Biomedical subjects

C Gross

Publications and source records attributed to C Gross.

At least 73 records · Page 4Linked to original sources

PubMed1998

Treatment of early recurrent prostate cancer with 1,25-dihydroxyvitamin D3 (calcitriol)

PURPOSE: Substantial experimental and epidemiological data indicate that 1,25-dihydroxyvitamin D3 (calcitriol) has potent antiproliferative effects on human prostate cancer cells. We performed an open label, nonrandomized pilot trial to determine whether calcitriol therapy is safe and efficacious for early recurrent prostate cancer. Our hypothesis was that calcitriol therapy slows the rate of rise of prostate specific antigen (PSA) compared with the pretreatment rate. MATERIALS AND METHODS: After primary treatment with radiation or surgery recurrence was indicated by rising serum PSA levels documented on at least 3 occasions. Seven subjects completed 6 to 15 months of calcitriol therapy, starting with 0.5 microg. calcitriol daily and slowly increasing to a maximum dose of 2.5 microg. daily depending on individual calciuric and calcemic responses. Each subject served as his own control, comparing the rate of PSA rise before and after calcitriol treatment. RESULTS: As determined by multiple regression analysis, the rate of PSA rise during versus before calcitriol therapy significantly decreased in 6 of 7 patients, while in the remaining man a deceleration in the rate of PSA rise did not reach statistical significance. Overall the decreased rate of PSA rise was statistically significant (p = 0.02 Wilcoxon signed rank test). Dose dependent hypercalciuria limited the maximal calcitriol therapy given (range 1.5 to 2.5 microg. daily). CONCLUSIONS: This pilot study provides preliminary evidence that calcitriol effectively slows the rate of PSA rise in select cases, although dose dependent calciuric side effects limit its clinical usefulness. The development of calcitriol analogues with decreased calcemic side effects is promising, since such analogues may be even more effective for treating prostate cancer.

Aged↗

PubMed1998

Bilateral nephrectomy: the best, but often overlooked, treatment for refractory hypertension in hemodialysis patients.

Bilateral nephrectomy for treatment of refractory hypertension in chronic hemodialyzed patients has been infrequently carried out. We analyzed the benefits of this operation on blood pressure, clinical state, drug treatment, and quality of life. In 10 hemodialyzed patients with refractory hypertension, systolic (SBP) and diastolic (DBP) blood pressure were measured 1 month before nephrectomy bilateral and 3, 6, 9, and 12 months after. In addition, the use of antihypertensive drugs before and after surgery was evaluated. Four patients had SBP and DBP values characteristic of malignant hypertension. In all 10 patients hypertension responded neither to reduction of plasma volume by ultrafiltration nor to multiple antihypertensive drug therapy. Hypertensive crises were associated with cerebral hemorrhage in two patients, severe encephalopathy with persistent neural dysfunction in one patient, and encephalopathy and diplopia in another. Three months after bilateral nephrectomy blood pressure decreased significantly (P < .005) and was normal in nine patients. In one noncompliant patient with intradialytic body weight increases of nearly 10%, blood pressure was still elevated. Malignant or drug-resistant hypertension with hypertensive crises is an indication for bilateral nephrectomy. The clinical state and quality of life improved in all patients in the present study and antihypertensive treatment is no longer necessary.

Adult↗

PubMed1998

Will commercial managed care patients accept residents as their primary care providers?

We conducted a telephone survey of patients in a university-based medical practice to determine if there was a difference across payer class in patients' willingness to have supervised housestaff physicians function as their primary care providers. Overall, commercial managed care patients were more likely to object to seeing housestaff physicians than were Medicaid or Medicare patients (50% vs 32% or 23%, respectively). However, prior outpatient care by a resident physician significantly increased patient willingness to be cared for by a resident. This effect of prior care by a resident was noted in the managed care as well as the Medicaid and Medicare populations. Although there may have been self-selection, our data demonstrate that a significant proportion of managed care patients who have had residents as their primary care providers are amenable to continuing this practice.

