骨质疏松症与维生素D受体基因多态性的相关性

背景：骨质疏松是多基因调控疾病,峰值骨量变化和骨量丢失均受遗传因素影响。 目的：通过观察维生素D受体基因 ApaⅠ多态性在山东半岛汉族人群中的分布规律及与骨质疏松的关系,探讨原发性骨质疏松症的遗传易感因素。 方法：选取367名长期居住在山东半岛地区无亲缘关系的汉族人群。将受试者分为骨密度正常组227例,骨质疏松组63例,骨质疏松性骨折组77例。 结果与结论：实验人群维生素D受体基因的基因型频率分布符合Hardy-Weinberg平衡定律(χ² =1.583, P > 0.05)。基因型频率分布依次为aa型占53.1%,Aa型占10.6%,AA型占36.3%。年龄与不同部位骨密度值之间呈负相关(P< 0.01),体质量指数与骨密度值之间呈正相关(P < 0.01),在将年龄和体质量指数进行校正后发现aa基因型在腰椎(P < 0.05)、wards三角(P < 0.05)骨密度较低。运用χ2检验分析骨密度正常组各基因型与骨质疏松性骨折组之间差异无显著性意义(χ² =4.795,  P > 0.05)。结果证实,山东半岛地区汉族人群中,维生素D受体基因ApaⅠ酶切位点多态性与原发性骨质疏松症存在关联,提示维生素D受体基因ApaⅠ酶切位点多态性在决定个体骨质疏松症遗传易感性方面起重要作用。     

Association between total serum calcium and the A986S polymorphism of the calcium-sensing receptor gene

Serum calcium is under tight physiological control, but it is also a quantitative trait with substantial genetic regulation. Mutations of the CASR gene cause familial hypocalciuric hypercalcemia or autosomal dominant hypoparathyroidism, depending on whether they decrease or increase, respectively, ligand binding to the receptor protein. We described an association between ionized calcium and a common polymorphism (A986S) found in the cytoplasmic tail of this G protein-coupled receptor. We report here on an independent study of 387 healthy young women. Genotyping was performed by allele-specific amplification and serum chemistries were measured by automated clinical assay. Frequencies of SS, AS, and AA genotypes were 6, 107, and 274, respectively, yielding a 986S allele frequency of 15.4%. Mean total serum calcium (Ca(T)) was significantly higher in the SS (9.88 +/- 0.29 mg/dL, P = 0.015) and AS groups (9.45 +/- 0.05 mg/dL, P = 0.002), than in the AA group (9.23 +/- 0.04 mg/dL). In multiple regression modeling, the A986S genotype remained an independently significant predictor of Ca(T) (P < 0.0001) when serum albumin, globulin, inorganic phosphate, and creatinine covariates were included. These data are the first to show significant association between a common polymorphism and concentrations of a serum electrolyte. The A986S polymorphism is also a potential predisposing factor in disorders of bone and mineral metabolism.     

Vitamin D receptor gene polymorphisms are linked to and associated with adult height

Background: The vitamin D receptor (VDR) gene is important to human stature, as it mediates metabolic pathways, calcium homeostasis, and phosphate homeostasis, which influence growth.

Methods: We examined the relationship between VDR and adult height in 1873 white subjects from 406 nuclear families. Four SNPs, namely –4817A/G at intron 1, FokI C/T at exon 2 start codon, BsmI A/G at intron 8, and TaqI T/C at exon 9 in VDR were tested for linkage and association with adult height variation by the program QTDT (quantitative transmission disequilibrium test). The bT haplotype of the BsmI and TaqI loci was further tested for its association with height in unrelated samples randomly chosen from the 406 nuclear families by traditional population association methods.

Results: All four tested SNPs were linked to adult height. Within family associations with height were detected at BsmI and TaqI loci (p = 0.048 and 0.039, respectively). Analyses based on BsmI/TaqI haplotypes also revealed evidence for linkage (p = 0.05) and association (p = 0.001) with height. The bT haplotype was significantly associated with higher adult height (p = 0.033, within family association test). Such an association might be female specific and influenced by menstrual status.

Conclusions: Our results strongly suggest that VDR may be linked to and associated with adult height variation in white popuations.

     

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.     

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

Decreased cerebral blood flow causes cognitive impairments and neuronal injury in vascular dementia. In the present study, we reported that donepezil, a cholinesterase inhibitor, improved transient global cerebral ischemia-induced spatial memory impairment in gerbils. Treatment with 5 mg/kg of donepezil for 21 consecutive days following a 10-min period of ischemia significantly inhibited delayed neuronal death in the hippocampal CA1 region. In Morris water maze test, memory impairment was significantly improved by donepezil treatment. Western blot analysis showed that donepezil treatment prevented reductions in p-CaMKII and p-CREB protein levels in the hippocampus. These results suggest that donepezil attenuates the memory deficit induced by transient global cerebral ischemia and this neuroprotection may be associated with the phosphorylation of CaMKII and CERB in the hippocampus.     

