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Genetics
COMPARISON OF THE MANDIBLE SKELETAL STRUCTURES OF DOWN SYNDROME USING A NEW BONE STRUCTURE ANALYTICAL METHOD
S. K. Kumasaka1*, K. N. Nakamura2, T. T. Takahashi3, A. M. Miyagi1, I. K. Kashima2
1Dept. of Dentistry for Special Patients, Kanagawa Dental College, 82 Inaoka-cho, Kanagawa, Japan
2Dept. of Oral and Maxillofacial Radiology, Kanagawa Dental College, 82 Inaoka-cho, Kanagawa, Japan
3Dept of Anatomy, Kanagawa Dental College, 82 Inaoka-cho, Kanagawa, Japan
A visual and quantitative analysis of the mandibular bone trabeculae of 40 patients with Down syndrome and 54 normal persons by means of panoramic tomography was performed with a morphological filter and star volume analysis.
There was a significant difference (P<0.001, Mann-Whitney U test) between the pattern distributions of the Down and normal subjects (n=31) of less than 50 years of age. The star volume analysis also showed a significant difference between Down and normal groups within each age range (P<0.001, ANOVA test) and the Vt values for all the Down syndrome subjects was similar to that of the normal subjects 70 years of age (no significant difference in ages).
There were significant differences in the skeletal patterns of the normal subjects and those with Down syndrome. This would seem to indicate some systemic influence on the mandibular bone of the Down syndrome subjects, quite possibly the influence of trisomy 21. This influence resulted in a presumably weaker bone structure resembling that of normal subjects over 70 years of age. Further, the combination of a morphological filter and star volume analysis proved a useful tool in this analysis and may prove equally useful in the assessment other bone abnormalities.
BONE MASS DIFFERENCES BETWEEN 9-YEAR OLD BLACK AND WHITE, URBAN SOUTH AFRICAN CHILDREN
S. A. Norris1*, J. M. Pettifor1, N. Cameron2, T. De Wet1, L. Vidulich1, E. Cumin1
1University of the Witwatersrand, RSA
2University of Loughborough, UK
We investigated inter-ethnic differences in bone mass variables of a cohort of white (males=47; females=52) and black (males=159; females=139) South African children living in Johannesburg. Bone mineral density (BMD; g/cm2) of the hip, lumbar spine and radius was determined using Dual-energy X-ray Absorptiometry (Hologic QDR-4500A). Metacarpal indices (length (mm), outer diameter (OD; mm) and inner diameter (ID; mm)) of the second metacarpal were measured from an x-ray of the left hand to determine cortical thickness.
The mean results, corrected for height, weight and bone age, are shown in the table below. Contrary to American findings, we found no significant inter-ethnic BMD differences at the lumbar spine and radial sites. However, black males and females did have greater hip BMD (5% and 10% respectively) than white males and females. The metacarpal indices indicate that black males and females have greater OD and ID dimensions, but, significantly less cortical thickness (20% and 14% respectively) than white males and females.
This study supports earlier findings that there is no inter-ethnic differences in appendicular bone mass after adjusting for height, weight and bone age in prepubertal South African children. Furthermore, the data seems to mimic findings from premenopausal South African women where no inter-ethnic differences at the lumbar spine and radial sites were found, but where inter-ethnic differences of the hip was evident with black women having greater hip BMD than white women. The implications would suggest that South African black women may have a lower risk of fracturing the hip, but may not be protected against systemic osteoporosis as anticipated.
| Ethnic differences in bone mass variables. | ||||
| Variable | White males |
Black males |
White females |
Black females |
| Total hip BMD | 0.700 | 0.740b | 0.603 | 0.671c |
| Total lumbar spine BMD | 0.549 | 0.535 | 0.523 | 0.553 |
| Total radial BMD | 0.406 | 0.393 | 0.385 | 0.379 |
| OD | 6.49 | 6.85a | 6.43 | 6.61a |
| ID | 3.37 | 4.10c | 3.29 | 3.76c |
| OD-ID | 3.12 | 2.75b | 3.14 | 2.85b |
| OD-(ID/OD) | 0.48 | 0.40c | 0.49 | 0.43c |
| (a) p<0.05, (b) p<0.001, (c) P<0.0001 | ||||
POLYMORPHISMS IN THE ANDROGEN AND ESTROGEN RECEPTOR ALPHA GENES ARE ASSOCIATED WITH BMD IN MIDDLE-AGED FINNISH MEN
T. Remes1*, S. B. Väisänen2,3, J. Huuskonen4, A. Mahonen1, I. M. Penttilä2,3, P. Mäenpää1, H. Kröger4, R. Rauramaa2,5
1Department of Biochemistry, University of Kuopio, Finland
2Kuopio Research Institute of Exercise Medicine and Department of Physiology, University of Kuopio, Finland
3Department of Clinical Chemistry, Kuopio University Hospital, Finland
4Department of Surgery, Kuopio University Hospital, Finland
5Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Finland
