Vitamin D receptor (VDR) gene polymorphisms and age onset in type 1 diabetes mellitus

Abstract

Vitamin D receptor is a mediator of immune responses through the action of vitamin D, which is capable of regulate the insulin secretion by the pancreas. Since polymorphisms in the vitamin D receptor (VDR) gene might modulate vitamin D function, and thus immunologic response, VDR is possibly able to influence the predisposition to type 1 diabetes mellitus (T1DM). The aim of this work was to perform an association study among VDR polymorphisms and T1DM susceptibility, as well as the correlation with the disease onset. Two hundred and four T1DM patients and 217 controls, from Northeast Brazil, were genotyped for five tagSNPs, covering the whole VDR gene. Our results indicated an association between rs1540339 and rs4760648 SNPs (p?=?0.02 and p?=?0.03, respectively) and T1DM. No association was found with T1DM onset and age at diagnose. To our knowledge, this is the first association study in T1DM where the whole VDR gene was analyzed, and our results indicate that VDR polymorphisms could be important for T1DM susceptibility, but do not seem to be associated to age at disease onset.     

CTLA-4 promoter polymorphisms are associated with latent autoimmune diabetes in adults

The cytotoxic T lymphocyte antigen-4 (CTLA-4) molecule is an important regulator of T-cell activation and a susceptibility candidate for autoimmune diseases. To evaluate the impact of CTLA-4 promoter allelic variants of the CTLA-4 gene in latent autoimmune diabetes in adults (LADA), the MH30 (rs231806), -1147 (rs16840252), and -318 (rs5742909) single nucleotide polymorphisms (SNPs) were studied in a population of Estonian origin, including 61 LADA patients and 230 controls. The MH30 GG genotype (p = 0.0051) and the G allele (p = 0.0023) were significantly associated with LADA. The frequency distribution of alleles and genotypes of rs16840252 and rs5742909 SNPs were not significantly different between the patient and control groups. The frequency of the CTLA-4 GCC (p = 0.000073) haplotype was significantly higher in LADA patients, whereas the frequency of the CTLA-4 CCC (p = 0.0019) was significantly lower in LADA patients in comparison with the control group. The current study confirms the involvement of CTLA-4 gene promoter polymorphisms in the susceptibility of LADA and extends our previous findings of associations with other CTLA-4 polymorphisms.     

Association of MYO9B haplotype with type 1 diabetes

MYO9B (myosin IXB) polymorphisms were associated with celiac disease and ulcerative colitis susceptibility, presumably through alteration of the intestinal permeability. Recently this gene was also associated with several diseases with an autoimmune component, such as rheumatoid arthritis and systemic lupus erythematosus. We aimed to test, for the first time, the potential role of MYO9B polymorphisms in type 1 diabetes (T1D), an autoimmune condition preceded by changes in intestinal barrier integrity. Three previously associated MYO9B polymorphisms (rs962917, rs2279003, and rs2305764) were studied in 316 T1D patients and 706 ethnically matched controls. Minor alleles of those polymorphisms were more frequent in diabetic patients than in controls and the haplotype carrying major alleles in those positions, rs962917*G/rs2279003*C/rs2305764*G, significantly reduced the risk of T1D in the Spanish population (p = 0.004; OR [95% confidence interval] = 0.68 [0.52-0.90]). Our data suggest an involvement of this MYO9B chromosomal region in T1D predisposition, indicating extensive influence on autoimmune diseases.     

KCNQl基因多态性与2型糖尿病易感性相关研究

目的探讨KCNQ1基因单核苷酸多态性（SNPs）与2型糖尿病易感性的关系。方法应用基质辅助激光解吸附电离飞行时间质谱（MALDFFOF—Ms）平台以及MassARRARY—iPLEX技术,分别对238例2型糖尿病患者和240例正常对照组KCNQl基因的三个单核苷酸多态性位点（rs231361、rs231359和rs2237892）进行基因分型,并分析KCNQI基因位点在两组间的差异。结果rs2237892存在CC、TC、TT三种基因型多态性,在对照组中的基因型频率分别为45．5％、40．7％、13．8％,在病例组中的基因型频率分别为44．4％、49．6％、6．0％,该位点在对照组和病例组中分布差异有统计学意义（x2=9．334,P=0．009）。相较于cc基因型,TT基因型其OR（95％CI）分别为0．416（0．206-0．840）（P=0．014）。位点rs231361和rs231359均存在三种多态性,但在病例组和对照组间差异无统计学意义。结论KCNQ1基因位点rs2237892与2型糖尿病易感性相关,位点rs231361和rs231359与2型糖尿病易感性不相关。     

