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。     

Association of vitamin D receptor gene polymorphisms with bone mineral density in postmenopausal women of Hellenic origin

OBJECTIVES: There are numerous indications that genetic factors play an important role in the pathogenesis of osteoporosis, a common condition characterized by reduced bone mass and increased fracture risk. The vitamin D receptor (VDR) gene has been suggested as a possible candidate gene for the regulation of bone mass but the relationship between VDR polymorphisms and bone mineral density (BMD) is controversial and has not been confirmed by all workers in different ethnic groups studied. METHODS: In order to evaluate the contribution of the VDR alleles in bone mass loss, the BsmI, ApaI and TaqI polymorphisms in the VDR gene were studied in 126 postmenopausal women. RESULTS: It was found that the bb, aa and TT genotypes and the bAT and baT haplotypes were associated with a lower BMD measured at the forearm. CONCLUSIONS: Our analysis reveals a significant association between VDR gene alleles and bone mass in the population studied.     

Linkage disequilibrium between polymorphisms in the human TNFRSF1B gene and their association with bone mass in perimenopausal women

Osteoporosis is a multifactorial disease with a strong genetic component characterized by reduced bone density and increased fracture risk. A candidate locus for regulation of hip bone mineral density (BMD) has been identified on chromosome 1p36 by linkage analysis. One of the positional and functional candidate genes located within this region is the tumour necrosis factor receptor superfamily member 1B (TNFRSF1B). In order to investigate whether allelic variation in TNFRSF1B contributes to regulation of bone mass, we studied several polymorphisms of this gene in a population based cohort study of 1240 perimenopausal women from the UK. We studied a T676G change in exon 6 (196: Met-Arg) and three SNPs (G593A, T598G, and T620C) in the 3'UTR of the gene. The 3'UTR SNPs were in strong linkage disequilibrium (LD) with each other (P<0.00001), and the exon 6 SNP was in LD with G593A and T598G (P<0.00001). We found no association between T676G alleles and BMD at the spine or hip. However, haplotype analysis showed that subjects homozygous for the A593-T598-C620 haplotype (n=85) had femoral neck BMD values 5.7% lower than those who did not carry the haplotype (n=1155; P<0.00008) and this remained significant after correcting for confounding factors and multiple testing (P<0.0009). Regression analysis showed that the ATC haplotype accounted for 1.2% of the population variance in hip BMD and was the second strongest predictor after body weight. In summary, our work supports the view that allelic variation in the 3'UTR of TNFRSF1B gene contributes to the genetic regulation of bone mass, with effects that are specific for femoral neck BMD.     

Vitamin D receptor gene as a candidate gene for Parkinson disease

Vitamin D and vitamin D receptor (VDR) have been postulated as environmental and genetic factors in neurodegeneration disorders including multiple sclerosis (MS), Alzheimer disease (AD), and recently Parkinson disease (PD). Given the sparse data on PD, we conducted a two-stage study to evaluate the genetic effects of VDR in PD. In the discovery stage, 30 tagSNPs in VDR were tested for association with risk as a discrete trait and age-at-onset (AAO) as a quantitative trait in 770 Caucasian PD families. In the validation stage, 18 VDR SNPs were tested in an independent Caucasian cohort (267 cases and 267 controls) constructed from a genome-wide association study (GWAS). In the discovery dataset, SNPs in the 5' end of VDR were associated with both risk and AAO with more significant evidence of association with AAO (P= 0.0008-0.02). These 5' SNPs were also associated with AD in another study. In the validation dataset, SNPs in the 3' end of VDR were associated with AAO (P= 0.003) but not risk. The 3' end SNP has been associated with both MS and AD in previous studies. Our findings suggest VDR as a potential susceptibility gene and support an essential role of vitamin D in PD.     

Association of vitamin D receptor and estrogen receptor gene polymorphisms with bone mass in postmenopausal Korean women

