Vitamin D receptor gene polymorphisms influence susceptibility to type 1 diabetes mellitus in the Taiwanese population

OBJECTIVE: Vitamin D and its receptor have been suggested to play a role in the pathogenesis of type 1 diabetes mellitus. We have therefore studied the influence of vitamin D receptor (VDR) gene polymorphisms on susceptibility to type 1 diabetes, and rates of glutamic acid decarboxylase (GAD65) autoantibody and islet cell autoantibody (ICA512) positivity. SUBJECTS: AND MEASUREMENTS One hundred and fifty-seven type 1 diabetic patients and 248 unrelated normal controls were recruited for this study. Genomic DNA was extracted from peripheral blood leucocytes. All type 1 diabetic patients and controls were genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP), for three restriction sites in the VDR gene, BsmI, ApaI and TaqI. The chi2 test was used to compare the frequency of the VDR gene polymorphisms in patients and normal controls. The association of VDR gene polymorphisms in type 1 diabetes with the presence of GAD65 and ICA512 autoantibodies were also examined using the chi2 test. RESULTS: The allele frequency of the BsmI and ApaI polymorphisms, but not TaqI polymorphism, differed between patients and controls (BsmI P = 0.015; ApaI P = 0.018; TaqI P = 0.266). However, after correction for the three different polymorphisms tested, only the BsmI was significant (pc = 0.045). CONCLUSIONS: Vitamin D receptor gene polymorphisms were associated with type 1 diabetes in a Taiwanese population. However, functional studies are needed to establish the role of the vitamin D receptor in the pathogenesis of type 1 diabetes mellitus.     

Vitamin D receptor gene polymorphism is associated with Graves' disease in the Japanese population

Susceptibility to Graves' disease (GD), which is determined by environmental and genetic factors, is conferred by genes in the human leukocyte antigen (HLA) and genes unlinked to HLA, including the CTLA-4 gene. We recently described the association of GD with the vitamin D receptor (VDR) exon 2 initiation codon (VDR-FOK:I) polymorphism. An association of some VDR genotypes with osteoporosis, primary hyperparathyroidism, and some autoimmune diseases, such as insulin-dependent diabetes mellitus and multiple sclerosis, has been reported. We investigated the distribution of VDR gene polymorphism in 180 Japanese patients with GD (48 males and 132 females) and 195 controls (67 males and 128 females). A VDR allelic polymorphism was assessed by BSM:I endonuclease restriction after specific PCR amplification. Genotypic polymorphism was clearly defined as BB (no restriction site on both alleles), bb (restriction site on both alleles), or Bb (heterozygous). The distribution of genotype frequencies differed between patients with GD and controls (chi(2) = 7.53; 2 degrees of freedom; P: = 0.023). The relative risk conferred by at least 1 B allele (BB or Bb) was 1.5. We also found an association between VDR-APA:I polymorphism and GD. No relation was detected between this polymorphism and the VDR-FOK:I polymorphism in the patients. The present results support the association of the VDR gene with GD in Japanese by showing that the VDR gene could be a non-HLA-linked gene predisposing an individual to GD. The role of the VDR gene polymorphism should be further studied in other populations, and the distribution of other polymorphisms, such as the polyadenylase polymorphism further down the VDR 3'-untranslated region, should be studied in terms of GD susceptibility.     

