Interaction between the vitamin D receptor gene and collagen type Ialpha1 gene in susceptibility for fracture.

Osteoporosis is a common disease with a strong genetic component. Polymorphisms in the vitamin D receptor (VDR) gene have been implicated in osteoporosis but explain only a small part of the genetic effect on bone mineral density (BMD) while their effect on fractures is still uncertain. Recently, a G to T polymorphism in an Sp1 site in the collagen type Ialpha1 (COLIA1) gene was found to be associated with reduced BMD and with increased fracture risk. To analyze the combined influence of polymorphisms in the VDR gene and the COLIA1 gene in determining the susceptibility to osteoporotic fracture, we studied 1004 postmenopausal women. The "baT" VDR haplotype, constructed from three adjacent restriction fragment length polymorphisms, was found to be overrepresented among fracture cases (p = 0.009). This corresponded to an odds ratio (OR) of 1.8 (95% CI, 1.0-3.3) for heterozygous carriers and 2.6 (95% CI, 1.4-5.0) for homozygous carriers of the risk haplotype. The effect was similar for vertebral and nonvertebral fractures and, most importantly, independent of BMD. We observed significant interaction (p = 0.03) between VDR and COLIA1 genotype effects. Fracture risk was not VDR genotype-dependent in the COLIA1 "reference" group (genotype GG) while in the COLIA1 "risk" group (genotypes GT and TT) the risk of fracture was 2.1 (95% CI, 1.0-4.4) for heterozygous and 4.4 (95% CI, 2.0-9.4) for homozygous carriers of the VDR risk haplotype. We conclude that both the VDR and the COLIA1 polymorphisms are genetic markers for osteoporotic fracture in women, independent of BMD. Our data indicate that interlocus interaction is likely to be an important component of osteoporotic fracture risk.     

Studies of Bone Density, Quantitative Ultrasound, and Vertebral Fractures in Relation to Collagen Type I Alpha 1 Alleles in Elderly Women

Previous studies have demonstrated that an Sp1 binding site polymorphism in the collagen type I gene (COLIA1) is related to reduced bone mineral density (BMD) and osteoporotic fractures in certain populations, particularly in the elderly. We have examined the relationship among these COLIA1 Sp1 alleles, BMD, quantitative ultrasound properties of bone, and fractures in a population-based cohort of elderly women from the UK. The study group comprised 314 women aged 75 years and over who agreed to participate in a clinical study of bisphosphonate therapy in preventing bone loss at the hip. Women were enrolled regardless of the presence or absence of osteoporosis, but those with other diseases that might affect skeletal metabolism were excluded. The genotype distribution for the Sp1 polymorphism was in Hardy-Weinberg equilibrium (SS - 78%; Ss - 20%; ss - 2%) but the proportion of individuals who carried the "s" allele (22%) was significantly lower than previously observed in another study of the UK population (37.1%) (P < 0.001). There were no significant associations between COLIA1 genotypes and metacarpal cortical index, BMD of the forearm, tibial SOS, calcaneal SOS, or calcaneal BUA. While there was a trend towards lower BMD values at the hip in patients with Ss and ss genotypes, this was not statistically significant (SS = 0.721 +/- 0.14; Ss = 0.704 +/- 0.13; ss = 0.683 +/- 0.20 P = 0.6). Prevalent vertebral fractures occurred in 22% of subjects and prior fractures of the wrist, ankle, and hip were reported by 20%, but there was no significant difference in COLIA1 genotype distribution between fracture patients and controls. We conclude that COLIA1 Sp1 alleles are not significantly associated with BMD, ultrasound properties of bone, or fractures in this population-based sample of elderly women.     

Relationship among VDR (BsmI and FokI), COLIA1, and CTR polymorphisms with bone mass,bone turnover markers,and sex hormones in men

