Insulin-like growth factor I gene microsatellite repeat, collagen type Ialpha1 gene Sp1 polymorphism, and bone disease in primary biliary cirrhosis

BACKGROUND: Genetic factors have been implicated in the pathogenesis of osteoporosis, a common disorder in primary biliary cirrhosis. Insulin-like growth factor I (IGF-I) gene microsatellite repeat polymorphism was found to be associated with osteoporosis in some studies, and collagen-Ialpha1 (COLIA1) Sp1 s allele was associated with lower bone mineral density in primary biliary cirrhosis. IGF-I treatment restored osteopenia and reduced fibrogenesis in experimental cirrhosis. We investigated IGF-I and COLIA1 gene polymorphisms and bone mineral density in Hungarian primary biliary cirrhosis patients. PATIENTS AND METHODS: Seventy female patients with primary biliary cirrhosis were enrolled (mean age 57.6 years, range 37-76 years; all anti-mitochondrial antibody M2-positive; stage II-IV). One hundred and thirty-nine age-matched female subjects served as controls (mean age 55.9 years, range 43-72 years). COLIA1 and IGF-I polymorphisms were determined by polymerase chain reaction. Bone mineral density was measured by dual-energy X-ray absorptiometry in the lumbar spine and femoral neck. RESULTS: The IGF-I was not different between primary biliary cirrhosis patients and controls. The genotype frequency of COLIA1 polymorphism was also not different between primary biliary cirrhosis patients and controls. However, the s allele was significantly less frequent in patients with primary biliary cirrhosis. Osteoporosis was detected in 22 patients. The IGF-I 192/192 genotype was associated with higher femoral-neck z-scores compared with other genotypes. CONCLUSION: In contrast to previous studies, the s allele was less frequent in patients with primary biliary cirrhosis, and its presence was not associated with bone mineral density. Since IGF-I polymorphism was associated with bone mineral density, it may be hypothesised that not COLIA1 but IGF-I together with other genetic and environmental factors may be involved in the complex regulation of bone mineral density in primary biliary cirrhosis.     

Genetic association of vitamin D receptor polymorphisms with primary biliary cirrhosis and autoimmune hepatitis.

Autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) are immune-mediated chronic inflammatory diseases of the liver of unknown etiology. Genetic factors appear to be involved in the pathogenesis of both diseases. 1,25-Dihydroxyvitamin D(3) has been implicated as an immunomodulator, which acts through its own receptor (VDR). Polymorphisms of the VDR have been linked to a variety of autoimmune diseases. In this study VDR polymorphisms were analyzed in 123 patients with AIH, 74 patients with PBC, and 214 controls. VDR polymorphisms were assessed by BsmI, TaqI, ApaI, and Fok endonuclease digestion after specific polymerase chain reaction (PCR) amplification. We found a significant association between the BsmI polymorphisms in PBC patients in comparison with controls (chi(2) = 9.49, P =.009). Furthermore we detected a significant association of the Fok polymorphims in AIH patients in comparison to controls (chi(2) = 9.71, P =.008) indicating a genetic link of VDR polymorphisms to autoimmune liver diseases such as PBC and AIH in German patients. These findings contribute to the knowledge of the complex events determining immunologic tolerance in the liver. Further studies are needed to elucidate the mechanisms by which the vitamin D receptor contributes to the development of autoimmune diseases.     

Vitamin D receptor,oestrogen receptor-alpha gene and interleukin-1 receptor antagonist gene polymorphisms in Hungarian patients with primary biliary cirrhosis

BACKGROUND : Genetic factors have been implicated in the pathogenesis of osteoporosis, a common disorder in primary biliary cirrhosis. Oestrogen receptor-alpha gene, vitamin D receptor gene and interleukin-1 receptor antagonist gene are all attractive candidates for osteoporosis susceptibility. We investigated the polymorphisms of the above genes and bone disease in Hungarian patients with primary biliary cirrhosis. PATIENTS AND METHODS : Thirty-three female patients with primary biliary cirrhosis were enrolled (age range, 39-72 years; anti-mitochondrial antibody M2 positive, stage II-IV). Eighty-four healthy and 76 osteoporotic age matched female subjects served as controls. Vitamin D receptor BsmI, interleukin-1 receptor antagonist gene variable- number tandem repeat and oestrogen receptor-alpha PvuII and XbaI polymorphisms were determined. Bone mineral density was measured by dual energy X-ray absorptiometry (XR26, Norland) in lumbar spine and femoral neck. RESULTS : The genotype frequency of vitamin D receptor BsmI (BB, 57.5%; Bb, 33.3%; bb, 9.1%) and oestrogen receptor-alpha PvuII (PP, 18.2%; Pp, 75.6%; pp, 6.2%) and XbaI (XX, 9.1%; Xx, 90.9%; xx, 0%) of the primary biliary cirrhosis patients was different from that of the healthy and osteoporotic control groups (P < 0.03 for each). Osteoporosis (t score < -2.5) was present in 42.4% of the patients. Osteoporotic primary biliary cirrhosis patients were older and had a longer disease history (P = 0.01 for both). No association was found between the polymorphisms and bone mineral density values at either position. CONCLUSIONS : We confirmed previous findings concerning the higher frequency of vitamin D receptor BsmI BB genotype in patients with primary biliary cirrhosis. The oestrogen receptor-alpha PvuII and XbaI Pp and Xx genotypes were more frequent in primary biliary cirrhosis patients, while interleukin-1 receptor antagonist gene variable-number tandem repeat polymorphism was not different. Since none of the polymorphisms was associated with bone mineral density, it is unlikely that these polymorphisms are essential in predicting bone mineral density in primary biliary cirrhosis.     

