Fang, Y.

Vitamin D-binding protein polymorphisms are not associated with development of (multiple) basal cell carcinomas (Letter To Editor)

2010-12-01T00:00:00Z

Vitamin D-binding protein (VDBP) single nucleotide polymorphisms (SNP) may affect skin carcinogenesis. The objective was to test the association between two functional VDBP SNPs and the susceptibility to (multiple) basal cell carcinomas (BCCs). Of the 7983 participants, 5790 (72.5%) and 5823 (72.9%) participants were genotyped for rs7041 and rs4588, respectively, and three haplotypes (Gc1s, Gc2 and Gc1f) were analysed. Two hundred and thirty-three persons developed a BCC of whom 122 (52.4%) developed multiple BCCs during a mean follow-up of 11.6 years. The VDBP genotype was not associated with (multiple) BCC development using Cox proportional hazards and Andersen-Gill analyses, respectively. Stratifying age groups demonstrated that in the youngest age-group, the A/T variant of rs7041 was associated with BCC development [adjusted hazard ratio (HR) = 1.88 (95%CI 1.10-3.20)], while homozygote Gc1s carriers had a significantly lower BCC risk [adjusted HR = 0.53 (95%CI 0.31-0.91)]. In conclusion, the VDBP polymorphisms were not associated with susceptibility to (multiple) BCCs, but age-gene interactions were observed.

Vitamin D receptor: A new risk marker for clinical restenosis after percutaneous coronary intervention (Article)

2010-03-01T00:00:00Z

Objective: Restenosis is the main drawback of percutaneous coronary intervention (PCI). Inherited factors may explain part of the risk of restenosis. Recently, the vitamin D receptor (VDR) has been shown to be involved not only in bone metabolism but also in modulating immune responses and cell proliferation. Since the inflammatory response is implicated in restenosis, VDR-gene variants could therefore contribute to the risk of restenosis. Methods/results: Systematic genotyping for 15 haplotype tagging single-nucleotide polymorphisms (SNPs) of the VDR gene was performed with the high throughput TaqMan allelic discrimination assays in the Genetic Determinants of Restenosis (GENDER) population. A haplotype-based survival analysis revealed an association of haplotypes in blocks 2, 3 and 4 of the VDR-gene with the risk of clinical restenosis (p-values 0.01, 0.04 and 0.02 respectively). After adjustment for clinical risk factors for restenosis, the individual effect of the block 2 AA haplotype (p = 0.011) persisted. Conclusions: The present study indicates that VDR plays a role in restenosis after PCI. Therefore, VDR genotype may be used as risk marker for restenosis and may contribute to individual patient screening prior to PCI in clinical practice.

The winners in China's urban housing reform (Article)

2010-01-01T00:00:00Z

Housing reform in China has proceeded on two tracks: privatization of public housing and development of a new private housing sector. During this period of transition, rents have remained relatively low in the remaining public housing, and purchase prices offered to occupants of public housing have been well below market prices. Although these rents and prices are partly based on known formulas, there is considerable variability in how much people pay for similar apartments. This study uses 2000 Census data to estimate the housing subsidy received by the remaining renters in the public sector and purchasers of public housing, based on private sector prices for housing of comparable quality and size. The paper also analyzes variation in the estimated discount from market prices that these people receive. The findings show that the biggest winners in China's transition from socialist housing allocation are those who were favored in the previous system, based on such factors as residence status, education and occupation.

Vitamin D binding protein genotype and osteoporosis (Article)

2009-08-01T00:00:00Z

Osteoporosis is a bone disease leading to an increased fracture risk. It is considered a complex multifactorial genetic disorder with interaction of environmental and genetic factors. As a candidate gene for osteoporosis, we studied vitamin D binding protein (DBP, or group-specific component, Gc), which binds to and transports vitamin D to target tissues to maintain calcium homeostasis through the vitamin D endocrine system. DBP can also be converted to DBP-macrophage activating factor (DBP-MAF), which mediates bone resorption by directly activating osteoclasts. We summarized the genetic linkage structure of the DBP gene. We genotyped two single-nucleotide polymorphisms (SNPs, rs7041 = Glu416Asp and rs4588 = Thr420Lys) in 6,181 elderly Caucasians and investigated interactions of the DBP genotype with vitamin D receptor (VDR) genotype and dietary calcium intake in relation to fracture risk. Haplotypes of the DBP SNPs correspond to protein variations referred to as Gc1s (haplotype 1), Gc2 (haplotype 2), and Gc1f (haplotype3). In a subgroup of 1,312 subjects, DBP genotype was found to be associated with increased and decreased serum 25-(OH)D3for haplotype 1 (P = 3 × 10-4) and haplotype 2 (P = 3 × 10-6), respectively. Similar associations were observed for 1,25-(OH)2D3. The DBP genotype was not significantly associated with fracture risk in the entire study population. Yet, we observed interaction between DBP and VDR haplotypes in determining fracture risk. In the DBP haplotype 1-carrier group, subjects of homozygous VDR block 5-haplotype 1 had 33% increased fracture risk compared to noncarriers (P = 0.005). In a subgroup with dietary calcium intake <1.09 g/day, the hazard ratio (95% confidence interval) for fracture risk of DBP hap1-homozygote versus noncarrier was 1.47 (1.06-2.05). All associations were independent of age and gender. Our study demonstrated that the genetic effect of the DBP gene on fracture risk appears only in combination with other genetic and environmental risk factors for bone metabolism.