Type 1 diabetes in Japan

Type 1 diabetes is a multifactorial disease which results from a T-cell-mediated autoimmune destruction of the pancreatic beta cells in genetically predisposed individuals. The risk for individuals of developing type 1 diabetes varies remarkably according to country of residence and race. Japan has one of the lowest incidence rates of type 1 diabetes in the world, and recognises at least three subtypes of the condition: acute-onset (‘classical’), slow-onset, and fulminant type 1 diabetes. The incidence rate of type 1 diabetes in children aged 0–14 years in Japan increased over the period from 1973–1992, but remained constant over the last decade, averaging 2.37 cases per 100,000 persons per year; the incidence does not appear to have increased in older age groups. Although there are few reports regarding the incidence and prevalence of type 1 diabetes in adult-onset patients, it appears that the prevalence of type 1 diabetes in adults is more than twice that in childhood-onset patients and that two-thirds of them have a slow-onset form of type 1 diabetes. Differences and similarities in the association of MHC and non-MHC genes with type 1 diabetes are observed in Japan and in countries with Caucasoid populations. Highly susceptible class II HLA haplotypes identified in patients of Caucasoid origin are rarely seen in Japanese patients, whereas protective haplotypes are universal. Non-MHC genes associated with susceptibility to type 1 diabetes in both Japanese and Caucasoid patients include polymorphisms in the insulin gene, the cytotoxic T-lymphocyte antigen 4 (CTLA4) gene, the interleukin-18 (IL18) gene and the major histocompatibility complex class I chain-related gene A (MICA) gene. Fulminant type 1 diabetes is a unique subtype of type 1 diabetes that accounts for about 20% of acute-onset type 1 diabetes, and is seen mainly in adults. The challenge for the future is to investigate the underlying pathogenesis of beta cell destruction, including the genetic or environmental factors that may modify the form of onset for each subtype of Japanese type 1 diabetes.     

Vitamin D receptor gene BsmI polymorphism B allele, but not BB genotype, is associated with systemic lupus erythematosus in a Han Chinese population

The vitamin D receptor (VDR) gene is a candidate gene for susceptibility to autoimmune disorders. Association studies of VDR polymorphisms and risk of systemic lupus erythematosus (SLE) have often produced conflicting results in different ethnic backgrounds. The aim of this study is to test the association between VDR gene BsmI polymorphism and the genetic susceptibility to SLE in a Han Chinese population. Three hundred and thirty-seven patients with SLE and 239 healthy controls were genotyped for the VDR gene BsmI polymorphism (rs1544410) by polymerase chain reaction and restriction fragment length polymorphism analysis in this study, after which the relationship between BsmI polymorphisms and the mRNA expression of VDR, as well as clinical manifestations in patients with SLE, was evaluated. It was found that the frequency of B allele was significantly increased in SLE relative to the control group (χ(2)?=?4.681, p?=?0.031), although the distribution of VDR BsmI polymorphism genotype frequencies did not differ significantly between patients and controls (χ(2)?=?4.098, p?=?0.129). Moreover, VDR B allele was found to be associated with lupus nephritis (p?=?0.027) and also with production of anti-nucleosome antibodies (p?=?0.037). The mRNA of VDR was markedly down-regulated in patients with VDR B allele compared with that in patients without B allele (p?=?0.016). Our results indicate a possible role of genetic factors (the VDR B allele) in influencing disease susceptibility in Han Chinese patients. Also, VDR B allele is associated with the development of nephritis and the down-regulation of VDR mRNA expression in SLE.     

Vitamin D receptor initiation codon polymorphism in Japanese patients with Graves' disease.

Recent studies have shown that related genetic influences on bone mineral density (BMD) and bone turnover are related to allelic variations in the vitamin D receptor (VDR) gene. Osteoporosis as a complication of hyperthyroidism is characterized by increased rates of both bone formation and bone resorption. In addition, VDR gene polymorphism influences susceptibility to some autoimmune diseases such as insulin-dependent diabetes mellitus (IDDM) and multiple sclerosis (MS). In the gene encoding the VDR, we investigated the distribution of a VDR-FokI polymorphism that changes the predicted protein sequence. The subjects were 131 female Japanese patients with Graves' disease and 150 female controls. The distribution of genotype frequencies differs between Graves' disease and controls (chi2 = 5.99, degrees of freedom = 2, p = 0.0386). We found overexpression of F allele (69% vs. 61%, p = 0.0472) and homozygote FF (48% vs. 33%, p = 0.0118) in Graves' disease patients compared with controls. We also correlated a VDR-FokI polymorphism with BMD in the distal radius and biochemical markers of bone turnover in patients with Graves' disease in remission. Although generally no significant association was seen between age-adjusted BMD and genotype, patients in remission for >5 years showed significantly lower age-adjusted BMD in Ff heterozygotes than in ff homozygotes (Z = 1.14 ff vs. Z = -0.43 Ff, p < 0.05). Moreover, serum concentrations of bone alkaline phosphatase were significantly greater in Ff homozygotes than in FF homozygotes (78 +/- 12 vs. 59 +/- 10, p < 0.05). The genotypes did not differ in serum concentrations of osteocalcin, urinary hydroxyproline, or urinary deoxypyridinoline. Our results indicate, for the first time, an association between Graves' disease and a VDR polymorphism in the Japanese and suggest that a VDR-FokI polymorphism may affect bone mineral metabolism and can predict risk of osteoporosis as a complication of Graves' disease in patients in remission.     