Genetic association of vitamin D receptor polymorphisms with autoimmune hepatitis and primary biliary cirrhosis in the Chinese

BACKGROUND: Autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) are two autoimmune diseases of unknown etiology. Genetic factors appear to be involved in the pathogenesis of both diseases. Vitamin D has been shown to exert multiple immunomodulatory effects, which acts through its own receptor (VDR). Polymorphisms of VDR had been implicated in several autoimmune diseases. In the present study, the association between Chinese patients with AIH, PBC and the polymorphisms in exon 2, intron 8 and exon 9 of vitamin D receptor genes was studied. METHODS: Four candidate gene loci were investigated in 49 patients with AIH, 58 patients with PBC, and 160 healthy controls. The VDR polymorphisms were assessed by FokI, BsmI, ApaI, and TaqI endonuclease digestion after specific polymerase chain reaction (PCR) amplification. RESULTS: The result show a significant difference in FokI polymorphism between AIH patients and controls (chi(2) = 5.47, P = 0.019), and a significant association in BsmI polymorphisms between PBC patients and controls (chi(2) = 6.52, P = 0.01). Furthermore the distribution of FokI, BsmI, ApaI, and TaqI gene types differed between Chinese healthy controls and Caucasian healthy controls. CONCLUSION: It is suggested that there is a genetic link of VDR polymorphisms to autoimmune liver diseases such as AIH and PBC in Chinese patients. Further studies are needed to elucidate the mechanisms by which VDR polymorphisms contribute to the lose of immune tolerance in autoimmune diseases.     

Collagen type Ialpha1 gene polymorphism in idiopathic osteoporosis in men

OBJECTIVE: To analyse the distribution of polymorphism of the collagen type Ialpha1 gene (COL1A1) and its relationship with bone metabolism and bone turnover in men with idiopathic osteoporosis. METHODS: A total of 35 male patients with idiopathic osteoporosis, aged 50.4 +/- 10.3 yr, and 60 healthy males (controls), aged 47 +/- 17 yr, were included in the study. Serum osteocalcin, 25-hydroxyvitamin D and parathyroid hormone were determined in all patients. The COL1A1 Sp1 genotypes (SS, SS:, ss) were assessed by restriction enzyme digestion (BAL:1) of DNA amplified by the polymerase chain reaction. RESULTS: Patients with idiopathic osteoporosis had a higher frequency of the s allele than men in the control group (29 vs 11%, P: = 0.003) and a higher frequency of the SS: genotype (patients, 48% SS, 46% SS:, 6% ss; controls, 80% SS, 18% SS:, 2% ss; P: = 0.003). No significant differences between genotypes were observed in serum concentrations of osteocalcin, vitamin D or parathyroid hormone among either the patients or the controls. CONCLUSION: This study suggests that, in men with idiopathic osteoporosis, there is a high prevalence of the s allele and the SS: genotype that is unrelated to other parameters of bone metabolism.     

The role of vitamin D receptor gene polymorphisms in bone biology

The role of vitamin D and its receptor (VDR) in skeletal metabolism is well known but the vitamin D endocrine system seems to play an important role in other metabolic pathways as well, such as those involved in osteoarthritis, the immune response and cancer. One approach to understand the vitamin D endocrine system is to study the influence of variations in the DNA sequence of important proteins of this system. For example, deleterious mutations in the VDR gene cause 1,25-dihydroxyvitamin D-resistant rickets, a rare monogenetic disease. More subtle sequence variations (polymorphisms) in the VDR gene occur much more frequently but their effects are poorly understood. Their influence on the vitamin D endocrine system is currently under scrutiny in relation to a number of so-called complex diseases and traits such as osteoporosis. The interpretation of polymorphic variations in the VDR gene is severely hindered by the fact that several of the polymorphisms used have unknown effects. However, current data indicate that dozens of additional polymorphic variations exist in the VDR gene that could each have different types of consequences. Therefore, efforts are focussed on finding novel sequence variations and to study their interaction in molecular- and cell-biological experiments as well as in genomic epidemiological studies. The ultimate goal of this approach is to identify the combinations of functional sequence variants that modulate the vitamin D endocrine system and confer risk of disease.     