Aged↗

PubMed1998

De novo protein synthesis is essential for thermotolerance acquisition in a Saccharomyces cerevisiae trehalose synthase mutant.

Heat shock (25 degrees C to 37 degrees C for 30 min) acquisition of thermotolerance (at 50 degrees C) was observed in a yeast trehalose synthase mutant and the corresponding control strain. The acquisition of thermotolerance in the control strain was maintained for a significantly longer time than in the trehalose synthase mutant. The heat shock was associated with the synthesis of specific heat shock proteins and, in the case of the control strain, also trehalose accumulation. Inhibition of protein synthesis during the heat shock totally abolished acquisition of thermotolerance in both strains but not trehalose accumulation in the control. It was concluded that trehalose may only be required for prolonged stress protection while heat shock proteins are required for heat shock acquisition of thermotolerance.

Fungal Proteins↗

PubMed1998

Hepatic iron overload: direct HFE (HLA-H) mutation analysis vs quantitative iron assays for the diagnosis of hereditary hemochromatosis.

Among patients with hepatic iron overload, the distinction between hereditary hemochromatosis (HH), a common yet treatable genetic disease, and other causes of siderosis remains problematic. The recent discovery of a specific homozygous mutation (C282Y) in a novel major histocompatibility complex class I-like gene (named HLA-H or HFE) in 80% to 100% of well-characterized cases of HH suggests that direct DNA-based mutation analysis may help resolve this dilemma. To assess the clinical utility of direct HLA-H mutation analysis in a typical diagnostic setting, we measured genotypic and phenotypic parameters of iron overload in 37 subjects with biopsy-proven hepatic siderosis (2+ or greater) and in 127 healthy control subjects. The prevalence of C282Y homozygotes was significantly greater in the hepatic siderosis group (32%) than in the control group (0%), confirming the association between this homozygous mutation and hepatic iron overload. In the hepatic siderosis group, C282Y homozygotes had significantly higher hepatic iron and ferritin levels, a significantly lower prevalence of hepatitis C virus or alcoholic liver disease, but no significant difference in the saturation of serum transferrin. Of the 20 subjects with a hepatic iron index (HII) in the previously defined "hemochromatosis range" (>1.9), 9 (45%) were C282Y homozygotes. Of the 11 nonhomozygous subjects with an HII greater than 1.9 (presumed false-positive HIIs), 10 (91%) had hepatic cirrhosis compared with 3 of 9 (33%) homozygotes with an HII greater than 1.9 who had cirrhosis (P<.02). The HII thus has poor diagnostic specificity for predicting genotypic HH in patients with cirrhosis. We conclude that direct determination of the HLA-H C282Y genotype may be the single best diagnostic test for HH, particularly in patients with cirrhosis, for whom the HII is quite nonspecific.

Adult↗

PubMed1998

Evaluation of cerebral vasospasm after early surgical and endovascular treatment of ruptured intracranial aneurysms.