Osteoporosis is a disease characterized by low bone mineral density (BMD) and up to 80% of its variance is under genetic control. Although osteoporosis is more frequent in women, one-third of hip fractures also occur in men. Much information on genetic factors and bone density has been obtained in women, but only a few studies have been performed in osteoporotic men. We have evaluated the relationship between polymorphisms for several candidate genes such as vitamin D receptor (VDR), collagen type Ia1 (COLIA1), and calcitonin receptor (CTR) in a sample of unrelated Italian men (n = 253, mean age 58.41 +/- 15.64 SD). We found no significant differences in BMD when subjects were stratified for their VDR (BsmI and FokI) and COLIA1 genotypes. BMD both at the lumbar spine and at the femoral neck were associated with polymorphism of CTR gene. The CC genotype of CTR gene had the lowest BMD value (P <0.05 and P <0.01 at the spine and hip, respectively) and its prevalence was significantly over-represented in the subgroup of men with prior hip or vertebral fracture as compared with controls (P = 0.004% c2 = 11.10). The men with the CC genotype also showed significantly lower body mass index (BMI), serum sex hormone binding globulin (SHBG), estradiol, total alkaline phosphatase-(total AP) and bone alkaline phosphatase (bone AP) levels and significantly higher free androgen index (FAI). In conclusion, the polymorphism of CTR gene but not VDR and COLIA1 is associated with osteoporosis incidence and the levels of alkaline phosphatase and estradiol. The lower BMD in CC genotype is apparently associated in males with depressed bone formation and lower estradiol levels.     

Polymorphism in the type I collagen (COLIA1) gene and risk of fractures in postmenopausal women.

Twin and family studies have demonstrated that a large part of a population's variance in bone mineral density (BMD) is attributable to genetic factors. A polymorphism in the collagen type I alpha1 (COLIA1) gene has recently been associated with low bone mass and fracture incidence. We analyzed the relationship between COLIA1 gene polymorphism, lumbar spine and hip BMD, and fracture prevalence in a population of 319 postmenopausal women classified by WHO standards, including 98 nonosteoporotic women (NOPW) and 221 osteoporotic postmenopausal women (OPW), divided into 139 osteoporotic women without fracture (OPWnF) and 82 osteoporotic women with fracture (OPWwF). The COLIA1 genotype was assessed by polymerase chain reaction and BalI endonuclease digestion. Genotype frequencies for the total group were 49.2% GG homozygotes, 39.5% GT heterozygotes, and 11.3% TT homozygotes. We found significant differences in the percentage of homozygous TT between NOPW and OPW (6.1% and 13.6%, respectively). Significantly, the occurrence of genotype TT in OPWnF was 6.2%, and 28% in OPWwF. We observed no associations between the COLIA1 genotype and lumbar spine and hip BMD. The prevalence of fractures varied significantly by genotype: GG, 26.1%; GT, 15.9%; and TT, 58.3%. Logistic regression analysis of fracture prevalence showed that, for prevalent fractures, the women with the TT genotype had a 5.9-fold increased risk when compared with the other genotypes (GG + GT). When prevalence was adjusted for age, body mass index, and BMD, the fracture risk was 4.8 for the TT group vs. the genotype GG, whereas it was 0.6 for the GT genotype. In conclusion, we found the COLIA1 Sp1 TT genotype to be associated with an increased fracture risk in postmenopausal women. Interestingly, this genotype-dependent risk could not be explained completely by BMD differences.     

Association Between COLIA1 Sp1 Alleles and Femoral Neck Geometry

Genetic factors play an important role in the pathogenesis of osteoporosis by affecting bone mineral density and other predictors of osteoporotic fracture risk such as ultrasound properties of bone and skeletal geometry. We previously identified a polymorphism of a Sp1 binding site in the Collagen Type 1 Alpha 1 gene (COLIA1) that has been associated with reduced BMD and an increased risk of osteoporotic fractures in several populations. Here we looked for evidence of an association between COLIA1 Sp1 alleles and femoral neck geometry. The study group comprised 153 patients with hip fracture, and 183 normal subjects drawn at random from the local population. Femoral neck geometry was assessed by analysis of pelvic radiographs in the fracture patients and DXA scan printouts in the population-based subjects. The COLIA1 genotypes were detected by polymerase chain reaction and were in Hardy Weinberg equilibrium: "SS" = 222 (66%); "Ss" = 105 (31.3%); and "ss" = 9 (2.7%). There was no significant difference in hip axis length or femoral neck width between the genotype groups, but femoral neck-shaft angle was increased by about 2 degrees in the Ss/ss genotype groups (n = 114) when compared with SS homozygotes (n = 222) (P = 0.001). Previous studies have suggested that an increased femoral neck-shaft angle may increase the risk of hip fracture in the event of a sideways fall by influencing the forces that act on the femoral neck. The association COLIAI genotype and increased femoral neck angle noted here may therefore contribute to the BMD-independent increase in hip fracture risk noted in previous studies of individuals who carry the 's' allele.     