Heterogeneity of vitamin D receptor gene association with celiac disease and type 1 diabetes mellitus

OBJECTIVE: Vitamin D has been shown to exert multiple immunomodulatory effects and is known to suppress T-cell activation by binding to the vitamin D receptor (VDR). To determine whether VDR gene polymorphisms are related to the susceptibility to celiac disease, we investigated its implication as a candidate gene in the Basque population. Because celiac disease and type 1 diabetes share common susceptibility loci, we also analyzed families with type 1 diabetes mellitus. METHODS: A total of 37 families with celiac disease and 64 type 1 diabetic families of Basque origin with at least one affected offspring were genotyped for four VDR restriction-site polymorphisms (Fok I, Bsm I, Apa I and Taq I). The AFBAC approach was used to test for association. RESULTS: Comparison of VDR genotypes of the patients with those of 88 healthy individuals identified "ff" as a risk genotype for celiac disease [p = 0.01; OR = 3.45 (1.12-10.79)]. On the other hand, a significantly higher frequency of haplotype "fBAt" was observed in the type 1 diabetic group [p(c) = 0.02; OR = 4.4 (1.5-15.3)]. CONCLUSION: Our findings suggest that polymorphisms within the vitamin D receptor gene are markers of susceptibility to or protection from autoimmune diseases, although, at least in the Basque population, association of VDR variants with celiac disease and type 1 diabetes seems to be heterogeneous.     

Vitamin D receptor gene polymorphism and its association with Parkinson's disease in Chinese Han population

Vitamin D plays an important role in neurodegenerative disorders as a crucial neuro-immunomodulator, and accumulating data have provided evidence for that vitamin D receptor (VDR) gene is a candidate gene for susceptibility to Parkinson's disease (PD). In this study, we performed a case-control study to demonstrate whether the risk for the development of onset of sporadic PD might be influenced by VDR gene polymorphisms in a Chinese cohort. Two hundred and sixty PD patients and 282 matched-healthy controls were genotyped for two representative single nucleotide polymorphisms (SNPs) in VDR gene (FokI C/T and BsmI G/A) by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) analysis in. Results from our study revealed that FokI C allele carriers were likely to associate with an increased risk of PD (P = 0.004) as well as early-onset PD (EOPD) (P = 0.010). Moreover, the frequency of FokI C allele was significantly increased in PD group and late-onset PD (LOPD) group relative to the control groups respectively (P = 0.023 and P = 0.033, respectively). For BsmI polymorphisms, no significant difference in genotype or allele distribution was found between PD patients and the controls, as well as gender- and age-related differences between PD patients and the controls subgroup. This study demonstrated a possible association between the VDR FokI T/C polymorphism and PD, indicating that VDR polymorphisms may well change genetic susceptibility to sporadic PD in a Han Chinese population.     

The CTLA4 +49 A/G polymorphism is not associated with susceptibility to type 1 diabetes mellitus in the Portuguese population

CTLA4 genetic polymorphisms have been associated with type 1 diabetes. We genotyped 207 patients and 249 controls for the most frequently investigated polymorphism of the CTLA4 gene (+49A/G (rs231775)). No significant differences were observed, suggesting that this polymorphism is not strongly associated with type 1 diabetes in the Portuguese population.     

