维生素D受体起始密码子基因多态性与系统性红斑狼疮相关性研究

目的 检测维生素D受体(VDR)基因多态性在系统性红斑狼疮(SLE)患者中的分布,探讨其与SLE发病的相关性.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VDR起始密码子(FokI)多态性位点和基因型在271例SLE患者和130名健康对照组中的分布情况.采用χ2检验和方差分析进行统计学处理.结果 SLE患者及健康对照组VDR FokI多态性基因型和等位基因分布均不处于Hardy-Weinberg平衡(SLE组χ2=7.883,P=0.019;健康对照组:χ2=7.288,P=0.026).VDR FokI多态性等位基因F和f的分布频率在健康对照组分别为48.8%和51.2%,在SLE组分别为60.9%(χ2=10.39,P=0.001)和39.1%(χ2=10.39,P=0.001);F等位基因个体发生SLE的比值比(OR)为1.630(95%CI=1.210～1.1%,χ2=10.39,P=0.001).基因型FF、Ff和ff分布频率在健康对照组中分别为25.4%、46.9%和27.7%,在SLE组中分别为42.8%(χ2=11.417,P=0.001)、36.2(χ2=4.251,P=0.039)和21.0%(χ2=2.187,P=0.139);FF和Ff基因型个体发生SLE的OR分别为2.200(95%CI=1.385～3.493,χ2=11.417,P=0.001)和0.641(95%C1=0.419～0.979,χ2=4.251,P=0.039).进一步分析发现,不同VDR FokI多态性基因型SLE患者之间疾病活动性积分(SLEDAI)差异无统计学意义(P=0.382).但与FF和ff基因型SLE患者对照,Ff基因型SLE患者中浆膜炎的发生率更高(P=0.001),而且具有更高阳性率的抗双链DNA(dsDNA)抗体(P=0.001)、抗Sm抗体(P=0.047)和抗组蛋白抗体(P=0.001),但皮疹发生率较低(P=0.005).结论 VDR FokI多态性位点F等位基因和F/F及F/f基因型与SLE发病易感性有关,而且F/f杂合子患者更容易发生浆膜炎和产生抗dsDNA抗体、抗Sm抗体和抗组蛋白抗体.     

Estrogen receptor alpha gene polymorphisms are associated with estradiol levels in postmenopausal women

OBJECTIVE: Postmenopausal estradiol (E(2)) levels vary widely between individuals and this variation is an important determinant of diseases such as osteoporosis. It has been suggested that the estrogen receptor alpha (ESR1) gene may influence peripheral E(2) levels, but the role of common sequence variations in the ESR1 gene is unclear. METHODS: In 631 postmenopausal women and 528 men from the Rotterdam Study, a population-based, prospective cohort study of individuals aged 55 years and over, ESR1 PvuII-XbaI haplotypes were determined and correlated with plasma E2 levels. RESULTS: In women, haplotype 1 (T-A) was significantly associated with an allele-dose-dependent decrease in E(2). After adjusting for age, body mass index, years since menopause and testosterone levels, plasma E(2) levels decreased by 1.90 pmol/l per allele copy of this haplotype (P < 0.05). Extreme genotypes, representing 23 and 27% of the population, varied by 3.93 pmol/l. No association with plasma testosterone was observed. In a subset of 446 women, no association of genotype with plasma concentrations of dehydroepiandrosterone sulfate, androstenedione or estrone was seen. In men, none of the sex hormone levels was associated with the ESR1 PvuII-XbaI haplotypes. CONCLUSION: We have demonstrated a role for genetic variations in the ESR1 gene in determining post-menopausal E(2) levels in women.     

