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Biomedical subjects

S F Grant

Publications and source records attributed to S F Grant.

17 recordsLinked to original sources
PubMed2001

The inheritance of rheumatoid arthritis in Iceland.

OBJECTIVE: Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis. Although there is a large body of evidence suggesting that RA is immune mediated, the etiology remains unresolved. Twin studies have shown disease concordance rates of approximately 15% in monozygotic twins and 4% in dizygotic twins, while the estimated risk ratio for siblings of RA patients ranges from 5 to 8. Our goal was to use genealogic data from Iceland to further investigate the genetic component of RA. METHODS: Data were obtained from a population-based, computerized genealogy database that was developed to examine multigenerational relationships among individuals in the relatively homogeneous population of Iceland. Using an algorithm, the minimum founder test, we calculated the least number of founders required to account for a list of RA patients, and compared it with 1,000 sets of same-sized matched control groups. In addition, we estimated the kinship coefficient and risk ratios for relatives of the RA patients. RESULTS: Several familial clustering tests demonstrated that the RA patients were more related to each other than were the average control set of Icelanders. A significantly fewer number of founders was necessary to account for our patient list than for the random sets of matched controls (P < 0.001), and the average pairwise identity-by-descent sharing was greater among the patients than among the control sets (P < 0.001). In addition, there was an increased risk of RA in first- and second-degree relatives of the patients; e.g., for siblings, the risk ratio was 4.38 (95% confidence interval 3.26-5.67), and for uncles/aunts, the risk ratio was 1.95 (95% confidence interval 1.52-2.43). CONCLUSION: The familial component of RA is shown to extend beyond the nuclear family, thus providing stronger evidence for a significant genetic component to RA.

Algorithms↗
PubMed2001

Sentinel node staging of early breast cancer using lymphoscintigraphy and the intraoperative gamma detecting probe.

Lymphoscintigraphy combined with intraoperative gamma-probe detection of sentinel lymph nodes in patients with inoperable early primary breast cancers is effective for staging the disease. The clinical alternative is axillary lymph node dissection, which is a far more invasive procedure and is accompanied by significant morbidity. Accuracy of staging is enhanced by immunohistochemical staining of micrometastases, which pathologists can easily perform for one to three sentinel lymph nodes, but not for 20 to 30 nodes, using axillary dissection procedure. Optimum methodology is presented for performing sentinel lymph node imaging and is important for accurate identification of sentinel node(s).

Breast Neoplasms↗
PubMed2001

A COL1A1 Sp1 binding site polymorphism predisposes to osteoporotic fracture by affecting bone density and quality.

Osteoporosis is a common disease with a strong genetic component. We previously described a polymorphic Sp1 binding site in the COL1A1 gene that has been associated with osteoporosis in several populations. Here we explore the molecular mechanisms underlying this association. A meta-analysis showed significant associations between COL1A1 "s" alleles and bone mineral density (BMD), body mass index (BMI), and osteoporotic fractures. The association with fracture was stronger than expected on the basis of the observed differences in BMD and BMI, suggesting an additional effect on bone strength. Gel shift assays showed increased binding affinity of the "s" allele for Sp1 protein, and primary RNA transcripts derived from the "s" allele were approximately three times more abundant than "S" allele--derived transcripts in "Ss" heterozygotes. Collagen produced from osteoblasts cultured from "Ss" heterozygotes had an increased ratio of alpha 1(I) protein relative to alpha 2(I), and this was accompanied by an increased ratio of COL1A1 mRNA relative to COL1A2. Finally, the yield strength of bone derived from "Ss" individuals was reduced when compared with bone derived from "SS" subjects. We conclude that the COL1A1 Sp1 polymorphism is a functional genetic variant that predisposes to osteoporosis by complex mechanisms involving changes in bone mass and bone quality.

Aged↗
PubMed2001

Genetic control of bone density and turnover: role of the collagen 1alpha1, estrogen receptor, and vitamin D receptor genes.