Vitamin D receptor initiation codon polymorphism in Japanese patients with Graves' disease.

Recent studies have shown that related genetic influences on bone mineral density (BMD) and bone turnover are related to allelic variations in the vitamin D receptor (VDR) gene. Osteoporosis as a complication of hyperthyroidism is characterized by increased rates of both bone formation and bone resorption. In addition, VDR gene polymorphism influences susceptibility to some autoimmune diseases such as insulin-dependent diabetes mellitus (IDDM) and multiple sclerosis (MS). In the gene encoding the VDR, we investigated the distribution of a VDR-FokI polymorphism that changes the predicted protein sequence. The subjects were 131 female Japanese patients with Graves' disease and 150 female controls. The distribution of genotype frequencies differs between Graves' disease and controls (chi2 = 5.99, degrees of freedom = 2, p = 0.0386). We found overexpression of F allele (69% vs. 61%, p = 0.0472) and homozygote FF (48% vs. 33%, p = 0.0118) in Graves' disease patients compared with controls. We also correlated a VDR-FokI polymorphism with BMD in the distal radius and biochemical markers of bone turnover in patients with Graves' disease in remission. Although generally, no significant association was seen between age-adjusted BMD and genotype, patients in remission for fewer than 5 years showed significantly lower age-adjusted BMD in Ff heterozygotes than in ff homozygotes (z = 1.14 ff vs. z = -0.43 Ff, p < 0.05). Moreover, serum concentrations of bone alkaline phosphatase were significantly greater in Ff homozygotes than in FF homozygotes (78 +/- 12 vs. 59 +/- 10, p < 0.05). The genotypes did not differ in serum concentrations of osteocalcin, urinary hydroxyproline, or urinary deoxypyridinoline. Our results indicate, for the first time, an association between Graves' disease and a VDR polymorphism in the Japanese and suggest that a VDR-FokI polymorphism may affect bone mineral metabolism and can predict risk of osteoporosis as a complication of Graves' disease in patients in remission.     

Association between vitamin D receptor polymorphism and type 2 diabetes or metabolic syndrome in community-dwelling older adults: the Rancho Bernardo Study

Vitamin D receptor (VDR) polymorphism influences susceptibility to type 1 diabetes, but the association with type 2 diabetes is not clear. We investigated the association between VDR polymorphism and type 2 diabetes and metabolic syndrome in a community-based study of unrelated older adults without known diabetes. Oral glucose tolerance test (75 g), plasma glucose and insulin measurement, homeostasis model assessment (HOMA), and VDR genotyping were performed. The distributions of genotype frequencies of ApaI, BsmI, and TaqI polymorphism did not differ between persons with and without diabetes, but the frequency of aa genotype of ApaI polymorphism was marginally higher in persons with type 2 diabetes (P =.058). Fasting plasma glucose (P <.05) and prevalence of glucose intolerance (P <.05) were significantly higher in nondiabetic persons with aa genotype compared with those with AA genotype. The bb genotype of BsmI polymorphism was associated with insulin resistance as assessed by HOMA after adjustment for age, sex, body mass index (BMI), and calcium and vitamin D use in persons without diabetes (P <.05). Our research suggests that ApaI polymorphism may be associated with glucose intolerance independent of defective insulin secretion and BsmI polymorphism with insulin resistance in a nondiabetic Caucasian population.     

