The CTLA4 -819 C/T and +49 A/G dimorphisms are associated with Type 1 diabetes in Egyptian children

BACKGROUND:

Type 1 diabetes (T1D) is an organ-specific autoimmune disease characterized by T cell-mediated destruction of pancreatic islets. T cell proliferation is negatively regulated by cytotoxic lymphocyte antigen-4 (CTLA-4). CTLA-4 polymorphisms are associated with T1D in some but not all populations.

AIMS:

The study was conducted to investigate the association of the C-819T and A+49G single nucleotide polymorphisms (SNP) of CTLA-4 gene in T1D patients in the Egyptian population.

METHODS:

The association of the C-819T SNP in intron 1 and A+49G SNP in exon 1 of the CTLA-4 gene with T1D were investigated in 396 Egyptian patients ≤14 years old and 396 control subjects >24 years old, with the same ratio of males to females in both groups. The diagnosis of T1D was made on the basis of ketoacidosis or ketosis with severe symptoms of acute onset at presentation and continuous dependence on insulin. Controls were negative for anti-GAD antibodies and were greater than 24 years of age. Genotyping was performed using single strand conformation polymorphism (SSCP), temperature gradient gel electrophoresis (TGGE), and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).

RESULTS:

The results demonstrated an association of the C-819T and A+49G SNPs in the CTLA-4 gene with T1D patients (P=0.0047) and (P=0.000575), respectively. Moreover, this association was stratified by gender and age to female patients with age at onset 0-5 years old (P=0.0186) and (P=0.00115) more than male patient with the age at onset 0-5 years old (P= 0.3120) and (P=0.345161), respectively.

CONCLUSION:

The results support an association of the C-819T and A+49G SNPs in the CTLA-4 gene with Egyptian children, specifically, females of onset age 0-5 years old.     

Association of cytotoxic T lymphocyte-associated antigen 4 gene single nucleotide polymorphism with type 1 diabetes mellitus in Madurai population of Southern India

Type 1 diabetes mellitus formerly called juvenile diabetes, is an organ specific T-cell mediated autoimmune disease characterized by the progressive loss of function of the insulin producing beta-cells of the islets of Langerhans. Cytotoxic T lymphocyte-associated antigen 4 gene (CTLA-4) has been proposed as a candidate gene for conferring susceptibility to autoimmunity. Association of CTLA-4 gene polymorphism is well established in autoimmune endocrinopathies across world population. The present study was conducted to investigate the association of CTLA-4 exon 1 49A/G polymorphism with TIDM in Madurai, a city in Southern India. Fifty three clinically proven T1DM patients and 53 control subjects with no history of autoimmune disease were recruited for the study. Genomic DNA was extracted from peripheral blood. CTLA-4 exon 1 49 A/G polymorphism was assessed using PCR-RFLP methods. Our findings revealed a significant association of CTLA-4 exon 1 49 A/G polymorphism with T1DM in Madurai population.     

1型糖尿病患者骨密度的变化及相关因素分析(英文)

目的:观察1型糖尿病患者骨密度(bone mineral density,BMD)的变化及其影响因素。方法:采用双能X线骨密度仪测定108例1型糖尿病患者及106例非糖尿病人群腰椎1至4(L1、L2、L3、L4、、L1-4总体)及左侧髋部(股骨颈、大转子、ward's三角、股骨干及左髋总体)骨密度,同时测定受试者年龄、身高、体重、腰围、臀围,1型糖尿病患者病程、糖化血红蛋白(HbA1c)等指标,利用多元回归分析1型糖尿病患者骨密度的相关因素。结果:L1-4总体BMD和左髋总体BMD与年龄、HbA1c呈负相关,与BMI呈正相关(P0.05);左髋总体BMD与性别有关(P0.05)。结论:1型糖尿病患者BMD低于对照人群,1型糖尿病患者的性别、年龄、BMI、HbA1c水平与BMD关系密切。     

Polymorphism A/G in position +49 of CTLA4 exon 1 in multiple sclerosis in Russians

The association of multiple sclerosis (MS) with alleles A and G of the cytotoxic T-lymphocyte antigen 4 (CTLA4) gene, a candidate gene for autoimmune disorders, was studied. The allele polymorphism results from single nucleotide substitution (A/G) in position +49 of exon 1 and leads to substitution Thr-->Ala in the leader peptide. The case-control study involved two groups of ethnic Russians: 168 MS patients and 209 healthy subjects from central Russia. Genotype frequencies were in agreement with the Hardy-Weinberg equilibrium in both groups (P > 0.05). The controls significantly differed in CTLA4 allele and genotype frequencies from Mongoloids but not from other Caucasians. No association was observed between MS and CTLA4. In addition, the combined association with MS was analyzed for both the CTLA4 alleles and allele groups of HLA DRB1. The results showed that the CTLA4 dimorphism does not affect susceptibility to MS in ethnic Russians, be these stratified or not with regard to DRB1 alleles corresponding to serologic specificities DR1 to DR16.     