OBJECTIVE: To document the influence of the treatment modality (early surgery versus early endovascular treatment) on measures of cerebral vasospasm in a nonrandomized series of 156 patients treated within 72 hours of aneurysmal subarachnoid hemorrhage. METHODS: The following parameters were prospectively collected in a computerized data base and retrospectively analyzed for association with vasospasm-related ischemic infarctions: 1) Hunt and Hess (H&H) grade, 2) Fisher grade, 3) highest mean cerebral blood flow velocity (CBFVMAX) and maximum percent change in mean CBFV (%deltaCBFV) as recorded by transcranial Doppler ultrasound, 4) incidence of repeat subarachnoid hemorrhage, 5) incidence of delayed ischemic neurological deficits, 6) incidence of delayed ischemic infarctions, and 7) Glasgow Outcome Scale score. RESULTS: Forty-one patients (26.3%) suffered ischemic infarctions. The ischemic infarction rate was correlated with higher H&H grade (P = 0.002), higher Fisher grade (P = 0.05), higher CBFVMAX (P < 0.001) and %deltaCBFV (P = 0.01), occurrence of repeat subarachnoid hemorrhage, occurrence of delayed ischemic neurological deficits, and endovascular treatment (P = 0.02). CONCLUSION: The infarction rate was higher with endovascular treatment versus surgery (37.7 versus 21.6%), as a result of a skewed Fisher Grade 4 infarction pattern in the endovascular treatment group versus the surgery treatment group (66.7 versus 24.5%). We suspect that unremoved subarachnoid/intracerebral clots contributed to the higher infarction rate with endovascular treatment. When patients with Fisher Grade 4 and H&H Grade V were excluded from analysis, the difference in infarct incidence between the treatment groups no longer reached statistical significance (Fisher Grades 1-3, P = 0.49; H&H Grades I-IV, P = 0.96).

Adult↗

PubMed1998

Transcriptional and translational regulation of major heat shock proteins and patterns of trehalose mobilization during hyperthermic recovery in repressed and derepressed Saccharomyces cerevisiae.

Patterns of heat shock gene transcription and translation, as well as trehalose content, were investigated in both glucose (repressed) and acetate (derepressed) grown cells of Saccharomyces cerevisiae during heat shock and subsequent return of cells to 25 degrees C. Heat-shocked cells (37 degrees C for 30 min), grown in either glucose- or acetate-supplemented media, initially acquired high thermotolerance to a 50 degrees C heat stress, which was progressively lost when cultures were allowed to recover at 25 degrees C and subsequently exposed to a second heat stress. In all cases, with the notable exception of repressed cells of a relatively thermosensitive strain, inhibition of protein synthesis and coincident decrease in trehalose accumulation during the heat shock had little effect on the kinetics of loss of thermotolerance. Heat shock at 37 degrees C elicited a marked increase in transcription and translation of genes encoding major heat shock proteins (hsps). During recovery at 25 degrees C, both metabolic activities were suppressed followed by a gradual increase in hsp mRNA transcription to levels observed prior to heat shock. De novo translation of hsp mRNAs, however, was no longer observed during the recovery phase, although immunodetection analyses demonstrated persistence of high levels of hsps 104, 90, 70, and 60 in cells throughout the 240-min recovery period. In addition, while heat shock induced trehalose was rapidly degraded during recovery in repressed cells, levels remained high in derepressed cells. Results therefore indicated that the progressive loss of induced thermotolerance exhibited by glucose- and acetate-grown cells was not closely correlated with levels of hsp or trehalose. It was concluded that both constitutive and de novo synthesized hsps require heat shock associated activation to confer thermotolerance and this modification is progressively reversed upon release from the heat-shocked state.

Acetates↗

PubMed1998

Lack of correlation between start codon polymorphism of the vitamin D receptor gene and bone mineral density in premenopausal French women: the OFELY study.

Previous studies have demonstrated an association between bone mineral density (BMD) and a start codon polymorphism (SCP) of the vitamin D receptor (VDR) gene in pre- and postmenopausal Caucasian and Japanese women. The SCP can be determined by a restriction fragment length polymorphism defined by the FokI restriction endonuclease. VDR alleles containing the FokI site are denoted by f and alleles lacking the site by F. In this study, the association between BMD and the SCP was examined in a group of 174 premenopausal French women who previously had been studied for a relationship between BMD and the VDR BsmI polymorphism. The SCP genotypes of the French women were FF 40%, Ff 44%, and ff 16% and they were independent of the BsmI genotype. BMD was measured by dual-energy X-ray absorptiometry at the lumbar spine, proximal femur, forearm, and total body. In contrast to previous reports, there was no association of BMD with SCP genotype in this group of Caucasian women at any site. We also measured several biochemical indices of calcium homeostasis and bone turnover. We found no statistically significant associations between SCP genotype and calcium, parathyroid hormone, or vitamin D levels. There was a 33.5% higher level of the skeletal resorption marker N-telopeptides of type I collagen in the women with the ff genotype when compared with women with the FF genotype (p = 0.004). Other bone turnover markers failed to show an association with SCP genotype. In summary, the SCP genotype may not be associated with reduced BMD in all geographical or ethnic populations.