Prediction of Osteoporotic Fractures by Bone Densitometry and COLIA1 Genotyping: A Prospective, Population-Based Study in Men and Women

Osteoporosis is a common disease with a strong genetic component, characterized by reduced bone mineral density and increased fracture risk. Although the genetic basis of osteoporosis is incompletely understood, previous studies have identified a polymorphism affecting an Sp1 binding site in the COLIA1 gene that predicts bone mineral density and osteoporotic fractures in several populations. Here we investigated the role of COLIA1 genotyping and bone densitometry in the prediction of osteoporotic fractures in a prospective, population-based study of men (n= 156) and women (n= 185) who were followed up for a mean (± SEM) of 4.88 ± 0.03 years. There was no significant difference in bone density, rate of bone loss, body weight, height, or years since menopause between the genotype groups but women with the “ss” genotype were significantly older than the other genotype groups (p= 0.03). Thirty-nine individuals sustained 54 fractures during follow-up and these predominantly occurred in women (45 fractures in 30 individuals). Fractures were significantly more common in females who carried the COLIA1“s” allele (p= 0.001), although there was no significant association between COLIA1 genotype and the occurrence of fractures in men. Logistic regression analysis showed that carriage of the COLIA1“s” allele was an independent predictor of fracture in women with an odds ratio (OR) [95% CI] of 2.59 [1.23–5.45], along with spine bone mineral density (OR = 1.57 [1.04–2.37] per Z-score unit) and body weight (OR = 1.05 [1.01–1.10] per kilogram). Moreover, bone densitometry and COLIA1 genotyping interacted significantly to enhance fracture prediction in women (p= 0.01), such that the incidence of fractures was 45 times higher in those with low BMD who carried the “s” allele (24.3 fractures/100 patient-years) compared with those with high BMD who were “SS” homozygotes (0.54 fracture/100 patient-years). We conclude that in our population, COLIA1 genotyping predicts fractures independently of bone mass and interacts with bone densitometry to help identify women who are at high and low risk of sustaining osteoporotic fractures. Received: 16 November 2000 / Accepted: 9 June 2000     

Vitamin D Receptor Gene Polymorphisms, Bone Mass, Bone Loss and Prevalence of Vertebral Fracture: Differences in Postmenopausal Women and Men

Bone mineral density (BMD), the major determinant of fracture risk, is under strong genetic control. Although polymorphisms of the vitamin D receptor (VDR) gene have been suggested to account for some of the genetic variation in bone mass, the influence of VDR genotypes on osteoporosis remains controversial. Previous published studies have focused mainly on women, but the pattern of response in men has not been determined. Using the BsmI restriction enzyme, we studied the influence of the different VDR genotypes on bone mass, bone loss and the prevalence of vertebral fractures in a population-based sample of both sexes (n = 326). BMD was measured at the lumbar spine and femoral neck, with a 4-year interval, using dual-energy X-ray absorptiometry. Vertebral fractures were assessed by two lateral radiographs at the beginning and end of the study. The prevalence of the three possible VDR genotypes was similar to those in other Caucasian populations and no differences were found between men and women. Women with the favorable bb genotype showed significantly higher BMD values at the lumbar spine and femoral neck, and a positive rate of BMD change at the femoral neck compared with women with the BB and Bb genotypes. Moreover, women with the bb genotype showed a trend toward a lower prevalence and incidence of vertebral fractures (p= 0.07). We have not found any differences between VDR genotypes in men. In conclusion, VDR gene polymorphisms are related to bone mass and bone loss in women; also a trend in the prevalence of vertebral fractures was observed in postmenopausal women but not in men. Received: 8 June 1998 / Accepted: 7 December 1998     

Association of the VDR translation start site polymorphism and fracture risk in older women.