The aim was to investigate associations between the polymorphic locuses of androgen receptor (AR) and estrogen receptor alpha (ERalpha) genes and BMD in a controlled randomized exercise intervention trial for four years. Additionally, potential associations between these polymorphisms and serum testosterone, sex hormone-binding globulin (SHBG), and estradiol concentrations were evaluated. Subjects were a population-based, randomly selected group of middle-aged men. The PvuII RFLP-marker of ERalpha and the CAG repeat length of AR were analyzed. BMDs of the lumbar spine (L2-L4) and proximal femur were measured at the baseline as well as two and four years later with dual-energy X-ray absorptiometry (DXA). There were no differences between the exercise and reference groups in any measured parameters. Therefore, the present analyses were done in both groups combined. At the baseline and during the two- and four-year follow-ups, the BMDs of the subjects with the shortest CAG repeats (15 to 17 repeats) were related to higher lumbar BMD values than the BMDs of the subjects with the longest CAG repeats (22 to 26 repeats) (p<0.10 at the baseline and p<0.05 at the two- and four-year follow-ups). Similarly, the subjects with the shortest CAG repeats had higher BMD in femoral neck and proximal femur. At the baseline, circulating free testosterone concentrations were highest in the subjects with the longest repeats and lowest in the subjects with the shortest repeats (p<0.05). With respect to the estrogen receptor, after four years, the subjects with the PP genotype showed an increase (5.4%, p<0.001) in lumbar spine BMDs while in the pp genotype, no change was detected. The PP genotype associated with a BMD increase in the proximal femur while, in the Pp and pp genotype groups, the BMD decreased (p<0.04). A similar trend was seen in femoral neck BMDs. We conclude that middle-aged Finnish men with short CAG repeat sequences in the AR have better lumbar and femoral BMD values than men with long CAG repeat sequences. In addition, men with the ER genotype PP appear to have smallest risk of bone loss in the lumbar spine and proximal femur during aging.
POLYMORPHISM AT THE TYPE I COLLAGEN (COLIA1) AND RELATIVE RISK OF OSTEOPOROSIS AND VERTEBRAL FRACTURES IN POSTMENOPAUSAL WOMEN
M. Bernad1*, C. Gonzalez3, M. Escalona4, M. L. Gonzalez5, J. Fernandez1, M. V. Garces2, E. Martin Mola1, L. Carreño3, M. E. Martinez2
1Rheumatology Unit, Hosp. La Paz, Madrid, Spain
2Biochemistry Unit, Hosp. La Paz, Madrid, Spain
3Rheumatology Unit, Hosp. Gregorio Marañon, Madrid, Spain
4Medicine and Experimental Surgery, Hosp. Gregorio Marañon, Madrid, Spain
5Biochemistry Unit, Militatry Hospital Gómez Ulla, Madrid, Spain
OBJECTS Twin and family studies have demonstrated that an important degree of the population variance in bone mineral density (BMD) is attributable to genetic factors. A polymorphism in the collagen type I a 1 (COLIA1) gene has recently been associated with low bone mass and fracture incidence.
METHODS We analyzed the relationship between COLIA1 gene polymorphism, lumbar spine and hip BMD, T-score and fracture incidence in a population of 319 postmenopausal women classified by WHO standards: 98 non-osteoporotic women (NOPW) (57.4±6.2 yrs), 146 osteoporotic women without fracture (OPW without fracture: OPWnF) (60.0±5.2 yrs) and 75 osteoporotic women with fracture (OPW with fracture: OPWwF) (61.2±6.3 yrs). The COLIA1 genotype was assessed by polymerase chain reaction and Bal I endonuclease digestion. Genotype frequencies for the total group were 49.2% "SS" homozygotes, 39.5% "Ss" heterozygotes and 11.3% "ss" homozygotes.
RESULTS We found significant differences in the percentage of homozygous "ss" between NOPW and OPW (6.1% and 13.6% respectively). However, the incidence of genotype "ss" in OPWnF was 6.2% and 28% in OPWwF. We observed no associations between the COLIA1 genotype and lumbar and hip BMD. However, the lumbar spine T-scores were lower in the "ss" group than in the "Ss" and "ss" group. The incidence of fractures (64 vertebral and 11 colles) varied significantly by genotype: "SS" 21.7%; "Ss" 15.9%; and "ss" 58.3% (c2 = 15.43; p<0.0001); this resulted in a fracture odds ratio of 5.96 (95% confidence interval 2.26-15.69). Logistic regression analysis of fracture prevalence showed that for prevalent fractures, the women with "ss" group had 4.17 times risk of the woman "SS" + "Ss" groups. When prevalence was adjusted for BMD and T-scores, the respective fracture risk was 2.6 and 2.94 for the "ss" group versus the other genotypes (SS+Ss).
CONCLUSION A slight association was found between lumbar T-score and gene COLIA1 polymorphism. Expression of the "ss" allele seems to be related with a higher incidence of fracture in postmenopausal women, and was independent of bone mineral density.
THE GENOTYPIC COMPONENT AFFECTS MAINLY CORTICAL BONE OF YOUNG OSEOPOROTIC SUBJECTS
C. Baudoin1, M. Cohen-Solal1,2, J. Beaudreuil1,2, M. C. de Vernejoul1,2*
1INSERM U 349, Paris, France
2Fédération de Rhumatologie, Paris, France
Our aim was to estimate the respective effect of genes and environment, in families of osteoporotic patients in order to individualize the best phenotypic marker to investigate genes associated with osteoporosis.