Genetic factors are known to influence both the peak bone mass and probably the rate of change in bone density. A range of regulatory and structural genes has been proposed to be involved including collagen 1alpha (COL1A1), the estrogen receptor (ER), and the vitamin D receptor (VDR), but the actual genes involved are uncertain. We therefore studied the role of the COL1A1 and VDR loci in control of bone density by linkage in 45 dizygotic twin pairs and 29 nuclear families comprising 120 individuals. The influences on bone density of polymorphisms of COL1A1, VDR, and ER were studied by association both cross-sectionally and longitudinally in 193 elderly postmenopausal women (average age, 69 years) over a mean follow-up time of 6.3 years. Weak linkage of the COL1A1 locus with bone density was observed in both twins and families (p = 0.02 in both data sets), confirming previous observations of linkage of this locus with bone density. Association between the MscI polymorphism of COL1A1 and rate of lumbar spine bone loss was observed with significant gene-environment interaction related to dietary calcium intake (p = 0.0006). In the lowest tertile of dietary calcium intake, carriers of "s" alleles lost more bone than "SS" homozygotes (p = 0.01), whereas the opposite was observed in the highest dietary calcium intake (p = 0.003). Association also was observed between rate of bone loss at both the femoral neck and the lumbar spine and the TaqI VDR polymorphism (p = 0.03). This association was strongest in those in the lowest tertile of calcium intake, also suggesting the presence of gene-environment interaction involving dietary calcium and VDR, influencing bone turnover. No significant association was observed between the PvuII ER polymorphism alone or in combination with VDR or COL1A1 genotypes, with either bone density or its rate of change. These data support the involvement of COL1A1 in determination of bone density and the interaction of both COL1A1 and VDR with calcium intake in regulation of change of bone density over time.

Absorptiometry, Photon↗
PubMed2000

Long PCR detection of the C4A null allele in B8-C4AQ0-C4B1-DR3.

The genes coding for the two components of complement 4 (C4), C4A and C4B, are located within the major histocompatibility complex (MHC) on the short arm of chromosome 6. Several studies have shown that deficiency of C4A is associated with systemic lupus erythematosus (SLE), rheumatoid arthritis and scleroderma. A large deletion covering most of the C4A gene and the 21-hydroxylase-A (21-OHA) pseudogene found on the extended haplotype B8-C4AQ0-C4B1-DR3 is estimated to account for approximately two-thirds of C4A deficiency in Caucasian SLE patients. Detection of this C4A null allele has been technically difficult due to the high degree of homology between C4A and C4B, with protein analysis and restriction fragment length polymorphism (RFLP) analysis using Southern blotting being the only approaches available. In this study, a long PCR strategy was used to rapidly genotype for the C4A deletion through specific primer design. The methodology makes use of the unique sequence of the G11 gene upstream of C4A and the sequence of a 6.4 kb retrotransposon, the human endogenous retrovirus HERV-K(C4), which is present in intron 9 of C4A but absent in the case of the deletion.

Alleles↗
PubMed2000

Sentinel node staging of early breast cancer using lymphoscintigraphy and the intraoperative gamma-detecting probe.

Sentinel node staging for breast cancer is increasingly used in place of axillary lymph node dissection but is not yet universally accepted. The problems of non-standardized methodologies and lack of consensus on the optimum techniques to identify sentinel nodes are being addressed. Complementary use of radionuclide imaging before surgery, intraoperative probe detection, and blue dye have yielded the best reported sensitivities for finding a sentinel node (94%). The importance of imaging is summarized as identifying sentinel node(s), distinguishing sentinel from secondary nodes, guiding surgical incision planning, and facilitating lower doses. The learning curve phenomenon, which applies to the surgeon and the nuclear medicine physician, has been recognized; measures to minimize it are being implemented. Radiation exposure to operating room and pathology personnel is very low; estimates of exposure to the surgeon's hands are 0.2% of the annual whole body dose received by every human being from natural background and cosmic sources.

Breast Neoplasms↗
PubMed1999

Association of polymorphism at the type I collagen (COL1A1) locus with reduced bone mineral density, increased fracture risk, and increased collagen turnover.

OBJECTIVE: To examine the relationship between a common polymorphism within intron 1 of the COL1A1 gene and osteoporosis in a nested case-control study. METHODS: We studied 185 healthy women (mean +/- SD age 54.3+/-4.6 years). Bone mineral density (BMD) was measured using dual x-ray absorptiometry, and fractures were determined radiographically. The COL1A1 genotype was assessed using the polymerase chain reaction and Bal I endonuclease digestion. RESULTS: Genotype frequencies were similar to those previously observed and in Hardy-Weinberg equilibrium: SS 61.1%, Ss 36.2%, and ss 2.7%. Carriage of at least one copy of the "s" allele was associated with a significant reduction in lumbar spine BMD (P = 0.02) and an increased risk of total fracture (P = 0.04). Urinary pyridinoline levels were significantly elevated in those with the risk allele (P < 0.05). CONCLUSION: These data support the findings that the COL1A1 gene polymorphism is associated with low BMD and fracture risk, and suggest a possible physiologic effect on total body turnover of type I collagen.