HLA-DQA1 and HLA-DQB1 in Celiac disease predisposition: practical implications of the HLA molecular typing

Celiac disease (CD) is a multifactorial disorder with an estimated prevalence in Europe and USA of 1:100 and a female:male ratio of approximately 2:1. The disorder has a multifactorial etiology in which the triggering environmental factor, the gluten, and the main genetic factors, Human Leukocyte Antigen (HLA)-DQA1 and HLA-DQB1 loci, are well known. About 90-95% of CD patients carry DQ2.5 heterodimers, encoded by DQA1*05 and DQB1*02 alleles both in cis or in trans configuration, and DQ8 molecules, encoded by DQB1*03:02 generally in combination with DQA1*03 variant. Less frequently, CD occurs in individuals positive for the DQ2.x heterodimers (DQA1≠*05 and DQB1*02) and very rarely in patients negative for these DQ predisposing markers. HLA molecular typing for Celiac disease is, therefore, a genetic test with a negative predictive value. Nevertheless, it is an important tool able to discriminate individuals genetically susceptible to CD, especially in at-risk groups such as first-degree relatives (parents, siblings and offspring) of patients and in presence of autoimmune conditions (type 1 diabetes, thyroiditis, multiple sclerosis) or specific genetic disorders (Down, Turner or Williams syndromes).     

Relationships between Mitochondrial Function and Metabolic Flexibility in Type 2 Diabetes Mellitus

Introduction

Mitochondrial dysfunction, lipid accumulation, insulin resistance and metabolic inflexibility have been implicated in the etiology of type 2 diabetes (T2D), yet their interrelationship remains speculative. We investigated these interrelationships in a group of T2D and obese normoglycemic control subjects.

Methods

49 non-insulin dependent male T2D patients and 54 male control subjects were enrolled, and a hyperinsulinemic-euglycemic clamp and indirect calorimetry were performed. A muscle biopsy was taken and intramyocellular lipid (IMCL) was measured. In vivo mitochondrial function was measured by PCr recovery in 30 T2D patients and 31 control subjects.

Results

Fasting NEFA levels were significantly elevated in T2D patients compared with controls, but IMCL was not different. Mitochondrial function in T2D patients was compromised by 12.5% (p<0.01). Whole body glucose disposal (WGD) was higher at baseline and lower after insulin stimulation. Metabolic flexibility (ΔRER) was lower in the type 2 diabetic patients (0.050±0.033 vs. 0.093±0.050, p<0.01). Mitochondrial function was the sole predictor of basal respiratory exchange ratio (RER) (R² = 0.18, p<0.05); whereas WGD predicted both insulin-stimulated RER (R² = 0.29, p<0.001) and metabolic flexibility (R² = 0.40, p<0.001).

Conclusions

These results indicate that defects in skeletal muscle in vivo mitochondrial function in type 2 diabetic patients are only reflected in basal substrate oxidation and highlight the importance of glucose disposal rate as a determinant of substrate utilization in response to insulin.     

Critical Amino Acid Variants in HLA-DRB1 and -DQB1 Allotypes in the Development of Classical Type 1 Diabetes and Latent Autoimmune Diabetes in Adults in the Japanese Population

The effects of amino acid variants encoded by the human leukocyte antigen (HLA) class II on the development of classical type 1 diabetes (T1D) and latent autoimmune diabetes in adults (LADA) have not been fully elucidated. We retrospectively investigated the HLA-DRB1 and -DQB1 genes of 72 patients with classical T1D and 102 patients with LADA in the Japanese population and compared the frequencies of HLA-DRB1 and -DQB1 alleles between these patients and the Japanese populations previously reported by another institution. We also performed a blind association analysis with all amino acid positions in classical T1D and LADA, and compared the associations of HLA-DRB1 and -DQB1 amino acid positions in classical T1D and LADA. The frequency of DRß-Phe-13 was significantly higher and those of DRß-Arg-13 and DQß-Gly-70 were significantly lower in patients with classical T1D and LADA than in controls. The frequencies of DRß-His-13 and DQß-Glu-70 were significantly higher in classical T1D patients than in controls. The frequency of DRß-Ser-13 was significantly lower and that of DQß-Arg-70 was significantly higher in LADA patients than in controls. HLA-DRß1 position 13 and HLA-DQß1 position 70 could be critical amino acid positions in the development of classical T1D and LADA.     

