) and dizygotic (DZ) twins before and during a 2-h hyperinsulinemic euglycemic clamp including 3-(3)H-tritiated glucose and indirect calorimetry. PARTICIPANTS: A random sample of young (22-31 yr; n = 89) and elderly (57-66 yr; n = 69) same sex MZ and DZ twin pairs identified through the Danish Twin Register were studied. RESULTS: We found a major genetic component in the control of basal and insulin-stimulated GLUT4 mRNA expression in young and elderly twins. GLUT4 gene expression increased upon insulin stimulation in both young and elderly twins. Multiple regression analysis revealed that both basal and insulin-stimulated GLUT4 mRNA expressions were positively related to birth weight and total body aerobic capacity and were higher in MZ vs. DZ twins as well as in males vs. females. Both basal and insulin-stimulated expressions of GLUT4 were independently and significantly related to whole-body in vivo insulin action, nonoxidative glucose metabolism, and glucose oxidation. CONCLUSION: We show that skeletal muscle GLUT4 gene expression in twins is significantly and independently related to glucose metabolism and is determined by both genetic and nongenetic factors, including zygosity and birth weight.

Adult↗

PubMed2005

Overexpression of immediate early genes in active Graves' ophthalmopathy.

CONTEXT: In Graves' ophthalmopathy a major problem is an increase in the intraorbital adipose tissue volume. OBJECTIVE: The aim of this work was to define mechanisms of orbital adipogenesis. DESIGN: This was an open-label prospective study. SETTING: The study was conducted at the Clinic of Endocrinology, University Hospital. PARTICIPANTS: The study consisted of patients (n = 5) with severe ophthalmopathy with affection of the optic nerve and thyroid healthy controls (n = 5). INTERVENTIONS: We performed lateral decompression of orbital tissue in patients unresponsive to corticosteroids and restorative surgery of the upper eyelid in thyroid healthy controls. MAIN OUTCOME MEASURE: We made large-scale measurements of gene expression, with microarray technique based on determination of fluorescence intensities in cases and controls. RESULTS: A marker of adipose tissue, stearoyl-coenzyme A desaturase, was overexpressed in ophthalmopathy, and selection criteria were set to favor identification of genes known to be expressed in normal adipogenesis. The immediate early gene, cysteine-rich, angiogenic inducer, 61 (CYR61), was overexpressed in addition to 15 other immediate early genes (IEGs), and the expression of selected IEGs was confirmed with RT-PCR: CYR61, cyclooxygenase-2, dual-specificity phosphatase 1, B cell translocation gene 2, and early growth response 1. CYR61-responsive genes, known to participate in inflammation, IL-1beta, matrix metalloproteinase-3, and vascular endothelial growth factor were also overexpressed. Patients showed greater expression of CYR61 in the active than the chronic phase of ophthalmopathy, indicating that CYR61 is a marker of disease activity. Cyclooxygenase-2, the target gene of IL-1beta, was also overexpressed, although all patients had been treated with corticosteroids. CONCLUSION: Adipocyte-related IEGs are overexpressed in active ophthalmopathy, and CYR61 may have a role in both orbital inflammation and adipogenesis and serve as a marker of disease activity.

Adipose Tissue↗

PubMed2005

Dipping and variability of blood pressure and heart rate at night are heritable traits.

BACKGROUND: Blunted nocturnal blood pressure dipping (NBPD) as well as high variability in blood pressure (BPV) and low variability in heart rate (HRV), are associated with increased cardiovascular morbidity and mortality. The aim of this study was to determine whether these traits are heritable. METHODS: We studied 260 healthy siblings without antihypertensive drugs from 118 Swedish families. The BPV and HRV were defined as the standard deviation of BP and heart rate values recorded during 24 h, daytime (6 am to 10 pm), and night-time (10 pm to 6 am). The NBPD was defined as the ratio between night-time and daytime BP. Heritability was estimated with a maximal likelihood method implemented in the Solar software package with and without adjustment for significant covariates. RESULTS: At night, significant heritability was found for systolic (33%, P < .05), diastolic (36%, P < .05), and mean (42%, P < .01) BPV. After covariate adjustment the corresponding heritability values were 23% (P = .08), 29% (P < .05), and 37% (P < .05). Daytime BPV was not heritable. The heritability of NBPD was 38% (P < .05) for systolic, 9% (P = .29) for diastolic, and 36% (P < .05) for mean BP, but after adjustment only systolic NBPD was significant (29%, P < .05). Heart rate was highly heritable both during daytime (57%, P < .001) and night-time (58%, P < .001), but the variability of heart rate, after adjustment, was only significant at night (37%, P < .05). CONCLUSIONS: Our data suggest that BPV and HRV are partially under genetic control and that genetic loci of importance for these traits could be mapped by linkage analysis.

Adult↗

PubMed2005

Haplotype construction of the FRDA gene and evaluation of its role in type II diabetes.

A GAA-repeat in the X25 gene is causing Friedreich's ataxia (FRDA), a common neurodegenerative disease and >20% of FRDA patients develop type II diabetes (T2D). Linkage has previously been detected between T2D and chromosome 9p13-q21, the region that harbours the X25 gene, but association studies of this gene in T2D have been contradicting. Here, we examined whether genetic variation in the X25 gene is associated with risk for T2D. The GAA-repeat and 18 single nucleotide polymorphisms (SNPs) covering the X25 gene were genotyped in 220 trios in which the affected offspring had abnormal glucose tolerance. Any nominally significant findings were examined in an independent sample consisting of 523 individuals with T2D and 326 healthy controls. Previously reported results were analysed together with our data using a meta-analysis approach. There was no association between the GAA-repeat and T2D susceptibility in our study, which was supported by the meta-analysis including all previous publications. One SNP (rs2498429), 8.2 kb downstream of X25, was nominally associated with T2D in the trios (P=0.02) and showed a trend of association in the same direction in the case-controls (P=0.08; combined permuted P=0.01). Further analysis showed that the nine-marker haplotype containing the rare allele of rs2498429 was nominally associated with T2D in the trios (P<0.01) as well as in the case-controls (P=0.03). In conclusions, this study excludes a role of genetic variation within the X25 gene, but instead suggests that genetic variation downstream the X25 gene, may increase risk for T2D.

Adult↗