Association between vitamin D receptor FokI. Polymorphism and serum parathyroid hormone level in patients with chronic renal failure

We investigated the relationship between vitamin D receptor (VDR) start codon polymorphism and serum levels of PTH, calcidiol, and calcium in 64 Spanish patients with chronic renal failure (CRF). An exon 2 fragment of the VDR gene was amplified by PCR, and cleaved with the restriction enzyme FokI. The alleles were identified according to the digestion pattern obtained as F (absence of restriction site) and f (presence of restriction site). Genotype frequencies in the patient population were 54.7% FF, 28.1% Ff and 17.2% ff, vs 46.7% FF, 43.3% Ff and 10% ff in a healthy control population. The difference between the two populations was statistically significant (p<0.01). Within the patient population, mean serum PTH level in the FF group was significantly higher (159.77+/-25.69 pg/ml) than in both the Ff and ff groups (106.67+/-19.07 and 77.55+/-15.85 pg/ml, respectively; p<0.05). However there were no significant differences in serum levels of calcidiol or calcium among genotypes. These results suggest that FokI polymorphisms of the VDR gene may determine parathyroid response in CRF patients.     

Calcium-sensing receptor gene polymorphism is not associated with bone mineral density in Italian postmenopausal women

OBJECTIVE: Calcium-sensing receptor (CaR) is a candidate gene for osteoporosis susceptibility. Several CaR polymorphisms have been identified and an association between the A986S genotype and serum calcium levels has been found in Canadian postmenopausal women. We investigated whether the presence of 986S allele was associated with bone mineral density (BMD) and osteoporotic fractures. DESIGN: The study group consisted of 164 Italian postmenopausal women without fragility fracture (Fx(-)) and 55 women with fracture (Fx(+)). METHODS: A fragment of exon 7 of CaR gene containing three polymorphisms (A986S, R990G and Q1011E) was amplified by PCR and sequenced. Anthropometric characteristics and BMD were evaluated. RESULTS: The A986S polymorphism was the most commonly observed (27.9%), whereas the other two CaR polymorphisms, R990G and Q1011E, occurred in a minority of cases (8.8 and 5.5% respectively). There was no significant difference in the frequency distribution of any CaR allele between Fx(-) and Fx(+) patients. Body mass index was found to predict BMD at the lumbar spine and femoral neck. The A986S polymorphism and Years since menopause were not independent predictors of BMD at any site. As far as fracture occurrence, there was no statistically significant difference in the prevalence of fractures between women carrying or not carrying the 986S allele. CONCLUSIONS: Our data do not support a role of A986S CaR polymorphism in BMD and in the prevalence of fragility fractures in Italian postmenopausal women.     

The thyroid hormone, parathyroid hormone and vitamin D associated hypertension

Thyroid disorders and primary hyperparathyroidism have been known to be associated with increases in blood pressure. The hypertension related to hypothyroidism is a result of increased peripheral resistance, changes in renal hemodynamics, hormonal changes and obesity. Treatment of hypothyroidism with levo-thyroxine replacement causes a decrease in blood pressure and an overall decline in cardiovascular risk. High blood pressure has also been noted in patients with subclinical hypothyroidism. Hyperthyroidism, on the other hand, is associated with systolic hypertension resulting from an expansion of the circulating blood volume and increase in stroke volume. Increased serum calcium levels associated with a primary increase in parathyroid hormone levels have been also associated with high blood pressure recordings. The mechanism for this is not clear but the theories include an increase in the activity of the renin-angiotensin-aldosterone system and vasoconstriction. Treatment of primary hyperparathyroidism by surgery results in a decline in blood pressure and a decrease in the plasma renin activity. Finally, this review also looks at more recent evidence linking hypovitaminosis D with cardiovascular risk factors, particularly hypertension, and the postulated mechanisms linking the two.     

Parathyroid hormone and vitamin D levels are independently associated with calcific aortic stenosis.