1型糖尿病患者骨密度的变化及相关因素分析

目的：观察1 型糖尿病患者骨密度（bone mineral density,BMD）的变化及其影响因素。方法：采用双能X 线骨密度仪测定108 例1 型糖尿病患者及106 例非糖尿病人群腰椎1 至4（L1、L2、L3、L4、、L1-4 总体）及左侧髋部（股骨颈、大转子、ward＇s 三角、股骨干及左髋总体）骨密度,同时测定受试者年龄、身高、体重、腰围、臀围,1 型糖尿病患者病程、糖化血红蛋白（HbA1c）等指标,利用多元回归分析1型糖尿病患者骨密度的相关因素。结果：L1-4 总体BMD 和左髋总体BMD 与年龄、HbA1c 呈负相关,与BMI呈正相关（P〈0.05）;左髋总体BMD 与性别有关（P〈0.05）。结论：1型糖尿病患者BMD 低于对照人群,1型糖尿病患者的性别、年龄、BMI、HbA1c 水平与BMD 关系密切。     

The Type 1 Diabetes - HLA Susceptibility Interactome - Identification of HLA Genotype-Specific Disease Genes for Type 1 Diabetes

Background

The individual contribution of genes in the HLA region to the risk of developing type 1 diabetes (T1D) is confounded by the high linkage disequilibrium (LD) in this region. Using a novel approach we have combined genetic association data with information on functional protein-protein interactions to elucidate risk independent of LD and to place the genetic association into a functional context.

Methodology/Principal Findings

Genetic association data from 2300 single nucleotide polymorphisms (SNPs) in the HLA region was analysed in 2200 T1D family trios divided into six risk groups based on HLA-DRB1 genotypes. The best SNP signal in each gene was mapped to proteins in a human protein interaction network and their significance of clustering in functional network modules was evaluated. The significant network modules identified through this approach differed between the six HLA risk groups, which could be divided into two groups based on carrying the DRB1*0301 or the DRB1*0401 allele. Proteins identified in networks specific for DRB1*0301 carriers were involved in stress response and inflammation whereas in DRB1*0401 carriers the proteins were involved in antigen processing and presentation.

Conclusions/Significance

In this study we were able to hypothesise functional differences between individuals with T1D carrying specific DRB1 alleles. The results point at candidate proteins involved in distinct cellular processes that could not only help the understanding of the pathogenesis of T1D, but also the distinction between individuals at different genetic risk for developing T1D.     

The study of CTLA-4 and vitamin D receptor polymorphisms in the Romanian type 1 diabetes population

Several studies suggested that part of the genetic susceptibility for Type 1 diabetes (TIDM) is encoded by some polymorphisms of CTLA-4 gene (2q33) and of Vitamin D Receptor gene (VDR; 12q12-14). Our aim was to assess their contribution to TIDM genetic susceptibility in the Romanian population. We typed CTLA-4 49 A/G and VDR Fok I (F/f), Apa I (A/a) and Taq I (T/t) polymorphisms by Sequence Specific Primer PCR (SSP-PCR) in 204 Romanian diabetic families (756 individuals: 212 TIDM probands and 544 unaffected parents and siblings). We studied alleles transmission using the Transmission Disequilibrium Test (TDT). We found an increased transmission of CTLA-4 49G allele to diabetics (54.8%, p=0.11). The transmission of F (56.1%, p=0.063), a (55.7%, p=0.061) and T (51.8%, p=0.37) alleles of VDR gene to diabetics was increased but did not reach statistical significance. In conclusion we found the same increased transmission of CTLA-4 49 G allele to diabetics as previously reported. VDR Foq I F allele seems to be predisposing while Taq I T allele seems to be protective.     