The vitamin D receptor gene is associated with Alzheimer's disease

Vitamin D may have a role in brain function. Low levels have been frequently associated with cognitive decline and may contribute to diseases of the nervous system. The vitamin D receptor (VDR) is widely expressed in human brain. Vitamin D appears to be neuroprotective and may regulate inflammation in the brain. We examined two VDR polymorphisms, Apa1 and Taq1. We used DNA from 255 Alzheimer's disease (AD) cases and 260 cognitively screened elderly controls from the longitudinal cohort of the Oxford Project to Investigate Memory and Ageing (OPTIMA). The presence of each of the linked alleles, Apa1 T and Taq1 G, was associated with the risk of AD, particularly in people <75 years old: odds ratios ≥3.0 and p ≤ 0.005. We also found preliminary evidence of interactions associated with AD between these polymorphisms and two other genes involved in the regulation of inflammation, interleukin-10 (IL10) and dopamine β-hydroxylase (DBH): synergy factors ≥3.4, uncorrected p < 0.05. These associations are biologically plausible and are consistent with a role for vitamin D in AD. Nevertheless, we consider this to be a hypothesis-generating study, which needs to be replicated in a larger dataset.     

A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia

An excess dopaminergic activity may be implicated in the etiology of schizophrenia. Our objective was to identify nucleotide variants in the 5' region of the dopamine D2 receptor gene (DRD2) and to clarify their effects on schizophrenia. We identified two polymorphisms, the A-241G and -141C Ins/Del, by examination of 259 bp in the 5'-flanking region and 249 bp of exon 1 of DRD2. Reporter constructs containing the -141C Del allele cloned into a luciferase reporter plasmid drove 21% (Y-79 cells) and 43% (293 cells) expression compared with the -141C Ins allele. In a case-control study, the -141C Del allele frequency was significantly lower in 260 schizophrenic patients than in 312 controls (OR = 0.60, 95%CI 0.44-0.81, P < 0.001). No significant association was found between the A-241G polymorphism and in vitro luciferase activity, or in allele frequency between the patients versus controls. These findings show that the -141C Ins/Del may be a functional polymorphism in the 5'-promoter region of DRD2 and may affect the susceptibility to schizophrenia.      

Dopamine receptor D4 gene is not associated with major psychoses

We previously reported an association between dopamine receptor D4 (DRD4) gene exon 1 variants and delusional disorder. The aim of this investigation was to study the DRD4 gene exon 1 and 3 variants in schizophrenia, delusional, bipolar, and unipolar disorders. We studied 651 inpatients affected by schizophrenia (n = 229), delusional (n = 86), bipolar (n = 210), and unipolar (n = 126) disorders (DSM III-R) and 471 healthy controls; these were typed for DRD4 variants at the first and third exon using polymerase chain reaction techniques. DRD4 variants were not associated with schizophrenic and delusional subjects even when possible confounders like gender and onset were considered. A marginal association between DRD4 exon 3 variants with unipolar (excess of DRD4*2/4, p = 0.004) and bipolar (excess of DRD4*2/4, p = 0.001) disorders was observed, both associations drop to insignificance when corrected for multiple testing. Our results exclude that coding variants of the DRD4 exon 1 and 3 may play a major role in conferring susceptibility to major psychoses; moreover, we could not replicate the association of DRD4 exon 1 variant with delusional disorder. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:486–491, 1999. © 1999 Wiley-Liss, Inc.     

Vitamin D receptor (VDR) gene polymorphism and osteoporosis risk in White British men

Abstract

In this study, VDR gene ApaI (rs7975232), BsmI (rs 1544410) and TaqI (rs731236) genotypes were compared in men with osteoporosis and male controls. Osteoporosis affects around 20% of all men and overall mortality in the first year after hip fracture is significantly higher in men than women, yet the genetic basis of osteoporosis is less well studied in males. This study consisted of White British males; 69 osteoporosis patients and 122 controls. BMDs at the lumbar spine (vertebrae L1–L4) and hip (femur neck) were measured by dual-energy X-ray absorptiometry (DEXA). The VDR gene ApaI, BsmI and TaqI genotypes were determined by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) and association analysis was carried out at genotype and haplotype level. Our study suggests that TaqI polymorphism CC genotype frequency is lower in controls and further analysis of genotypes and BMD revealed a significant effect of TaqI polymorphism on Lumbar spine BMD. Two haplotypes (GCC and AAT) were associated with increased osteoporosis risk. In conclusion, VDR gene TaqI polymorphism in recessive mode had a significant effect on lumbar spine BMD within our study. Haplotypes GCC and AAT increase the risk of osteoporosis among White British males.     

