Rivka Dresner Pollak

Femoral neck osteopenia in patients with inflammatory bowel disease.

Objective:The mechanism of bone loss in patients with inflammatory bowel disease (IBD) is not completely understood. The aim of this study was to assess indices of bone turnover and bone mineral density (BMD) in the lumbar spine and femoral neck in IBD patients.Methods:Sixty-three patients with Crohns disease and 41 with ulcerative colitis were studied. Serum bone-specific alkaline phosphatase (B-ALP), osteocalcin, parathyroid hormone (PTH), 25 hydroxyvitamin D, interleukin-6 (IL-6), and urinary N-telopeptide cross linked type 1 collagen (NTX) were determined. BMD of the lumbar spine and femoral neck was determined by dual x-ray absorptiometry in 59 patients.Results:In the femoral neck 42% of the patients had osteopenia (−2.5 SD < BMD T score < −1 SD) and another 41% had osteoporosis (BMD T score < −2.5). In the spine 34% of the patients had osteopenia and additional 42% had osteoporosis. BMD T scores were lower in the femoral neck compared to the spine. Reduced BMD was unrelated to gender, disease type, lifetime corticosteroid dose, but inversely correlated with disease duration (r =−0.36, p < 0.05). Serum IL-6 was higher in IBD patients compared to controls. A reduced level of osteocalcin, a marker of bone formation, was present in 7% of patients and an increase in NTX, a marker of bone resorption, in 25% of them. Osteoporotic IBD patients (spine or hip BMD T score < −2.5) had increased serum IL-6, osteocalcin and PTH level compared to nonosteoporotic patients.Conclusions:There is a high prevalence of reduced BMD at the spine and femoral neck in IBD patients, which is more severe in the hip. Bone turnover in osteoporotic IBD patients is associated with an increase in osteocalcin, PTH and IL-6. IL-6 may play a role in the pathogenesis of bone loss in IBD.

Bone mineral metabolism in adults with β-thalassaemia major and intermedia

Bone disease is an important cause of morbidity in older patients with β‐thalassaemia major and intermedia. We studied 27 women and 23 men with β‐thalassaemia major (37) and intermedia (13) whose mean age was 32·3 ± 9·7 years. Bone mineral density (BMD) of the lumbar spine, femoral neck and distal radius was determined by dual‐energy X‐ray absorbiometry (DXA). The longitudinal change in BMD over a mean of 5·6 years was determined in 19 patients. Serum 25‐hydroxyvitamin D, insulin growth factor‐1 (IGF‐1), bone formation markers bone‐alkaline phosphatase, osteocalcin and the resorption marker urinary N‐telopeptide cross‐linked type 1 collagen (NTx) were determined. The BsmI vitamin D receptor (VDR) gene polymorphism was analysed. Reduced BMD (Z‐score < −2) was present in 89%, 62% and 73% of patients in the spine, hip and radius respectively. Vitamin D deficiency was found in 62%, decreased IGF‐1 in 72% and increased urinary NTx in 84% of patients. Serum IGF‐1 correlated with spine and hip BMD (r = 0·4, r = 0·39, P < 0·01 respectively), and NTx correlated with the hip BMD Z‐score (r = 0·35 P < 0·05). The mean annual percentage change in spine BMD was −1·36%. Patients with the VDR BB genotype had lower spine BMD than patients with the bb genotype. In conclusion, bone loss continues in adult thalassaemia patients and is associated with increased bone resorption and decreased IGF‐1. The BsmI VDR gene polymorphism is associated with osteopenia in thalassaemia.

The Familial Mediterranean Fever ( MEVF ) Gene as a Modifier of Crohn's Disease

OBJECTIVES:Crohns disease (CD) has been reported to be more frequent among non-Ashkenazi Jewish patients suffering from familial Mediterranean fever (FMF). Interestingly, functional similarities between the CD susceptibility gene (NOD2/CARD15) and the FMF gene (MEFV) have been described: both belong to the death domain containing protein family, important in the regulation of apoptosis, cytokine processing and inflammation.AIMS:To investigate the prevalence of MEFV mutations in Jewish non-Ashkenazi CD patients and its putative effect on CD presentation.METHODS:Germline DNA of 105 Israeli CD patients of non-Ashkenazi and mixed Ashkenazi–non-Ashkenazi ethnic background was analyzed for three most common MEFV mutations: M694V, V726A, and E148Q. Five patients (4.7%) with a clinical diagnosis of FMF were included. Data obtained from each patient included: age of onset, disease location, and behavior, the presence of extraintestinal manifestations of CD and therapeutic regimens.RESULTS:The overall prevalence of mutation carriers among non-FMF-CD patients was 13% (13/100). A stricturing disease pattern was observed in 56% (10/18) of all carriers, FMF-CD, and non-FMF-CD patients, and in 25% (22/87) of noncarriers (OR: 3.7, 95% CI: 1.3–10.5, p = 0.015). The prevalence of fistulas was comparable in both groups. Extraintestinal manifestations were significantly more frequent among carriers than noncarriers (65%vs 32%, OR 3.9, 95% CI = 1.3–11.5, p = 0.015). No differences were observed in disease location and disease severity.CONCLUSIONS:MEFV mutations are not associated with CD susceptibility, yet the presence of these mutations appears to be associated with a stricturing disease pattern and extraintestinal disease manifestations of CD.

