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Biomedical subjects

L A Rubin

Publications and source records attributed to L A Rubin.

At least 19 recordsLinked to original sources
PubMed2001

Association between total serum calcium and the A986S polymorphism of the calcium-sensing receptor gene.

Serum calcium is under tight physiological control, but it is also a quantitative trait with substantial genetic regulation. Mutations of the CASR gene cause familial hypocalciuric hypercalcemia or autosomal dominant hypoparathyroidism, depending on whether they decrease or increase, respectively, ligand binding to the receptor protein. We described an association between ionized calcium and a common polymorphism (A986S) found in the cytoplasmic tail of this G protein-coupled receptor. We report here on an independent study of 387 healthy young women. Genotyping was performed by allele-specific amplification and serum chemistries were measured by automated clinical assay. Frequencies of SS, AS, and AA genotypes were 6, 107, and 274, respectively, yielding a 986S allele frequency of 15.4%. Mean total serum calcium (Ca(T)) was significantly higher in the SS (9.88 +/- 0.29 mg/dL, P = 0.015) and AS groups (9.45 +/- 0.05 mg/dL, P = 0.002), than in the AA group (9.23 +/- 0.04 mg/dL). In multiple regression modeling, the A986S genotype remained an independently significant predictor of Ca(T) (P < 0.0001) when serum albumin, globulin, inorganic phosphate, and creatinine covariates were included. These data are the first to show significant association between a common polymorphism and concentrations of a serum electrolyte. The A986S polymorphism is also a potential predisposing factor in disorders of bone and mineral metabolism.

Adolescent↗
PubMed2001

Wintertime vitamin D insufficiency is common in young Canadian women, and their vitamin D intake does not prevent it.

OBJECTIVE: We asked whether women self-reporting the recommended consumption of vitamin D from milk and multivitamins would be less likely to have low wintertime 25-hydroxyvitamin D (25(OH)D) levels. METHODS: This cross-sectional study enlisted at least 42 young women each month (age 18-35 y, 796 women total) through one year. We measured serum 25(OH)D and administered a lifestyle and diet questionnaire. RESULTS: Over the whole year, prevalence of low 25(OH)D (<40 nmol/l) was higher in non-white, non-black subjects (25.6% of 82 women) than in the white women (14.8% of 702 white women, P<0.05). Of the 435 women tested during the winter half of the year (November-April), prevalence of low 25(OH)D was not affected by vitamin D intake: low 25(OH)D occurred in 21% of the 146 consuming no vitamin D, in 26% of the 140 reporting some vitamin D intake, up to 5 microg/day (median, 2.5 microg/day), and in 20% of the 149 women reporting vitamin D consumption over 5 microg/day (median, 10 microg/day). INTERPRETATION: The self-reported vitamin D intake from milk and/or multivitamins does not relate to prevention of low vitamin D nutritional status of young women in winter. Recommended vitamin D intakes are too small to prevent insufficiency. Vitamin D nutrition can only be assessed by measuring serum 25(OH)D concentration.

Adolescent↗
PubMed2000

Vitamin D-receptor genotypes as independent genetic predictors of decreased bone mineral density in primary biliary cirrhosis.

BACKGROUND & AIMS: Hepatic osteodystrophy is a complication of primary biliary cirrhosis (PBC). Allelic polymorphisms of the vitamin D receptor (VDR) gene are related to bone mineral density (BMD) in normal cohorts and those with primary osteoporosis. We sought to establish the prevalence of reduced bone mass in PBC, correlate BMD with VDR gene polymorphisms, and identify risk factors for the development of hepatic osteodystrophy. METHODS: Seventy-two female patients with PBC were evaluated prospectively. Clinical information, BMD assessment, disease severity, and osteoporosis risk factors were documented, and multivariate regression modeling was performed. RESULTS: Twenty-four percent of the patients were osteoporotic at the lumbar spine and 32% at the femur. Severe bone loss (z score <-2.0) occurs 4 times more frequently in patients with PBC compared with controls. Body weight (P = 0.003) and postmenopausal status (P = 0.012) correlated independently with BMD. VDR genotype (P = 0.01) correlated with lower BMD at the spine only. CONCLUSIONS: Osteoporosis is a common complication of PBC. VDR genotype predicts lower BMD in patients with PBC. Studies are warranted to investigate the mechanism(s) by which VDR as well as other candidate genes may contribute to the development of hepatic osteodystrophy in PBC.

