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Homozygous Carriers (homozygous + carrier)
Selected AbstractsPeroxisome proliferator activated receptor delta genotype in relation to cardiovascular risk factors and risk of coronary heart disease in hypercholesterolaemic menJOURNAL OF INTERNAL MEDICINE, Issue 6 2003J. Skogsberg Abstract. Objectives., Peroxisome proliferator activated receptor delta (PPARD) is a transcription factor implicated in the regulation of genes involved in cholesterol metabolism. We recently discovered a common polymorphism in the 5,-untranslated region (5,-UTR) of the human PPARD, +294T/C, that is associated with an increased plasma low-density lipoprotein cholesterol (LDL-C) concentration in healthy subjects. Whether the +294C allele is associated with LDL-C elevation independently of the background lipoprotein phenotype and whether it confers increased risk of coronary heart disease (CHD) is unknown. Against this background, we investigated the relationships between the PPARD polymorphism and plasma lipoprotein concentrations and the risk for contracting CHD in the West of Scotland Coronary Prevention Study (WOSCOPS). Design., A nested case,control study of participants in a randomized double-blind placebo-controlled trial of pravastatin in mildly-to-moderately hypercholesterolaemic men. Subjects., A total of 580 cases of incident CHD and 1160 individuals who remained free of CHD (controls). Main outcome measures., Plasma lipoprotein con-centrations and risk of CHD according to PPARD genotype. Results., Individuals carrying the rare PPARD +294C allele had a significantly lower high-density lipoprotein cholesterol (HDL-C) concentration than subjects homozygous for the common T-allele. Homozygous carriers of the C-allele also showed a tendency towards higher risk of CHD compared with homozygous carriers of the T-allele. In addition, a gene,gene interaction involving the PPARD polymorphism and the PPAR alpha L162V polymorphism may influence the plasma LDL-C concentration. Conclusions., PPARD plays a role in cholesterol metabolism in man. [source] Genetic Determinants of Alcohol Addiction and Metabolism: A Survey in ItalyALCOHOLISM, Issue 2 2001Roberta Pastorelli Background: Although multiple genes are involved in alcoholism and can contribute differently to the risk of dependence and liver damage, no studies have investigated susceptibility to addiction in combination with susceptibility to liver damage due to differences in ethanol metabolism. Methods: We evaluated the role of three polymorphic genes related to alcohol metabolism (CYP2E1) and, possibly, dependence (DRD2 and SLC6A4 promoter) in a series of 60 alcoholics admitted to a specialized referral center in Florence, Italy. Eighteen had a diagnosis of liver cirrhosis. A control series of 64 blood donors were identified at the same hospital. Genotyping was done by polymerase chain reaction-restriction fragment length polymorphism methods. Results: No difference was found in the frequency of the CYP2E 1 Rsa I c2 allele (2.5% among alcoholics and 4.7% among controls) and the Dra I C allele (6.7% and 10.1%). Similarly, no difference was found in the frequency of the DRD2 A1 allele (15.8% and 13.3%) and the B1 allele (10.8% and 8.6%). The proportion of controls with a combined B1 genotype (B1/B1 or B1/B2) was significantly associated with smoking (p= 0.03). The distribution of the S and L allele of the SLC6A4 gene was similar in the two groups, with 15% and 14%, respectively, homozygous S/S carriers. A significant association, however, emerged in the group of alcoholics, with a five times higher risk for S/S carriers of developing cirrhosis (p < 0.05). This association with liver persisted even after exclusion of the subgrouped of 10 hepatitis C virus positive alcoholics. Conclusions: Overall, our results provided no evidence of an increased susceptibility to develop alcoholism that was associated with the three genotypes investigated, either alone or in combination. An increased risk of developing liver cirrhosis for S/S homozygous carriers among alcohol-dependent patients was observed for the first time. [source] Impact of environmental and hereditary risk factors on the clinical manifestation of thrombophilia in homozygous carriers of factor V:G1691AJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 3 2004S. Ehrenforth Summary.,Background:,Limited data exist on the clinical manifestations of homozygous factor (F)V:G1691A mutation (FV Leiden) and the impact of environmental and genetic risk factors. Objectives:,To assess the contribution of these factors on the thrombophilic phenotype. Patients and methods:,In a retrospective