BACKGROUND: In calcific aortic valve disease, the early lesion is similar to atherosclerotic plaque, but later calcification prevails. Parathyroid hormone (PTH) and vitamin D are the principal calcium pool regulators, so the present study was designed to assess their association with aortic stenosis (AS) in patients with significant coronary artery disease (CAD), and preserved renal function. METHODS AND RESULTS: The 122 consecutive patients with AS (mean gradient > or =30 mmHg) plus CAD, and 101 patients with nonobstructive aortic sclerosis (mean gradient < or =10 mmHg) plus CAD, as controls, were prospectively enrolled. The AS patients were older (71+/-7 vs 66+/-7 years; p<0.001), had higher serum intact (i)PTH (51.4 [39-70] vs 37.4 [27-50] pg/ml; p<0.001), and lower plasma vitamin D (32.0 [25-40] vs 35.8 [27-55] nmol/L; p=0.003) levels than those with aortic sclerosis. The groups did not differ significantly in creatinine level (93 [82-105] vs 96 [85-107] micromol/L, p=0.19), calcium - phosphate product, occurrence of hypertension, smoking, diabetes, dyslipidemia, or body mass index. The iPTH (odds ratio (OR) 1.04, 95% confidence interval (CI) 1.02-1.05; p<0.001) and vitamin D levels (OR 0.97, 95% CI 0.95-0.99; p=0.003) were independently associated with AS. CONCLUSION: Higher serum iPTH with lower vitamin D levels were independently associated with calcific AS in CAD patients.     

Serum pentosidine levels are positively associated with the presence of vertebral fractures in postmenopausal women with type 2 diabetes

CONTEXT: Although type 2 diabetic patients are at increased risk of fractures, bone mineral density (BMD) may not be useful for assessing the risk. Recent studies have reported that increased bone content of pentosidine (PEN) is associated with its plasma concentration and bone fragility. OBJECTIVE AND METHODS: To examine the association between serum PEN levels and vertebral fractures (VFs) in Japanese type 2 diabetic patients (77 males older than 50 yr and 76 postmenopausal females), we compared parameters including BMD, PEN, serum bone-specific alkaline phosphatase, and urinary levels of N-telopeptide between those with and without VFs. RESULTS: Comparison of diabetic subjects with and without VFs revealed no significant differences in BMD values or bone metabolic markers in either gender. In contrast, PEN levels in women with VFs were significantly higher than in those without VFs (0.0440+/-0.0136 vs. 0.0321+/-0.0118 microg/ml; P<0.001). Multivariate logistic regression analysis adjusted for age, height, weight, hemoglobin A1c, estimated glomerular filtration rate, the presence of diabetic complications, histories of taking insulin or pioglitazone, risk factors for osteoporosis, and lumbar BMD identified PEN levels as a factor associated with the presence of VFs in postmenopausal diabetic women independent of BMD, risk factors for osteoporosis, diabetic status, and renal function (odds ratio 2.50, 95% confidential interval 1.09-5.73 per sd increase; P=0.0302). CONCLUSION: PEN levels, but not BMD, may be useful for assessing the risk of prevalent VFs in postmenopausal diabetic women and may reflect bone quality in this group.     

Vitamin D receptor gene polymorphisms are associated with the risk of fractures in postmenopausal women, independently of bone mineral density

CONTEXT: Osteoporosis is a systemic disease with a strong genetic component. Vitamin D receptor (VDR) gene polymorphisms explain only a small part of the genetic influence on the level of bone mineral density (BMD), whereas their effect on fracture remains uncertain. OBJECTIVE: The objective of this study was to investigate the relationships between VDR genotypes and fracture risk. DESIGN: A prospective population-based cohort was studied. SUBJECTS: A total of 589 postmenopausal women (mean age, 62 yr) were followed prospectively during a median (interquartile) of 11 (1.1) yr. MAIN OUTCOME MEASURE: The study measured incidents of vertebral and nonvertebral fractures. RESULTS: VDR allele B was significantly and dose dependently overrepresented in women who fractured, including 34 and 86 women with first incident vertebral and nonvertebral fragility fractures, respectively. This corresponded to an odds ratio of 1.5 (95% confidence interval, 0.95-2.40) for heterozygous carriers (bB, n = 286) and 2.10 (95% confidence interval, 1.16-3.79) for homozygous carriers (BB, n = 90) of the B allele, compared with women with the bb genotype (n = 213). VDR genotype groups did not differ for demographics, physical activity, grip strength, personal and maternal history of fracture, and calcium intake. The association was independent of BMD of the spine, hip, and radius, and of the BMD loss at the radius. The relationship between VDR polymorphisms and fracture risk was not altered after adjustment for baseline circulating levels of bone turnover markers, estradiol, dehydroepiandrosterone sulfate, SHBG, IGF-I, intact PTH, and 25 hydroxyvitamin D. CONCLUSION: VDR genotypes are associated with the risk of fracture in postmenopausal women independently of BMD, rate of postmenopausal forearm BMD loss, bone turnover, and endogenous hormones. The mechanisms by which VDR genotypes influence bone strength remain to be determined.     

