Vitamin D receptor gene polymorphisms,bone mineral density and bone turnover: FokI genotype is related to postmenopausal bone mass

The relationship between vitamin D receptor (VDR) intragenic polymorphisms FokI, BsmI, ApaI and TaqI and bone mineral density (BMD) or biochemical markers of bone remodeling were investigated in 114 Czech postmenopausal women, on the average 62.5+/-8.9 years of age. Restriction fragment length polymorphisms in the VDR gene were assessed by PCR amplification and digestion with restriction enzymes FokI, BsmI, ApaI, and TaqI recognizing polymorphic sites in the VDR locus. Bone mineral density was measured at the lumbar spine and at the hip by dual-energy X-ray absorptiometry (DEXA, g/cm2). After adjusting for age and the body mass index (BMI), subjects with the ff genotype had 9.4% lower BMD at the hip than those with the Ff genotype (p=0.0459, Tukey's test). FF individuals had an intermediate BMD at the hip. A similar pattern of lower lumbar spine BMD was also found in ff individuals, but it did not reach statistical significance. There was no relationship between BsmI, ApaI and TaqI VDR polymorphisms and BMD at any skeletal site. Subjects with Aa (ApaI) genotypes had higher levels of propeptide of type I collagen (PICP) than homozygous AA (p=0.0459, Tukey's test). In FokI, BsmI and TaqI restriction sites the biochemical markers of bone remodeling did not differ by genotype. In addition, no significant difference was observed in VDR genotypic distribution between osteoporotic women and non-osteoporotic controls in the study group. To conclude, the FokI genotype of the vitamin D receptor gene is related to bone mass at the hip in Czech postmenopausal women, whereas the importance of remaining VDR genotypes was not evident.     

Association between VDR Apal Polymorphism and Hip Bone Mineral Density Can Be Modified by Body Mass Index:A Study on Postmenopausal Chinese Women

Osteoporosis is a major public health problem for old people.Genetic factors are considered tobe major contributors to the pathogenesis of postmenopausal osteoporosis.The vitamin D receptor(VDR)gene is a prominent candidate gene for the regulation of postmenopausal bone mass;however,despite exten-sive studies,controversy remains regarding its association with postmenopausal body mineral density(BMD)variation.In this study,a total of 260 healthy postmenopausal Chinese women were genotyped at the VDRApaI locus using polymerase chain reaction(PCR)-restriction fragment length polymorphism (RFLP).Rawhip BMD was significantly associated with VDR ApaI polymorphism with and without adjusting for age(P=0.015 and 0.040,respectively).This genetic effect can explain 3.32% of hip BMD variation.However,the significant association vanished after correcting for both age and body mass index(BMI)(P=0.169).Inaddition,we observed a significant association between VDR ApaI polymorphism with unadjusted BMI(P=0.042)or BMI adjusted for age(P=0.049).The raw hip BMD was also found to be significantly corre-lated with BMI(r=0.517,P=0.0001),with BMI explaining 26.35% of the variation of hip BMD.All of thesefacts prompt us to conclude that the significant association between the VDR ApaI genotype and hip BMDmay be modified by BMI in postmenopausal Chinese women.Our findings may partially explain the earlierinconsistent association results concerning the VDR gene and BMD,and highlight the importance of incorpo-rating covariates such as BMI into osteoporosis association studies.     

Association between VDR ApaI Polymorphism and Hip Bone Mineral Density Can Be Modified by Body Mass Index： A Study on Postmenopausal Chinese Women