Absorptiometry, Photon↗
PubMed1999

The relationship between selected physiological variables of rowers and rowing performance as determined by a 2000 m ergometer test.

The aim of this study was to establish the relationship between selected physiological variables of rowers and rowing performance as determined by a 2000 m time-trial on a Concept II Model B rowing ergometer. The participants were 13 male club standard oarsmen. Their mean (+/- s) age, body mass and height were 19.9+/-0.6 years, 73.1+/-6.6 kg and 180.5+/-4.6 cm respectively. The participants were tested on the rowing ergometer to determine their maximal oxygen uptake (VO2max), rowing economy, predicted velocity at VO2max, velocity and VO2 at the lactate threshold, and their velocity and VO2 at a blood lactate concentration of 4 mmol x l(-1). Percent body fat was estimated using the skinfold method. The velocity for the 2000 m performance test and the predicted velocities at the lactate threshold, at a blood lactate concentration of 4 mmol x l(-1) and at VO2max were 4.7+/-0.2, 3.9+/-0.2, 4.2+/-0.2 and 4.6+/-0.2 m x s(-1) respectively. A repeated-measures analysis of variance showed that the three predicted velocities were all significantly different from each other (P<0.05). The VO2max and lean body mass showed the highest correlation with the velocity for the 2000 m time-trial (r = 0.85). A stepwise multiple regression showed that VO2max was the best single predictor of the velocity for the 2000 m time-trial; a model incorporating VO2max explained 72% of the variability in 2000 m rowing performance. Our results suggest that rowers should devote time to the improvement of VO2max and lean body mass.

Adolescent↗
PubMed1998

Relation of alleles of the collagen type Ialpha1 gene to bone density and the risk of osteoporotic fractures in postmenopausal women.

BACKGROUND: Osteoporosis is a common disorder with a strong genetic component. One way in which the genetic component could be expressed is through polymorphism of COLIA1, the gene for collagen type Ialpha1, a bone-matrix protein. METHODS: We determined the COLIA1 genotypes SS, Ss, and ss in a population-based sample of 1778 postmenopausal women using a polymerase-chain-reaction-based assay. We then related the genotypes to bone mineral density and the occurrence of osteoporotic fractures in these women. RESULTS: As compared with the 1194 women with the SS genotype, the 526 women with the Ss genotype had 2 percent lower bone mineral density at the femoral neck (P=0.003) and the lumbar spine (P=0.02); the 58 women with the ss genotype had reductions of 4 percent at the femoral neck (P= 0.05) and 6 percent at the lumbar spine (P=0.005). These differences increased with age (P=0.01 for modification by age of the effect of COLIA1 on femoral-neck bone density, and P=0.004 for modification of the effect on lumbar-spine bone density). Women with the Ss and ss genotypes were overrepresented among the 111 women who had incident nonvertebral fractures (relative risk per copy of the s allele, 1.5; 95 percent confidence interval, 1.1 to 2.1). CONCLUSIONS: The COLIA1 polymorphism is associated with reduced bone density and predisposes women to osteoporotic fractures.

Age Factors↗
PubMed1998

Collagen Ialpha1 Sp1 polymorphism, bone mass, and bone turnover in healthy French premenopausal women: the OFELY study.