CDKAL1基因rs7754860位点G<C多态性与2型糖尿病易感关系的Meta分析*◆

背景：遗传学研究显示2型糖尿病可能存在遗传易感性,但研究结论存在一定的差异。 目的：探讨CDKAL1(细胞周期素依赖激酶5调节亚单位相关蛋白1类似物1)基因rs7754860位点G相似文献   

Association of the proprotein convertase subtilisin/kexin-type 2 (PCSK2) gene with type 2 diabetes in an African American population

In a genome-wide scan for type 2 diabetes (T2DM) in African American (AA) families, ordered subsets analysis (OSA) provided evidence for linkage to chromosome 20p in a subset with later age at diagnosis (max LOD 2.57, P=0.008). The proprotein convertase subtilisin/kexin-type 2 (PCSK2) gene is within the LOD-1 interval of this linkage peak. Twenty-nine single nucleotide polymorphisms (SNPs) were genotyped across this gene in 380 unrelated AA individuals with T2DM and end-stage renal disease (T2DM-ESRD), 278 AA controls, 96 European Americans (EA) and 120 Yoruba Nigerian (YRI) controls. In addition, 22 ancestry-informative markers (AIMs) were genotyped in all AA subjects, 120 YRI, and 282 EA controls. ADMIXMAP was used to model the distributions of admixture and generate score tests of allelic and haplotypic association. Association with T2DM was observed among 4 SNPs: rs2021785 (admixture-adjusted Pa=0.00014), rs1609659 (Pa=0.028), rs4814597 (Pa=0.039) and rs2269023 (Pa=0.043). None of the PCSK2 SNPs were associated with age at T2DM diagnosis. A variant in the PCKS2 gene, rs2021785, appears to play a role in susceptibility to T2DM in this AA population.     

Allelic variants in the PHTF1-PTPN22, C12orf30 and CD226 regions as candidate susceptibility factors for the type 1 diabetes in the Estonian population

Background  

Type 1 diabetes is a multifactorial disease with a strong genetic component. The aim of the study was to assess the impact of single nucleotide polymorphisms (SNPs) in several genes as susceptible markers in the risk of type 1 diabetes in the Estonian population. Methods: The rs6679677 (1p13), rs17696736 (12q24) and rs763361 (18q22) were genotyped in a total of 230 controls and 154 type 1 diabetes patients of Estonian origin.     

Genetic polymorphisms of G protein-coupled receptor 65 gene are associated with ankylosing spondylitis in a Chinese Han population: A case-control study

ObjectiveThis study aimed to assess the association between two tag single nucleotide polymorphisms (SNPs) (rs68177277 and rs11624293) of G protein-coupled receptor 65 (GPR65) gene and ankylosing spondylitis (AS) susceptibility in a Chinese Han population.Methods673 patients with AS diagnosed according to the modified New York criteria and 679 age- and gender-matched healthy controls were recruited. SNP genotyping for rs68177277 and rs11624293 polymorphisms were performed using the SNPscan technique. Disease activity was assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI).ResultsGenotype and allele distribution of rs11624293 but not rs68177277 were significantly different between AS and controls (p = 0.004 and p = 0.002). Compared to the wild-type T/T genotype and T allele at rs11624293, the frequencies of C/T genotype and C allele were significantly higher in AS than controls after adjusting for age and gender (OR = 1.527, 95%CIs: 1.190–1.958; OR = 1.515, 95%CIs: 1.183–1.942, respectively). Dominant and co-dominant model of rs11624293 were predictive of AS susceptibility. In AS patients, the genotype of rs11624293 was significantly associated with BASFI scores in those with low disease activity (BASDAI < 4, p = 0.007).ConclusionsThe results of our study suggest that rs11624293 polymorphism of GPR65 gene is associated with the susceptibility and severity of AS in Chinese Han population.     

Polymorphisms of the TNFAIP3 region and Graves' disease

Abstract

Autoimmune thyroid disease (AITD) is a multifactorial organ-specific autoimmune disorder, and both genetic susceptibility and environmental factors are involved in its etiology. TNFAIP3 encodes the ubiquitin-modifying enzyme (A20), a key regulator of inflammatory signaling pathways. The aim of the present study was to evaluate the association between TNFAIP3 gene polymorphisms and AITD in Chinese Han population. Three single nucleotide polymorphisms (SNPs) in TNFAIP3 gene locus (rs598493, rs610604 and rs661561) were detected in a set of 667 patients with AITD and 301 controls in Han Chinese population using the Matrix Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometer (MALDI-TOF-MS) Platform. Compared with those of the controls, the frequencies of GG genotype of rs598493, the AA genotype of rs610604, the allele G and GG genotype of rs661561 were significantly increased in Graves' disease (GD) patients. However, the frequencies of AG genotype of rs598493 and AC genotype of rs610604 were significantly decreased in GD patients. The ATC haplotype (rs598493, rs661561 and rs610604) was associated with a decreased risk of GD. No significant differences in the three SNPs were observed between HT patients and controls. Our study shows a clear association between the polymorphisms of TNFAIP3 gene and GD, not HT, suggesting that TNFAIP3 gene is likely to be a genetic susceptibility factor to GD.     