We evaluated the association between the VDR translation start site polymorphism and osteoporotic phenotypes among 6698 older white women. Women with the C/C genotype had lower wrist BMD and an increased risk of wrist and all non-spine/low-trauma fractures. The high frequency of this variant confers a population attributable risk that is similar to several established risk factors for fracture. INTRODUCTION: The vitamin D receptor (VDR) is a nuclear receptor that regulates bone formation, bone resorption, and calcium homeostasis. A common C to T polymorphism in exon 2 of the VDR gene introduces a new translation start site and a protein that differs in length by three amino acids (T = 427aa, C = 424aa; rs10735810). MATERIALS AND METHODS: We conducted genetic association analyses of this polymorphism, BMD, and fracture outcomes in a prospective cohort of 6698 white American women >or=65 years of age. Incident fractures were confirmed by physician adjudication of radiology reports. There were 2532 incident nontraumatic/nonvertebral fractures during 13.6 yr of follow-up including 509 wrist and 703 hip fractures. RESULTS: Women with the C/C genotype had somewhat lower distal radius BMD compared with those with the T/T genotype (CC=0.358 g/cm(2), CT=0.361 g/cm(2), TT=0.369 g/cm(2), p=0.003). The C/C genotype was also associated with increased risk of non-spine, low traumatic fractures (HR: 1.18; 95% CI: 1.04, 1.33) and wrist fractures (HR: 1.33; 95% CI: 1.01, 1.75) compared with the T/T genotype in age-adjusted models. Further adjustments for distal radius BMD only slightly attenuated these associations. The VDR polymorphism was not associated with hip fracture. The population attributable risk (PAR) of the C/C genotype for incident fractures was 6.1%. The PAR for established risk factors for fracture were: low femoral neck BMD (PAR=16.3%), maternal history of fracture (PAR=5.1%), low body weight (PAR=5.3%), corticosteroid use (PAR=1.3%), and smoking (PAR=1.6%). Similar PAR results were observed for wrist fractures. CONCLUSIONS: The common and potentially functional VDR translation start site polymorphism confers a modestly increased relative risk of fracture among older white women. However, the high frequency of this variant confers a population attributable risk that is similar to or greater than several established risk factors for fracture.     

Performance of COLIA1 Polymorphism and Bone Turnover Markers to Identify Postmenopausal Women with Prevalent Vertebral Fractures

Some studies have suggested that bone turnover markers (BTM) and collagen type I alpha 1 gene (COLIA1) may be useful in the prediction of rates of future bone loss, and may therefore provide information about fracture risk. Our study aimed to examine the association of the COLIA1 genotype with the risk of vertebral fracture and to investigate the predictive value of this genetic factor in comparison with bone mineral density (BMD) and BTM, in ambulatory postmenopausal Spanish women. We determined the COLIA1 polymorphism by polymerase chain reaction, BMD by dual-energy X-ray absorptiometry and BTM in 43 postmenopausal women with prevalent vertebral fracture and a control group of 101 postmenopausal women without fracture. There was a significant overrepresentation of the ‘T’ allele in fractured women (p= 0.029). BTM exhibited no differences between women with or without fractures or COLIA1 genotype groups. After adjusting for all other variables, the osteoporosis densitometric criteria variable was the most strongly associated with fracture (OR = 5 [1.8–13.3]) followed by COLIA1 (OR = 2.1 [1–4.3] per copy of the ‘T’ allele). Our study shows that COLIA1 is associated with prevalent vertebral fracture independently of bone mass, and the performance of this genetic factor to assess prevalent vertebral fracture is better than bone turnover markers. Received: 29 June 2001 / Accepted: 11 December 2001     

Enhancement of Absolute Fracture Risk Prognosis with Genetic Marker: The Collagen I Alpha 1 Gene

An important objective of genetic research in osteoporosis is to translate genotype data into the prognosis of fracture. The present study sought to develop a prognostic model for predicting osteoporotic fracture by using information from a genetic marker and clinical risk factors. It was designed as a prospective epidemiological study which involved 894 women of Caucasian background aged 60+ years who had been followed for a median of 9 years (from 1989 and 2008, range 0.2–18 years). During the follow-up period, fragility fracture was ascertained by X-ray reports for all women. Bone mineral density (BMD) at the femoral neck was measured by dual-energy X-ray absorptiometry. Genotypes of the Sp1 binding site in the first intron of the collagen I alpha 1 (COLIA1) gene polymorphism were determined by polymerase chain reaction, digestion with BalI restriction enzyme, and agarose gel electrophoresis. The relationship between COL1A1 genotype and fracture was assessed by the Cox proportional hazards model, from which nomograms were developed for individualizing the risk of fracture. The distribution of COL1A1 genotypes was consistent with the Hardy-Weinberg equilibrium law: GG (63.8%), GT (32.6%), and TT (3.6%). During the follow-up period, there were 322 fractures, including 77 hip and 127 vertebral fractures. There was an overrepresentation of the TT genotype in the fracture group (6.2%) compared with the nonfracture group (2.3%). Compared with carriers of GT and GG, women carrying the TT genotype had increased risk of any fracture (relative risk [RR] = 1.91, 95% CI 1.21–3.00), hip fracture (RR = 3.67, 95% CI 1.69–8.00), and vertebral fracture (RR = 3.36, 95% CI 1.81–6.24). The incorporation of COL1A1 genotypes improved the risk reclassification by 2% for any fragility fracture, 4% for hip fracture, and 5% for vertebral fracture, beyond age, BMD, prior fracture, and fall. Three nomograms were constructed for predicting fracture risk in an individual woman based on age, BMD, and COLIA1 genotypes. These data suggest that the COLIA1 Sp1 polymorphism is associated with the risk of fragility fracture in Caucasian women and that the polymorphism could enhance the predictive accuracy of fracture prognosis. The nonograms presented here can be useful for individualizing the short- and intermediate-term prognosis of fracture risk and help identify high-risk individuals for intervention for appropriate management of osteoporosis.     