糖耐量减低患者维生素D、维生素D受体基因FokI多态性与胰岛素抵抗的相关性研究

目的 探讨IGT者25羟基维生素D3（25-OH-VD3）、维生素D受体（VDR）基因FokI多态性与IR的相关性。 方法 选取IGT者（IGT组）94例及正常对照（NC）组54名,采用PCR-RLFP检测VDR基因FokI多态性,ELISA检测25-OH-VD3,比较各组基因型及等位基因频率。 结果 ⑴与NC组比较,IGT组血清25-OH-VD3较低[（22.05±2.37） vs （32.04± 2.64） ng/ml,P〈0.05];⑵与NC比较,IGT组“f”等位基因频率升高（46.8% vs 25.9%,FF：30.9% vs 57.4%;Ff： 46.9% vs 33.3%;ff：22.3% vs 9.3%,P〈0.05）。与FF基因型比较,Ff/ff基因型患IGT危险增加（OR=2.613,95%CI=1.239～5.512,P=0.018;OR=4.490,95%CI=1.496～13.473,P=0.010）。与F型比较,携带“f”等位基因患IGT风险增加（OR=2.465,95%CI=1.188～5.116,P=0.023）。Ff、ff基因型与FF型比较,HOMA-IR增高（P〈0.05）;VDR基因FokI位点ff基因型者较其它两种基因型IR更明显（P〈0.01）;⑶Logistic回归分析显示,VDR基因FokI ff与IR呈正相关（OR=1.761,95%CI：1.050～2.970,P〈0.05）,25-OH-VD3与IR呈负相关（β=-1.187,OR=0.461,95%CI：0.187～0.741,P〈0.05）。 结论 血清25-OH-VD3水平与IR呈负相关,VDR基因FokI可能与IGT者IR有关。     

Prevalence of pathologic vitamin D and parathyroid hormone levels in geriatric patients

Diseases of the bone have always to be considered in geriatric patients, especially because of the therapeutic consequences in osteomalacia (3/100) and hyperparathyreodism (1/100). Therefore calcium, phosphate and alkaline phosphatase should be measured in geriatric patients. The high prevalence of pathologic vitamin D measurements (78/100) in spring points to the importance of outdoor activities.     

维生素D受体基因FokⅠ多态性与2型糖尿病及其合并动脉粥样硬化的相关性

目的探讨维生素D受体（VDR）基因FokⅠ的多态性与T2DM及其合并动脉粥样硬化（AS）之间的相关性。方法通过提取全血DNA,PCR扩增VDR基因,FokⅠ酶切扩增产物,检测大连地区T2DM合并AS者（AS组）,DM非AS者（non-AS组）及健康对照者（NC组）的基因型。应用单因素非条件logistic回归分析研究VDR基因变异对T2DM及合并AS的影响。结果（1）VDR基因FokⅠ酶切位点各基因型在T2DM组和NC组中分布具有统计学差异（P〈0．01）。（2）AS组和non-AS组VDR基因FokⅠ酶切各基因型分布无统计学差异（P〉0．05）。（3）VDR等位基因f与T2DM呈显著正相关,等位基因F与T2DM呈显著负相关。结论在大连地区的汉族人群中,VDR基因FokⅠ的多态性与T2DM相关,而与T2DM合并AS无关。等位基因f是T2DM的易感基因,而等位基因F对T2DM具有保护作用。     

The Fok1 vitamin D receptor gene polymorphism is associated with plasma renin activity in Caucasians