Adult↗
PubMed2000

Alleles of the estrogen receptor alpha-gene and an estrogen receptor cotranscriptional activator gene, amplified in breast cancer-1 (AIB1), are associated with quantitative calcaneal ultrasound.

Quantitative bone ultrasound (QUS) has a significant heritable component. Because estrogen is required for attainment of peak bone mass, we studied alleles of two genes, estrogen receptor alpha (ER1) and amplified in breast cancer-1 (AIB1), for their association with QUS. In a volunteer sample of 663 white women aged 18-35 years, bone ultrasound attenuation (BUA), speed of sound (SOS), and heel stiffness index (SI), the latter consisting of the component measures of BUA and SOS, were measured at the right calcaneus by QUS. Subjects were genotyped for the ER1 polymorphisms Xba I and Pvu II and for the AIB1 polyglutamine tract polymorphism. In a multiple regression analysis, ER1 genotype was an independent predictor of QUS-SI (p = 0.03). Because AIB1 and ER1 enhance gene expression in a coordinate manner, we also searched for interactions. A gene-by-gene interaction effect was seen for QUS-SI (p = 0.009), QUS-BUA (p = 0.03), and QUS-SOS (p = 0.004). These remained significant after the inclusion of clinically relevant variables into the final regression model. Overall, these clinical and genetic factors accounted for up to 16% of the variance in peak QUS; the genetic markers alone accounted for 4-7%. This is the first demonstration of specific genetic effects on calcaneal QUS encoded by alleles of genes directly involved in mediating estrogen effects on bone.

Adolescent↗
PubMed1999

A986S polymorphism of the calcium-sensing receptor and circulating calcium concentrations.

BACKGROUND: The regulation of extracellular calcium concentration by parathyroid hormone is mediated by a calcium-sensing, G-protein-coupled cell-surface receptor (CASR). Mutations of the CASR gene alter the set-point for extracellular ionised calcium [Ca2+]o and cause familial hypercalcaemia or hypocalcaemia. The CASR missense polymorphism, A986S, is common in the general population and is, therefore, a prime candidate as a genetic determinant of extracellular calcium concentration. METHODS: We genotyped the CASR A986S variant (S allele frequency of 16.3%) in 163 healthy adult women and tested samples of their serum for total calcium, albumin, total protein, creatinine, phosphate, pH, and parathyroid hormone. A prospectively generated, random subset of 84 of these women provided a whole blood sample for assay of [Ca2+]o. FINDINGS: The A986S genotype showed no association with total serum concentration of calcium, until corrected for albumin. In a multivariate regression model, biochemical and genetic variables accounted for 74% of the total variation in calcium. The significant predictors of serum calcium were: albumin (p<0.001), phosphate (p=0.02), parathyroid hormone (p=0.007), pH (p=0.001), and A986S genotype (p=0.009). Fasting whole-blood [Ca2+]o also showed an independent positive association with the 986S variant (p=0.013). INTERPRETATION: The CASR A986S variant has a significant effect on extracellular calcium. The CASR A986S polymorphism is a likely candidate locus for genetic predisposition to various bone and mineral disorders in which extracellular calcium concentrations have a prominent part.

Adolescent↗
PubMed1999

Bone mineral density testing and osteoporosis education improve lifestyle behaviors in premenopausal women: a prospective study.