Osteoporosis is a major public health problem for old people. Genetic factors are considered to be major contributors to the pathogenesis of postmenopausal osteoporosis. The vitamin D receptor (VDR) gene is a prominent candidate gene for the regulation of postmenopausal bone mass; however, despite extensive studies, controversy remains regarding its association with postmenopausal body mineral density (BMD) variation. In this study, a total of 260 healthy postmenopausal Chinese women were genotyped at the VDR ApaI locus using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). Raw hip BMD was significantly associated with VDR ApaI polymorphism with and without adjusting for age (P=0.015 and 0.040, respectively). This genetic effect can explain 3.32% of hip BMD variation. However, the significant association vanished after correcting for both age and body mass index (BMI) (P=0.169). In addition, we observed a significant association between VDR ApaI polymorphism with unadjusted BMI(P=0.042) or BMI adjusted for age (P=0.049). The raw hip BMD was also found to be significantly correlated with BMI (r=0.517, P=0.0001), with BMI explaining 26.35% of the variation of hip BMD. All of these facts prompt us to conclude that the significant association between the VDR ApaI genotype and hip BMD may be modified by BMI in postmenopausal Chinese women. Our findings may partially explain the earlier inconsistent association results concerning the VDR gene and BMD, and highlight the importance of incorporating covariates such as BMI into osteoporosis association studies.     

Dehydroepiandrosterone status in postmenopausal women is determined by the gene for the vitamin D receptor.

Data documenting the indirect interaction of vitamin D and bone metabolism via hormonal systems are rare. The authors analysed the predictive role of the vitamin D receptor (VDR) gene for circulating sex steroids and their precursors in postmenopausal women. Using the PCR technique, the polymorphic FokI, ApaI, TaqI and BsmI sites of the VDR gene were determined in relation to serum dehydroepiandrosterone sulphate (DHEAS), androstenedione (AD), testosterone, and estradiol levels. After adjustment to body mass and years since menopause, circulating DHEAS was higher in the Ff genotype than in ff (p < 0.001) and FF genotypes (p < 0.05, ANCOVA followed by least significant difference multiple comparison tests). The Ff genotype also contributed to the highest BMD at the hip (p < 0.01 as compared to ff genotype) and at the spine (p < 0.05). No significant associations were found between ApaI, TaqI and BsmI polymorphisms and serum DHEAS or between FokI, ApaI, TaqI or BsmI and serum androstenedione, testosterone or estradiol. The study shows that the VDR gene predicts synthesis and/or metabolism of sexual steroid preursor DHEA in parallel with bone mineral density (BMD). The results indicate that DHEA production and bone mass share a common genetic control through VDR.     

Factors associated with estrogen receptors-alpha (ER-alpha) and -beta (ER-beta) and progesterone receptor abundance in obese and non obese pre- and post-menopausal women

There is scarce information about the factors associated with estrogen receptors (ER) at menopause. In 113 volunteers pre- and post-menopausal healthy women, grouped as with and without obesity, estrogen receptors-alpha and -beta, and progesterone receptor (PR) were measured by immunohistochemistry in skin punch biopsies obtained from the external gluteal area. In pre-menopausal women, biopsies and a blood sample were performed between days 7 and 14 of the cycle. Serum hormone levels were measured by immunoradiometric assay or radioimmunoassay. After menopause, ER and PR amounts decreased significantly. At pre-menopause, obese women had lower PR levels than non obese (P<.006). In the post-menopausal group, obese women showed higher ER-alpha (P<.03) and ER-beta (P<.02) levels than the non obese group. In the analysis of factors associated with the amount of steroid receptors for the total group, log[ER-alpha], log[ER-beta], and log[PR] were associated with age (P<.002, <.005, and <.004, respectively). The log[ER-alpha] was also associated with log[FSH] (P<.0008); meanwhile, the log[PR] showed a marginal correlation with log[FSH]. In pre-menopausal women no factor associated with any of the three receptors was found. In post-menopausal women log[ER-alpha] was associated with log[estrone] and log[DHEAS] (P<.003 and <.02, respectively). log[PR] was associated with BMI (P<.002), years since menopause (P<.05), and log[DHEAS] (P<.003). We concluded that ER and PR diminish sharply at post-menopause. At this stage the amount of receptors depends on several factors such as BMI, years since menopause, and androgen precursors.     