Adult↗

PubMed1998

The vitamin D receptor gene start codon polymorphism: a functional analysis of FokI variants.

The vitamin D receptor (VDR) gene contains a start codon polymorphism (SCP) which is three codons upstream of a second start site (ATG). The SCP genotype can be determined with the restriction enzyme FokI, where "f" indicates the presence of the restriction site and the first ATG, while "F" indicates its absence. Recent evidence suggests that the ff genotype is correlated with lower bone mineral density (BMD) in some populations. The SCP results in alternate VDRs that differ structurally, with the F variant (F-VDR) being three amino acids shorter than the f variant (f-VDR). To determine whether there are functional differences between the f-VDR and the F-VDR, we studied the two VDR forms expressed in COS-7 cells. The proteins were distinguishable from one another on Western blots by their different mobilities, confirming the larger size of f-VDR. Ligand binding studies showed no significant differences between the affinities of the two VDR forms for [3H]-1,25-dihydroxyvitamin D3 ([3H]-1,25(OH)2D3) (Kd = 131+/-78 pM, f-VDR; Kd = 237+/-190 pM, F-VDR; p = 0.24); however, a 2-fold difference in affinity can not be discriminated by this method. There were no differences in the abilities of the two receptor forms to bind DNA as determined by electrophoretic mobility shift assays. The ability of the two VDR forms to transactivate target genes was investigated using three different vitamin D responsive luciferase reporter constructs: 24-hydroxylase, osteocalcin, and osteopontin. In these transactivation experiments, 1,25(OH)2D3 dose-response (0.1-10 nM) curves revealed that the ED50 values for transactivation were indistinguishable between the two VDR forms. Additionally, cultured human fibroblasts with FF, Ff, and ff genotypes had similar sensitivity to 1,25(OH)2D3 with respect to the induction of 24-hydroxylase mRNA. In summary, we were unable to detect significant differences in ligand affinity, DNA binding, or transactivation activity between f-VDR and F-VDR forms. We must emphasize, however, that the sensitivity of the methods used limits our ability to detect minor differences in VDR affinity and function. In conclusion, we cannot define a mechanism whereby the SCP in the VDR might contribute to population differences in BMD.

Analysis of Variance↗

PubMed1997

The differential binding of E2F and CDF repressor complexes contributes to the timing of cell cycle-regulated transcription.

B- myb and cdc25C exemplify different groups of genes whose transcription is consecutively up-regulated during the cell cycle. Both promoters are controlled by transcriptional repression via modules consisting of an E2F binding site (E2FBS) or the related CDE plus a contiguous CHR co-repressor element. We now show that the B- myb repressor module, which is derepressed early (mid G1), is preferentially recognized by E2F-DP complexes and that a mutation selectively abolishing E2F binding impairs regulation. In contrast, the cdc25C repressor module, which is derepressed late (S/G2), interacts selectively with CDE-CHR binding factor-1 (CDF-1). E2F binding, but not CDF-1 binding, requires specific nucleotides flanking the E2FBS/CDE core, while CDF-1 binding, but not E2F binding, depends on specific nucleotides in the CHR. Swapping these nucleotides between the two promoters profoundly changes protein binding patterns and alters expression kinetics. Thus predominant CDF-1 binding leads to derepression in late S, predominant E2F binding results in up-regulation in late G1, while promoters binding both E2F and CDF-1 with high efficiency show intermediate kinetics. Our results support a model where the differential binding of E2F and CDF-1 repressor complexes contributes to the timing of promoter activity during the cell cycle.