OBJECTIVE: To examine the relationship between vitamin D receptor (VDR) and estrogen receptor (ER) gene polymorphism and bone mineral density (BMD). DESIGN: Polymorphisms at the VDR FokI and ER PvuII and XbaI gene sites, serum bone-specific alkaline phosphatase, urinary N-telopeptide of type I collagen, and BMD at the lumbar spine and proximal femur were analyzed in 229 postmenopausal Korean women. RESULTS: The distribution of ER PvuII and XbaI and VDR FokI restriction fragment length polymorphisms was as follows: pp 39.3%, Pp 46.3%, PP 14.4%, xx 34.1%, Xx 61.1%, XX 4.8%. ff 17.0%, Ff 43.7%, and FF 39.3%, respectively (upper-case letters signify the absence, and lower-case letters signify the presence of the restriction site). After adjusting for potential confounding factors such as age, body mass index, and menopause duration, ER PvuII was independently associated with BMD at the lumbar spine and XbaI polymorphism BMD at the femoral neck. The lumbar spine BMD in the pp genotype was 7.5% lower than in the PP genotype, and the femoral neck BMD was 4.8% lower in the Xx genotype than in the xx genotype. By itself, the VDR FokI polymorphism was not related to BMD, but by combining the FokI genotype (FF) with ER genotypes, such as ppxx and the PpXx, the difference in the BMD at the Ward's triangle became significant. There were no significant differences in the levels of biochemical markers between the genotypes of three polymorphisms. CONCLUSION: ER polymorphisms, singly and in relation to VDR FokI polymorphism, influence bone mass in Korean women.     

Single nucleotide polymorphism screening and association analysis – exclusion of integrin β7 and vitamin D receptor (chromosome 12q) as candidate genes for asthma

BACKGROUND: The human genes coding for integrin beta 7 (ITGB7) and vitamin D receptor (VDR) are two of the several candidate genes for asthma and related phenotypes found in a promising candidate region on chromosome 12q that has been identified in multiple genomewide screens and candidate gene approaches. METHODS: All exons, including parts of the neighbouring introns, and the predicted promoter region of the ITGB7 gene were screened for common polymorphisms in 32 independent asthmatic and healthy probands, resulting in the detection of two single nucleotide polymorphisms (SNPs) unknown so far. In addition to these SNPs, five already described SNPs of the ITGB7 and one in the human VDR gene were analysed in a Caucasian sib pair study of 176 families with at least two affected children, using matrix assisted laser desorption/ionization time of flight mass spectrometry. All confirmed SNPs were tested for linkage/association with asthma and related traits (total serum IgE level, eosinophil cell count and slope of the dose-response curve after bronchial challenge). RESULTS: Two new variations in the ITGB7 gene were identified. The coding SNP in exon 4 causes a substitution of the amino acid GLU by VAL, whereas the other variation is non-coding (intron 3). None of the eight analysed SNPs, of either the ITGB7 or the VDR genes, showed significant linkage/association with asthma or related phenotypes in the family study. CONCLUSIONS: These findings indicate that neither the human ITGB7 nor the VDR gene seem to be associated with the pathogenesis of asthma or the expression of related allergic phenotypes such as eosinophilia and changes in total IgE level.     

Confirmation of an association between single nucleotide polymorphisms in the VDR gene with respiratory syncytial virus related disease in South African children

Respiratory syncytial virus is a leading cause of lower respiratory tract infection in infants. Disease severity has been linked to host immune responses and polymorphisms in genes associated with innate immunity. A large‐scale genetics study of single nucleotide polymorphisms (SNPs) in children in the Netherlands identified SNPs in the vitamin D receptor (VDR) and JUN genes which have a strong association with an increased risk of developing bronchiolitis following the first respiratory syncytial virus (RSV) infection. The Toll‐like receptor 4 (TLR4) gene has two SNPs which have been associated previously with RSV disease severity in various populations. The aim of this study was to determine if these SNPs may be associated with RSV disease in African children in South Africa. RSV patient (n = 296) and control (n = 113) groups were established (median ages: 3 and 3.5 months) and DNA extracted from the collected specimens. Real‐time polymerase chain reaction using hydrolysis probes was used to screen for SNPs in the VDR (Thr1Meth; rs10735810), TLR4 (Asp299Gly; rs4986790 and Thr399Ile; rs4986791) and JUN (c.750G/A; rs11688) genes. Carriers of the VDR (Thr1Meth) SNP minor T allele were more prone to RSV disease than individuals in the control group. The TLR4 (Asp299Gly), TLR4 (Thr399Ile), and JUN (c.750G/A) SNPs showed no significant association with RSV disease. It is concluded that children carrying the minor T allele of the VDR (Thr1Meth) SNP may be predisposed to RSV disease, as this SNP was identified as a risk factor for severe RSV disease in South African children, confirming the findings in the Netherlands. J. Med. Virol. 83:1834–1840, 2011. © 2011 Wiley‐Liss, Inc.     

Association of vitamin D receptor genotypes with early onset rheumatoid arthritis.