Sequenom质谱法分析细胞毒性T淋巴细胞相关分子4基因多态性与宫颈癌易感性的关系

目的 探索细胞毒性T淋巴细胞相关分子4(cytotoxic T-lymphocyte-associated protein 4,CTLA4)基因单核苷酸多态性(single nucleotide polymorphism,SNPs)与宫颈癌易感性的关系.方法 应用sequenom MassARRAY时间飞行质谱系统对100例宫颈癌及100名健康对照者 CTLA4基因20个多态位点(CTLA4_1～CTLA4_20)进行基因型分型,统计分析基因型频率和肿瘤易感性的关系.结果 与正常人群中最常见的 CTLA4基因单倍型-1576A、-318C和1402G相比,带有单倍型-1576G、-318T或1402A的个体均显著增加宫颈癌的风险(P<0.05),相对风险度的比值比及其95%可信区间分别为2.87(1.75～4.76),4.02(1.72～9.09)和4.51(1.46～13.88),而其余基因型与宫颈癌发病风险没有显著的相关性;其中rs5742909易感位点与先前的报道相一致.而双荧光素酶报告基因实验进一步证明,位于基因启动子区域的rs11571316多态位点能显著影响报告基因的表达活性.结论 CTLA4基因启动子区域的SNP可能通过影响 CTLA4基因的表达水平来影响个体对宫颈癌的易感性.

Abstract：

Objective To evaluate the association between single nucleotide polymorphisms (SNPs) of cytotoxic T-lymphocyte-associated protein 4 (CTLA4) gene and susceptibility to cervical cancer. Methods One hundred patients and 100 healthy controls from Hubei province were genotyped for 20 polymorphic loci using Sequenom. Results The frequency of rs11571316 G allele and rs5742909 T allele, which are localized in the promoter region, and rs11571319 A allele, which is downstream of the gene, were significantly higher in patients than in controls. Luciferase assay showed that, as the previously reported rs5742909 T allele, rs11571316 G allele could significantly increase the expression of the reporter gene. Conclusion SNPs in the promoter region of CTLA4 gene might increase the susceptibility to cervical cancer by increasing CTLA4 gene expression.     

Multiple sclerosis association study with the TENR-IL2-IL21 region in a Spanish population

Polymorphisms from the TENR-IL2-IL21 block in the 4q27 chromosome were recently associated with type 1 diabetes, celiac disease, rheumatoid arthritis and psoriasis. We undertook this study to investigate the potential role of polymorphisms rs3136534, rs6822844 and rs2069762 (−330 T/G IL2 ) in multiple sclerosis (MS) (805 patients of Spanish Caucasian origin and 952 health controls). We did not find evidence for association with any single nucleotide polymorphisms (SNPs) tested. Allele and genotype frequencies of the SNPs, which were studied, were similar in DRB1*15 -positive or DRB1*15 -negative patients. After stratification of MS patients by clinical course, a weak association was observed with rs2069762 G allele and haplotype bearing this allele with secondary progressive MS, although these cases represent 22% of the MS cases. Our results did not show major influence of TENR-IL2-IL21 locus on susceptibility or disease progression in MS. However, we could not exclude completely the effect in MS for this region. Additional studies, using much larger sample sizes and analysis of additional polymorphisms in the gene and its flanking region, will be required to ascertain their contributions to MS susceptibility.     