One way to decrease the risk of osteoporosis is to maximize peak bone mass. Peak bone mass may be moderately influenced by lifestyle behaviors: increasing calcium and exercise, decreasing alcohol intake and smoking may increase peak bone mass. We examined the effects of osteoporosis education and bone mineral density (BMD) testing on self-reported lifestyle behaviors in 669 premenopausal women enrolled in a prospective study to assess determinants of peak bone mass. Study participants completed a questionnaire that assessed lifestyle behaviors, received pamphlets about osteoporosis, and had BMD testing. One year later, the women completed a similar questionnaire. After education about osteoporosis and BMD testing, women reported that they were less likely to smoke (odds ratio [OR] = 0.55; 95% confidence interval [95% CI]: 0.28-1.0), consume alcohol (OR = 0.13; 95% CI: 0.04-0.34), and caffeinated beverages (OR = 0. 43; 95% CI: 0.27-0.68). Women were more likely to use calcium supplements (OR = 4.3; 95% CI: 3.04-6.2), vitamin D supplements (OR = 12.6; 95% CI: 7.4-22.9), and drink at least one glass of milk a day (OR = 13.3; 95% CI: 7.8-23.9). Further, women with low bone mass were more likely to use calcium supplements (OR = 1.7; 95% CI: 1.2-2.3) and vitamin D supplements (OR = 1.6; 95% CI:1.1-2.2) compared with women who had normal bone mass. Thus, our intervention improved self-reported lifestyle behaviors in premenopausal women. Such behaviors may ultimately increase peak bone mass and decrease the risk of developing osteoporosis.

Adult↗
PubMed1999

Determinants of peak bone mass: clinical and genetic analyses in a young female Canadian cohort.

Peak bone mass has been shown to be a significant predictor of risk for osteoporosis. Previous studies have demonstrated that skeletal mass accumulation is under strong genetic control, and efforts have been made to identify candidate loci. Determinants of peak bone mass also include diet, physical activity, hormonal status, and other clinical factors. The overall contribution of these factors, genetic and nongenetic, and their interaction in determining peak bone density status have not been delineated. Six hundred and seventy-seven healthy unrelated Caucasian women ages 18-35 years were assessed. A detailed, standardized interview was conducted to evaluate lifestyle factors, menstrual and reproductive history, medical conditions, medication use, and family history of osteoporosis. Bone mineral density (BMD) was measured at the lumbar spine (L2-L4) and the femoral neck (hip) using dual-energy X-ray absorptiometry. Genotyping of the vitamin D receptor (VDR) locus at three polymorphic sites (BsmI, ApaI, and TaqI) was performed. In bivariate analyses, BMD at the lumbar spine and hip was positively correlated with weight, height, body mass index (BMI), and level of physical activity, both now and during adolescence, but negatively correlated with a family history of osteoporosis. Hip, but not spine BMD, correlated positively with dietary intake of calcium, and negatively with amenorrhea of more than 3 months, with caffeine intake, and with age. Spine, but not hip BMD, correlated positively with age and with number of pregnancies. VDR haplotype demonstrated significant associations with BMD at the hip, level of physical activity currently, and BMI. In multivariate analysis, independent predictors of greater BMD (at the hip or spine) were: age (younger for the hip, older for the spine), greater body weight, greater height (hip only), higher level of physical activity now and during adolescence, no family history of osteoporosis, and VDR genotype (hip only). Weight, age, level of physical activity, and family history are independent predictors of peak BMD. Of these factors, weight accounts for over half the explained variability in BMD. VDR alleles are significant independent predictors of peak femoral neck, but not lumbar spine BMD, even after adjusting for family history of osteoporosis, weight, age, and exercise. However, the overall contribution of this genetic determinant is modest. Taken together, these factors explained approximately 17% and 21% of the variability in peak spine and hip BMD, respectively, in our cohort. Future research should be aimed at further evaluation of genetic determinants of BMD. Most importantly, understanding the critical interactive nature between genes and the environment will facilitate development of targeted strategies directed at modifying lifestyle factors as well as earlier intervention in the most susceptible individuals.

Adolescent↗
PubMed1998

Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently than does vitamin D2.