Ala45Thr variation in neuroD1 gene is associated with early-onset type 2 diabetes with or without diabetic pedigree in Chinese

Objective: Based on onset-age stratified analysis may be useful to determine the association of NeuroD1-Ala45Thr variation with susceptibility to genetic heterogeneous type 2 diabetes mellitus (T2DM), we investigated the Ala45Thr variation in unrelated early-onset and late-onset T2DM with or without diabetic pedigree and unrelated non-diabetic control subjects in Chinese. Methods: 175 early-onset and 194 late-onset type 2 diabetic patients were further divided into two subgroups according to with or without diabetic pedigree respectively. This NeuroD1-Ala45Thr variation were screened by PCR-direct sequencing in above 369 type 2 diabetic patients and 87 unrelated non-diabetic control subjects. We then compared the distribution of the Ala45Thr variation among the groups, searching for the predictive trends. Results: Frequencies of the variant (AA + GA genotype) in early-onset T2DM are obviously elevated, especially among diabetic pedigree subjects when compared to non-diabetic controls (p= 0.003) and late-onset T2DM subjects (p = 0.014). However, no significant differences were observed between late-onset T2DM with or without diabetic pedigree and non-diabetic control subjects. Conclusions: Our results suggest that 1) the NeuroD1-Ala45Thr variation may itself have an important role in susceptibility to or be in disequilibrium with early-onset T2DM in Chinese; 2) the Ala45Thr may affect the onset pattern of T2DM, i.e., early-onset but not late-onset T2DM in Chinese; and 3) onset-age stratified analysis may be useful to determine the association of NeuroD1-Ala45Thr variation with susceptibility to genetic heterogeneous T2DM in Chinese.     

Risk for Coexistent Autoimmune Diseases in Familial and Sporadic Type 1 Diabetes is Related to Age at Diabetes Onset

ObjectiveType 1 diabetes (T1D) is frequently associated with other autoimmune diseases (AIDs). Although most of T1D patients are sporadic cases (S-T1D), 10% to 15% have a familial form (F-T1D) involving 2 or more first-degree relatives. This study evaluated the effect of T1D family aggregation and age onset on AIDs occurrence.MethodsIn this observational, cross-sectional, case-control, single center study, we enrolled 115 F-T1D and 115 S-T1D patients matched for gender, age, T1D age onset, and duration. With respect to T1D age onset (before or after 18 years), both groups were further subdivided into young- or adult-onset F-T1D and young- or adult-onset S-T1D. The presence of organ-specific antibodies and/or overt AIDs was evaluated.ResultsThe F-T1D group had a higher percentage of AIDs (29.8% vs 18.4%, P = .04) and a significant earlier onset of AIDs at Cox regression analysis (P = .04) than the S-T1D group. Based on multivariate analysis, the adult-onset F-T1D subgroup had the highest prevalence of both additional organ-specific antibodies (60.5%) and overt AIDs (34.9%), whereas the adult S-T1D subgroup was the least frequently involved (29.1% and 12.7%, respectively). In F-T1D patients, offsprings develop T1D and AIDs earlier than their parents do.ConclusionsIn T1D patients, familial aggregation and adult-onset of T1D increase the risk for coexistent AIDs. These clinical predictors could guide clinicians to address T1D patients for the screening of T1D-related AIDs.     

Polymorphism A/G in Position +49 of CTLA4 Exon 1 in Multiple Sclerosis in Russians

The association of multiple sclerosis (MS) with alleles A and G of the cytotoxic T-lymphocyte antigen 4 (CTLA4) gene, a candidate gene for autoimmune disorders, was studied. The allele polymorhism results from single nucleotide substitution (A/G) in position +49 of exon 1 and leads to substitution Thr Ala in the leader peptide. The case–control study involved two groups of ethnic Russians: 168 MS patients and 209 healthy subjects from central Russia. Genotype frequencies were in agreement with the Hardy–Weinberg equilibrium in both groups (P > 0.05). The controls significantly differed in CTLA4 allele and genotype frequencies from Mongoloids but not from other Caucasians. No association was observed between MS and CTLA4. In addition, the combined association with MS was analyzed for both the CTLA4 alleles and allele groups of HLA DRB1. The results showed that the CTLA4 dimorphism does not affect susceptibility to MS in ethnic Russians, be these stratified or not with regard to DRB1 alleles corresponding to serologic specificities DR1 to DR16.     