藏族妇女维生素D受体基因BsmⅠ多态性与骨量无关

测定藏族妇女维生素D受体基因BsmI单核苷酸多态性和跟骨定量超声参数。结果显示不同基因型组对应的定量超声参数差异无统计学意义,年轻妇女和绝经后妇女的基因型分布频率差异也无统计学意义,未发现藏族VDR基因的BsmI多态性与峰值骨量的获得和骨量丢失速率相关。     

A 4-year treatment with clodronate plus calcium and vitamin D supplements does not improve bone mass in primary biliary cirrhosis

IntroductionInternational guidelines for managing osteoporosis in cirrhosis or severe cholestasis indicate a <−2.5 t-score as a cut-off for medical treatment, while no treatment is recommended in the case of osteopenia (t-scores ranging from −1.0 to −2.5).AimWe conducted a prospective study in primary biliary cirrhosis with a view to optimizing the rationale for the medical treatment of bone loss.MethodsAll naïve post-menopausal women with primary biliary cirrhosis were enrolled in the study. Bone metabolism was evaluated by measuring 25-hydroxy-vitamin D, parathyroid hormone, osteocalcin. Bone mineral density was assessed at the lumbar spine by dual-photon X-ray absorptiometry at the baseline and every 2 years for up to 4 years. Patients with either osteopenia or osteoporosis received the following treatment: oral calcium carbonate (1000 mg/day) + vitamin D3 (880 IU/day) + i.m. disodium clodronate 100 mg every 10 days for 4 years.ResultsNinety-six patients completed the study: 30 had a normal bone mineral density (group 1), 37 had osteopenia (group 2), 29 had osteoporosis (group 3). No significant differences in biochemical parameters of bone metabolism were observed between the three groups. A total of 288 bone mineral density measurements were taken. Linear regression analysis failed to reveal significant changes in t-score over the follow-up in all groups.ConclusionsA 4-year treatment with clodronate + calcium/vitamin D3 supplements does not significantly improve osteoporosis or osteopenia in primary biliary cirrhosis women in menopause, but prevents the natural bone loss in these patients. Extensive international trials are warranted to optimize the prevention and treatment of bone loss in primary biliary cirrhosis.     

Association of low bone mass with vitamin d receptor gene and calcitonin receptor gene polymorphisms in juvenile idiopathic arthritis

OBJECTIVE: To compare bone density with polymorphisms in the calcitonin receptor (CTR) and vitamin D receptor (VDR) genes in 50 patients with juvenile idiopathic arthritis and 80 matched controls. METHODS: Bone mineral density (BMD) was measured by dual energy x-ray absorptiometry at the lumbar spine. Genomic DNA was isolated from EDTA blood samples by standard procedures. Polymerase chain reaction was performed using genomic DNA and 100 pmol of each oligonucleotide primer for VDR and CTR genes. Products from genomic PCR were digested by Alu I enzyme for CTR polymorphism and Fok I enzyme for VDR polymorphism. RESULTS: In the total population, higher prevalence of CC genotype (41.5%) for the CTR gene and FF genotype (59.8%) for the VDR gene was found, in agreement with data for Caucasian populations. No significant differences in distribution of CTR and VDR genotypes were observed between patients and controls. However, patients with TT genotype had lumbar BMD (L-BMD) that was lower in comparison to those with CC genotype (p = 0.04). For VDR gene polymorphism, we observed that patients with ff genotype had lower L-BMD in comparison with FF genotype (p = 0.02). Patients with heterozygosity for the 2 genotypes showed intermediate L-BMD. The differences in L-BMD among these groups did not seem to be related to corticosteroid therapy. CONCLUSION: Our data suggest that patients with particular VDR and CTR genotypes may be at higher risk to lose bone mass.     

