Evidence for association between vitamin D receptor BsmI polymorphism and type 1 diabetes in Japanese

Type 1 diabetes is considered to be T-helper 1 (Th1) type autoimmune disease. Because the vitamin D receptor is expressed on CD4+T cells and is known to affect cytokine responses, several groups have investigated the association between the vitamin D receptor gene BsmI polymorphism and type 1 diabetes. However, this issue is still controversial; therefore, we examined this gene polymorphism in a large number of type 1 diabetic patients as a multi-center collaborative study in Japan. A total of 1,373 subjects, including 774 cases and 599 control subjects of Japanese origin, were studied. The frequency of carriers of the BB genotype in type 1 diabetic patients was significantly higher than that in controls (p<0.01, odds ratio 3.65). Moreover, IFN-gamma production upon anti-CD3 stimulation in the BB genotype group was significantly higher than that in the Bb and bb genotype groups (p<0.05), suggesting that the polyclonal T cell response in BB genotype patients is Th1 dominant. Based upon these results, we propose that it may be worthwhile to focus on subjects with the BB genotype of this gene polymorphism as having high risk for type 1 diabetes.     

Vitamin D receptor BsmI polymorphism and osteoporosis risk in post-menopausal women

Introduction

Many studies have suggested that the vitamin D receptor polymorphism BsmI might be associated with the risk of osteoporosis development in post-menopausal women. However, the results have been inconsistent. The aim of this meta-analysis was to derive a more precise evaluation of the relationship.

Material and methods

Published literature from PubMed, EMBASE and the CNKI database was searched. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of any association.

Results

Ten case-control studies were included with a total of 1,403 osteoporosis cases and 2,144 healthy controls. In the overall analysis, no significant association was found between BsmI polymorphism and osteoporosis risk (BB vs. bb: OR = 0.76, 95% CI = 0.39–1.48; BB vs. Bb: OR = 0.90, 95% CI = 0.71–1.15; dominant model: OR = 1.20, 95% CI = 0.74–1.93; recessive model: OR = 0.83, 95% CI = 0.53–1.30). In the subgroup analysis by ethnicity, the results showed similar result that BsmI polymorphism m had no association with osteoporosis.

Conclusions

Results from the current meta-analysis suggest that vitamin D receptor BsmI polymorphism may not be a risk factor for osteoporosis in post-menopausal women.     

Association of vitamin D receptor gene polymorphism and Parkinson's disease in Koreans

1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3), which is the biologically active form of vitamin D, has anti-inflammatory effects and can prevent experimental Parkinson's disease (PD). 1,25(OH)2D3 exerts most of its actions only after it binds to its specific nuclear receptors. Eighty-five Korean patients with PD and 231 unrelated healthy individuals were evaluated to determine if vitamin D receptor gene (VDRG) BsmI polymorphisms were markers for the susceptibility to PD in Korean patients. Each polymorphism was detected using polymerase chain reaction (PCR)-based restriction analysis. In addition, the relationship between the BsmI polymorphisms and the clinical manifestations of PD was evaluated. Overexpression of the b allele (91.2 vs. 85.7%; p=0.069) and homozygote bb (84.7 vs. 72.7%; p=0.043) was found in the PD patients compared with the controls. These results show for the first time an association between PD and a VDRG polymorphism, which might be involved in the pathogenesis of PD, or in the linkage disequilibrium of the VDRG to another pathogenic gene locus.     