Dopamine receptor D4 gene is not associated with major psychoses.

We previously reported an association between dopamine receptor D4 (DRD4) gene exon 1 variants and delusional disorder. The aim of this investigation was to study the DRD4 gene exon 1 and 3 variants in schizophrenia, delusional, bipolar, and unipolar disorders. We studied 651 inpatients affected by schizophrenia (n = 229), delusional (n = 86), bipolar (n = 210), and unipolar (n = 126) disorders (DSM III-R) and 471 healthy controls; these were typed for DRD4 variants at the first and third exon using polymerase chain reaction techniques. DRD4 variants were not associated with schizophrenic and delusional subjects even when possible confounders like gender and onset were considered. A marginal association between DRD4 exon 3 variants with unipolar (excess of DRD4*2/4, p = 0.004) and bipolar (excess of DRD4*2/4, p = 0.001) disorders was observed, both associations drop to insignificance when corrected for multiple testing. Our results exclude that coding variants of the DRD4 exon 1 and 3 may play a major role in conferring susceptibility to major psychoses; moreover, we could not replicate the association of DRD4 exon 1 variant with delusional disorder.     

CYP4A11基因多态性与心肌梗死相关

目的 研究在不同性别中CYP4A11基因多态性与心肌梗死的关系.方法 166例心肌梗死患者和158例对照组,选择CYPA11基因的3个SNPs(rs9332978、rs3890011和rs1126742),应用TaqMan SNP基因分型法进行基因分型,并应用病例对照的研究方法进行相关性分析.结果 rs3890011的基因分型在心肌梗死组和对照组之间的分布存在明显差异(P＜0.05),心肌梗死组携带GG基因型(GG vs CC+ GC)高于对照组(P＜0.05),在排除吸烟、高血压、糖尿病等混杂因素后,仍存在显著性差异(95％ CI:1.138～2.432,P＜0.01).结论 CYP4A11基因的rs3890011多态性与心肌梗死相关,rs3890011的GG基因型可作为心肌梗死易感基因标记.     

Vitamin D receptor gene polymorphism as possible risk factor in rheumatoid arthritis and rheumatoid related osteoporosis

Objective

To study the role of VDR polymorphisms as risk factor for RA and osteoporosis, and whether osteoporosis complicating RA is due to RA or VDR polymorphisms.

Methods

VDR gene polymorphisms ApaI, TaqI, BsmI and FokI were typed by RFLP for 128 RA patients, 30 postmenopausal osteoporotic females and 150 healthy controls.

Results

Significant differences were found between patients and healthy controls in the frequency of BsmI and TaqI (Pc < 0.05) but no significant associations were found for FokI and ApaI polymorphisms except for aa genotype (Pc < 0.001). Titers of RF were higher with aa and bb genotypes. Anti-CCP and CRP levels were higher with aa genotype and more bone loss was associated with Bb genotype. Ff genotype frequency was higher in RA patients with osteoporosis than those without osteoporosis.

Conclusions

The ApaI, BsmI and TaqI polymorphisms may be a susceptibility risk factors for RA and the Ff genotype may be responsible for development of osteoporosis in RA Egyptian patients. However, the present study needs to be replicated in a large number of patients from allover the Egypt and also in multi-ethnic populations.     

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.     

A dopamine D2 receptor gene-related polymorphism is associated with schizophrenia in a Spanish population isolate

Numerous lines of evidence have highlighted the involvement of the dopamine system in the pathophysiology of schizophrenia. Association studies of dopaminergic genes such as the dopamine D2 receptor gene (DRD2), however, have produced contradictory results. To test the hypothesis that DRD2 polymorphisms are associated with schizophrenia, we investigated two DRD2-related polymorphisms (TaqI A1/A2 or rs1800497 and -141-C Ins/Del or rs1799732) in a Spanish population isolate from northern Spain consisting of 165 controls and 119 patients with schizophrenia. The TaqI A1 allele was less frequent in schizophrenic patients than in controls (P=0.002). A similar association was found for the TaqI A2/A2 genotype (P=0.0003). No association was found for the DRD2 -141-C Ins/Del polymorphism. The strong association between a potentially functional polymorphism, downstream of the DRD2 gene and schizophrenia, suggests that the direct or indirect functional effects of this polymorphism, acting on either the ANKK1 or DRD2 genes, may play a role in the pathophysiology of schizophrenia.