COLIA1 Sp1 Polymorphism Predicts Response of Femoral Neck Bone Density to Cyclical Etidronate Therapy

Genetic factors are important in the pathogenesis of osteoporosis but less is known about their possible role in predicting response to anti-osteoporotic therapy. Previous studies have shown that a polymorphic Sp1 binding site in the collagen type 1 alpha 1 gene (COLIA1) is associated with bone mineral density (BMD) and osteoporotic vertebral fracture. In this study we sought to determine if the COLIA1 Sp1 polymorphism might also act as a predictor of the response to treatment of osteoporosis with bisphosphonate therapy. The study group comprised 108 perimenopausal women with osteopenia who had been randomized to receive cyclical etidronate therapy for 2 years with a 1-year treatment-free follow-up as part of a randomized placebo controlled trial. Bone mineral density was measured at the lumbar spine and femoral neck by dual X-ray absorptiometry and genotyping performed on DNA extracted from peripheral blood leukocytes using standard techniques. The distribution of COLIA1 genotypes was similar to that previously reported in Caucasians with 69 (63.9%) "SS" homozygotes, 38 (35.2%) "Ss" heterozygotes, and 1 (0.9%) "ss" homozygote. There was no association between COLIA1 genotype and response of lumbar spine BMD during etidronate treatment or the follow-up phase. The response of femoral neck (FN) BMD, however, differed significantly between the genotype groups throughout the study period, such that FN BMD increased by 0.56%, 2.36%, 1.82%, and 1.32 % after 1, 2, 2.5, and 3 years, respectively in the "SS" genotype group, compared with -1.56%, -0.62%, -0.37%, and -0.66% in the "Ss/ss" genotype groups (P = 0.002). The data presented here show that site-specific heterogeneity exists in the response of BMD to cyclical etidronate therapy, which is related to COLIA1 genotype. Our data raise the possibility that COLIA1 genotyping could be used to target etidronate therapy to those most likely to respond in terms of FN BMD, with potential benefits in terms of economic cost and clinical outcome.     

Vitamin D receptor gene polymorphisms are associated with increased risk and progression of renal cell carcinoma in a Japanese population

AIM: Biological and epidemiologic data suggest that 1 alpha, 25 dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) levels may influence development of renal cell carcinoma. The vitamin D receptor (VDR) is a crucial mediator for the cellular effects of 1,25(OH)(2)D(3) and additionally interacts with other cell signaling pathways that influence cancer progression. VDR gene polymorphisms may play an important role in risk of incidence for various malignant tumors. This study investigated whether VDR gene polymorphisms were associated with increased risk and prognosis of renal cell carcinoma (RCC) in a Japanese population. METHODS: To analyze risk of RCC depending on VDR polymorphism, a case-control association study was performed. The VDR gene polymorphisms at three locations, BsmI, ApaI and TaqI, were genotyped in 135 RCC patients and 150 controls in a Japanese population. Logistic regression models were used to assess the genetic effects on prognosis. RESULTS: Significant differences in the ApaI genotype were observed between RCC patients and controls (chi(2) = 6.90, P = 0.032). No statistical significant difference was found in the BsmI and TaqI polymorphisms. The frequency of the AA genotype in the ApaI polymorphism was significantly higher in the RCC patients than in the controls (odds ratio, 2.59; 95% confidence intervals, 1.21-5.55; P = 0.012). Multivariate regression analysis showed that the AA genotype was an independent prognostic factor for cause-specific survival (relative risk 3.3; P = 0.038). CONCLUSION: The AA genotype at the ApaI site of the VDR gene may be a risk of incidence and poor prognosis factor for RCC in the Japanese population. Additional studies with a large sample size and investigation of the functional significance of the ApaI polymorphism in RCC cells are warranted.     