Vitamin D receptor gene polymorphisms and susceptibility of hand osteoarthritis in Finnish women

We examined whether polymorphisms of the vitamin D receptor (VDR) gene was associated with individual risk of hand osteoarthritis (OA). Radiographs of both hands of 295 dentists and of 248 teachers were examined and classified for the presence of OA using reference images. The VDR ApaI and TaqI genotypes were determined by PCR-based methods. No association was observed between the VDR polymorphisms and the odds of overall hand OA. However, the carriers of the VDR t allele or At haplotype were at almost half the odds of symmetrical hand OA (odds ratio [OR] = 0.60, 95% confidence interval [CI] = 0.38-0.94 and OR = 0.59, 95% CI = 0.38-0.93, respectively) compared with the carriers of the T allele and of the non-At haplotype, respectively. Increased odds of this disease, on the contrary, was observed for women with two copies of the VDR a allele (OR = 1.93, 95% CI = 1.99-3.70) compared with women with the AA genotype. Conversely, the VDR a allele carriage was associated with a tendency of lowered odds of osteophyte (OR = 0.51, 95% CI = 0.25-1.03). When the genotype data were used to construct haplotypes, the VDR AaTt joint genotype appeared to pose a remarkably lower odds (OR = 0.26, 95% CI = 0.08-0.91) of osteophyte compared with the AAtt joint genotype. As a novel finding we observed a joint effect of a low calcium intake and VDR polymorphisms on symmetrical OA; the OR was 2.64 (95% CI = 1.29-5.40) for carriers of the aT haplotype with low daily calcium intake compared with non-carriers of the haplotype with high daily calcium intake. Our results suggest that VDR gene polymorphisms play a role in the etiology of symmetrical hand OA. Moreover, the association between the VDR gene and OA may be modified by calcium intake.     

Association analysis of vitamin D receptor gene polymorphisms with bone mineral density in young women with Graves' disease

Graves' (GD) hyperthyroidism induces accelerated bone turnover that leads to decreased bone mineral density (BMD). The role of the VDR gene in predisposition to primary osteoporosis has been recognized. Recent studies show associations between the VDR gene polymorphisms and susceptibility to autoimmune diseases. Here we analyzed if VDR gene polymorphisms: BsmI, ApaI, TaqI, and FokI may predispose women with Graves' hyperthyroidism to BMD reduction or to disease development. The subjects were 75 premenopausal female Polish patients with GD and 163 healthy women. The genotyping was performed by the use of the restriction fragment length polymorphism analysis (RFLP). We studied the association of the VDR polymorphisms and their haplotypes with patients' BMD and also SNPs and haplotypes association with Graves' disease. We found a strong linkage disequilibrium for the BsmI, ApaI, and TaqI polymorphims that formed three most frequent haplotypes in Graves' women: baT (47.9%), BAt (34.9%), and bAT (16.4%). We did not show statistically significant association of analyzed VDR polymorphisms or haplotypes with decreased bone mineral density in Graves' patients. However, the presence of F allele had a weak tendency to be associated with Graves' disease (with OR=1.93; 95% CI: 0.97-3.84; p=0.058). In conclusion: VDR gene polymorphisms do not predict the risk of decreased BMD in Polish women with Graves'. It may be speculated that the F allele carriers of the VDR-FokI polymorphism are predisposed to Graves' disease development.     

The effect of FokI vitamin D receptor polymorphism on bone mineral density in Jordanian perimenopausal women

CONTEXT:

Osteoporosis is a polygenic, multifactorial disease that is characterized by demineralization of bone, and thus presented with decreasing bone mineral mass. Vitamin D receptor (VDR) gene polymorphisms in the 3’-end region (as determined by the enzymes BsmI and ApaI) have been inconsistently associated with bone mineral mass. Another important VDR start codon polymorphism (as determined by the enzyme FokI) has been found to be related to adult bone mineral density (BMD) in pre-and post-menopausal American women.

AIMS:

This study aims to investigate the prevalence of the FokI VDR gene polymorphism in Jordanian perimenopausal women and study its relationship with bone mineral density.

MATERIALS AND METHODS:

DNA was isolated from 90 controls (Mean age = 50.41 ± 1.29 y), and 120 patients with symptomatic vertebral fractures (Mean age = 49.14 ± 3.19 y). Restriction Fragment Length Polymorphism (RFLP) analysis of FokI was performed on DNA samples.

STATISTICAL ANALYSIS:

Data was analyzed using SPSS v19 and Microsoft Excel 2007.