VDR polymorphisms influence the immune response in type 1 diabetic children from Santiago, Chile

OBJECTIVE: To evaluate the influence of ApaI, BsmI and TaqI polymorphisms of the VDR gene and HLA-DQB1* alleles in type 1 diabetic children and to assess their possible relationship with circulating levels of 25-hydroxyvitamin D(3), auto-antibodies, and INFgamma/TGFbeta1 cytokines levels in Chilean cases and controls. METHODS: DNA and serum samples from 216 newly diagnosed type 1 diabetic and 203 unrelated control children were evaluated for IA-2 and GAD(65) auto-antibodies, 25-hydroxyvitamin D(3) levels, HLA-DQB1* alleles, and VDR gene polymorphisms. RESULTS: The frequency of the b allele and the bb genotype in type 1 diabetic patients was significantly lower compared with the control group (0.635 versus 0.749, p<0.01 and 0.370 versus 0.567, p<0.04). 25-Hydroxyvitamin D(3) levels showed no differences between type 1 diabetic and healthy children. In cases, 25-hydroxyvitamin D(3) levels were not associated with a special auto-antibodies profile according to the presence or absence of GAD(65)(+) or IA-2(+). The haplotype combination BAT was higher in cases (0.062 versus 0.019, p<0.0022) and bAT was more frequent in controls (0.266 versus 0.180, p<0.003). In cases, the aaBbTT genotype showed the most significant increase in TGFbeta1 level across the VDR categories. Finally, when considering the HLA class II risk genotype (DQB1*0302) and the VDR genotypes (AabbTT and aabbTT), higher levels of GAD(65), IA-2 and TGFbeta1 were observed among diabetic children. CONCLUSION: We found an association between a VDR polymorphism (BsmI) and type 1 diabetes. An association was found of AabbTT and aabbTT genotypes and the HLA-DQB1*0302 allele with high levels of GAD(65), IA-2 and TGFbeta1.     

血浆纤溶酶原激活物抑制因子基因启动子多态性与2型糖尿病伴发冠心病的关系

目的从分子遗传水平进行基因多态性研究，以探讨２型糖尿病易伴发冠心病的内在原因。方法对８１例２型糖尿病患者、９３例非糖尿病（非ＤＭ）患者进行口服糖耐量试验、血脂分析、血浆纤溶酶原激活物抑制因子（ＰＡＩ１）基因多态性分析。结果２型糖尿病和非ＤＭ相比ＰＡＩ１基因启动子４Ｇ频率明显增加（４２％和３１％，Ｐ＜０００１）；２型糖尿病伴冠心病与不伴冠心病相比，ＰＡＩ１基因启动子４Ｇ频率及４Ｇ／４Ｇ基因型频率存在明显差异（５２％和３０％，３２％和１４％；Ｐ分别＜０００１、００５）；非２型糖尿病伴冠心病与不伴冠心病相比，ＰＡＩ１基因启动子４Ｇ频率及４Ｇ／４Ｇ基因型频率则无明显差异（３１％和３１％，８％和１６％，均为Ｐ＞００５）。结论ＰＡＩ１基因４Ｇ等位基因可能是糖尿病合并冠心病的内在危险因素     

No association of the 94T/G polymorphism in the adiponectin gene with diabetic complications

AIM: This study examined a possible association of the T/G polymorphism at nucleotide 94 in the adiponectin gene with the prevalence of diabetic complications. METHODS: The study was performed in 696 patients with type 1 diabetes and type 2 diabetes. Genotyping was performed by means of polymerase chain reaction and subsequent cleavage by using SmaI restriction endonuclease. RESULTS: The 94G/G genotype was significantly more prevalent in patients with type 2 diabetes (2.2%) than in type 1 diabetics (0.0%) (p = 0.02), whereas no differences were found for frequencies of the 94T/T and the 94G/T genotypes, respectively. In patients with type 1 diabetes, 45 of 239 patients were heterozygous for the 94T/G polymorphism (carrier rate (CR): 18.8%; allele frequency (AF): 0.094). In type 2 diabetics, 71 of 457 patients were heterozygous and 10 patients were homozygous for the 94G/G genotype (CR: 17.7%; AF: 0.10). No association with diabetic nephropathy, diabetic neuropathy or diabetic retinopathy was found for either genotype in patients with type 1 and type 2 diabetes. CONCLUSIONS: The 94T/G polymorphism in the adiponectin gene is not associated with diabetic complications. The significance of a higher prevalence of the G allele in type 2, compared to type 1 diabetes remains to be clarified.     