Methods. We recruited 83 osteoporotic probands (47 women and 36 men) and 95% members of their families (90 siblings and 83 children). Male probands and their families were 18 years younger than female probands. Families were split between "young" and "old" according to the median age of male (52 years old) and female (68 years old) probands. We measured bone mineral density at femoral neck (FN) and the lumbar spine (LS) that was adjusted on age, height, weight and hormonal status (Z-score). We analyzed the means, using mixed linear model, and the familial resemblance, based on the intraclass and interclass correlations using pairwise estimator. Actual environment was evaluated by classes.
Results. At both sites, in the families of osteoporotic patients the mean Zscores were significantly negative, without differences between generations and genders. At FN, the means Zscore was lower in famillies of male proband (-0.57±0.96, female probands: -0.18±0.85, p=0.012). However this difference was mainly due to the younger age of male probands (young families: -0.58±0.94, old families: -0.11±0.83, p=0.006). These Zscore did not differ at LS. The phenotypic resemblance was quite high within families of male probands at FN (proband-children r=0.47, children-children r=0.81) but also at the LS for the children-children correlation (r=0.78). Classes determined by environmental factors were different at the LS and FN and explained 19% of the variance Zscore at FN and 30% at LS. After adjustment on environment, high genotypic resemblance persisted in families of male probands. In families of proband women, the genotypic resemblance was only observed among children and at the FN.
Conclusion. Young osteoporotic patients, mostly male in our study, are mainly concerned by the genetic component that was more obvious at the FN suggesting that actual environmental effect predominates at LS, mainly composed of trabecular bone and masks in older subjects the genotypic resemblance.
A LARGE CONSANGUINEOUS OSTEOPOROSIS FAMILY WITH 20 AFFECTED INDIVIDUALS
P. Dincer1, B. O. Yildiz2*, B. Balci1, M. Bayraktar2
1Hacettepe University Faculty of Medicine Dept of Medical Biology, Ankara, Turkey
2Hacettepe University Faculty of Medicine Dept of Internal Medicine Division of Endocrinology, Ankara, Turkey
Osteoporosis is a major public health problem. Herein we present a study of large consanguineous osteoporosis family with three generations and at present 20 patients.
Our index patient was a 66 years old man who came to the clinic because of back pain. His past medical history revealed that he had no known systemic illnesses. Radiograph of the lumbar vertebrae showed a compression fracture at the level of L3, T score of lumbar vertebrae and total hip were -4.32, and -2.32 respectively. Bone turnover markers were normal.
Because the family history was positive for osteoporosis, the patient's relatives were invited to be evaluated for osteoporosis. A total of 39 close relatives out of more than 1000 individuals in this family had their bone density measured (18 DEXA, 33 calcaneal QUS measurements) with an assessment of their risk factors for osteoporosis. The patient's four brothers (60, 69, 71, 78 years) and 52 years old premenopausal sister were osteoporotic on BMD of the lumbar spine. The sister and 78 years old brother were osteoporotic, the others were osteopenic at the total hip on BMD. The patient's 64 years old wife was osteoporotic at the lumbar spine on BMD. The patient's three sons (32, 34, 41 years) and three daughters (34, 36, 46 years) were osteoporotic on BMD of the lumbar spine and osteopenic on BMD of the total hip.
Eleven nephews (age range 29-51 y), 10 nieces (22-48 y) and 5 children of nephews (5 boys 17-22 y) had their bone density measured. Only 3 nephews, 1 niece and 2 children had normal BMD values. Three nephews (28,37,40 y) and 4 nieces (33,36,38,39 y) were osteoporotic and all the others were osteopenic.
Our aim is to genotype this family for candidate loci. Estrogen receptor gene (ESR1) has been implicated as one of the candidate genes. Linkage studies using polymorphic markers of the 6q25.1 locus were performed. We found no evidence for linkage to this region. This family is the largest family with osteoporosis reported. Consanguinity in the family will allow homozygosity mapping to detect responsible genes. Further genetic analyses are being performed.
RELATION BETWEEN THE COLIA1 POLYMORPHISM AND BONE MINERAL DENSITY IN HEALTHY POSTMENOPAUSAL WOMEN
P. Mezquita-Raya1*, M. Muñoz-Torres1, F. López-Rodríguez1, J. M. Quesada-Gómez2, F. Luque2, E. Torres-Vela1, J. D. Luna3, F. Escobar-Jiménez1
1Bone Metabolic Unit, Endocrinology Division, University Hospital "San Cecilio", Granada, Spain
2Endocrinology Division, University Hospital "Reina Sofia", Cordoba
3Biostatistics Department, School of Medicine, Granada, Spain
Bone mass and its mineral content are under genetic control. Collagen type I-a-1 gene has been reported to account for most of the well established genetic influence on bone mass, associated to a low bone mineral density (BMD) and osteoporotic fractures in some studies. However, discordant studies have been published and it is still not clear whether ColIa1 influences bone mass in postmenopausal women.