IL2RA Genetic Heterogeneity in Multiple Sclerosis and Type 1 Diabetes Susceptibility and Soluble Interleukin-2 Receptor Production

Multiple sclerosis (MS) and type 1 diabetes (T1D) are organ-specific autoimmune disorders with significant heritability, part of which is conferred by shared alleles. For decades, the Human Leukocyte Antigen (HLA) complex was the only known susceptibility locus for both T1D and MS, but loci outside the HLA complex harboring risk alleles have been discovered and fully replicated. A genome-wide association scan for MS risk genes and candidate gene association studies have previously described the IL2RA gene region as a shared autoimmune locus. In order to investigate whether autoimmunity risk at IL2RA was due to distinct or shared alleles, we performed a genetic association study of three IL2RA variants in a DNA collection of up to 9,407 healthy controls, 2,420 MS, and 6,425 T1D subjects as well as 1,303 MS parent/child trios. Here, we report “allelic heterogeneity” at the IL2RA region between MS and T1D. We observe an allele associated with susceptibility to one disease and risk to the other, an allele that confers susceptibility to both diseases, and an allele that may only confer susceptibility to T1D. In addition, we tested the levels of soluble interleukin-2 receptor (sIL-2RA) in the serum from up to 69 healthy control subjects, 285 MS, and 1,317 T1D subjects. We demonstrate that multiple variants independently correlate with sIL-2RA levels.     

HLA DOA1 and DOB1 loci in Honduran women with cervical dysplasia and invasive cervical carcinoma and their relationship to human papillomavirus infection.

Molecular and epidemiological studies have demonstrated that certain types of human papillomavirus (HPV), mainly HPV-16 and HPV-18, are the primary causes of cervical cancer and its precursor lesions; there is now evidence for a clear association with specific HLA class I and class II loci contributing independently to the expression of cervical cancer. Among Honduran women carcinoma of the cervix is the most common type of cancer, and infections with high-risk HPV types are highly prevalent. To study the interactive role of viral-host genetics, we performed PCR amplification of DNA and sequence-specific oligonucleotide probe typing on cervical scrapes from 49 women [24 with cervical intraepithelial neoplasia stage III or cervical cancer (severe cases) and 25 with stage I or II cervical intraepithelial neoplasia (mild cases)] and 75 control subjects to look for possible associations between HPV and HLA class II DQA1 and DQB1 alleles in the development of dysplasias and invasive cancer. This analysis revealed a predominance of HLA-DQA1*0301 among severe-case patients [relative risk (RR) = 3.45, p = 0.008), whereas DQA1*0501 was negatively associated (RR = 0.30, p = 0.03), suggesting a protective effect of this allele. HPV typing showed a decreased relative risk among the HPV-16 or HPV-18 carrying patients and other HPV-related positive patients in the presence of DQB1*0602 compared with positive control subjects (p = 0.04). No statistically significant allele frequency difference was observed between mild dysplasia cases and control subjects. The results suggest that DQA1*03011, which is in linkage desequilibrium with all HLA-DR4 alleles, confers an increased risk for severe cervical dysplasia and invasive cancer, whereas DQA1*0501, which is in several DR52 haplotypes, has a protective effect. Furthermore, specific HLA-DQB1 sequences may be important in determining the immune response to HPV peptides and may affect the risk for cervical cancer after HPV infection in mestizo Honduran women.     

Genetic and immunologic aspects of type 1 diabetes mellitus

Prediction of type 1 diabetes mellitus (IDDM) and its identification in preclinical period is one of the central problems in modern medicine. They are based comprehensive genetic, immunologic and metabolic evaluations. We observed four hundred seven first-degree relatives of patients with IDDM (240 families in which one of the children or one of the parents had IDDM) have been included in the study. The study of HLA-DQA1, HLA-DQB1 polymorphic alleles and DRB1 genes and their combinations. The genetic study included searching HLA loci (HLA-DQA1, HLA-DQB1 polymorphic alleles and DRB1 genes) loci. To evaluate the genetic risk two approaches we used: first--carrying predisposing HLA-DQ alleles and DRB1-genes and it's combination (mainly associated in Russian population was DRB1*04-DQB1*0302, DRB1*04-DQA1*0301, DQA1*0301-DQB1*0302, DQA1*0301-DQB1*0302 and four susceptible alleles in A- and B- chains (Asp 57-, Arg 52+)) and second--IBD (identity by descent), in Russian population HLA-identical for 2 haplotypes sibs had risk of development of IDDM of 18%, for 1 haplotype--3%, for 0 haplotype-0.9%. The antibodies (ICA, IAA) prevalence rate has not depended on availability of predisposing HLA-DQ alleles and DRB1-genes and haploidentity of normal sibs and sibs with IDDM. However, GADA prevalence rate in groups having high predisposed alleles has been noticed as significantly higher (28.6%) comparing with 7.7% in groups that had no predisposing alleles (p < 0.05). The comparison of antibodies prevalence rate to sibs HLA-identity has shown the significant increase or GADA prevalence rate in group of siblings identical for one haplotype comparing with non-identical sibs (27.3% and 0% respectively, p < 0.001).     