Vitamin D Receptor Gene Polymorphisms and Bone (Doctoral Thesis)

2005-12-21T00:00:00Z

Staphylococcus aureus nasal carriage is not associated with known polymorphism in the Vitamin D receptor gene (Article)

2005-02-01T00:00:00Z

The vitamin D endocrine system has been shown to influence the immune response and polymorphisms in the vitamin D receptor (VDR) gene have been associated with susceptibility to infectious diseases. We determined if the Cdx2, FokI and BsmI-ApaI-TaqI polymorphisms in the VDR gene were associated with nasal carriage of Staphylococcal aureus. We defined the S. aureus nasal carriage status (persistent, intermittent or non-carriage) for a group of more that 2000 elderly volunteers. The prevalence of persistent S. aureus nasal carriage was 18%, which was, however, not associated with any of the variant VDR genotypes. Our study into genetic determinants of S. aureus carriage patterns is the largest in the field, but still we found no association between VDR gene variation and S. aureus nasal carriage.

Promoter and 3'-untranslated-region haplotypes in the vitamin d receptor gene predispose to osteoporotic fracture: the rotterdam study (Article)

2005-01-01T00:00:00Z

Polymorphisms of the vitamin D receptor gene (VDR) have been shown to be associated with several complex diseases, including osteoporosis, but the mechanisms are unknown and study results have been inconsistent. We therefore determined sequence variation across the major relevant parts of VDR, including construction of linkage disequilibrium blocks and identification of haplotype alleles. We analyzed 15 haplotype-tagging SNPs in relation to 937 clinical fractures recorded in 6,148 elderly whites over a follow-up period of 7.4 years. Haplotype alleles of the 5' 1a/1e, 1b promoter region and of the 3' untranslated region (UTR) were strongly associated with increased fracture risk. For the 16% of subjects who had risk genotypes at both regions, their risk increased 48% for clinical fractures (P = .0002), independent of age, sex, height, weight, and bone mineral density. The population-attributable risk varied between 1% and 12% for each block and was 4% for the combined VDR risk genotypes. Functional analysis of the variants demonstrated 53% lower expression of a reporter construct with the 1e/1a promoter risk haplotype (P = 5 x 10(-7)) in two cell lines and 15% lower mRNA level of VDR expression constructs carrying 3'-UTR risk haplotype 1 in five cell lines (P = 2 x 10(-6)). In a further analysis, we showed 30% increased mRNA decay in an osteoblast cell line for the construct carrying the 3'-UTR risk haplotype (P = .02). This comprehensive candidate-gene analysis demonstrates that the risk allele of multiple VDR polymorphisms results in lower VDR mRNA levels. This could impact the vitamin D signaling efficiency and might contribute to the increased fracture risk we observed for these risk haplotype alleles.

Height in pre- and postmenopausal women is influenced by estrogen receptor alpha gene polymorphisms (Article)

2004-01-01T00:00:00Z

The estrogen receptor alpha gene (ESR1) is known to be involved in metabolic pathways influencing growth. We have performed two population-based association studies using three common polymorphisms within this candidate gene to determine whether these are associated with variation in adult stature. In 607 women, aged 55-80 yr, from the Rotterdam Study, the ESR1 PvuII-XbaI haplotype 1 (px) and the L allele of the TA repeat polymorphism (<18 TA repeats) were significantly associated with an allele dose-dependent decrease in height. The per allele copy of ESR1 PvuII-XbaI haplotype 1 height was 0.9 cm shorter (P trend = 0.02) and 1.0 cm/allele copy of the TA repeat L allele (P trend = 0.003). These results were independent of age, age at menarche and menopause, and lumbar spine bone mineral density and remained significant after participants with vertebral fractures were excluded. In 483 men from the Rotterdam Study we found no association with height. In 1500 pre- and perimenopausal women from the Eindhoven Study a similar association was observed; women were 0.5 cm shorter per allele copy of the ESR1 haplotype 1 (P for trend = 0.03). In conclusion, we demonstrate a role for genetic variations in the estrogen receptor alpha gene in determining adult stature in women.