multicenter cohort study 165 individuals with homozygous FV:G1691A mutation, of whom 129 had previous venous thromboembolism (VTE), were included. To study the role of environmental risk factors, patients were compared by the use of a standardized questionnaire to 165 sex- and age-matched individuals (reference group A); of these, two had previous VTE. To assess the role of genetic risk factors, factor (F)II:G20210A and MTHFR:C677T were determined in individuals homozygous for FV:G1691A and in 177 healthy individuals without previous VTE (reference group B). Results:,The first VTE occurred significantly earlier in women (median age 25 years) than men (35.5 years). In 81% of women and 29% of men an environmental risk factor was present before first VTE. Oral contraceptives increased the risk of thrombosis 4-fold [odds ratio (OR) 4.0, 95% confidence interval (CI) 1.7, 10.4] in women with homozygous FV:G1691A. Postoperative and post-traumatic VTE as first manifestation occurred in 13% and 15% of surgical/traumatic events in patients and in 0.7% and 1.8% in reference group A, respectively (OR 19.7, 95% CI 2.5, 154 and OR 9.2, 95% CI 1.1, 79.4). Heterozygous FII:G20210A was more prevalent in symptomatic patients (11.7%) compared with reference group B (2.8%, OR 4.6, 95% CI 1.6, 13.2). The prevalence of homozygous MTHFR:C677T genotype was similar in patients and reference group B. Conclusions:,Our study supports the concept of thrombophilia as a multifactorial disorder. The knowledge of coexisting factors predisposing to VTE is useful for medical advice for primary and secondary prophylaxis in these patients. [source] The role of fatty acid hydrolase gene variants in inflammatory bowel diseaseALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2009M. STORR Summary Background, Recent studies suggest a role for the endocannabinoid system, including fatty acid amide hydrolase (FAAH), in intestinal inflammation. Aim, To analyse FAAH expression and the FAAH 385 C/A (p.Pro129Thr; rs324420) single nucleotide polymorphism (SNP) in-patients with Crohn's disease (CD) and ulcerative colitis (UC). Patients and methods, Genomic DNA from 1008 individuals (CD: n = 435; UC: n = 167; controls: n = 406) was analysed for the FAAH 385 C/A SNP. We determined FAAH mRNA expression by quantitative PCR in CD and UC lesions as well as in intestinal epithelial cells (IECs). Results, There were no significant differences regarding the frequency of this SNP in the three study groups (CD, UC, controls). However, CD patients homozygous for the FAAH p.Pro129Thr polymorphism were more likely to develop a severe disease phenotype associated with fistulas (P = 0.03, OR 3.12, 95% CI 1.08,8.98) and extra-intestinal manifestations (P = 0.005, OR 4.29, CI 1.49,12.35). In UC, homozygous carriers had an earlier disease onset than wild-type carriers (P = 0.01). FAAH mRNA expression correlated with IL-8 mRNA expression in CD lesions (r = 0.53). However, pro-inflammatory stimuli did not significantly increase FAAH mRNA expression in IECs. Conclusion, The FAAH p.Pro129Thr polymorphism may modulate the CD phenotype. [source] Liver pathology in compound heterozygous patients for hemochromatosis mutationsLIVER INTERNATIONAL, Issue 4 2002Maximilian Schöniger-Hekele Abstract: Background: While hepatic pathology of homozygous carriers of the C282Y mutation of the HFE haemochromatosis gene is well defined, the impact of the C282Y/H63D compound heterozygous carrier state is unknown. Aims: To evaluate the range of hepatic pathology in C282Y/H63D compound heterozygous patients. Patients: 25 C282Y/H63D compound heterozygous patients with and without known underlying liver disease underwent liver biopsies for evaluation or abnormal liver tests. Eleven cadaveric liver donors with HFE wild type served as controls. Methods: Mutations in the HFE gene were detected by polyacrylamide gel electrophoresis (PAGE) separation of digested polymerase chain reaction (PCR)-amplificates. The extent of light microscopic changes of liver architecture were studied on haematoxylin, eosin (H. E.) stains. In addition, the extent and the distribution of iron deposition was graded on Prussian blue-stained sections and hepatic iron was quantified by atom absorption spectroscopy. Serum ferritin concentration and the transferrin saturation index were measured using routine laboratory methods. Results: Patients without underlying liver disease (n = 15): Hepatic inflammation was seen in only 8% but fibrosis was found in 36% of compound heterozygous patients. Eighty six percent of those patients had stainable iron predominantly found in Rappaport's zone 1 and 2, but all had a liver iron-index < 1.9. Transferrin