Identification of a novel Tru9 I polymorphism in the human vitamin D receptor gene

We found a novel Tru9 I restriction polymorphism in intron 8 of the vitamin D receptor (VDR) gene in healthy French Caucasians. It corresponds to a substitution of A for G at nucleotide +443 bp from the end of exon 8. The allelic frequency of G and A in 151 unrelated subjects was 0.894 and 0.106, respectively. This polymorphism is located in the reverse primer binding site of primers that have been frequently used in the literature to genotype a BsmI restriction polymorphism. The presence of the Tru9I A allele may result in allele drop-out when the BsmI restriction fragment length polymorphism (RFLP) is genotyped with the original set of primers. This novel Tru9I polymorphism may be useful for analysis of the VDR gene. Received: August 2, 1999 / Accepted: September 21, 1999     

维生素D受体Fok Ⅰ基因多态性对SLE患者维生素D受体表达的影响

目的:检测维生素D受体(VDR)FokⅠ基因多态性与系统性红斑狼疮(SLE)的相关性,以及对SLE患者VDR mRNA表达的影响。方法:应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)分析技术检测VDRFokI基因位点及基因型在271例SLE患者和130例健康人中的分布情况;并应用实时定量聚合酶链反应(RT-PCR)技术检测VDR mRNA在48例SLE患者和38例健康对照组的表达。结果:VDRFokⅠ多态性等位基因F和f频率在SLE组和健康对照组有统计学差异(P=0.001),携带F等位基因个体发生SLE的相对危险度(OR)为1.630(95%CI=1.210-2.196,P=0.001);FF纯合子基因型频率在SLE组也明显高于健康对照组(42.8%vs25.4%,χ2=11.417,P=0.001)。同时,携带F等位基因的SLE患者(FF基因型和Ff基因型患者),浆膜炎发生率(P=0.001)及抗ds-DNA抗体(P=0.001)、抗Sm抗体(P=0.047)和抗组蛋白抗体(P=0.001)阳性率较F等位基因阴性SLE患者(ff基因型患者)明显升高。VDR mRNA在48例SLE患者表达下调,其?Ct值(?Ct值越大,表达量越小)为9.26±2.37,高于健康对照组的7.82±3.05(P=0.026)。而在SLE患者,携带F等位基因患者的VDR mRNA的?Ct值明显高于F等位基因阴性患者(10.54±1.88vs7.15±3.78,P=0.019)。结论:VDRFokⅠ多态性与SLE发病易感性有关,而且携带F等位基因的患者更容易发生浆膜炎和产生抗ds-DNA抗体和抗Sm抗体等自身抗体,此可能与F等位基因下调SLE患者的VDR mRNA表达有关。     

重庆地区绝经妇女骨质疏松症与维生素D受体基因多态性的关系

目的：探讨在重庆市区生活10年以上的汉族绝经妇女骨质疏松症与维生素D受体基因多态性的关系。方法：用聚合酶链反应－限制性片段长度多态性技术检测了40例绝经后患骨质疏松症的妇女和21名同龄绝经后无骨质疏松症的妇女的维生素D受体基因多态性。结果：骨质疏松组维生素D受体基因型bb、Bb、BB频率分别为82．5％、17．5％及0，无骨质疏松组分别为85．71％、14．29％及0，两组差异无显著性（P＞0．05）。结论：就目前调查例数看，重庆地区汉族妇女骨质疏松与BB基因型无明显相关性。     

Raloxifene administration in post-menopausal women with osteoporosis: effect of different BsmI vitamin D receptor genotypes