Objectives 25‐Hydroxyvitamin D (25(OH)D) deficiency and excess activity of the renin–angiotensin system (RAS) are both associated with cardiovascular disease. Vitamin D interacts with the vitamin D receptor (VDR) to negatively regulate renin expression in mice; however, human studies linking genetic variation in the VDR with renin are lacking. We evaluated (i) whether genetic variation in the VDR at the Fok1 polymorphism was associated with plasma renin activity (PRA) in a population of hypertensives and a separate population of normotensives and (ii) whether the association between Fok1 genotype and PRA was independent of 25(OH)D levels. Design/Patients/Measurements Genetic association study, assuming an additive model of inheritance, of 375 hypertensive and 146 normotensive individuals from the HyperPATH cohort, who had PRA assessments after 1 week of high dietary sodium balance (HS) and l week of low dietary sodium balance (LS). Results The minor allele (T) at the Fok1 polymorphism was significantly associated with lower PRA in hypertensives (LS: β = ?0·22, P < 0·01; HS: β = ?0·19, P < 0·01); when repeated in normotensives, a similar relationship was observed (LS: β = ?0·17, P < 0·05; HS: β = ?0·18, P = 0·14). In multivariable analyses, both higher 25(OH)D levels and the T allele at Fok1 were independently associated with lower PRA in hypertensives; however, 25(OH)D was not associated with PRA in normotensives. Conclusions Genetic variation at the Fok1 polymorphism of the VDR gene, in combination with 25(OH)D levels, was associated with PRA in hypertension. These findings support the vitamin D–VDR complex as a potential regulator of renin activity in humans.     

Serum leptin levels are associated with bone mass in nonobese women

Both serum leptin and bone mineral density are positively correlated with body fat, generating the hypothesis that leptin may be a systemic and/or local regulator of bone mass. We investigated 214 healthy, nonobese Australian women aged 20-91 yr. Bone mineral content, projected bone area, and body fat mass were measured by dual energy x-ray absorptiometry and fasting serum leptin levels by RIA. Associations between bone mineral content (adjusted for age, body weight, body fat mass, and bone area) and the natural logarithm of serum leptin concentrations were analyzed by multiple regression techniques. There was a significant positive association at the lateral spine, two proximal femur sites (Ward's triangle and trochanter), and whole body (partial r(2) = 0.019 to 0.036; all P < 0.05). Similar trends were observed at the femoral neck and posterior-anterior-spine. With bone mineral density the dependent variable (adjusted for age, body weight, and body fat mass), the association with the natural logarithm of leptin remained significant at the lateral spine (partial r(2) = 0.030; P = 0.011), was of borderline significance at the proximal femur sites (partial r(2) = 0.012 to 0.017; P = 0.058 to 0.120), and was not significant at the other sites. Our results demonstrate an association between serum leptin levels and bone mass consistent with the hypothesis that circulating leptin may play a role in regulating bone mass.     

Oestrogen receptor alpha genotype, and interactions between vitamin D receptor and transforming growth factor-beta1 genotypes are associated with quantitative calcaneal ultrasound in postmenopausal women

OBJECTIVE: Quantitative ultrasound (QUS) of bone is a new radiation-free, low-cost method that measures both bone mass and quality. We investigated associations between QUS parameters and polymorphisms of vitamin D receptor (VDR), oestrogen receptor alpha (ERalpha) and transforming growth factor-beta1 (TGF-beta1) genes in postmenopausal women residing in a community. DESIGN: QUS and anthropometric characteristics were measured in postmenopausal women, and compared with regard to the VDR, ERalpha and TGF-beta1 genotypes. PATIENTS: Among the 552 women who participated in the population-based Chung-Up osteoporosis prevalence study, 206 postmenopausal women, aged 60-69 years, were included. MEASUREMENTS: Broadband ultrasound attenuation (BUA) and speed of sound (SOS) were measured at the left calcaneus using QUS measurement of bone, and a stiffness index (SI) was calculated. We determined the BsmI and FokI polymorphisms of VDR gene and the XbaI and PvuII polymorphisms of ERalpha gene using the polymerase chain reaction-restriction fragment length polymorphism method, and Tau29 --> C polymorphism of TGF-beta1 gene using an allele-specific polymerase chain reaction assay. RESULTS: The XbaI polymorphism of ERalpha gene was significantly associated with SI (T-score) and BUA (P = 0.040 and P = 0.024, respectively). There were no significant differences in any QUS parameters among the genotypes of VDR and TGF-beta1. However, significant genetic interactions between the VDR and TGF-beta1 genotypes, were noted (P = 0.017 for SI and P = 0.028 for BUA between the BsmI and Tau29 --> C polymorphisms; P = 0.038 for SI and P = 0.035 for BUA between the FokI and T29 --> C polymorphisms). The combined genotypes between the BsmI and T29 --> C polymorphisms or between the FokI and T29 --> C polymorphisms, were significantly associated with the QUS parameters. CONCLUSIONS: This study indicates that the XbaI polymorphism of ERalpha gene may influence the Quantitative ultrasound parameters in postmenopausal women, and suggests the need for further investigations about the interactions between the VDR and TGF-beta1 genes.     