Polymorphisms in the sclerosteosis/van Buchem disease gene (SOST) region are associated with bone-mineral density in elderly whites (Article)

2004-01-01T00:00:00Z

Osteoporosis has a strong genetic component, but the genes involved are poorly defined. We studied whether the sclerosteosis/van Buchem disease gene (SOST) is an osteoporosis-risk gene by examining its association with bone-mineral density (BMD). Mutations in SOST result in sclerosteosis, and alterations in the SOST gene expression may be causal in the closely related van Buchem disease. We used a set of eight polymorphisms from the SOST gene region to genotype 1,939 elderly men and women from a large population-based prospective-cohort study of Dutch whites. A 3-bp insertion (f=0.38) in the presumed SOST promoter region (SRP3) was associated with decreased BMD in women at the femoral neck (FN) (P=.05) and lumbar spine (LS) (P=.01), with evidence of an allele-dose effect in the oldest age group (P=.006). Similarly, a G variant (f=0.40) in the van Buchem deletion region (SRP9) was associated with increased BMD in men at the FN (P=.007) and LS (P=.02). In both cases, differences between extreme genotypes reached 0.2 SD. We observed no genotype effects on fracture risk, for the 234 osteoporotic fractures validated during 8.2 years of follow-up and for the 146 vertebral prevalent fractures analyzed. We did not find association between any of several frequent haplotypes across the SOST gene region and BMD. We did find evidence of additive effects of SRP3 with the COLIA1 Sp1 polymorphism but not with haplotypes of 3' polymorphisms in the vitamin-D receptor gene. The SOST-COLIA1 additive effect increased with age and reached 0.5 SD difference in BMD at LS in the oldest age group (P=.02). The molecular mechanism whereby these moderate SOST genotype effects are mediated remains to be elucidated, but it is likely to involve differences in regulation of SOST gene expression.

Cdx-2 polymorphism in the promoter region of the human vitamin D receptor gene determines susceptibility of fracture in the elderly (Article)

2003-09-01T00:00:00Z

A Cdx-2 binding site polymorphism (G to A) in the promoter region of the human vitamin D receptor gene was reported. In an ecological study in eight ethnic groups and an association study in 2848 elderly whites, we found the A-allele to be associated with decreased fracture risk. Our findings expand previous similar findings in a Japanese study to whites and show a relationship with fracture risk of this functional polymorphism. INTRODUCTION: A single nucleotide polymorphism (SNP) within a binding site of the intestinal-specific transcription factor Cdx-2 in the promoter region of the human vitamin D receptor (VDR) gene was previously reported. It was found to modulate the transcription of the hVDR gene and to be associated with decreased bone mineral density in a small group of postmenopausal Japanese women. In this study, we investigated the relationship between the VDR Cdx-2 genotype and risk of fracture. METHODS: We first determined the location of this SNP in the VDR gene by sequencing analysis, and we developed an allele-specific multiplex polymerase chain reaction test to determine the Cdx-2 genotype. We then performed an ecological study in eight ethnic groups and an association analysis in a large epidemiological cohort of 2848 Dutch white men and women, > or = 55 years old. RESULTS AND CONCLUSIONS: The location of the G to A substitution was found in the promoter region of exon le (le-G-1739A) of the VDR gene. By comparing the frequency of the A-allele in eight different ethnic groups, we observed a negative correlation between prevalence of the A-allele and published hip fracture incidence rates in these ethnic groups (p = 0.006 for men and p = 0.02 for women), suggesting a protective effect of this allele on fracture risk. Subsequently, in the association study, the A-allele (population frequency 19%) was observed to have a protective effect on occurrence of osteoporotic fractures, especially for nonvertebral fracture in women (relative risk of AA versus GG genotype is 0.2; 95% CI, 0.05-0.8). This effect remained after adjustment for age, weight, and bone mineral density. We conclude that the A-allele of the VDR Cdx-2 polymorphism is present in whites, albeit at low frequency, and show a protective effect of this allele on risk of fracture.

Association of 5' estrogen receptor alpha gene polymorphisms with bone mineral density, vertebral bone area and fracture risk (Article)