Impact of exercise training on insulin sensitivity, physical fitness, and muscle oxidative capacity in first-degree relatives of type 2 diabetic patients

First-degree relatives of type 2 diabetic patients (offspring) are often characterized by insulin resistance and reduced physical fitness (VO2 max). We determined the response of healthy first-degree relatives to a standardized 10-wk exercise program compared with an age-, sex-, and body mass index-matched control group. Improvements in VO2 max (14.1 +/- 11.3 and 16.1 +/- 14.2%; both P < 0.001) and insulin sensitivity (0.6 +/- 1.4 and 1.0 +/- 2.1 mg x kg(-1) x min(-1); both P < 0.05) were comparable in offspring and control subjects. However, VO2 max and insulin sensitivity in offspring were not related at baseline as in the controls (r = 0.009, P = 0.96 vs. r = 0.67, P = 0.002). Likewise, in offspring, exercise-induced changes in VO2 max did not correlate with changes in insulin sensitivity as opposed to controls (r = 0.06, P = 0.76 vs. r = 0.57, P = 0.01). Skeletal muscle oxidative capacity tended to be lower in offspring at baseline but improved equally in both offspring and controls in response to exercise training (delta citrate synthase enzyme activity 26 vs. 20%, and delta cyclooxygenase enzyme activity 25 vs. 23%. Skeletal muscle fiber morphology and capillary density were comparable between groups at baseline and did not change significantly with exercise training. In conclusion, this study shows that first-degree relatives of type 2 diabetic patients respond normally to endurance exercise in terms of changes in VO2 max and insulin sensitivity. However, the lack of a correlation between the VO2 max and insulin sensitivity in the first-degree relatives of type 2 diabetic patients indicates that skeletal muscle adaptations are dissociated from the improvement in VO2 max. This could indicate that, in first-degree relatives, improvement of insulin sensitivity is dissociated from muscle mitochondrial functions.     

Influence of the PPAR-gamma2 Pro12Ala and ACE I/D polymorphisms on insulin sensitivity and training effects in healthy offspring of type 2 diabetic subjects.

Aerobic endurance training improves insulin sensitivity, and is of great importance in the prevention and treatment of type 2 diabetes. The improvement in insulin sensitivity and cardiovascular function through exercise is highly variable among individuals, and is probably partly determined by genetic components. This study evaluated the peroxisome proliferation-activated receptor-gamma2 ( PPAR-gamma2) Pro12Ala polymorphism and the angiotensin converting enzyme ( ACE) I/D polymorphism with respect to any potential influence that these highly prevalent polymorphisms may impose on changes in insulin sensitivity and maximal aerobic capacity induced by exercise. Seventy-nine healthy first-degree relatives of type 2 diabetic patients were compared to a control group consisting of 54 subjects without any family history of type 2 diabetes. All subjects had a normal OGTT. The groups were comparable with respect to age (34 +/- 7 vs. 33 +/- 7 years), gender ((m/f) 43/36 vs. 30/24) and BMI (25.7 +/- 2.6 vs. 25.3 +/- 2.5 kg/m (2)); p (all) = NS. Furthermore, a subgroup of 29 offspring and 17 control subjects were engaged in a standardized training program lasting ten weeks. Insulin sensitivity (hyperinsulinemic euglycemic clamp technique) and VO (2)max (exhaustive exercise test) was assessed before and after the training period. We will demonstrate the allelic frequency of the Ala-allele of the Pro12Ala polymorphism to be lower in offspring to type 2 diabetic patients (13.3 %) compared to control subjects (21.3 %); p < 0.05. In offspring only, the Pro12Ala polymorphism of the PPAR-gamma2 gene appeared to enhance weight changes brought about by exercise (Deltaweight = - 0.3 +/- 1.4 kg vs. - 1.8 +/- 1.8 kg; p < 0.05; (Pro/Pro vs. Pro/Ala + Ala/Ala) - suggesting possible gene-environment or gene-gene interactions. The ACE I/D polymorphism was not of significant importance in determining the capability of responding to exercise in terms of improvement in insulin sensitivity or maximal aerobic capacity.