BACKGROUND: The vitamin D receptor (VDR) gene polymorphism has been considered a factor influencing the effectiveness of the anti-osteoporotic treatments. The aim of this study was to correlate the effectiveness of raloxifene treatment in post-menopausal women with osteoporosis to BsmI VDR genotypes. METHODS: Between January and August 2000, 75 Italian osteoporotic women were enrolled and treated with raloxifene at a dose of 60 mg/day. At entry and after 1 year of treatment, lumbar bone mineral density (BMD), serum osteocalcin (OC) and urinary creatinine-corrected free deoxypyridinoline (DPD) levels were evaluated. DNA was extracted from blood and analysed with restriction endonuclease BsmI for VDR gene. RESULTS: After treatment, a significant increase in lumbar BMD and a significant reduction in serum OC and urinary DPD levels were observed. The percentage of change (mean +/- SD) in lumbar BMD, and in serum OC and urinary DPD levels was significantly different in homozygous bb (1.58 +/- 0.80, -5.15 +/- 2.36 and -7.71 +/- 2.89 for BMD, OC and DPD respectively) in comparison with BB (4.13 +/- 2.26, -13.59 +/- 4.68 and -15.16 +/- 4.65 for BMD, OC and DPD respectively) BsmI VDR genotypes. Heterozygous Bb VDR patients showed an intermediate percentage (mean +/- SD) of BMD, serum OC and urinary DPD change (2.49 +/- 1.54, -8.69 +/- 2.60 and -10.52 +/- 2.56 for BMD, OC and DPD respectively) not significantly different in comparison with homozygous BB and bb. CONCLUSIONS: In post-menopausal women with osteoporosis the effectiveness of raloxifene treatment on bone metabolism seems to be controlled by different BsmI VDR genotypes.     

阿昌族与汉族维生素D受体基因FokⅠ多态性

目的 了解维生素D受体基因多态性在中国不同民族中的分布。方法 应用聚合酶链反应一限制性片段长度多态性分析、基因测序等技术检测68名阿昌族人和92名汉族人的维生素D受体基因Fok Ⅰ多态性，比较两组维生素D受体基因型和等位基因的分布频率。结果在68名阿昌族人中FF基因型占18％、Ff基因型占35％、ff基因型占47％，而在92名汉族人中FF基因型占22％、Ff基因型占52％、ff基因型占26％。两组维生素D受体基因型的分布频率差异有显著性(x^2=7．716，P=0．021)。结论 阿昌族与汉族维生素D受体基因Fok Ⅰ多态性分布频率差异有显著性。     

阿昌族与汉族维生素D受体基因Fok多态性

目的　了解维生素 D受体基因多态性在中国不同民族中的分布。方法　应用聚合酶链反应 -限制性片段长度多态性分析、基因测序等技术检测 6 8名阿昌族人和 92名汉族人的维生素 D受体基因Fok 多态性 ,比较两组维生素 D受体基因型和等位基因的分布频率。结果　在 6 8名阿昌族人中 FF基因型占 18%、Ff基因型占 35 %、ff基因型占 4 7% ,而在 92名汉族人中 FF基因型占 2 2 %、Ff基因型占 5 2 %、ff基因型占 2 6 %。两组维生素 D受体基因型的分布频率差异有显著性 (χ2 =7.716 ,P=0 .0 2 1)。结论　阿昌族与汉族维生素 D受体基因 Fok 多态性分布频率差异有显著性。     

维生素D受体基因多态性与乳腺癌的相关性

目的：研究维生素D受体基因的多态性与乳腺癌的关系。方法：收集86例乳腺癌患者及134名对照,用聚合酶链反应－限制性片段长度多态性方法,在维生素D受体基因的3’端分析了两个限制性酶切位点（ApaI及TaqI）的多态分布。结果：发现TaqI位点等位基因在两个群体间分布的差异有显著性（P＝0．0004）。进一步对基因型进行分析发现,Tt、tt基因型与乳腺癌相关。而ApaI位点两等位基因未发现在两群体中存在差异。对ApaI及TaqI两座位的单体型进行分析,发现tA间存在连锁不平衡。在两群体中分析单体型的分布发现tA在病例中的比例明显高于对照人群,提示tA单体型与乳腺癌相关。两个位点等位基因及单体型与临床指标的分析均未发现阳性结果。结论：维生素D受体基因的多态怀与乳腺癌有关,提示维生素D受体基因与乳腺癌有关。     

BsmI, TaqI, ApaI and FokI polymorphisms in the vitamin D receptor (VDR) gene and the risk of osteoporosis: a meta-analysis