Enzyme-to-enzyme channeling in the early steps of glycolysis in rat pancreatic islets

+49 A/G polymorphism of CTLA-4 gene has been suggested to be associated with type 1 diabetes in some populations. However, a functional significance of the +49 A/G polymorphism is unknown, because it is believed the polymorphism does not affect the function of the CTLA-4 molecule. In this study, we examined the +49 A/G polymorphism of the CTLA-4 gene in 30 Japanese type 1 diabetic patients (14 type 1B and 16 type 1A) and 40 non-diabetic subjects in a case-control study, and stratified patients according to genotype of the polymorphism. The distribution of genotype frequencies differed between type 1 diabetic patients and controls (p<0.01). When the subjects were subdivided into type 1A and type 1B subgroups, a significant difference in G allele frequency was found only between type 1B patients and controls, whereas G allele frequency tended to be higher in type 1A diabetic patients than controls. Type 1B patients displayed more severe metabolic decompensation (higher plasma glucose concentration, lower urinary C-peptide levels, higher insulin requirement, and higher serum amylase levels), and were found to be more prone to diabetic ketoacidosis than type 1A patients. After stratification by genotype, differences in urinary C-peptide and serum amylase levels between type 1A and type 1B patients were found to be due to differences in the GG genotype subgroup, whereas in the AG subgroup those differences disappeared. In conclusion, the +49 A/G polymorphism of CTLA-4 gene was associated with the occurrence of type 1B diabetes in a Japanese population, and type 1B diabetics with a GG genotype were associated with more severe cell dysfunction than their type 1A counterparts.     

Lack of association of the vitamin D receptor gene with Graves' disease in UK Caucasians

OBJECTIVE: Vitamin D modulates the immune system by suppressing the proliferation of activated T cells, with its actions being directed through the vitamin D receptor (VDR). A number of single nucleotide polymorphisms (SNPs) have been identified in the VDR gene, of which several have been associated with autoimmune diseases, including type 1 diabetes and Graves' disease (GD) in Japanese females. The aim of this study was to test for association of polymorphisms of the VDR gene in the genetic susceptibility to GD in UK Caucasians. DESIGN: Target DNA for five previously published SNPs, four novel SNPs and one microsatellite marker was amplified by the polymerase chain reaction (PCR). Subsequent genotyping was performed using restriction fragment length polymorphism (RFLP) or microsatellite genotyping analysis, according to the type of VDR polymorphism. PATIENTS: We obtained DNA from a case-control dataset consisting of 768 patients with GD and 864 control subjects. All patients and control subjects were Caucasians born in the UK, and all gave informed, written consent. MEASUREMENTS: Frequencies of the alleles and genotypes of the ten VDR gene polymorphisms were compared between patients and control subjects using the chi2 test. Odds ratios were calculated using Woolf's method with Haldane's modification for small numbers and D prime (D') was calculated to assess the level of linkage disequilibrium (LD) between the ten polymorphisms. RESULTS: No differences in allele or genotype frequencies were observed between GD cases and control subjects for any of the nine SNPs studied. The S allele of the PolyA microsatellite marker was slightly more frequent in GD cases when compared with control subjects (chi2= 4.364, P = 0.04). Strongest LD between markers was observed towards the 3' end of the VDR gene but there was no evidence of association with disease. CONCLUSION: This is the largest and most comprehensive study of the VDR gene in GD to date and these data suggest that these polymorphisms of the VDR gene do not contribute to GD susceptibility in the UK.     