AIMS: to determine the relation between the ColIa1 gene, BMD and prevalent vertebral fractures in a non treated group of healthy, except for osteoporosis, postmenopausal women.
PATIENTS AND METHODS: we studied 144 postmenopausal women (61±7 yr). All were Caucasian, community-dwelling, ambulatory, in a good health except for osteoporosis and did not have secondary causes for low BMD or medications that might affect bone density. ColIa1 polymorphism was typed by polymerase chain reaction. Genotypic polymorphism was defined as SS, Ss and ss. We determined BMD at lumbar spine (LS) and femoral neck (FN) measured by DEXA (Hologic QDR1000) and the existence of prevalent vertebral fractures.
RESULTS: There were 46.6% SS homozygotes, 49.3% Ss heterozygotes, and 5.7% ss homozygotes. Bone mass at lumbar spine and femoral neck was significantly different among three genotypes, with higher values in subjects SS homozygotes. The genotype-specific differences account for a 2.9% of variance in BMD at LS after adjustment for body mass index and years since menopause. The percentage of subjects with vertebral fracture and osteoporosis differed significantly among the three genotypes, and was higher in Ss and ss compared with SS. The probability of presenting a vertebral fracture was significantly higher in the group of subjects with genotypes Ss and ss, even after adjusting by BMD, years since menopause and body mass index (OR: 3.04 [CI95%: 1.24 - 7.5]).
CONCLUSION: Our study shows that ColIa1 polymorphism is associated with low bone mass and prevalent vertebral fractures, in a sample of noninstitutionalized women referred to a speciality osteoporosis clinic.
POLYMORPHISM AT THE SP 1 BINDING SITE IN THE COLLAGEN (COLIA1) GENE AND DOES NOT PREDICT BONE MINERAL DENSITY IN POSTMENOPAUSAL CANARIAN WOMEN.
M. Sosa1*, A. Torres2, E. Salido2, D. Hernández1, M. Benítez1, J. Gómez1, Y. Barrios2, P. Betancor3
1University of Las Palmas de Gran Canaria. Hospital University Insular, Service of Internal Medicine
2University of La Laguna. Investigation Unit.
3University of Las Palmas de Gran Canaria. Hospital Dr. Negrín, Service of Internal Medicine
Background.
Although the genes that regulate bone mineral density (BMD) are incompletely defined, a great number of publications suggest that several genes are involved. A polymorphism at the Sp1 binding site within the promoter region of collagen (COL1A1) has recently been strongly associated with reduced BMD although some other studies did not find this association. We examined whether the unfavourable "s" allele was associated with low BMD in 109 canarian postmenopausal women.
Methods.
We studied 109 consecutive postmenopausal women. We assessed BMD by Dual X-ray Absorptiometry (DXA)(Hologic QDR 1000), and by Quantitative Computed Tomography (QCT). Genotyping using the Sp 1 polymorphism was carried out.
Results. There were no significant differences by COL1A1 genotype groups for age, weight, height, Body Mass Index (BMI) and fertile years. BMD measurements are shown in Table 1. No significant differences were also found.
Conclusions: Sp1 polymorphism in the COL1A1 gene are unlikely to be of clinical value in identifying Canarian women who are at risk of postmenopausal osteoporosis.
| Comparison of BMD values by DXA and QCT. | |||
| SS | Ss and ss | p value | |
| DXA | |||
| L2-L4 (g/cm2) | 0.845±0.182 | 0.877±0.229 | NS |
| Femoral neck (g/cm2) | 0.690±0.120 | 0.704±0.183 | NS |
| Trochanter (g/cm2) | 0.586±0.117 | 0.580±0.157 | NS |
| Intertrochanter (g/cm2) | 0.895±0.166 | 0.914±0.208 | NS |
| Total (g/cm2) | 0.766±0.135 | 0.772±0.185 | NS |
| Ward´s (g/cm2) | 0.503±0.140 | 0.515±0.190 | NS |
| QCT. L2-L3 (mg/cm3) | 116.1±53.9 | 143.7±77.5 | NS |
THERE IS NO ASSOCIATION BETWEEN THE POLYMORPHISM OF ESTROGEN RECEPTOR GENE AND TRANSSEXUAL MEN
M. Sosa1*, A. Torres2, E. Salido2, E. Arbelo1, Y. Barrios2, M. C. Navarro3, P. Betancor1
1University of Las Palmas de GC, Hospital University Insular, Bone Metabolic Unit
2Investigation Unit. University of La Laguna
3University of Las Palmas de Gran Canaria, Department of Nursery
Background: Transsexualism is a poorly studied condition. The fact is that these biological men feel themselves as women and so they behave: wearing make-up, women clothes, and self-administrating great amounts of estrogens to obtain female secondary characters. Its aetiology is not known and no one study has been published describing the distribution of oestrogen receptors in transsexuals.
Methods: 24 transsexuals were studied in the Bone Metabolic Unit of our Hospital from January 1999 to November 2000. 26 healthy men comprised the control group. Age, weight, height, Body Mass Index (BMI) were recorded. We collected some blood and performed the polymorphism of oestrogen gene, using XbaI and PvuII as restriction enzymes.