saturation was found elevated in 36% of compound heterozygous patients. Patients with liver fibrosis showed significantly higher ferritin levels than patients without liver fibrosis (1110 ng/mL versus 307 ng/mL, p < 0.05). Patients with underlying disease (n = 10): In compound heterozygous patients, 77% had hepatic inflammation and 88% fibrosis. Stainable iron (44%) was less frequently found than in patients without underlying liver disease. Hepatic iron-index in patients with underlying liver disease was always below 1.17; transferrin saturation was elevated in only 22% of the compound heterozygous patients. Histologic hepatic iron-index was significantly lower in patients with underlying disease (median 0.047) as compared to patients without underlying liver disease (median 0.274, P < 0.05). Conclusions: The underlying liver disease determines the extent of hepatic pathology seen in livers of compound heterozygous patients. However, considerable histologic fibrosis can also be found in compound heterozygous patients without underlying liver disease. [source] ORIGINAL ARTICLE: Leptin Gene (TTTC)n Microsatellite Polymorphism as well as Leptin Receptor R223Q and PPAR,2 P12A Substitutions are not Associated with Hypertensive Disorders in PregnancyAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 4 2010Annette Wiedemann Citation Wiedemann A, Vocke F, Fitzgerald JS, Markert UR, Jeschke U, Lohse P, Toth B. Leptin gene (TTTC)n microsatellite polymorphism as well as Leptin receptor R223Q and PPAR,2 P12A substitutions are not associated with hypertensive disorders in pregnancy. Am J Reprod Immunol 2010; 63: 310,317 Problem, Pregnancy-induced hypertension (PIH) affects up to 15% of all pregnancies. Disturbed placentation is one factor associated with PIH. Leptin and peroxisome proliferator activator receptors (PPAR) seem to play an important role in placentation, fetal development, and blood pressure regulation. Therefore, we investigated polymorphisms in the genes encoding leptin, the leptin receptor, and PPAR,2 in patients with PIH. Method of study, In this retrospective case,control study, 103 patients with PIH [gestational hypertension (GH) n = 39; preeclampsia n = 27; eclampsia n = 5; HELLP n = 32] and 100 controls were analyzed for the LEP tetranucleotide repeat (TTTC)n and the leptin receptor (LEPR) R223Q and PPAR,2 P12A substitutions. Statistical analysis was performed using the chi-square, Mann,Whitney U -, and Kruskal,Wallis tests (P < 0.05 significant). Results, The frequency of the three possible genotypes did not differ significantly between patients and controls [LEP (TTTC)n: P = 0.43; LEPR R223Q: P = 0.94; PPAR,2 P12A: P = 0.94]. However, postpartal diastolic blood pressure of PIH patients was significantly higher in homozygous carriers of the LEPR Q223-encoding allele as compared with patients carrying the wild-type allele (P < 0.01). Conclusion, Hypertensive disorders in pregnancy were not associated with the LEP, LEPR, and PPAR,2 polymorphisms studied. The role of other variations in the LEP and PPAR genes in the pathophysiology of PIH and in exacerbations are the objective of ongoing research. [source] A functional polymorphism in Pre-miR-146a gene is associated with prostate cancer risk and mature miR-146a expression in vivo,THE PROSTATE, Issue 5 2010Bin Xu Abstract BACKGROUND A G,>,C polymorphism (rs2910164) which is located in the sequence of miR-146a precursor, results in a change from a G:U pair to a C:U mismatch in its stem region. To explore whether rs2910164 plays any role in prostate cancer (CaP), we analyzed the association between miR-146a polymorphism and risk of CaP and the expression of miR-146a with different genotypes in CaP tissues in southern Chinese Han population. MATERIALS AND METHODS Two hundred fifty-one CaP and 280 control subjects were included in the cancer association study, and 15 CaP tissue samples were used to test the expression of the miRNA precursors by real-time quantitative reverse transcription PCR. RESULTS We found that subjects carrying CC homozygotes had a 0.65-fold reduced risk (95% CI,=,0.43,0.99) than those carrying GG/GC genotypes (P,=,0.03), and the C allele displayed a lower prevalence of CaP compared with the G allele (OR,=,0.73, 95% CI,=,0.57,0.94, P,=,0.01). Moreover, hsa-miR-146a quantification showed that homozygous carriers of the C-variant had significantly decreased miRNA levels compared to the carriers of the GG/GC genotype. CONCLUSIONS The natural genetic variation in pre-miR-146a affects the amount of mature miR-146a, contributes to the genetic predisposition to CaP. Prostate 70: 467,472, 2010. © 2009 Wiley-Liss, Inc. [source] | ||||||||||