Serum calcium,vitamin D and parathyroid hormone relationship among diabetic and non-diabetic pregnant women and their neonates

AimsThe purpose of the study was to determine the prevalence of osteomalacia and hypovitaminosis D among diabetic and non-diabetic pregnant women and in their neonates.MethodsSerum calcium, phosphorus, heat labile alkaline phosphatase, 25(OH) vitamin D and PTH were measured in 32 non-diabetic, 16 gestational diabetic and 8 Type 1 diabetic pregnant women and in cord blood of their newborn.ResultsAmong 32 non-diabetic subjects, 4 subjects (12.5%) had biochemical osteomalacia. 4 out of 16 gestational diabetic subjects (25%) had biochemical osteomalacia whereas 5 out of 8 Type 1 diabetic subjects (62.5%) had biochemical osteomalacia. Mean concentration of 25(OH) vitamin D in the non-diabetic group was 17.18 ± 9.88 ng/ml. Mean concentration of 25(OH) vitamin D in the Gestational diabetic group was 14.75 ± 6.90 ng/ml, while in Type 1 diabetic group, it was 7.81 ± 3.79 ng/ml. 50% of neonates of normal pregnant women had vitamin D deficiency whereas, 50% had vitamin D insufficiency. 40% of neonates of Gestational diabetic pregnant women had vitamin D deficiency whereas, 40% had vitamin D insufficiency.ConclusionVitamin D deficiency and biochemical osteomalacia was present in significant percentage of normal pregnant women and their neonates. Gestational diabetes and Type 1 diabetic women were more prone to develop vitamin D deficiency and biochemical osteomalacia.     

Plasma leptin levels are associated with abnormal fibrinolysis in men and postmenopausal women

BACKGROUND: Leptin is a crucial mediator of satiety signals and energy balance, and its circulating levels are increased in obesity. It has recently been shown that plasma leptin levels in humans correlate with circulating insulin and to insulin secretion. This indicates that leptin may be an important link in metabolic consequences of the insulin resistance syndrome. Whether this includes abnormalities in fibrinolysis has not been studied. METHODS AND RESULTS: Healthy subjects (n = 165; 85 men and 80 women) from the Northern Sweden MONICA population were investigated. Anthropometric measurements, oral glucose tolerance tests and sampling for plasma leptin, lipids, fibrinogen and fibrinolytic variables were made. Leptin levels were 342% higher in women than in men and were in both sexes strongly correlated to body mass index (BMI). After adjustments for age and BMI, leptin levels correlated significantly to pre/post glucoseload insulin levels in both sexes. After further adjustment for baseline insulin levels, leptin levels were in males significantly associated with increased waist circumference (P<0.001), low HDL cholesterol (P<0.05), low tPA activity (P<0.01) and high PAI-1 activity (P<0.001). In postmenopausal females, a significant association between leptin and low tPA activity/high PAI-1 activity was seen after adjustment for age and BMI (P<0.05). Conclusions. Circulating levels of leptin are associated with components of the insulin resistance syndrome, including defective fibrinolysis, in men and postmenopausal women. This suggests that leptin may be involved in the mediation of consequences of insulin resistance.