Bone mineral density (BMD) is under strong genetic control. Recent work has suggested that a polymorphism affecting an Sp1 binding site in the collagen I (COLI) A1 gene is associated with BMD and vertebral fracture in postmenopausal women. We analyzed this polymorphism in relation to BMD and bone turnover in 220 healthy premenopausal women aged 31-57 years. There were 61% SS homozygotes, 35% Ss heterozygotes, and 4% ss homozygotes, genotype frequencies similar to those previously reported in other Caucasian populations. Women in the three genotype groups were matched for age, body weight, physical activity, smoking habits, and oral contraceptive use, but height was greatest in the SS group and lowest in the ss group (p = 0.03). Between-group comparisons by analysis of variance (ANOVA) showed that COLI A1 genotype was significantly associated with spine BMD (p = 0.05), total body BMD (p = 0.046), and total body bone mineral content (BMC) (p = 0.02), but the differences between extreme genotypes were small (4, 5, and 10%, for spine BMD, total body BMD, and total body BMC, respectively). After adjustment for height, the differences between genotypes decreased and were no longer significant by ANOVA (p = 0.08, 0.17, and 0.33 for spine BMD, total body BMD, and total body BMC). Furthermore, no significant difference between genotypes was observed for femoral neck, trochanter, Ward's triangle, or forearm BMD. COLI A1 genotype was associated with serum C-terminal extension propeptide of type I collagen (p = 0.04), with lowest levels in ss individuals, but not with any other marker of bone formation (osteocalcin, alkaline phosphatase, and type I collagen N-terminal extension propeptide) or bone resorption (urinary excretion of type I collagen C and N telopeptide breakdown products). The COLI A1 Sp1 polymorphism is associated with height, peak total body BMD and BMC, and spine BMD. The genotype-specific differences account for only a small proportion of variance in BMD at these sites and are not significant after adjustment for height, suggesting that part of the effect on bone mass may be due to differences in body size. Our data support the view that COLI A1 may be a candidate gene for regulation of bone mass, but our results must be treated with caution, in view of the small number of ss individuals, and will require confirmation in larger studies.

Adult↗
PubMed1998

An Sp1 binding site polymorphism in the COLIA1 gene predicts osteoporotic fractures in both men and women.

Genetic factors play an important role in the pathogenesis of osteoporosis, and recent studies have shown that a polymorphic Sp1 binding site in collagen type I alpha1 (COLIA1) gene is associated with bone mass and vertebral fractures in women from the U.K. Information on the predictive value of the COLIA1 Sp1 polymorphism in other populations is limited, however, and no studies have yet been performed in osteoporotic males. In view of this, we analyzed COLIA1 genotypes in relation to bone density and biochemical markers of bone turnover and the presence of osteoporotic fractures in a case-control study of Danish men and women. COLIA1 genotype was determined by polymerase chain reaction analysis of genomic DNA extracted from peripheral blood samples and related to bone mass, biochemical markers of bone turnover, and the presence of fracture in a study of 375 osteoporotic vertebral fracture patients and normal controls. There was no significant effect of COLIA1 genotype on bone mass or biochemical markers when data from the control group (n = 195) and fracture group (n = 180) were analyzed separately. However, the genotype distribution was significantly different in the fracture cases compared with age-matched controls (chi2 = 16.48, n = 249,p = 0.0003) due mainly to over-representation of the ss genotype in the fracture patients (14.3% vs. 1.4%), equivalent to an odds ratio for vertebral fracture of 11.83 (95% confidence interval 2.64-52.97) in those with the ss genotype. Similar differences in genotype distribution between osteoporotic patients and controls were observed in both men (chi2 = 11.52, n = 95, p = 0.0032, OR = 2.04) and women (chi2 = 6.90, n = 154, p = 0.032, OR = 1.37). In keeping with the above, logistic regression analysis showed that the ss genotype was an independent predictor of osteoporotic fracture (p = 0.028). This study confirms that the COLIA1 Sp1 polymorphism is significantly associated with osteoporotic vertebral fractures. The association is seen in both men and women, and the effect on fracture risk appears to be partly independent of bone mineral density. Our results raise the possibility that genotyping at the Sp1 site could be of clinical value in identifying individuals at risk of osteoporotic fractures in both genders.

Adult↗
PubMed1997

Polymorphisms of the interleukin-6 gene are associated with bone mineral density.