The C677T Mutation in the Methylenetetrahydrofolate Reductase (MTHFR) Gene and Vascular Dementia

OBJECTIVE: To determine the association between the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and vascular dementia in Ashkenazi and non‐Ashkenazi Jews.

Ethnic differences in the frequency of the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene in healthy Israeli populations.

Hyperhomocysteinemia is an independent risk factor for arteriosclerotic vascular disease. It can result from deficiencies of co-factors required for homocysteine metabolism and/or from genetic disorders of its metabolism. The association between the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and vascular disease is controversial, and may be affected by ethnic origin. A unique feature of the Israeli population is its ethnic diversity. The aim of this study was to study the frequency of the C677T MTHFR mutation in healthy Israeli ethnic groups. The frequency of the mutation was determined in 897 young healthy Jewish and Muslim Arab Israelis of eight different ethnic groups. Marked ethnic differences in the frequency of mutant homozygotes were found, ranging from 2% in Yemenite Jews, 4% in Sephardic Jews, 9% in Oriental Jews, 10% in Muslim Arabs, 16% in North African Jews, and 19% in Ashkenazi Jews. The frequency of mutant homozygotes was significantly higher in Ashkenazi Jews compared to Yemenites Oriental Jews, Sephardic Jews, and Muslim Arabs (chi2 = 12.35p < 0.001, chi2 = 8.17p = 0.004, chi2 = 6.04p = 0.01, chi2 = 6.54 p = 0.01, respectively). Our findings demonstrate the need for matching ethnic background in patients and controls when studying the association between the C677T MTHFR mutation and any disease.

The BsmI Vitamin D Receptor Gene Polymorphism in Israeli Populations and in Perimenopausal and Osteoporotic Ashkenazi Women

Background: The association between vitamin D receptor (VDR) gene polymorphisms and bone mineral density (BMD) is controversial, and may be effected by ethnic ancestry and age. Aims: To determine the distribution of the BsmI VDR gene polymorphism in healthy Israeli populations, and to study its association with BMD in perimenopausal and osteoporotic Ashkenazi women. Methods: Allele and genotype frequencies of the VDR gene defined by BsmI restriction site were determined in 634 healthy Israelis of seven ethnic groups, 90 Ashkenazi perimenopausal women and in 75 Ashkenazi osteoporotic women. Genotype-related differences in spinal and femoral neck BMD were determined in Ashkenazi perimenopausal women. Allele and genotype frequencies in Ashkenazi osteoporotic women were compared with Ashkenazi controls. Results: The frequency of the BB genotype was higher in Yemenites compared with Ashkenazi and Libyan Jews (23, 11 and 8%, respectively, p < 0.05), and lower in Ashkenazi compared with Iraqi and Persian Jews (11, 20 and 21%, respectively, p = 0.05). BMD did not vary by genotype in perimenopausal women, nor were there differences in the frequencies of the B allele or the BB genotype in osteoporotic women compared with controls. Conclusions: There is ethnic variability in the frequency of the BsmI VDR gene polymorphism. In Ashkenazi perimenopausal and osteoporotic women this polymorphism is not associated with BMD.

Estrogen receptor alpha gene polymorphism is associated with coronary artery disease severity

Background: Estrogens have beneficial effects on the cardiovascular system partially mediated by estrogen receptor alpha (ERa). Alternations in ERa expression may affect the atheroprotective role of estrogens. We hypothesized that genetic variation in the ragulatory region of the ERa gene is associated with the angiographic severity of CAD. Methods: We studied 496 consecubve patients (72% man. 28% women) who had coronary angiography. Severity of CAD was assessed by: 1) the number of major coronary vessels with at least one >50% narrowing (NMCV); 2) the number of vessels with any narrowing (NCV); 3) the total number of narrowings (NN). The length of the dinucleotide repeat thymine & adenine (TA repeats) upstream of axon 1 of the ERu gene, was determined by PCR. The median number of TA repeats was used to catagorrza the population into 3 groups: long alleles genotype (both alleles 218 repeats), short alleles genotype (both alleles ~18 repeats), and mrxed genotype (short 5 long allele). Since the contribution of genetic factors is expected to be more prominent in younger subjects, patients ware divided into younger and older groups, age55 (n=126) vs. age>55 (n=368). The relationship between TA length and the severity of CAD was assessed by analysis of covarranca, stratified by age group. Sex and major CAD risk factors (diabetes, hypertension, hyperlipidemia, smoking, obesfty, family history) ware included as confounding factors. Results: Young patients with long alleles genotype had a significantly greater number of harrowed coronary artehes compared to those with short alleles genotype (NCV 3.722.4 vs. 2.5_+1.8, respectively, ~~0.02). Similarly. young patients with long alleles had a higher total number of coronary narrowings compared to those with short alleles (NN 4.k2.7 vs. 3.1 i2.2. respectively, pcO.02). A trend towards a higher NMCV rn young pattents with long alleles was also observed (NMCV 2.021 .I vs. 1.6

Association of oestrogen receptor alpha gene polymorphism with the angiographic extent of coronary artery disease

3.9. long vs. short. p=NS). These differences were not observed in older patients. Conclusion: The length of the TA dkwcleotide repeat in the regulatory region of the ERu gene is associated with the angiographic severity of CAD in young subjects, Independent of the major coronary rusk factors.