3T3 Cells↗

PubMed1997

Subthalamic stimulation elicits hemiballismus in normal monkey.

High frequency stimulation (HFS) of the subthalamic nucleus (STN) reduces parkinsonian symptoms in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkey and in human patients. The effects of stimulation on normal waking primates have never been evaluated. While low frequency stimulation has no effect, HFS induces dyskinesias contralateral to the stimulated STN resembling human hemiballismus and those obtained in primates after neurotoxic lesion or pharmacological blockade of the STN. In the normal monkey, HFS appears reversibly to incapacitate the STN and allow the emergence of involuntary proximal displacements, due to disinhibition of the thalamo-cortical pathway. In the MPTP-treated monkey HFS buffers STN overactivity and alleviates akinesia and rigidity by reducing inputs to the internal segment of the globus pallidus.

Animals↗

PubMed1997

Chronic administration of DL-allyl-glycine into the neostriatum, disorganises the firing modes of the nigral dopaminergic neurons in the rat.

Nigral dopaminergic (DA) neurons have been reported to fire according to three modes: very regular (pacemaker 42%) irregular (random 46%) and bursty (12%). The switch from simple spiking mode (pacemaker or random) to bursty firing would correspond to an increase in DA release necessary for the performance of a new motor act. As nigral DA cells are impinged upon by a high percentage of GABAergic afferents we blocked striatal GABAergic output neurons by chronic administration into the neostriatum of allyl-glycine, a glutamic acid decarboxylase (GAD) inhibitor. After treatment, rats presented hyperkinesia and hypertonia on the injected side and recordings showed a drastic change in the percentage distribution of nigral DA cell discharge patterns; 85% were 'random', 12% 'pacemaker' and 3% bursty. Such a disturbance, by impeding adapted DA release, may account for the hyperkinetic and dystonic disorders observed.

Animals↗

PubMed1997

Hereditary vitamin D resistant rickets caused by a novel mutation in the vitamin D receptor that results in decreased affinity for hormone and cellular hyporesponsiveness.

Mutations in the vitamin D receptor (VDR) result in target organ resistance to 1alpha,25-dihydroxyvitamin D [1,25(OH)2D3], the active form of vitamin D, and cause hereditary 1,25-dihydroxyvitamin D resistant rickets (HVDRR). We analyzed the VDR of a patient who exhibited three genetic diseases: HVDRR, congenital total lipodystrophy, and persistent mullerian duct syndrome. The patient was treated with extremely high dose calcitriol (12.5 microg/d) which normalized serum calcium and improved his rickets. Analysis of [3H]1,25(OH)2D3 binding in the patient's cultured fibroblasts showed normal abundance of VDR with only a slight decrease in binding affinity compared to normal fibroblasts when measured at 0 degrees C. The patient's fibroblasts demonstrated 1,25(OH)2D3-induction of 24-hydroxylase mRNA, but the effective dose was approximately fivefold higher than in control cells. Sequence analysis of the patient's VDR gene uncovered a single point mutation, H305Q. The recreated mutant VDR was transfected into COS-7 cells where it was 5 to 10-fold less responsive to 1,25(OH)2D3 in gene transactivation. The mutant VDR had an eightfold lower affinity for [3H]1,25(OH)2D3 than the normal VDR when measured at 24 degrees C. RFLP demonstrated that the patient was homozygous for the mutation while the parents were heterozygous. In conclusion, we describe a new ligand binding domain mutation in the VDR that causes HVDRR due to decreased affinity for 1,25(OH)2D3 which can be effectively treated with extremely high doses of hormone.

Calcitriol↗

PubMed1997

Effects of different schedules of MPTP administration on dopaminergic neurodegeneration in mice.