西北地区人群JAG2基因多态性与非综合征性唇腭裂的相关性研究

目的探讨JAG2基因多态性与西北地区人群非综合征性唇腭裂(nonsyndromic cleft lip with or without cleft palate,NSCLP)的相关性。方法采用病例-对照研究方法,选取NSCLP患者301例,正常对照304人,采用iMLDR™基因分型技术对JAG2基因的3个单核苷酸多态性(single nucleotide polymorphism,SNP)位点[rs741859(T/C)、rs11621316(A/G)以及rs1057744(C/T)]进行分型,比较其等位基因、基因型及所构建的单倍型在两组人群中的分布差异。结果rs741859位点等位基因C和T在NSCLP组和对照组中的分布差异有统计学意义。rs741859位点CT基因型可将NSCLP的患病风险显著降低至65%(P<0.05),将唇裂伴或不伴腭裂(cleft lip with or without cleft palate,CL/P)的患病风险降低至62%(P<0.05);而rs11621316、rs1057744处于同一连锁不平衡(linkage disequilibrium,LD)区域,连锁程度较高(r2>0.8),其基因型、等位基因在两组中的分布差异无统计学意义(P>0.05)。结论JAG2基因rs741859位点CT基因型可能是中国西北人群NSCLP的保护性基因型。     

Polymorphic variants of the IL2RA gene and susceptibility to type 1 diabetes in the Polish population

Polymorphic variants of the IL2RA gene, which encodes high-affinity alpha subunit (CD25) of the interleukin-2 receptor, were recently found to affect the risk of several autoimmune disorders. This study was aimed to investigate the association of selected IL2RA polymorphisms (rs11594656, rs3118470, rs2104286 and rs7093069) with type 1 diabetes (T1D) in a Polish cohort comprising 445 patients and 671 healthy control subjects. The minor A allele at rs11594656 was found significantly less frequently among T1D subjects, compared with the control group [P = 0.011; odds ratio (OR) = 0.77; 95% confidence interval (CI) = 0.629-0.942]. In contrast, the minor C allele at rs3118470 appeared to be significantly associated with the occurrence of T1D (P = 0.003; OR = 1.30; 95% CI = 1.094-1.550). Two other IL2RA single nucleotide polymorphisms (SNPs) did not show significant differences among investigated groups. In conclusion, the study confirms the association of the IL2RA locus with T1D in the Polish population.     

Association between GOLGB1 tag‐polymorphisms and nonsyndromic cleft palate only in the Brazilian population

Nonsyndromic oral clefts are common congenital birth defects that exhibit variable prevalence around the world, often influenced by population‐dependent genetic predisposition. Few studies have been performed with nonsyndromic cleft palate only (NSCPO), limiting the knowledge of the genetic risk factors related to this type of oral cleft. Genetic variants in golgin subfamily B member 1 (GOLGB1), a gene that is essential for normal murine palatogenesis, were analyzed in this study to establish its potential association with NSCPO risk in the Brazilian population. Five tag‐single nucleotide polymorphisms (SNPs) of GOLGB1 (rs1169, rs7153, rs9968051, rs9819530, and rs6794341), which capture the majority of alleles spanning within gene, were genotyped in a case–control study with 270 patients with NSCPO and 284 unrelated healthy controls. The samples were also genotyped for 40 biallelic polymorphic markers to characterize the genetic ancestry. After adjustment for co‐variants, the GOLGB1 tag‐SNPs and the haplotypes formed by those SNPs were not significantly associated with NSCPO in this Brazilian case–control cohort. Our results suggest that common polymorphisms of GOLGB1 are not associated NSCPO susceptibility in the Brazilian population.     

Association of the Single-Nucleotide Polymorphism and Haplotype of the Complement Receptor 1 Gene with Malaria

PurposeAlthough the polymorphisms of erythrocyte complement receptor type 1 (CR1) in patients with malaria have been extensively studied, a question of whether the polymorphisms of CR1 are associated with severe malaria remains controversial. Furthermore, no study has examined the association of CR1 polymorphisms with malaria in Chinese population. Therefore, we investigated the relationship of CR1 gene polymorphism and malaria in Chinese population.ResultsThere were no significant differences in the genotype, allele and haplotype frequencies of CR1 gene rs2274567 G/A, rs4844600 G/A, and rs2296160 C/T polymorphisms between patients with malaria and controls. Furthermore, there was no association of polymorphisms in the CR1 gene with the severity of malaria in Chinese population.ConclusionThese findings suggest that CR1 gene rs2274567 G/A, rs4844600 G/A, and rs2296160 C/T polymorphisms may not be involved in susceptibility to malaria in Chinese population.