Genetic and environmental determinants of peak bone mass in young men and women.

Peak bone mass is an important risk factor for the development of osteoporosis in later life. Previous work has suggested that genetic, intrauterine, and environmental factors all contribute to the regulation of bone mass, but the ways in which they interact with each other to do so remain poorly understood. In this study, we investigated the relationship between peak bone mass and polymorphisms of the vitamin D receptor (VDR), estrogen receptor (ER) a, and collagen type Ialpha1 (COLIA1) genes in relation to other factors such as birth weight, lifestyle diet, and exercise in a population-based cohort of 216 women and 244 men in their early 20s. Stepwise multiple regression analysis showed that body weight was the strongest predictor of bone mineral density (BMD) in women, accounting for 16.4% of the variance in spine BMD and 8.4% of the variance in femoral neck BMD. Other significant predictors were VDR genotype (3.8%) and carbohydrate intake (1.6%) at the spine and vitamin D intake (3.4%) and ER genotype (3.4%) at the femoral neck. Physical activity was the strongest predictor of BMD in men, accounting for 6.7% of the variance at the spine and 5.1% at the hip. Other significant predictors were body weight (5%) and ER PvuII genotype (2.8%) at the spine and weight (3.4%) and alcohol intake (2%) at the femoral neck. Birth weight was not a significant predictor of BMD at either site but COLIA1 genotype significantly predicted birth weight in women, accounting for 4.3% of the variance. We conclude that peak bone mass is regulated by an overlapping but distinct set of environmental and genetic influences that differ in men and women. However, much of the variance in BMD was unexplained by the variables studied here, which suggests that either most of the genes that regulate BMD remain to be discovered or major environmental influences on BMD exist that have not yet been identified.     

Susceptibility for Postmenopausal Osteoporosis: Interaction Between Genetic,Hormonal and Lifestyle Factors

Although previous studies have established the importance of genetic, hormonal and lifestyle factors separately, the integral role of these factors on bone mass in postmenopausal women is still controversial. We examined the association of the collagen 1-alpha-1 gene (COLIA1) and vitamin D receptor gene (VDR) polymorphisms, s-IGF-I, s-25OHD and lifestyle factors with bone mineral density (BMD) in postmenopausal women. We determined anthropometric parameters, lifestyle factors, serum levels of IGF-I and 25OHD, the COLIA1 Sp1 (Mscl) and VDR (Bsml, Taql) polymorphisms by PCR and BMD by dual X-ray absorptiometry in 141 ambulatory postmenopausal Spanish women. There were significant linear correlations between S-25OHD and BMD and between s-IGF-I and BMD. BMD was statistically higher in active subjects. Of the three different polymorphisms, only the COLIA1 Sp1 polymorphism was significantly associated with BMD. In the logistic regression model, the COLIA1 Sp1 polymorphism, S-25OHD, s-IGF-I and physical activity variables were independently associated with osteoporosis. Our study shows that COLIA1 Sp1 polymorphism, S-25OHD and s-IGF-I serum levels and physical activity are independently associated with BMD in postmenopausal Spanish women.     

老年胸腰段骨质疏松性椎体压缩骨折患者维生素D受体基因多态性与其骨密度及半定量分型的相关性分析

目的 探讨老年胸腰段骨质疏松性椎体压缩骨折(osteoporotic vertebral compression fracture,OVCF)患者维生素D受体(vitamin D receptor,VDR)基因多态性与其骨密度及半定量分型的相关性.方法 选取2016年3月至2019年3月我院94例老年OVCF患者作为观...     

Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is associated with osteoporotic vertebral fractures, but is a weak predictor of BMD

Osteoporosis is a common disease with a strong genetic component. Linkage studies have suggested linkage between BMD and loci on chromosome 1. The MTHFR gene is located on chromosome 1. MTHFR catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methylenetetrahydrofolate, which is used for homocysteine methylation to methionine. The rare genotype (TT) of the C677T polymorphism has previously been demonstrated to be associated with increased plasma homocysteine levels in individuals with inadequate plasma folate levels. Recently, the TT genotype has been found to be associated with reduced bone mass. We therefore examined if the C677T polymorphism in the MTHFR gene is associated with changes in bone mass and risk of osteoporotic fractures in 388 osteoporotic patients and 336 normal individuals. The distributions of the genotypes CC, CT and TT in women with osteoporotic vertebral fractures and normal controls were 43.5%, 42.2% and 14.3% and 52.0%, 42.0% and 8.0%, respectively, ²=5.62, P=0.06. Since studies of the functionality of this polymorphism have revealed that only the TT genotype is associated with biochemical changes, we also compared the prevalence of the TT genotype versus the CT- and CC genotypes in patients and controls and found that the TT genotype is significantly more common in women with vertebral fractures (14.3%) compared with normal controls (8.0%), ²=4.31, P<0.05. Logistic regression analysis demonstrated that vertebral fractures were significantly associated with BMD (lumbar spine) and height but only marginally with the MTHFR genotype (P=0.06). Multiple linear regression analysis revealed that weight, age and the MTHFR polymorphism were predictors of lumbar spine BMD in women. However, age- and gender-corrected BMD of the lumbar spine and the hip was not significantly different between MTHFR genotypes. Furthermore, individuals with the TT genotype did not have BMD significantly lower than the combined group of individuals with the CT- or CC genotypes. In conclusion, we have demonstrated that the rare TT genotype of the C677T polymorphism in the MTHFR gene is associated with increased risk of osteoporotic fractures in women and a weak predictor of lumbar spine BMD.     

Lack of Influence of Collagen Type Iα1 Sp1 Binding Site Polymorphism on the Rate of Bone Loss in a Cohort of Postmenopausal Danish Women Followed for 18 Years

A polymorphism in an Sp1 site in the collagen Iα1 (COLIA1) gene has recently been identified and the Ss and ss genotypes were shown to be potentially important determinants of low bone mass in postmenopausal women. Additionally, in a Dutch population, the association of the COLIA1 polymorphism with low bone mineral density (BMD) was more pronounced with increasing age, suggesting a genotype effect on the rate of bone loss. We have investigated the relationship between the COLIA1 Sp1 polymorphism and the rate of bone loss in a longitudinal study with a total of 133 postmenopausal women followed for 18 years. The frequencies of the genotypes were SS 70.7%, Ss 27.8%, ss 1.5% and were in Hardy-Weinberg equilibrium. No association of the COLIA1 genotype with rate of bone loss was detected and there was no difference between the genotype groups with respect to BMD at the femoral neck or lumbar spine. Women with the Ss or ss genotypes, who have been postulated to have low BMD, had even higher BMD at the lower forearm than women with the SS genotype. The levels of serum osteocalcin and urinary collagen type I degradation products were not found to be associated with the COLIA1 Sp1 polymorphism. In conclusion, this study does not support the hypothesis that the Ss COLIA1 genotype predisposes women to increased rate of bone loss or low BMD. However, because of a low absolute number of the ss genotype, it was not possible to reach a conclusion on this particular genotype with regard to an association with low BMD or rate of bone loss. Received: 25 January 1999 / Accepted: 12 January 2000     

Association of collagen Ialpha 1 Sp1 polymorphism with the risk of prevalent fractures: a meta-analysis.

Several studies have addressed the effect of the Spl polymorphism of the collagen Ialpha 1 (COLIA1) gene on the prevalence of fractures. The results are not in full agreement on whether this polymorphism is associated with fracture risk. To clarify this uncertainty, we performed a meta-analysis including 13 eligible studies with 3641 subjects. The COLIA1 Spl polymorphism showed a dose-response relationship with the prevalence of fractures. The risk was 1.25-fold (95% CI, 1.09-1.45) in Ss heterozygotes versus SS homozygotes, 1.68-fold (95% CI, 1.35-2.10) in ss homozygotes versus SS homozygotes, and 1.35 (95% CI, 1.04-1.75) for ss homozygotes versus Ss heterozygotes by random effects calculations. There was modest heterogeneity for these three effect estimates (p value for heterogeneity, 0.17, 0.16, and 0.08, respectively). The Sp1 polymorphism effects possibly were larger when the analysis was limited to studies considering only vertebral fractures (pooled risk ratios [RR], 1.30, 2.07, and 1.46, respectively). Conversely, the Spl polymorphism effects tended to be smaller in studies with mean patient age > or = 65 years than in studies with younger patients on average, but the differences were not formally significant. We estimated the total average attributable fraction (AF) of fractures due to the s allele in European/U.S. populations as 9.4%. The meta-analysis suggests an important role for the Spl polymorphism in the regulation of fracture risk; however, potential heterogeneity across ethnic groups, age groups, and skeletal sites may be important to clarify in future studies. Very large studies or meta-analyses are required to document subtle genetic differences in fracture risk.     