Results: Age, and BMI of controls and transsexuals showed no significant differences. The distribution of the different polymorphism of oestrogen gene were very similar in transsexuals and controls. No significant association was established between any particular polymorphism and the presence of transsexualism.
Conclusion: There is no significant association between the polymorphism of oestrogen gene and transsexualism.
| Polymorphism | Transsexuals | Control |
| pp | 10 | 8 |
| pP | 11 | 13 |
| PP | 3 | 5 |
| xx | 12 | 10 |
| xX | 12 | 13 |
| XX | 3 | |
| The distribution of the polymorphism of
estrogen gene in transsexuals and control. No estatistical association was found. |
||
A NUCLEOTIDE VARIANT ASSOCIATED WITH DECREASED BONE MINERAL DENSITY IN INTERLEUKIN 6 GENE PROMOTOR REGION
N. Ota1,2*, T. Nakajima1, T. Suzuki3, T. Hosoi3, H. Orimo3, S. Inoue4, Y. Shirai2, M. Emi1
1Department of Molecular Biology, Institute of Gerontology, Nippon Medical School
2Department of Orthopedics, Nippon Medical School
3Tokyo Metropolitan Institute of Gerontology and Hospital
4Department of Geriatrics, Faculty of Medicine, University of Tokyo, Hongo, Tokyo, Japan
Recently, interleukin-6(IL-6) was regarded as a potential osteoporotic factor, since it has stimulatory effects on cells of the osteoclast lineage; possibility of role of IL-6 in the pathogenesis of bone loss associated with estrogen deficiency has been implicated. We previously described association of interleukin-6 (IL-6) gene with bone mineral density as well as genetic linkage of IL-6 locus to human osteoporosis by sib pair linkage analysis. However the molecular mechanisms by which bone mineral density is regulated by this locus remains unknown. To investigate a possibilities that these genetic effects results from a sequence variation which may affects IL-6 gene expression or alters the IL-6 protein function, we searched for polymorphisms both 5' and 3' franking region and all five exons of IL-6 gene in Japanese population. We identified three single-nucleotide sequence variations; a C/G substitution at nt -643 in the promoter region, a G/A substitution at nt 4391 in 3' non-coding region, a AnTn tract variation around nt -447; the last one was previously observed in Caucasian. The first promoter variation created Bsr BI RFLP site; the frequency of minor allele (G allele) was 0.184. A significant correlation between presence of G allele and decreased bone mineral density was observed by analysis of variance. When BMD values were compared among three genotypical groups at nt -634, i.e., G/G, G/C, C/C, BMD was lowest among the G/ G homozygotes (mean±SD. = 0.278±0.062 g/cm2), BMD was highest in the C/C homozygotes (0.314±0.059 g/cm2), while BMD was intermediate among the heterozygotes (0.302±0.078 g/cm2)(p=0.0273). Given the several lines of evidence in genetic studies, we suggest that the IL-6 gene is one of the gene that affect bone metabolism, leading to pathogenesis of osteoporosis.
RELATIONSHIP BETWEEN COLLAGEN I ALPHA 1 SP1 AND VITAMIN D RECEPTOR GENE POLYMORPHISMS AND THE DEVELOPMENT OF BONE FRACTURES AFTER LIVER TRANSPLANTATION
A. Monegal*, L. Alvarez, M. J. Martínez de Osaba, J. Oriola, N. Guañabens, P. Peris, T. Ferró, A. Rimola, L. Grande, J.Muñoz-Gómez
Hospital Clinic, University of Barcelona, IDIBAPS, Spain
The aims of this study were to assess the influence of collagen I alpha 1 Sp1 (COLIA1) and vitamin D receptor gene polymorphisms (VDR) in the development of bone fractures in liver transplant (LT) patients.
The study included 23 LT patients who developed bone fractures after liver transplantation (13 males/ 10 females) and 24 non-fractured LT patients (17 males/ 7 females). Spinal X-rays were performed on all patients and non-vertebral fractures were confirmed radiographically. The COLIA1 Sp1 genotypes (SS, Ss, ss) were assessed by restriction enzyme digestion (Fnu 4HI) of PCR amplified DNA extracted from whole blood. In addition, analysis of the VDR gene exon 2 polymorphism (MM, Mm, mm genotypes) was performed by means of the Single-Strand Conformation Polymorphism (SSCP) technique.
In our study the age at the transplant procedure was higher in fractured patients than in non-fractured patients (mean±SD: 56.7±7.3 vs. 50.3±7.4 years, p=0.006). The frequency distribution of COLIA1 genotypes was: SS 60.9%, Ss 30.4%, ss 8.7% in fractured patients and SS 62.5%, Ss 16.7%, ss 20.8% in non-fractured patients, with no statistical differences between groups. Moreover, Odds Ratio for the development of fractures in Ss+ss group was 1.07 (95% confidence interval: 0.33-3.47). The genetic frequency for VDR genotypes in fractured patients was: MM 26.3%, Mm 52.6%, mm 21.1% and MM 15%, Mm 55%, mm 30% in non-fractured patients (p=ns). Odds Ratio for the development of fractures in MM group was 2.02 (95% confidence interval: 0.4-9.9).