CTLA-4 gene polymorphism confers susceptibility to primary biliary cirrhosis

BACKGROUND/AIM: Primary biliary cirrhosis (PBC) is an autoimmune cholestatic liver disease thought to develop through a complex interaction of genetic and environmental factors. It is characterised by T-cell-mediated non-suppurative destructive cholangitis. We have studied the polymorphic cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene, which encodes a molecule that is a vital negative regulator of T-cell activation, as a candidate susceptibility locus for PBC. This gene on chromosome 2q33 (designated IDDM12) is associated with susceptibility to both type 1 diabetes and autoimmune thyroid disease. METHODS: The CTLA-4 exon 1 polymorphism (A/G encoding for threonine or alanine, respectively) was genotyped via polymerase chain reaction in 200 Caucasoid PBC patients and 200 non-related geographically matched Caucasoid controls. RESULTS: There was significant overrepresentation of the G/A and G/G genotypes in PBC patients compared to controls (G/A 53% vs 40%; G/G 18.5% vs 10.5%, Odds Ratio (OR)=2.45 [95% CI 1.6-3.7], p=0.00006, chi2=19.4). Likewise, there was a significant difference in allele frequencies (G encoding alanine at codon 17, PBC 0.45 vs controls 0.305: OR=1.9 [1.4-2.5], p<0.0002). This association remained significant (p=0.00027) when patients with autoimmune thyroid disease were excluded from the analysis. CONCLUSIONS: The CTLA-4 exon 1 polymorphism is the first non-major histocompatibility complex gene to be identified as a susceptibility locus for PBC. Our data support the hypothesis that clinically distinct autoimmune disease may be controlled by a common set of susceptibility genes.     

Sex-specific association of PTPN22 1858T with type 1 diabetes but not with Hashimoto's thyroiditis or Addison's disease in the German population

BACKGROUND: Endocrine autoimmune disorders share genetic susceptibility loci, causing a disordered T-cell activation and homeostasis (HLA class II genes, CTLA-4). Recent studies showed a genetic variation within the PTPN22 gene to be an additional risk factor. MATERIALS AND METHODS: Patients with type 1 diabetes (n = 220), Hashimoto's thyroiditis (n = 94), Addison's disease (n = 121) and healthy controls (n = 239) were genotyped for the gene polymorphism PTPN22 1858 C/T. RESULTS: Our study confirms a significant association between allelic variation of the PTPN22 1858 C/T polymorphism and type 1 diabetes mellitus (T1D). 1858T was observed more frequently in T1D patients (19.3% vs 11.3%, P = 0.0009; odds ratio for allele T = 1.88, 95% confidence interval [1.3-2.7]). Furthermore, we found a strong association in female patients with T1D (P = 0.0003), whereas there was no significant difference between male patients with type 1 diabetes and male controls. No significant difference was observed between the distribution of PTPN22 C/T in patients with Hashimoto's thyroiditis or Addison's disease and healthy controls. CONCLUSION: The PTPN22 polymorphism 1858 C/T may be involved in the pathogenesis of type 1 diabetes mellitus by a sex-specific mechanism that contributes to susceptibility in females.     

Association of CTLA4 gene A-G polymorphism with type 1 diabetes in Chinese children

OBJECTIVE: The CTLA4 (cytotoxic T lymphocyte associated antigen-4) gene encodes the T cell receptor involved in the control of T cell proliferation and mediates T cell apoptosis. Thus it is a strong candidate gene for T cell-mediated autoimmune disease. There is polymorphism at position 49 in exon 1 of the CTLA4 gene, providing a A-G exchange. This polymorphism is reportedly associated with type 1 diabetes in Caucasians but not in a small data set of Chinese. We wished to test this polymorphism in a larger and more homogeneous data set of Chinese children with type 1 diabetes and normal adult controls. DESIGN: A population-based case-control study of a CTLA4 gene 49 A-G polymorphism was performed to look for an association with type 1 diabetes in Chinese children. PATIENTS: We analysed this polymorphism in 253 unrelated children (128 boys) with type 1 diabetes (age at diagnosis 7.1 +/- 3.7 years) and 91 randomly selected normal adults. All individuals were Han Chinese. RESULTS: The genotype and gene frequencies of children with type 1 diabetes differed significantly from those of adult controls (P = 0.0091 and P = 0.0051, respectively). Genotype CTLA4 49 G/G and G allele conferred a risk of type 1 diabetes (RR = 2.13, 95% CI = 1.31-3.46, P = 0.0022; RR = 1.68, 95% CI = 1.17-2.43, P = 0.0051, respectively). CONCLUSIONS: This study demonstrates that CTLA4 49 A-G polymorphism is associated with type 1 diabetes in Han Chinese children. The CTLA4 49 G allele confers an increased risk of type 1 diabetes.     