Although a valuable 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model of human Parkinson's disease has been developed, our knowledge of the course of nigral degeneration remains fragmentary. Experimental factors which could possibly influence the destructive process must be taken into account. To evaluate the impact of experimental design, we compared the effects of different schedules of injection of the same cumulative dose of MPTP, in mice, by measuring tyrosine hydroxylase immunoreactivity in the substantia nigra pars compacta. Massive injection of the total dose over 1 day (4 injections of 20 mg/kg) destroyed more dopaminergic neurons than did the long-term daily injections of a lower dose of MPTP (20 injections of 4 mg/kg). This suggests that different schedules of administration of MPTP might induce different mechanisms of neuronal death. These mechanisms need to be better understood if chronic models of intoxication that replicate the evolution of human Parkinson's disease more precisely are to be developed.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1997

The pulmonary homograft as aortic valve substitute: 7 years' follow up.

OBJECTIVE: The advantages of the aortic valve homograft high resistance to infective endocarditis, low risk of thromboembolism, low gradient and excellent long term results are well known. Trying to extend these advantages to a greater number of patients, we used pulmonary homografts as aortic valve substitute, based on the experimental evidence, that they can withstand the higher stress in systemic circulation. METHODS: From September 1988 to August 1994 175 patients (103 men, 72 women, mean age 61.75 +/- 12.92 years) underwent aortic valve replacement with a cryopreserved pulmonary homograft. All valves were taken from our own homograft bank. They were inserted freehand intraaortically, 162 in subcoronary position, 13 as intraaortic cylinder. All patients were followed clinically and by colorflow Doppler echocardiography in 3-12 month intervals. RESULTS: Patients, 8, died perioperatively (4.57%). None of the deaths was valve related. Patients, 2, had to be reoperated during the perioperative period due to severe valvular incompetence 165 patients were followed up to a period of 7.5 years (mean interval 3.83 +/- 1.45 years). Patients, 30, died, 13 deaths (7.42%) must be regarded as valve related. Patients, 22, (12.52%) had to be reoperated due to severe graft incompetence. Patients, 9 (5.14%), acquired prosthetic endocarditis. CONCLUSION: Due to our results, high rate of valve related deaths, high rate of graft failure and high rate of prosthetic endocarditis, we must state that the pulmonary homograft did not fulfil our expectations and presently we can not recommend it as an aortic valve substitute.

Aortic Valve↗

PubMed1997

Analysis of vitamin D analog-induced heterodimerization of vitamin D receptor with retinoid X receptor using the yeast two-hybrid system.

Several synthetic analogs of 1 alpha,25-dihydroxyvitamin D3 [1,25-(OH)2D3] are potent inducers of cellular differentiation and inhibitors of cell growth, yet they are less calcemic than 1,25-(OH)2D3 itself. The mechanisms by which these vitamin D analogs elicit a different profile of cellular activities than 1,25-(OH)2D3 are not fully understood. We propose that the analogs bind to the vitamin D receptor (VDR) to produce a conformational change that is more or less constrained than that induced by 1,25-(OH)2D3. This conformational change determines the extent of the VDR-retinoid X receptor (RXR) heterodimerization which, in turn, determines the interaction with other factors that specify the selectivity and magnitude of gene transactivation. We used the yeast two-hybrid system to evaluate a series of six vitamin D analogs for their ability to induce VDR-RXR heterodimerization. The VDR-RXR interaction was elicited by the analogs in a concentration-dependent manner. To evaluate how this activity compared with other known steps in 1,25-(OH)2D3 action, we also measured the ability of the same six analogs to bind to VDR, to enhance the binding of VDR-RXR to DNA, to transactivate a vitamin D-response element-reporter construct, and to inhibit proliferation in mammalian cells. Our results indicate that, for most analogs, the level of transcriptional activation correlates well with the strength of VDR-RXR heterodimerization in intact cells. We conclude that the yeast two-hybrid system provides a useful means to investigate heterodimerization potency and that this property contributes significantly to the overall pattern of analog activity. The yeast two-hybrid system, being an intact cell assay and easy to perform, may be a useful supplement to the conventional assays employed to screen vitamin D analogs.