In all species tested, except humans, biological differences between vitamins D2 and D3 are accepted as fact. To test the presumption of equivalence in humans, we compared the ability of equal molar quantities of vitamin D2 or D3 to increase serum 25-hydroxyvitamin D [25(OH)D], the measure of vitamin D nutrition. Subjects took 260 nmol (approximately 4000 IU) vitamin D2 (n=17) or vitamin D3 (n=55) daily for 14 d. 25(OH)D was assayed with a method that detects both the vitamin D2 and D3 forms. With vitamin D3, mean (+/-SD) serum 25(OH)D increased from 41.3+/-17.7 nmol/L before to 64.6+/-17.2 nmol/L after treatment. With vitamin D2, the 25(OH)D concentration went from 43.7+/-17.7 nmol/L before to 57.4+/-13.0 nmol/L after. The increase in 25(OH)D with vitamin D3 was 23.3+/-15.7 nmol/L, or 1.7 times the increase obtained with vitamin D2 (13.7+/-11.4 nmol/L; P=0.03). There was an inverse relation between the increase in 25(OH)D and the initial 25(OH)D concentration. The lowest 2 tertiles for basal 25(OH)D showed larger increases in 25(OH)D: 30.6 and 25.5 nmol/L, respectively, for the first and second tertiles. In the highest tertile [25(OH)D >49 nmol/L] the mean increase in 25(OH)D was 13.3 nmol/L (P < 0.03 for comparison with each lower tertile). Although the 1.7-times greater efficacy for vitamin D3 shown here may seem small, it is more than what others have shown for 25(OH)D increases when comparing 2-fold differences in vitamin D3 dose. The assumption that vitamins D2 and D3 have equal nutritional value is probably wrong and should be reconsidered.

Adult↗
PubMed1997

Estimating the strength of genetic effects: a comparison of maximum likelihood and transmission disequilibrium methods in the study of ankylosing spondylitis.

Here we compare several methods for evaluating associations in the analysis of family data. We applied the transmission disequilibrium test (TDT), and logistic regression, familial aggregation, and segregation analyses for the study of Ankylosing Spondylitis. All methods detected effects from B27 upon susceptibility for Ankylosing Spondylitis. However, the TDT was unable to detect effects from B40 and also could not include sex as a covariate during the analysis. Conditioning or not conditioning the data for the ascertainment event led to little difference in the estimated covariate effects, although the genetic model for residual effects not due to the covariates did change. Results from these studies provide further characterization of the relationship between HLA B27, B40, and sex upon risk for developing Ankylosing Spondylitis. We also identified potential effects from further genetic susceptibility.

Adolescent↗
PubMed1997

Calcium sensing receptor gene: analysis of polymorphism frequency.

The role that the Calcium Sensing Receptor (CASR) plays in extracellular calcium regulation had been ascertained through studies of inactivating as well as activating mutations of CASR gene in a number of multiplex families. We have extended these observations to a polymorphism analysis of the intercellular domain of CASR in a cohort of healthy young women. The results demonstrate significant allelic polymorphism as a result of nonconservative changes at two specific sites. Further studies will be required to determine what, if any, relationship this may have to CASR phenotype.

Adolescent↗
PubMed1995

Soluble interleukin-2 receptor alpha is elevated in sera of patients with benign ovarian neoplasms and epithelial ovarian cancer.