Genetic association of vitamin D receptor polymorphisms with autoimmune hepatitis and primary biliary cirrhosis in the Chinese

BACKGROUND: Autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) are two autoimmune diseases of unknown etiology. Genetic factors appear to be involved in the pathogenesis of both diseases. Vitamin D has been shown to exert multiple immunomodulatory effects, which acts through its own receptor (VDR). Polymorphisms of VDR had been implicated in several autoimmune diseases. In the present study, the association between Chinese patients with AIH, PBC and the polymorphisms in exon 2, intron 8 and exon 9 of vitamin D receptor genes was studied. METHODS: Four candidate gene loci were investigated in 49 patients with AIH, 58 patients with PBC, and 160 healthy controls. The VDR polymorphisms were assessed by FokI, BsmI, ApaI, and TaqI endonuclease digestion after specific polymerase chain reaction (PCR) amplification. RESULTS: The result show a significant difference in FokI polymorphism between AIH patients and controls (chi(2) = 5.47, P = 0.019), and a significant association in BsmI polymorphisms between PBC patients and controls (chi(2) = 6.52, P = 0.01). Furthermore the distribution of FokI, BsmI, ApaI, and TaqI gene types differed between Chinese healthy controls and Caucasian healthy controls. CONCLUSION: It is suggested that there is a genetic link of VDR polymorphisms to autoimmune liver diseases such as AIH and PBC in Chinese patients. Further studies are needed to elucidate the mechanisms by which VDR polymorphisms contribute to the lose of immune tolerance in autoimmune diseases.     

Association of vitamin D receptor gene polymorphisms in Iranian patients with inflammatory bowel disease

Background and Aims: The vitamin D receptor (VDR) gene maps to a region on chromosome 12 shown to be linked to inflammatory bowel disease (IBD). Many studies have recognized the relation of VDR gene polymorphisms with inflammatory and autoimmune disorders. Determining the frequency of these polymorphisms and their possible relation with IBD can improve understandings about the genetic background of these diseases. The objective of this study was to assess the association of VDR gene polymorphisms (Apa I, Taq I, Bsm I, Fok I) with IBD in Iran. Methods: In this case control designed study 150 patients with ulcerative colitis, 80 patients with Crohn's disease and 150 Age and Sex matched healthy controls from Iranian origin were enrolled. These patients were referred to a tertiary center during a two‐year period (2004–2006). Assessment of VDR gene polymorphisms was performed by the polymerase chain reaction—restriction fragment length polymorphism (PCR‐RFLP) method. The genotype–phenotype association for these polymorphisms was analyzed. Results: Only the frequency of the Fok I polymorphism was significantly higher in ulcerative colitis and Crohn's groups. The frequency of the polymorphic allele f was higher in ulcerative colitis and Crohn's patients comparing with controls (P = 0.011 and P < 0.001, respectively). The f/f genotype was also significantly more frequent (P < 0.001), while the F/F genotype was less presented in Crohn's patients compared to controls (P < 0.001). No genotype–phenotype association was observed with any mutations. Conclusions: This study suggests a probable association of the Fok I polymorphism in VDR receptor gene and Crohn's susceptibility in Iranian population.     