Animals↗

PubMed1997

Vitamin D receptor polymorphisms, bone mineral density, and bone metabolism in postmenopausal Mexican-American women.

Common polymorphisms in the vitamin D receptor (VDR) gene have been shown to correlate with bone mineral density (BMD). However, attempts to replicate the original findings in other populations have yielded variable results. These disparities may reflect ethnic or environmental differences in the expression of the VDR effect upon BMD. We examined a relatively ethnically homogeneous group of 103 healthy postmenopausal Caucasian women of Mexican descent living in Northern California. We determined the VDR genotype and measured the BMD at the lumbar spine and femoral neck by dual-energy X-ray absorptiometry, as well as several biochemical indices of mineral metabolism. The prevalence of the BB genotype, associated in previous studies with the lowest BMD, was 8% and highly linked to the tt genotype. Absolute and age-adjusted BMD at both hip and spine showed a trend toward lower BMD in the BB, AA, and tt genotypes, but this trend did not achieve statistical significance. There were no consistent intergroup differences in change in BMD over 2 years of follow-up, nor in mean serum concentrations of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, osteocalcin, or total urinary pyridinolines. Intact parathyroid hormone concentrations were significantly higher in subjects with the AA genotype, with a trend toward higher values in those with the BB and tt genotypes as well. Our data suggest that there may be a decrease in BMD associated with the B, A, and t alleles, but the intergroup difference in BMD is 0.2-0.5 standard deviations (SD) at the lumbar spine and 0.3 SD at the femoral neck, decreases that are smaller than previously reported. Given the relatively low prevalence of the BB/tt genotype in Mexican-American Caucasians, a larger sample would be required to detect a significant association between VDR alleles and differences in BMD of the magnitude suggested by our data. We conclude that a genotype effect of this magnitude, if present, would be clinically relevant, but the impact on BMD is too small to detect with statistical significance in a study of this size.

Aged↗

PubMed1997

The vitamin D receptor start codon polymorphism (FokI) and bone mineral density in premenopausal American black and white women.

This study examines the association between bone mineral density (BMD) and a start codon polymorphism (SCP) at the translation initiation site of the vitamin D receptor (VDR) gene. The thymine/cytosine (T/C) polymorphism in the first of two start (ATG) codons can be detected by a restriction fragment length polymorphism (RFLP) using the endonuclease FokI, which recognizes ATG as part of its restriction site. F indicates absence of the first ATG and a VDR that is shorter by three amino acids. The FokI genotype was determined in 154 premenopausal American women (72 black and 82 white) who were 20-40 years old. BMD of the total body, femoral neck, and lumbar spine were measured by dual-energy X-ray absorptiometry. The distribution of the SCP genotypes differed significantly by race (p < 0.001): 4% of blacks versus 18% of whites were ff homozygous and 65% of blacks versus 37% of whites were FF homozygous. There was no statistically significant interaction between race and SCP genotype in analyses of BMD at any skeletal site. In the group as a whole, the ff women had femoral neck BMD that was 7.4% lower than that of the FF women. The ff white women had total body BMD values that were 4.3% lower and femoral neck values that were 12.1% lower than FF white women. Total body and femoral neck BMD did not differ significantly by genotype in black women, and spine BMD did not differ by genotype in either race. Addition of the SCP genotype to analysis of covariance models comparing BMD of the black and white women reduced estimated differences in femoral neck BMD between the two groups by about 35%. In conclusion, the SCP polymorphism, detected with the endonuclease FokI, appears to influence peak bone density, particularly at the femoral neck. Racial differences in its distribution may explain some of the racial difference in femoral neck BMD.

Adult↗