The presence of certain vitamin D receptor (VDR) genotypes has been associated with low bone mineral density (BMD) in elderly populations as well as with accelerated bone loss in patients with rheumatoid arthritis (RA). In the present study, VDR genotypes from 120 Spanish patients with RA were investigated. Three VDR gene polymorphisms (BsmI, ApaI and TaqI) were investigated using polymerase chain reaction followed by enzymatic digestion. The distributions of VDR allelic frequencies were similar in patients and controls and therefore no influence of VDR polymorphisms on rheumatoid arthritis susceptibility could be demonstrated. However, in an analysis of the clinical features of the different VDR-related genetic subgroups, the BB/tt genotype, defined by the BsmI and TaqI restriction site polymorphisms, was identified to be weakly associated with an early onset RA in female patients. This VDR genotype has been associated with a low BMD level in various studies. When patients were stratified according to the presence of the shared HLA epitope SE, it was found that SE + female patients bearing the BB/tt genotype showed the earliest disease onset. The mechanisms by which the VDR polymorphism is associated with RA is unknown, but they could be related to the immunoregulatory properties of vitamin D.     

Genetic background of osteoporosis

Osteoporosis is a systemic disorder of decreased skeletal mass as measured by bone mineral density (BMD), and disturbed skeletal architecture and function which results in an increased risk for bone fractures with consecutively increased morbidity and mortality. Twin and family studies have shown an important genetic component of BMD of about 40-60%. This exceeds other well known factors influencing BMD such as environmental factors like dietary calcium, physical activity or several drugs and diseases. Therefore, interest increased in the genetic background of bone mineral density. Polymorphisms of the Vitamin D receptor gene were the first to be published in this area. Studies on other loci or candidate genes such as the estrogen receptor gene or the collagen type I alpha1 gene also showed associations with bone mineral density that could explain at least a part of the genetic background of osteoporosis. Recently published data suggest that these genetic markers of bone metabolism are important in interaction with each other or in certain bone-affecting diseases. In the future, genetic studies on osteoporosis will have to screen further relevant genes and markers for bone metabolism as well as to evaluate the complex interactions of genetic influences, so that it would be possible to calculate a patient's individual risk for osteoporosis in the context of environmental influences.     

Maternal vitamin D receptor genetic variation contributes to infant birthweight among black mothers

Racial disparity in pregnancy outcomes is one of the most striking and poorly understood inequalities in American health. Genetic variability may be an important host factor influencing disparate birth outcomes between non-Hispanic black (NHB) and non-Hispanic white (NHW) women. Race-specific allelic frequencies in the vitamin D receptor (VDR) gene suggest its potential as a gene involved in health disparities. The Healthy Pregnancy, Healthy Baby Study is a prospective cohort of pregnant women aimed at identifying genetic, social, and environmental contributors to disparities in pregnancy outcomes in Durham, NC. VDR haplotype tagging single nucleotide polymorphisms (SNPs) were genotyped via Taqman assays for 615 women. Analysis of variance was used to examine the association between maternal genotype and infant birthweight. Eight of 38 SNPs examined showed nominal significance among NHB women, with one VDR SNP (rs7975232) surpassing the multiple testing significance threshold. rs7975232, an anonymous polymorphism, is part of a VDR gene haplotype associated with variation in mRNA stability. mRNA stability can affect the amount of protein produced, thus directly affecting vitamin D levels and calcium homeostasis. In contrast to NHBs, there was no association between any VDR SNP and birthweight for NHWs. Genetic factors contributing to disparities in birth outcomes are not expected to be explained entirely by variation in a single gene. Nevertheless, our results suggest that maternal VDR gene polymorphisms do influence birthweight with differential effects accruing across racial groups. Further research identifying the functionality of VDR gene polymorphisms in pregnant women will improve our understanding of the underlying mechanisms influencing birthweight.     

Epistatic Interactions between Genomic Regions Containing the COL1A1 Gene and Genes Regulating Osteoclast Differentiation may Influence Femoral Neck Bone Mineral Density

Bone mineral density (BMD) is a primary risk indicator of osteoporotic fractures, which are largely determined by the actions of multiple genes. Genetic linkage studies have seldom explored epistatic interaction of genes for BMD. To evaluate potential genetic interactions for BMD at the femoral neck (FN) we conducted a variance component linkage analysis, to test epistatic effects between the genomic region containing the COL1A1 (collagen type I alpha 1) gene and the genomic regions containing genes regulating osteoclast differentiation (e.g. TNFRSF11A encoding RANK (receptor for activation of nuclear factor kappa B), TNFSF11 encoding RANKL (RANK ligand), IL1A (interleukin-1 alpha), IL6 (interleukin-6), etc) in 3998 Caucasian subjects from 434 pedigrees. We detected significant epistatic interactions between the regions containing COL1A1 with IL6 (p = 0.004) and TNFRSF1B encoding TNFR2 (tumor necrosis factor receptor 2) (p = 0.003), respectively. In summary, we identified the epistatic effects on BMD between regions containing several prominent candidate genes. Our results suggested that the IL6 and TNFRSF1B genes may regulate FN BMD variation through interactions with the COL1A1 gene, which should be substantiated by other, or population-based, association studies.     