In conclusion, in our study COLIA1 Sp1 and VDR gene (M/m) polymorphisms seem not to be related with the development of bone fractures after liver transplantation. Nevertheless, the small number of patients could limit the results of the study.
COLLAGEN TYPE IALPHA1 SP1 POLYMORPHISM, OSTEOPOROSIS AND OSTEOARTHRITIS IN OLDER MEN AND WOMEN
S. M. F. Pluijm1*, H. W. van Essen2, N. Bravenboer2, A. G. Uitterlinden3, J. H. Smit4, P. Lips1,2
1Institute for Research in Extramural Medicine (EMGO-Institute), Vrije Universiteit, Amsterdam, The Netherlands
2Endocrinology, Academic Hospital, Vrije Universiteit, Amsterdam, The Netherlands
3Department of Internal Medicine III, Erasmus University Medical School, Rotterdam, The Netherlands
4Department of Sociology and Social Gerontology, Vrije Universiteit, Amsterdam, The Netherlands
Osteoporosis (OP) and osteoarthritis (OA) are common skeletal disorders which are largely determined by genetic factors. Previous studies have demonstrated an inverse relationship between OP and OA. The aim of this study was to examine whether the collagen type Ialpha1 Sp1 (COLIA1) polymorphism is associated with osteoporosis and/or osteoarthritis in older men and women.
COLIA 1 genotype was determined in 970 participants (473 men and 497 women) of 65 years and older who were all participants of the Longitudinal Aging Study Amsterdam (LASA). In this total sample, fasting levels of serum osteocalcin (OC) and urine deoxypyridinolin (DPD) were determined. Quantitative ultrasound measurements (QUS) were assessed with the CUBA bone densitometer and prospective follow-up on fractures was obtained. In addition, self-reported OA was assessed with a questionnaire. In a subsample (N=517), which included participants who were living in the Western part of the Netherlands, total body bone mineral content (TBMC) and bone mineral density of the hip (femoral neck, trochanter, total hip) and lumbar spine were measured. In addition, prevalent vertebral deformities and OA of the spine (Kellgren score) were identified on radiographs.
Compared to men with the SS and Ss genotypes, men with the ss genotype had a higher risk of OA of the spine (OR=5.42; 95% CI: 1.61-18.2, after adjustment for age and body weight), whereas men with the Ss genotype tended to have an increased risk of self-reported OA (OR=1.57; 95% CI: 0.97-2.55, after adjustment for age and body weight). Moreover, higher levels of OC were found in men with the s allele compared to men without the s allele (SS, 1.98±0.06 nmol/l vs. Ss/ss, 2.16±0.09 nmol/l). Bone quality, as measured with QUS, BMD, bone markers, vertebral deformities and fractures were not associated with the COLIA1 polymorphism. In women, neither one of the measures of OA, nor one of OP, was found to be significantly associated with COLIA1.
In conclusion, the results of this study suggest that the COLIA1 genotype may be involved in the pathogenesis of OA in men. In contrast, we could not confirm the association previously reported between the COLIAI genotype and OP.
POLYMORPHISMS IN THE TRANSFORMING GROWTH FACTOR-1 AND BONE MASS AND BONE LOSS
F. A. Welsh*, D. M. Reid, S. H. Ralston
Aberdeen University, Aberdeen, UK
Transforming growth factor beta1 (TGF-beta1) is an abundant growth factor in human bone. It is synthesised by osteoblasts, stimulating pre-osteoblast differentiation and proliferation. TGF-beta1 also has profound effects on osteoclast proliferation and activity. Several polymorphisms have been previously identified in the TGF-beta1 gene, some of which have been found to be associated with bone mineral density in Italian and Japanese populations. The aim of this study was to investigate if these polymorphisms were predictors of bone mass and bone loss in a UK population of early postmenopausal women.
Five polymorphisms were examined using PCR and restriction enzyme digestion in a random sample of 356 women from the UK: G-800-A and C-509-T in the promoter, T29-C in exon 1 and 713-8delC and C788-T in exon 5. Bone mineral density was measured by DXA at the spine and the femoral neck in 1990 and again 1998.
The genotype effect on bone density was analysed at baseline and at follow-up using a one-way ANOVA. Lower bone density trends were seen in the spine with the C-509-T polymorphism (p=0.10) for the CT and TT alleles. Similar patterns were also found with the 713-8delC polymorphism and femoral neck bone density (p=0.12).
Trends towards bone loss were found for the G-800-A polymorphism at the spine (p=0.061) and at the femoral neck (p=0.06). This trend became significant when the combined GA and AA genotypes were compared to GG homozygotes at the spine (p=0.018) and the femoral neck (p=0.024). None of the remaining two polymorphisms studied were found to be significantly associated with BMD.
In conclusion: In a random sample of 356 women in the UK, trends towards reduced BMD have been observed with the G-800-A, C-509-T and 713-8delC polymorphisms of TGF-beta1. Only the G-800-A polymorphism was found to significantly affect bone loss, with the "A" allele shown to increase bone loss in both the spine and the femoral neck over an eight-year period.