Fat-soluble vitamin nutriture in primary biliary cirrhosis

We measured serum levels of vitamins A, E, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D, as well as levels of abnormal (des-gamma-carboxy) prothrombin, in 52 patients with primary biliary cirrhosis. Decreased serum levels of retinol (vitamin A) and 25-hydroxyvitamin D and elevated levels of abnormal prothrombin were common in these patients and correlated with the histologic stage of the disease and with the clinical severity of disease as judged by elevated serum bilirubin levels and decreased serum albumin levels. The increased levels of abnormal prothrombin were due primarily to vitamin K deficiency but also, in part, to the severity of the liver disease itself. Vitamin E deficiency was rare. Only 1 patient had clinical manifestations of fat-soluble vitamin deficiency, night blindness, and gastrointestinal bleeding related to a marked prolongation of the prothrombin time. Deficiencies of fat-soluble vitamins are most likely to be present in jaundiced patients with long-standing, severe cholestasis. We suggest that fat-soluble vitamin status be determined in all patients with primary biliary cirrhosis by appropriate blood tests and that vitamin supplements be given only to those patients who require them.     

Hyperparathyroidism and low serum osteocalcin despite vitamin D replacement in primary biliary cirrhosis

Thirty-six patients with primary biliary cirrhosis (PBC) receiving calcium and calciferol supplements (100,000 IU monthly by im injection) were investigated for their calcium, vitamin D, PTH, and osteocalcin status. The corrected plasma calcium concentrations in PBC patients were significantly greater than those in normal subjects. While the mean serum 25-hydroxycholecalciferol and 1,25-dihydroxyvitamin D concentrations in these patients were similar to those in normal subjects, the mean serum PTH concentration was significantly greater, and it was supranormal in 11 patients. Three patients had elevated corrected calcium concentrations; 1 of them had a concomitant increase in ionized calcium and a supranormal PTH level, and another had a high normal PTH. Ionized calcium concentrations were normal in the rest. Serum osteocalcin concentrations were significantly lower in the patients compared with those in normal subjects. These results indicate that PTH concentrations are frequently elevated in PBC patients despite adequate vitamin D supplementation and normal or even supranormal plasma calcium concentrations. Nonsuppression of PTH concentrations and autonomy of PTH secretion suggest that vitamin D deficiency and secondary hyperparathyroidism in such patients probably occur much earlier in the natural history of this disease than is currently realized. Persistent nonsuppressible hypersecretion of PTH probably contributes to the bone disease of primary biliary cirrhosis. The low osteocalcin concentrations probably reflect diminished osteoblastic activity, which may also contribute to osteopenia in these patients.     

Evaluation of the effects of vitamin D receptor and estrogen receptor 1 gene polymorphisms on bone mineral density in postmenopausal women

The aim of this study is to evaluate the effects of estrogen receptor 1 (ESR1) and vitamin D receptor (VDR) gene polymorphisms on bone mineral density (BMD) in a group of previously untreated osteoporotic women. Effects of demographic, environmental, and hormonal factors were also evaluated in this context. Fifty women who did not have a prior diagnosis or treatment of osteoporosis were compared with 50 nonosteoporotic postmenopausal women. Demographic and morphometric characteristics, medical history, dietary habits, exercise history, and sunlight exposure were recorded. The diagnosis of osteoporosis was made with regard to BMD measurements with DEXA. Blood samples were obtained for serum biochemistry, bone turnover markers, and VDR and ESR1 gene polymorphism analysis. Polymorphic sites of VDR and ESR1 genes were amplified by polymerase chain reaction and examined using restriction fragment length polymorphism. Bb genotype was significantly higher in the osteoporotic group when compared to controls (p = 0.022). Each 1 U decrease in the body mass index (BMI) increased the risk of osteoporosis by 8% independent of the genotype. We could not observe a significant effect of ESR1 polymorphism on BMD or osteoporosis risk. The interaction of ApaI and BsmI genotypes were found to be significant (p = 0.041) and the AaBb genotype, when corrected for BMI, was shown to increase the risk of osteoporosis five times (p = 0.005). However, the results demonstrated insignificant p values when correction for multiple testing was performed with the Bonferroni method in the logistic regression model. A predominance of Bb genotype of the VDR gene was evident in this group of postmenopausal Turkish women. Moreover, the combined genotype AaBb conferred a five times increased risk for osteoporosis when corrected for clinical variables.     

Vitamin D receptor gene polymorphisms and hepatocellular carcinoma in alcoholic cirrhosis

AIM: To assess the relationship between vitamin D re-ceptor (VDR) gene polymorphisms and the presence of hepatocellular carcinoma (HCC). METHODS: Two-hundred forty patients who underwent liver transplantation were studied. The etiologies of liver disease were hepatitis C (100 patients), hepatitis B (37) and alcoholic liver disease (103). A group of 236 healthy subjects served as controls. HCC in the explanted liver was detected in 80 patients. The following single nucle-otide gene polymorphisms of the VDR w...