维生素D受体基因起始密码和3‘端多态性与绝经后妇女骨密度的关系

目的：了解维生系D受体（vitamin d receptor,VDR)基因起始密码多态性和3'端多态性对北京地区汉族绝经后妇女骨密度（bone mineral density,BMD)值的影响是否具有协同作用。方法：应用聚合酶链反应－限制性片段长度多态性检测了110绝经后妇女VDR基因Fok 1和3'端多态性，同时用双能X线吸收法测定绝经后妇女腰椎2－4（L2－4）、股骨颈、Ward's三角和大转子区的BMD值。结果：被研究人群Fok I、Apa I、Bsm I和Taq I等位频率分布均符合Hardy-Weinberg定律。单独分析各基因型与绝经后妇女BMD值的关系，仅显示Bsm I基因型与BMD值有关联（P＜0．05）；协同分析Fok I基因型和Apa I、Bsm I、Taq I基因型与BMD值的关系，显示Fok I-Apa I基因型与绝经后妇女L2－4 BMD值显著相关（P＜0．001），而未见Fok I-Bsm I基因型与绝经后妇女各部位BMD值的关联，Fok I-Taq I基因型与股骨颈和大转子区部位BMD值有关联（P＜0．05）。此外，未发现VDR基因3'端多态性之间与各部位的BMD值有关联。结论：VDR基因Fok I多态性虽然与绝经后妇女BMD值无关联，但Fok I多态性和3'端多态性（Apa I和Taq I）对绝经后妇女BMD值的影响具有协同作用。     

Association of estrogen and vitamin D receptor gene polymorphisms with tooth loss and oral bone loss in Japanese postmenopausal women

OBJECTIVE: To investigate the relationship between estrogen receptor (ER) and vitamin D receptor (VDR) gene polymorphisms and tooth loss, oral bone loss, and postcranial bone mineral density (BMD) in Japanese postmenopausal women. DESIGN: Polymorphisms at the ER PvuII and XbaI and VDR BsmI gene sites, number of teeth remaining, oral bone mass, and BMD of the lumbar spine and the hip were evaluated in 149 Japanese postmenopausal women. RESULTS: The distribution of ER PvuII and XbaI and VDR BsmI restriction fragment length polymorphisms was as follows: pp, 30.2%; Pp, 49.7%; PP, 20.1%; xx, 71.8%; Xx, 22.5%; XX, 2.7%; bb, 76.5%; Bb, 22.2%; and BB, 1.3%. Analysis of covariance adjusted for confounding variables revealed that participants with pp allele had fewer teeth remaining than did those with P allele. There were no significant differences in oral bone mass and postcranial BMD among three alleles at the PvuII site. Participants with X and bb allele had less oral bone mass and lower postcranial BMD than did those with xx and B allele, respectively. We could not clarify the positive associations between XbaI and BsmI polymorphism and number of teeth. CONCLUSIONS: PvuII polymorphism was associated with tooth loss, but not with oral bone mass and postcranial BMD. XbaI and BsmI polymorphisms may be associated with bone mass or density; however, PvuII polymorphism might contribute to another unknown pathway related to tooth loss.     

Association of vitamin D receptor genotypes with early onset rheumatoid arthritis

The presence of certain vitamin D receptor (VDR) genotypes has been associated with low bone mineral density (BMD) in elderly populations as well as with accelerated bone loss in patients with rheumatoid arthritis (RA). In the present study, VDR genotypes from 120 Spanish patients with RA were investigated. Three VDR gene polymorphisms (BsmI, ApaI and TaqI) were investigated using polymerase chain reaction followed by enzymatic digestion. The distributions of VDR allelic frequencies were similar in patients and controls and therefore no influence of VDR polymorphisms on rheumatoid arthritis susceptibility could be demonstrated. However, in an analysis of the clinical features of the different VDR‐related genetic subgroups, the BB/tt genotype, defined by the BsmI and TaqI restriction site polymorphisms, was identified to be weakly associated with an early onset RA in female patients. This VDR genotype has been associated with a low BMD level in various studies. When patients were stratified according to the presence of the shared HLA epitope SE, it was found that SE + female patients bearing the BB/tt genotype showed the earliest disease onset. The mechanisms by which the VDR polymorphism is associated with RA is unknown, but they could be related to the immunoregulatory properties of vitamin D.     