A promoter polymorphism of the CYP27B1 gene is associated with Addison's disease, Hashimoto's thyroiditis, Graves' disease and type 1 diabetes mellitus in Germans

BACKGROUND: CYP27B1 hydroxylase catalyzes the conversion of 25 hydroxyvitamin D(3) (25OHD(3)) to 1,25(OH)(2)D(3), the most active natural vitamin D metabolite, which plays a role in the regulation of immunity and cell proliferation. We therefore investigated two single nucleotide polymorphisms in the CYP27B1 hydroxylase gene for an association with Addison's disease, Hashimoto's thyroiditis, Graves' disease and type 1 diabetes mellitus. METHODS: Patients with Addison's disease (n=124), Hashimoto's thyroiditis (n=139), Graves' disease (n=334), type 1 diabetes mellitus (n=252) and healthy controls (n=320) were genotyped for the promoter (-1260) C/A polymorphism and for the intron 6 (+2838) C/T polymorphism of the CYP27B1 gene. Patients and controls were compared using genotype-wise and allele-wise X(2) testing. RESULTS: A significant association was found between allelic variation of the promoter (-1260) C/A polymorphism and Addison's disease, Hashimoto's thyroiditis, Graves' disease and type 1 diabetes mellitus (P=0.0062, P=0.0173, P=0.0094 and P=0.0028 respectively). Significant differences were also observed for the intron 6 (+2838) C/T polymorphism (P=0.0058) in Hashimoto's thyroiditis but not for the other autoimmune endocrine diseases. CONCLUSIONS: The CYP27B1 promoter (-1260) C/A polymorphism appears to be associated with endocrine autoimmune diseases but the CYP27B1 intron 6 (+2838) C/T polymorphism appears to be associated only with Hashimoto's thyroiditis. These results imply a regulatory difference of the CYP27B1 hydroxylase to predispose to endocrine autoimmunity.     

Tumor necrosis factor-α (TNF-α) −863C/A promoter polymorphism is associated with type 2 diabetes in Tunisian population

Aims

Tumor necrosis factor α (TNFα) plays a key role in orchestrating the complex events involved in inflammation and immunity. Accordingly, TNF α has been implicated in a wide range of autoimmune and infectious diseases, but also in conditions such as obesity and insulin resistance. The aim of the present study was to investigate the association between the −863C/A polymorphism in the promoter of the TNFα gene and type 2 diabetes in the Tunisian population.

Methods

The polymorphism −863C/A in the TNFα gene was determined in 211 type 2 diabetes patients and 345 healthy controls using the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) analysis.

Results

A significant difference in genotype distribution and allele frequency was observed between patients and controls. Patients with type 2 diabetes had significantly higher frequency of the CA + AA genotypes compared to controls [35.5% vs. 22.3%; OR (95%CI), 1.91 (1.31–2.8); p = 0.001]. The type 2 diabetes patient group showed a significant higher frequency of the A allele compared to the controls (0.19 vs. 0.11; p = 0.001). After adjustment by a stepwise logistic regression method, hypertension, dyslipidemia, and CA + AA genotype were found to be significantly associated with T2D.

Conclusion

The present study showed a significant and independent association between the −863C/A polymorphism of the TNFα gene and type 2 diabetes in the Tunisian population.     

HLA antigens in Sardinian patients with diabetes mellitus

HLA-B8 and HLA-Bw15, two antigens associated with juvenile diabetes mellitus in Caucasians of North Europe, have a very low frequency in Sardinian population, who nevertheless have a high frequency of diabetes. The association between diabetes and HLA in Sardinian population has therefore been investigated in 60 patients with diabetes, mellitus (32 with juvenile diabetes and 28 with maturity onset diabetes) and 96 normal, unrelated random controls. No disturbance of HLA distributions was found in maturity onset diabetes, but the frequencies of B8 and Bw35 were increased among juvenile diabetics (18.7 percent and 28.1 percent respectively, compared with 2.0 and 11.4 percent in healthy controls). B18 antigen frequency was also increased, although not significantly, in juvenile diabetes mellitus (65.6 percent compared with 50 percent in controls). In contrast the frequency of HLA-Bw15 in two groups of diabetics differed little from that of controls.