2003-07-15T00:00:00Z

This study investigates the influence of genetic variation of the estrogen receptor alpha (ESR1) gene locus on several bone parameters in 2042 individuals of The Rotterdam Study, a prospective population-based cohort study of elderly subjects. We analysed three polymorphic sites in the 5' region of the ESR1 gene; a (TA)(n)-repeat in the promoter region, and molecular haplotypes of the PvuII and XbaI RFLPs in intron 1, and inferred long-range haplotypes (LRH) thereof. We observed only three of the possible four PvuII-XbaI haplotypes in our population. A comparison with other Caucasian populations showed similar haplotype frequencies, while in Asian and African populations these were different. Linkage disequilibrium (LD) analysis between the PvuII-XbaI haplotype and the (TA)(n) repeat showed strong LD between the two sites. Reconstruction of long range haplotypes over the entire 5' region, revealed six frequent LRH. In men, we did not observe an association between the ESR1 polymorphisms studied and bone parameters. In women, we demonstrated an allele dose effect of haplotype "px" (P=0.003) and a low number of (TA)(n) repeats (P=0.008) with decreased lumbar spine bone mineral density (BMD) (4.8% lower BMD in women homozygous for haplotype "px", representing 28% of the population, compared with homozygous non-carriers) and decreased vertebral bone area (2.3% difference between extreme genotypes; P=0.016). Most importantly, we found an increased vertebral fracture risk with evidence for an allele dose effect with an odds ratio of 2.2 (95%CI 1.3-3.5) for haplotype "px", and 2.0 (1.5-3.2) for a low number of (TA)(n) repeats. The ESR1 genotype dependent fracture risk is largely independent of BMD and bone area. Combination of risk alleles at both loci by long-range haplotyping improved the associations slightly, but because of the strong LD between the two polymorphic sites, we were unable to determine if any particular polymorphic site is driving the associations found. We conclude that ESR1 polymorphism in the 5' (promoter) region is associated with vertebral fracture risk, lumbar spine BMD and vertebral bone area in postmenopausal women, but not in men. The molecular mechanism underlying this association needs further study.

Estrogen receptor and gene haplotype is associated with radiographic osteoarthritis of the knee in the elderly men and woman (Article)

2003-07-01T00:00:00Z

OBJECTIVE: Genetic influences have been shown to play an important role in the etiology of osteoarthritis (OA), but the genes involved are ill-defined. We studied the association between polymorphisms in the estrogen receptor alpha (ERalpha) gene and the prevalence of radiographic OA of the knee. METHODS: The study group comprised 1,483 men and women from the Rotterdam Study. Direct molecular haplotyping was used to determine the relationship between 2 polymorphisms in the ERalpha gene (the Pvu II and Xba I restriction fragment-length polymorphisms). Radiographs of the knee were evaluated according to the Kellgren/Lawrence (K/L) score, along with separate scores for osteophytosis and joint space narrowing. RESULTS: Three different haplotype alleles were identified: px (54%), PX (34%), and Px (12%). Allele PX was associated with an increased prevalence of radiographic knee OA (K/L score >/=2). The prevalence of radiographic OA was 22% among subjects without allele PX, 24% among those carrying 1 copy, and 35% among subjects carrying 2 copies. The corresponding odds ratios, after adjustment for confounding factors, were 1.3 (95% confidence interval [95% CI] 0.9-1.7) for heterozygotes and 2.2 (95% CI 1.5-3.4) for homozygotes. Separate analyses for men and women showed similar risk estimates. The association appeared to be driven by osteophytosis and is somewhat consistent with the association observed in previous studies of these polymorphisms in relation to OA. CONCLUSION: This study shows that polymorphisms in the ERalpha gene are associated with radiographic OA of the knee, and in particular with osteophytosis, in both elderly men and elderly women.

Interaction between vitamin D receptor genotype and estrogen receptor alpha genotype influences vertebral fracture risk (Article)

2003-01-01T00:00:00Z

In view of the interactions of vitamin D and the estrogen endocrine system, we studied the combined influence of polymorphisms in the estrogen receptor (ER) alpha gene and the vitamin D receptor (VDR) gene on the susceptibility to osteoporotic vertebral fractures in 634 women aged 55 yr and older. Three VDR haplotypes (1, 2, and 3) of the BsmI, ApaI, and TaqI restriction fragment length polymorphisms and three ERalpha haplotypes (1, 2, and 3) of the PvuII and XbaI restriction fragment length polymorphisms were identified. We captured 131 nonvertebral and 85 vertebral fracture cases during a mean follow-up period of 7 yr. ERalpha haplotype 1 was dose-dependently associated with increased vertebral fracture risk (P < 0.001) corresponding to an odds ratio of 1.9 [95% confidence interval (CI), 0.9-4.1] per copy of the risk allele. VDR haplotype 1 was overrepresented in vertebral fracture cases. There was a significant interaction (P = 0.01) between ERalpha haplotype 1 and VDR haplotype 1 in determining vertebral fracture risk. The association of ERalpha haplotype 1 with vertebral fracture risk was only present in homozygous carriers of VDR haplotype 1. The risk of fracture was 2.5 (95% CI, 0.6-9.9) for heterozygous and 10.3 (95% CI, 2.7-40) for homozygous carriers of ERalpha haplotype 1. These associations were independent of bone mineral density. In conclusion, interaction between ERalpha and VDR gene polymorphisms leads to increased risk of osteoporotic vertebral fractures in women, largely independent of bone mineral density.