SP1 BINDING SITE POLYMORPHISM DISTRIBUTION OF THE COLLAGEN TYPE I ALPHA1 GENE AND ITS CORRELATION WITH BONE MINERAL DENSITY IN A YOUNG BRAZILIAN WOMEN POPULATION
E. R. Barros*, O. M. Hauache, A. C. Ramalho, J. G. H. Vieira, M. Lazaretti-Castro
Division of Endocrinology- Universidade Federal de São Paulo, Brazil
Introduction: Osteoporosis is a common disorder characterized by reduced bone mineral density and increased risk of fracture. Although it is a multifactorial disease, genetic factors are the most important ones on pathogenesis. Polymorphism of the collagen type I alpha (COLIa1) gene has been associated with bone mineral density (BMD).
Objective: Identify the Sp1 polymorphism distribution of COLIa1 gene in young women and its correlation with bone mineral density.
Methods: We studied 98 women with a mean age of 32.5±5.4 years (range 20-45 years), all of them in regular menses. All patients underwent bone densitometry of the femur neck and lumbar spine (Lunar DPX) and to a specific query. Polymorphism analysis was performed by polymerase chain reaction amplification, followed by Bal I digestion. We defined as "S" the allele with the absence of the restriction site and "s" when the restriction site was present. The polymorphism (G-T) is recognized by Bal I restriction enzyme. The data were presented in mean±SD and the statistical analysis was made using Student's t-test. Statistical significance was set at p<0.05.
Results: The polymorphism rate was 67.3% for the SS, 30.6% for Ss and 2.1% for ss genotypes. The Ss and ss patients were analyzed together and compared to SS patients. Age (32.4±5.4 and 32.5±5.5 yr) and body mass index (23.5±3.66 and 23.7±3.5 Kg/m2) did not differ between the two groups. The BMD of the group Ss/ ss was 1.170±0.131 g/cm2 in spine and 0.95±0.092 g/cm2 in femur, and of the group SS was 1.180±0.145 g/cm2 in spine and 0.958±0.122g/cm2 in femur, and there was no difference between the groups.
Conclusion: In this population, Sp1-binding site polymorphism rate found in the COLIa1 gene was similar to that observed in the literature. However, there was no correlation between genotype and lumbar or femur BMD.
APOLIPOPROTEIN E GENOTYPE INFLUENCES BONE LOSS AND BIOCHEMICAL MARKERS OF BONE TURNOVER IN ELDERLY POSTMENOPAUSAL WOMEN
J. K. Scariano*, P. J. Garry, G. Montoya, R. N. Baumgartner
University of New Mexico School of Medicine, Albuquerque, New Mexico, USA
Apolipoprotein E (ApoE) plays an important role in clearing lipids from plasma via hepatic receptors. At position 112 in ApoE, a substitution of arginine for cysteine creates a more basic protein (ApoE4) with greater binding affinity to its receptor. This results in a rapid clearance of triglyceride-rich ApoE4-containing lipoproteins, attenuating delivery of vitamin K into the skeleton. The presence of the ApoE4 polymorphism is associated with a significantly increased rate of vertebral bone loss in peri- and postmenopausal women not receiving estrogen replacement as well as other chronic diseases including Alzheimer's dementia, cardiovascular disease and hip and wrist fractures in hemodialysis patients and postmenopausal women. Preliminary data from the ongoing Aging Process Study at the University of New Mexico indicates that the ApoE4 allele significantly influences the rate of bone loss and levels of biochemical markers of bone turnover in postmenopausal (66-91 yr.) women. We compared eight ApoE+ women to 19 age-matched ApoE4- women. None of the women chosen for study were receiving hormone replacement therapy, bisphosphonates, statins, glucocorticoids, thyroid hormone nor any other medication known to affect bone turnover. The ApoE4+ women had a significantly decreased body mass index (22.9±2.4 vs. 25.6±3.9 kg/ m2, p=0.05) and serum levels of bone-specific alkaline phosphatase (23.3±4.3 vs. 30.2±9.4 U/L, p=0.01). Additionally, over a six year period, the ApoE4+ women experienced a significantly increased rate of total-skeleton bone loss measured by dual X-ray absorptiometry (-2.85±4.0 vs. +0.17±2.5%, p=0.04). Furthermore, we observed trends towards higher levels of the serum resorption marker NTx (25.6±18.0 vs. 17.7±4.5, p=0.26) as well as lower total body (0.963±0.084 vs. 1.107±0.073 g/cm2, p=0.19), spine (0.951±0.134 vs. 1.050±0.181 g/cm2, p=0.16) and femoral neck bone mineral density (0.716±0.074 vs. 0.727±0.115 g/cm2, p=0.79) in women having at least one ApoE4 allele. These results warrant further investigation of the influence of ApoE polymorphisms on biochemical markers of bone turnover and densitometric data involving larger numbers of postmenopausal women who are not receiving antiresorptive therapy.