RESULTS:

The results showed that in controls, the FF (−0.70 ± 0.51) genotype is associated with high lumbar spine BMD Z-score as compared to Ff (−1.25 ± 0.26) and ff (−1.66 ± 0.47) genotypes (P = 0.0095). In patients, the ff genotype was associated with lower lumbar spine BMD in T-score (−2.31 ± 0.17) and Z-score (−1.56 ± 0.09) genotypes (P = 0.031). No significant association was seen in the femoral neck BMD.

CONCLUSION:

FokI polymorphism may be associated with low BMD in our studied population; however, further studies including other polymorphisms and large sample number are needed.     

Role of vitamin D receptor gene polymorphisms and serum 25-hydroxyvitamin D level in Egyptian female patients with systemic lupus erythematosus

Recently, several studies have demonstrated the role of vitamin D receptor (VDR) polymorphisms in the development of systemic lupus erythematosus (SLE). We aimed to evaluate VDR (ApaI, BsmI, and FokI) gene polymorphisms and haplotypes as a risk factors and/or activity markers for SLE, and whether they influence 25-hydroxyvitamin (25(OH) D) level. One hundred and seven SLE patients and 129 controls were enrolled in this study. Disease activity in SLE patients was assessed using Disease Activity Index. Polymorphisms of VDR gene were detected using polymerase chain reaction restriction fragment length polymorphism. Serum 25(OH) D levels were measured using ELISA. We found that ApaI AA genotype, BsmI B allele, Bb, BB genotypes, FokI F allele and FF genotype frequencies of VDR were increased in SLE group. There were significant associations of VDR ApaI AA, BsmI BB, and FokI FF genotypes with lupus nephritis and higher SLE activity scores. Moreover, serum 25(OH) D levels were increased in SLE patients carrying FokI ff genotype compared with patients carrying FF genotype. VDR haplotypes aBF and ABF were associated with SLE risk. The ABF haplotype was associated with higher SLE activity scores and lower serum 25(OH) D concentrations. We observed that the presence of leuko/lymphopenia, renal disorders, higher SLE activity scores and higher anti-dsDNA levels were accompanied by a significant decrease of serum 25(OH)D concentrations. We concluded that The VDR genes polymorphisms, haplotypes, and decreased 25(OH) D levels were associated with risk and more activity scores of SLE.     

Vitamin D receptor polymorphisms in hypocalcemic vitamin D-resistant rickets carriers

BACKGROUND/AIMS: Hypocalcemic vitamin D-resistant rickets (HVDRR) is a rare autosomal recessive disorder characterized by severe rickets, hypocalcemia, secondary hyperparathyroidism, elevated levels of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], and occasionally, alopecia. In most cases, the disease is associated with mutations in the gene of the vitamin D receptor (VDR), the mediator of 1,25(OH)(2)D(3) action. The apparently healthy HVDRR heterozygotes express both normal and mutant VDR alleles, and they present higher levels of 1,25(OH)(2)D(3) than their respective controls. Because VDR function, except for the disease-causative mutations, might be influenced by the presence of certain polymorphisms, we investigated the distribution of four common VDR polymorphisms--BsmI, ApaI, TaqI and FokI--in HVDRR carriers compared with their respective controls. METHODS: Sixty-seven relatives of 2 HVDRR patients, all members of an extended Greek kindred, were included in the study. VDR allelic polymorphisms were assessed by restriction fragment length polymorphisms after specific polymerase chain reaction amplification. RESULTS: The distribution of genotypic and allelic frequencies differed between HVDRR carriers and their respective controls regarding BsmI and TaqI polymorphisms. The bb genotype and the T allele (presence of BsmI and absence of TaqI polymorphisms) were less frequent in the HVDRR carrier group than in the control group in a statistically significant manner (p = 0.029 and p = 0.025, respectively). CONCLUSIONS: Our findings showed that the apparently healthy HVDRR carriers present a different distribution of BsmI and TaqI VDR polymorphisms than their controls, suggesting that further investigation of the HVDRR carrier population may elucidate the implication of VDR alleles in VDR function and the vitamin D endocrine system.