Genetic factors play an important role in determining bone mass and several genes probably act as regulators of this process. Interleukin-6 (IL-6) is a candidate gene for regulation of bone density, since it has stimulatory effects on cells of the osteoclast lineage and has been implicated in the pathogenesis of bone loss associated with estrogen deficiency. Here we studied the relationship between bone mineral density (BMD) and a polymorphic AT rich minisatellite repeat in the 3' flank of the IL-6 gene in a cohort of 200 women. Six length variants were identified (designated A-F), but four of these were rare such that the last majority of individuals fell into one of two common genotypes: F/F (58.5%) and C/F (27.5%). There was a significant relationship between IL-6 genotype and bone mass at the lumbar spine as determined by analysis of variance (p = 0.04) and a similar trend for bone mass at the femoral neck (p = 0.11). When BMD values were compared in the two common genotypes, we found that spine BMD values were significantly higher in the C/F genotype (mean +/- SEM = 0.94 +/- 0.04 g/cm2) as compared with the F/F genotype (0.81 +/- g/cm2; p = 0.012). A similar trend was seen for hip BMD values, but here, the difference failed to reach statistical significance (p = 0.06). Further analysis showed that genotype-specific effects on bone mass were observed in both premenopausal and postmenopausal women and did not increase with age, suggesting that the association between IL-6 polymorphisms and bone density may be mediated by an effect on peak bone mass, rather than rate of bone loss. We conclude that bone mass is associated with two common polymorphisms of the IL-6 gene. Although the mechanisms that underlie this association will require further research, our data suggest that polymorphic variation at the IL-6 gene locus may contribute to the genetic regulation of bone mass.

Absorptiometry, Photon↗
PubMed1996

Vitamin D receptor polymorphism, bone mineral density, and osteoporotic vertebral fracture: studies in a UK population.

Bone mineral density is under strong genetic control and polymorphisms of the vitamin D receptor (VDR) have been suggested to account for some of the genetic variation in bone mass. However, the relationship between VDR polymorphisms and bone density is controversial and has not been confirmed by all workers. Since there is little information on the association between VDR genotype and bone mass in the UK, we studied VDR genotype, bone mineral density, and osteoporotic fracture in a cohort or pre- and postmenopausal women from the Northeast of Scotland. We found a highly significant "inverse" association between the VDR genotype and bone mineral density at the hip such that individuals of "bb" genotype had a femoral neck bone density of 0.79 standard deviation lower than individuals of BB genotype (p < 0.02). This contrasts with most previous studies in which the "bb" genotype has been associated with high bone density. A similar, but nonsignificant trend was seen for lumbar spine BMD. To study the clinical significance of this observation, we examined the distribution of VDR genotypes in a subgroup of patients with severe osteoporosis who had vertebral compression fractures (n = 44) as compared with with age-and gender-matched controls (n = 44). Despite the differences in BMD between genotypes, there was no significant excess of any specific VDR genotype in osteoporotic fracture patients, indicating that VDR genotyping may be of limited practical value in identifying patients at risk of vertebral fracture. This study confirms that there is a significant association between VDR genotype and bone mass in our population. The "inverse" relationship between VDR genotype noted in this, as compared with previous studies, would be consistent with a model whereby VDR polymorphisms are not the cause of reduced BMD, but rather, are in linkage disequilibrium with a disease-causing locus nearby.

Absorptiometry, Photon↗
PubMed1996

Reduced bone density and osteoporosis associated with a polymorphic Sp1 binding site in the collagen type I alpha 1 gene.

Osteoporosis is a common disease with a strong genetic component, characterized by reduced bone mass and increased fracture risk. Current evidence suggests that the inheritance of bone mass is under polygenic control but the genes responsible are poorly defined. Type I collagen is the major protein of bone encoded by the COLIA1 and COLIA2 genes. While these are strong candidates for the genetic regulation of bone mass, no abnormality of either gene has so far been defined in osteoporosis. In this study, we describe a novel G-->T polymorphism in a regulatory region of COLIA1 at a recognition site for the transcription factor Sp1(7) that is significantly related to bone mass and osteoporotic fracture. G/T heterozygotes at the polymorphic Sp1 site (Ss) had significantly lower bone mineral density (BMD) than G/G homozygotes (SS) in two populations of British women and BMD was lower still in T/T homozygotes (ss). The unfavourable Ss and ss genotypes were over-represented in patients with severe osteoporosis and vertebral fractures (54%), as compared with controls (27%), equivalent to a relative risk of 2.97 (95% confidence interval 1.63-9.56) for vertebral fracture in individuals who carry the 's' allele. While the mechanisms that underlie this association remain to be defined, the COLIA1 Sp1 polymorphism appears to be an important marker for low bone mass and vertebral fracture, raising the possibility that genotyping at this site may be of value in identifying women who are at risk of osteoporosis.

Binding Sites↗