POLYMORPHISMS IN THE TRANSFORMING GROWTH FACTOR-BETA1 GENE ARE NOT ASSOCIATED WITH OSTEOPOROTIC FRACTURES
B. L. Langdahl*, M. Carstens, L. Stenkjær, E. F. Eriksen
Dept of Endocrinology and Metabolism, Aarhus University Hospital, Aarhus Amtssygehus, Denmark
Transforming growth factor (TGF)-beta1 is the most abundant growth factor in human bone. It is produced by osteoblasts and inhibits osteoclast proliferation and activity and stimulates proliferation and differentiation of preosteoblasts. Several polymorphisms have been described in the TGF-beta1 gene. Previously, we and others have found associations between some these polymorphisms and bone mass. We therefore wanted to examine if these polymorphisms also are predictors of osteoporotic fractures.
The following polymorphisms: G-1639-A, C-1348-T, C-765insC, T29-C, G74-C, 713-8delC, C788-T and T816-20-C were examined using RFLP and sequencing in 271 osteoporotic patients with vertebral fractures and 329 normal individuals. Bone mineral density (BMD) was examined at the lumbar spine and the hip on Hologic densitometers.
Genotype distributions were in H-W equilibrium. C-765insC, T29-C, G74-C were in linkage disequilibrium (chi-sq=19.0-58.4, p=0.01-10-10). C-1348-T was in linkage disequlibrium with T29-C (chi-sq=133, p=10-25). G-1639-A, 713-8delC, C788-T and T816-20-C were in complete linkage equilibrium with the other polymorphisms.
The T816-20-C genotypes were distributed differently among osteoporotic patients and normal controls. The TT genotype was less common in individuals with osteoporotic fractures (chi-sq=6.02, p<0.05). No other differences in genotype distribution between patients and normal controls was demonstrated (chi-sq=0.08-4.32, ns).
BMD was higher in individuals with the TT-genotype (T816-20-C) at the lumbar spine: 0.960±0.173 g/cm2 compared with individuals with the TC or CC genotypes: 0.849±0.181 g/cm2 and 0.876?/-0.179 g/cm2, respectively (p<0.001, ANOVA). Similar differences between genotypes were found at the different hip regions as well as at the total hip. None of the other polymorphisms significantly affected BMD.
In conclusion: The TT genotype of the T816-20-C polymorphism is less common in patients with osteoporotic fractures and is associated with higher bone mass both at the lumbar spine and the hip. The other seven polymorphisms in the TGF-beta1 gene are not associated with osteoporotic fractures or with bone mass at the lumbar spine or the hip.
POLYMORPHISMS IN THE ESTROGEN RECEPTOR ALFA ARE ASSOCIATED WITH SERUM LEVELS OF ESTRADIOL AFTER MENOPAUSE AND EARLY POSTMENOPAUSAL BONE LOSS BUT NOT WITH PEAK BONE MASS OR RESPONSE TO HRT
B. L. Langdahl1*, P. Vestergaard1,2, B. Abrahamsen1,2, C. Brot2, P. Eiken2, S. P. Nielsen2, O. H. Sørensen2, H. Beck-Nielsen2, L. Mosekilde1,2, E. F.Eriksen1,2
1Dept of Endocrinology and Metabolism, Aarhus University Hospital, Aarhus Amtssygehus, Denmark
2Danish Osteoporosis Prevention Study Group
We have previously shown that a TA-repeat polymorphism in the promoter of the estrogen receptor alfa gene is associated with low bone mass and increased risk of osteoporotic fractures. Others have demonstrated associations between two polymorphisms in the first intron and bone mass and hysterectomy. Furthermore, a fourth polymorphism in the first exon is found to be associated with breast cancer. All four polymorphisms are in linkage. We therefore wanted to investigate if these polymorphisms affect age of menarche and menopause, the prevalence of hysterectomy, perimenopausal bone mass, early postmenopausal bone loss and response to HRT in a population based study of 1698 perimenopausal women. The women were included in the study 3-24 months after last menstrual bleeding. 593 were given HRT, 1031 were untreated. The women were followed by regular bone scans on Hologic 2000 densitometer and by questionnaires. In a subgroup of 508 women s-estradiol was measured at time of inclusion.
The TA-repeat polymorphism was examined by PAGE followed by Genescan analysis. The point mutations were analysed by RFLP using Bst UI and Pvu II and Xba I.
Mean number of TA-repeats was positively correlated with s-estradiol (p=0.005). Age at menarche tended to be higher in women with low number of TA-repeats (p=0.07, ANOVA) whereas age at menopause was unaffected by the polymorphisms. Menopausal height, weight, bone mass and levels of biochemical bone markers were not affected by the four polymorphisms.
Changes in bone mass after 5 years in the HRT treated women were not different between genotypes. However, in the untreated women the BB-genotype was associated with higher rates of bone loss compared with women with the Bb/bb-genetype. These differences were significant for the femoral neck (p<0.05), the total hip (p<0.01), the ultradistal forearm (p<0.02) and the total body (p<0.02).
In conclusion: The TA-repeat polymorphism in the estrogen receptor gene significantly influences serum levels of estradiol in early menopause and the Bst UI polymorphism affects bone loss in women not on HRT. The polymorphisms might compromise the responsiveness of the estrogen receptor alfa leading to increased serum levels of estradiol, that might affect fracture risk through the estrogen receptor beta or by other mechanisms.