BACKGROUND: Previous studies have established that soluble interleukin-2 receptor alpha (sIL-2R alpha) levels are elevated in ascites and sera from individuals with advanced ovarian cancer (International Federation of Gynecology and Obstetrics [FIGO] Stage III/IV). This study was undertaken to evaluate sIL-2R alpha levels in individuals with benign ovarian neoplasms and early stage ovarian cancer (FIGO Stage I/II). Comparison with CA 125 levels was performed to assess screening potential. METHODS: Sera from 92 healthy individuals, 61 with benign adnexal masses, 12 patients with FIGO Stage I/II ovarian cancers, and 27 patients with FIGO Stage III/IV ovarian cancers were assayed for sIL-2R alpha by enzyme-linked immunosorbent assay and CA 125 by radioimmunoassay. RESULTS: The mean serum sIL-2R alpha levels for benign pelvic masses, and Stage I/II and Stage III/IV epithelial ovarian cancer were 1507 +/- 82, 1631 +/- 274, and 2596 +/- 384 U/ml, respectively. The difference between mean serum sIL-2R alpha levels in individuals with benign adnexal masses and Stage III/IV epithelial ovarian cancer was statistically significant (P < 0.05). In addition, of the four individuals with FIGO Stage I/II ovarian cancer who had CA125 levels below 35 U/ml, the accepted upper limit of normal, three patients had elevated serum sIL-2R alpha levels. Eleven of 12 patients (92%) with potentially curable Stage I/II disease had elevated serum levels of either sIL-2R alpha or CA125 and 8 of 12 (67%) had elevations of both sIL-2R alpha and CA125. Sensitivity and specificity of a combination of CA 125 and soluble IL-2R alpha were 88.5% and 27.1%, respectively. CONCLUSION: Soluble interleukin-2 receptor alpha levels do not appear to differentiate between benign adnexal lesions and early malignancy; however, measurement of sIL-2R alpha levels in combination with CA125 warrants further evaluation to determine if together they will identify individuals with Stages I and II ovarian cancer.

Biomarkers, Tumor↗
PubMed1995

A fatal pulmonary complication of lupus in pregnancy.

Pulmonary vasculitis is an uncommon complication of systemic lupus erythematosus (SLE), and has not been previously documented in pregnancy. This case report describes the rapidly fatal course of a pregnant SLE patient, whose terminal illness was manifested by severe pulmonary hypertension and unexpected autopsy findings of medium and large vessel vasculitis. The relationship of these unusual manifestations to other clinical and serologic features of SLE, as well as novel therapeutic options, are discussed.

Adult↗
PubMed1995

Non-linkage of a T-cell receptor gamma chain microsatellite (D7S485) to rheumatoid arthritis in multiplex families.

A highly informative microsatellite marker, D7S485, from the T-cell receptor gamma (TCRG) locus, has been used to study segregation of TCRG genes in 26 multiplex rheumatoid arthritis (RA) families. We used the sib-pair method to assess excess identity-by-descent sharing among affected members in these families and the LINKAGE package of programs was used to calculate two-point lod scores for the D7S485 marker. There was no evidence for segregation of TCRG genes with RA in affected siblings and significantly negative lod scores were obtained from linkage analyses using both autosomal dominant and recessive models of inheritance.

Adolescent↗
PubMed1995

Major gene analysis for diseases and disorders of complex etiology.

Genetic analysis of complex diseases is undergoing a paradigm shift as the DNA technology and computational resources for analysis become more precise. In this review we compare the old paradigm for genetic disease analysis with the new, more powerful and efficient methods, which rely on the application of genetically linked markers. To illustrate the utility of the new approach, we apply it in the study of ankylosing spondylitis.

DNA↗
PubMed1994

Serum levels of soluble interleukin-2 receptor. A marker of disease activity in localized scleroderma.

OBJECTIVE: To determine whether circulating serum levels of soluble interleukin-2 receptor (sIL-2R) are elevated in patients with localized scleroderma, and if levels of sIL-2R can differentiate between active and inactive disease. METHODS: Seventeen patients with localized scleroderma were categorized by overall physician assessment into active, inactive, and indeterminate groups, according to disease activity. Serum sIL-2R levels were analyzed and correlated with disease activity. RESULTS: The mean sIL-2R level was significantly higher (P = 0.005) in those with active disease (1,675 +/- 823 units/ml) than in those with inactive disease (722 +/- 218 units/ml). CONCLUSION: Serum sIL-2R levels are elevated in patients with localized scleroderma. When present, elevated sIL-2R levels appear to be able to differentiate active from inactive disease. This fact also suggests cell-mediated immune activation in this condition. Further serial studies are required to assess the value and sensitivity of sIL-2R levels in measuring changes in disease activity.

Adolescent↗