DC-SIGN (CD209), pentraxin 3 and vitamin D receptor gene variants associate with pulmonary tuberculosis risk in West Africans

We investigated the role of DC-SIGN (CD209), long pentraxin 3 (PTX3) and vitamin D receptor (VDR) gene single nucleotide polymorphisms (SNPs) in susceptibility to pulmonary tuberculosis (TB) in 321 TB cases and 347 healthy controls from Guinea-Bissau. Five additional, functionally relevant SNPs within toll-like receptors (TLRs) 2, 4 and 9 were typed but found, when polymorphic, not to affect host vulnerability to pulmonary TB. We did not replicate an association between SNPs in the DC-SIGN promoter and TB. However, we found that two polymorphisms, one in DC-SIGN and one in VDR, were associated in a nonadditive model with disease risk when analyzed in combination with ethnicity (P=0.03 for DC-SIGN and P=0.003 for VDR). In addition, PTX3 haplotype frequencies significantly differed in cases compared to controls and a protective effect was found in association with a specific haplotype (OR 0.78, 95% CI 0.63-0.98). Our findings support previous data showing that VDR SNPs modulate the risk for TB in West Africans and suggest that variation within DC-SIGN and PTX3 also affect the disease outcome.     

Bone mineral density-affecting genes in Africans

BACKGROUND: We have recently reported the role of environmental exposure in the ethnic diversity of bone mineral density (BMD). Potential genetic difference has not been adequately assessed. PURPOSE: To determine allele frequencies of BMD-affecting genes and their association with BMD in Africans. METHODS: Allele frequencies at 18 polymorphic sites in 13 genes that affect BMD in Asians and/or Caucasians were determined in 143 recent immigrants (55 men and 88 women, 18-51 years of age) from sub-Saharan Sudan to the United States. Genetic association studies were performed. RESULTS: Among the 14 single-nucleotide polymorphisms (SNPs), 10 were significantly different in allele frequency between Sudanese and Asians, and 10 between Sudanese and Caucasians. Only the osteocalcin gene was not significantly different in allele frequency among Sudanese, Asians and Caucasians. Allele frequencies in the TGFB, COL1A1 and CSR genes were extremely low (<0.04) in the Sudanese. Frequencies of microsatellite alleles in four genes were significantly different among Sudanese, Asians and Caucasians. SNPs in the VDR and ERalpha genes were associated with BMD and/or BMC (bone mineral content) at several bone sites. CONCLUSIONS: Genetic difference may play a role in the ethnic diversity in BMD and/or BMC.     

Lack of association of vitamin D receptor gene polymorphisms with susceptibility to type 1 diabetes mellitus in the Portuguese population

The vitamin D receptor (VDR) gene is a candidate gene for susceptibility to autoimmune disorders. Association studies of VDR polymorphisms and risk of type 1 diabetes often produced conflicting results in different ethnic backgrounds. The aim of this study was to test for association between common VDR polymorphisms and the genetic susceptibility to type 1 diabetes in the Portuguese population. We genotyped 207 patients with type 1 diabetes and 249 controls for the FokI T>C (rs10735810), BsmI A>G (rs1544410), ApaI G>T (rs7975232), and TaqI C>T (rs731236) single nucleotide polymorphisms by polymerase chain reaction and restriction fragment length polymorphism analysis. The distribution of VDR genotype, allele, and haplotype frequencies did not differ significantly between patients and controls. These data suggest that the single nucleotide polymorphisms of the VDR gene are unlikely to contribute significantly to type 1 diabetes susceptibility in the Portuguese population.     

The vitamin D receptor FokI start codon polymorphism and bone mineral density in osteoporotic postmenopausal French women

This study examined the association between bone mineral density (BMD) and a T/C polymorphism in the first of the two initiation codons in the vitamin D receptor (VDR) gene. The polymorphism was detected using the restriction enzyme FokI, the F allele indicating absence of the first codon and the f allele its presence. The FokI genotype was determined in 124 postmenopausal osteoporotic French women who were 45-90 years old. The distribution of FokI genotypes in the osteoporotics did not differ significantly from that found in a control group. There were no significant differences by FokI genotype groups in our total sample of osteoporotic women for age, years since menopause, height, weight, and BMD at lumbar spine and femoral neck. However, when only those patients under the age of 75 years are analysed (98 subjects), those with the ff genotype (10% of the population) had a significantly lower BMD at the femoral neck than FF and Ff subjects. This suggests that the ff genotype of the VDR gene correlates with decreased BMD at the femoral neck in French postmenopausal women.