COLIA1 polymorphism contributes to bone mineral density to assess prevalent wrist fractures

Wrist fractures associated with postmenopausal women are only partially explained by osteoporosis. Recent studies have shown that polymorphism of an Spl binding site in the first intron of the collagen I alpha 1 gene (COLIA1) may determine risk for vertebral and nonvertebral fractures in post-menopausal women independent of bone mass. We investigated the relationship between the COLIA1 polymorphism, lumbar spine and femoral neck bone mineral density (BMD), ultrasound stiffness of the heel, anthropometric variables, and risk for wrist fractures in 126 Czech postmenopausal women with low bone mass who suffered one or more wrist fracture in the last 5 years and in 126 postmenopausal women with low bone mass without any fracture. Genotypes for the Spl COLIA1 polymorphism were determined by polymerase chain reaction, digestion with Ball restriction enzyme, and agarose gel electrophoresis. The test discriminates two alleles, S and s, which correspond to the presence of guanine and thymidine, respectively, at the first bases in the Spl-binding site in the first intron of the gene for CO-LIA1. No significant differences were found between the fracture and control group with regard to age, weight, and years since menopause. However, BMD of the lumbar spine and femoral neck and ultrasound stiffness of the heel were significantly lower in patients with prevalent wrist fracture. Femoral neck BMD was the strongest determinant of prevalent fracture of the wrist. COLIA1 genotyping significantly strengthened prediction of prevalent fracture of the wrist. After multivariate adjustment, women in the Ss group had 2.0 times the risk of the women in the SS group (95% confidence interval [CI] = 1.1-3.8), and the women in the ss group had 2.8 times the risk of the women in the SS group (95% CI = 0.5-14.6). The overall gene-dose effect was an odds ratio of 2.1 per copy of the "s" allele (95% CI = 1.2-3.8). In the stepwise logistic regression, COLIA1 acted synergistically with femoral neck BMD and weight in increasing prediction of wrist fracture. The results demonstrate that COLIA1 Sp1 polymorphism is associated with an increased risk of wrist fracture in postmenopausal women independent of BMD and may be helpful in clinical practice by identifying patients with an increased fracture risk.     

Genotypes and Haplotypes of the Estrogen Receptor Genes, but Not the Retinoblastoma-interacting Zinc Finger Protein 1 Gene, Are Associated with Osteoporosis

Osteoporosis is a common age-related disease with a strong genetic influence. Polymorphisms of ESR1 have consistently been shown to be associated with bone mineral density (BMD) and fracture; however, in regulating bone metabolism, ESR1 interacts with both ESR2 and RIZ1. We therefore examined the effects of polymorphisms in the ESR1, ESR2, and RIZ1 genes and their haplotypes on vertebral fractures and BMD in a case-control study comprising 462 osteoporotic patients and 336 controls. In ESR1, we found the variant C allele of the XbaI polymorphism to be associated with decreased risk of vertebral fractures in women (P < 0.01), whereas in men, the T allele seemed protective (P = 0.05). The variant G allele of the PvuII polymorphism decreased the risk of vertebral fractures independently of lumbar spine BMD in women (P = 0.04) but had no effect in men. Haplotype X-P-H (XbaI:C, PvuII:G, and a high number of TA repeats) was associated with decreased risk of vertebral fractures in women (P = 0.04) but not men. In ESR2, the G allele of the AluI polymorphism was associated with increased fracture risk (P = 0.04), and the haplotype that comprises rs1256031:T and AluI:A increased lumbar spine BMD by 0.04 ± 0.02 g/cm² (P < 0.05) and decreased the risk of vertebral fractures (P = 0.04). There was no effect of the RIZ1 polymorphism on BMD or fracture risk and no evidence of interaction between the polymorphisms and haplotypes thereof. We confirm that genetic variants in ESR1 and ESR2, but not RIZ1, are important in osteoporosis. We found no evidence of interaction between polymorphisms, but we found that the effects of genetic variants in ESR1 might be sex dependent.