A meta-analysis regarding BsmI, TaqI, ApaI and FokI polymorphisms in the vitamin D receptor (VDR) gene and their associations with osteoporosis in females is reported. The meta-analysis involved 14, seven, seven and three studies for BsmI, TaqI, ApaI and FokI polymorphisms, respectively. The studies were association studies with osteoporotic cases and controls free of osteoporosis that provided the genotype distribution of individual cases and controls. For the BsmI polymorphism, the allele contrast b vs. B showed heterogeneity among studies (p< 0.01, I2> 50%) and the random effects (RE) pooled odds ratio (OR) was non-significant: 0.94 [95% confidence interval (CI) 0.63-1.38]. Caucasians, postmenopausal cases and studies with WHO diagnostic criteria showed no association under any genetic contrast. However, in East Asians, the OR for the dominant model [fixed effects OR=0.14 (95% CI 0.04-0.50) and RE OR=0.16 (95% CI 0.03-0.84)] was significant, indicating prevention. Overall, for the TaqI, ApaI and FokI polymorphisms, the allele contrast showed heterogeneity and the pooled RE ORs were non-significant [OR=1.06 (95% CI 0.71-1.60), OR=0.99 (95% CI 0.72-1.37) and OR=1.17 (95% CI 0.76-1.80), respectively]. The allele contrast for Caucasians, East Asians, postmenopausal cases and studies with WHO diagnostic criteria showed no association for TaqI, ApaI, and FokI. The allele contrast of homozygotes, and the recessive and dominant models the results followed the same pattern as the allele contrast. Therefore, the relationship between the VDR polymorphisms and osteoporosis remains an unresolved issue and other probable genetic-environmental risk factors interacting with the above polymorphisms should be investigated.     

广州地区绝经后妇女维生素D受体基因多态性与骨密度关系的研究

目的：了解广州地区绝经后妇女维生素D受体基因多态性的分布，并进一步研究其与骨密度的关系。 方法：应用聚合酶链反应-限制性片段长度多态性（PCR-RFCP）等生物学技术检测203例绝经后广州地区妇女维生素D受体(VDR)基因型，同时用双能X线骨密度测量仪检测腰椎、股骨颈、瓦氏三角、大转子处骨密度（BMD）。 结果：203例受试对象中，VDR基因型分别为BB型17例（占8.3%）、Bb型60例（占29.6%），bb型126例（占62.1%）， b等位基因频率为76.85%、B等位基因频率为23.05%，基因型分布符合Hardy-Weinberg定律。分析其基因型与骨密度的关系显示：只有bb与Bb、BB基因型在腰椎骨密度存在差异（P<0.05）、Bb与BB的腰椎BMD无差异（P>0.05），其余部位3种基因型骨密度无差异（P>0.05）。 结论： VDR基因型与BMD间存在着一定关联，但尚不能作为预测广州绝经后妇女发生骨质疏松危险性的遗传标志。     

Analysis of Bsm I polymorphism of the vitamin D receptor (VDR) gene in Venezuelan female patients living in the state of Zulia with osteoporosis

Among genes implied on the osteoporosis genetics, the most studied gene worldwide is the receptor gene of D vitamin (VDR), through the characterization of Bsm I polymorphism. The main objective of this research was to analyze the Bsm I polymorphism of the VDR gene in a sample of 133 postmenopausal women distributed in three groups: 54 with osteoporosis, 24 with osteopenia and 55 normal controls for the disease. 28 of the women with osteoporosis presented the BB genotype, which is related in other countries to bone mineral density decrease, 20 had the Bb genotype, and 6 the bb genotype. Of the control group only 11 women presented the BB genotype, 36 showed the heterozygote genotype and 8 the bb genotype. The frequencies of the B and b alleles in the analyzed population were 0.6 and 0.4 respectively. The BB genotype was found in 52% of the group with osteoporosis, and in 20% of the control group, these findings are statistically significant, which suggest an association between the BB genotype and osteoporosis.