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PubMed1997

Hepatitis C virus replicative levels and efficiency of genotyping by specific PCR and antibody assay.

We studied factors which influence the detection of hepatitis C virus genotypes by the group-specific PCR of the sequence within the core region gene and by the newly developed genotype-specific NS4 antibody assay. Genotyping was performed on 75 hepatitis C virus carriers in Japan, where patients with hepatitis C viremia are exclusively infected with genotype 1b, 2a, and 2b. PCR failed to identify genotypes in 8 (11%) patients, whereas 12 (16%) patients, including the 8 patients mentioned above, could not be genotyped by the serological assay. Serological genotypes showed almost complete agreement with those found by the PCR except that double infection was revealed in only two of the eight patients serologically judged to be coinfected with genotypes 1 and 2. In each assay, disease activity and levels of viremia assessed by a competitive reverse transcription PCR assay were significantly lower in patients infected with untypeable isolates than in those infected with typeable ones (P < 0.01). The PCR could identify the genotypes of isolates from all 64 patients with levels of viremia of > or = 10(6) copies/ml, and the genotype-specific antibody responses were found in 60 (94%) patients. In contrast, isolates from only 3 (27%) of 11 patients with low levels of viremia (< 10(6) copies/ml) could be genotyped by the PCR (P < 0.00001), and these patients showed the genotype-specific antibody responses (P < 0.00001). These findings suggest that low levels of hepatitis C virus replication may reduce the efficiency of genotyping by serological assay as well as by PCR.

Adult↗
PubMed2003

Highly polymorphic microsatellite for identification of Candida albicans strains.

The polymorphism of a new microsatellite locus (CAI) was investigated in a total of 114 Candida albicans strains, including 73 independent clinical isolates, multiple isolates from the same patient, isolates from several episodes of recurrent vulvovaginal infections, and two reference strains. PCR genotyping was performed automatically, using a fluorescence-labeled primer, and in the 73 independent isolates, 26 alleles and 44 different genotypes were identified, resulting in a discriminatory power of 0.97. CAI was revealed to be species specific and showed a low mutation rate, since no amplification product was obtained when testing other pathogenic Candida species and no genotype differences were observed when testing over 300 generations. When applying this microsatellite to the identification of strains isolated from recurrent vulvovaginal infections in eight patients, it was found that 13 out of 15 episodes were due to the same strain. When multiple isolates, obtained from the same patient and plated simultaneously, were typed for CAI, the same genotype was found in each case, confirming that the infecting population was clonal. Moreover, the same genotype appeared in isolates from the rectum and the vagina, revealing that the former could be a reservoir of potentially pathogenic strains. This new microsatellite proves to be a valuable tool to differentiate C. albicans strains. Furthermore, when compared to other molecular genotyping techniques, CAI proved to be very simple, highly efficient, and reproducible, being suitable for low-quantity and very-degraded samples and for application in large-scale epidemiological studies.

Candida albicans↗
PubMed2005

APOE genotype and serum cholesterol in predicting risk for early death from ischemic stroke in men and women.

BACKGROUND: We recently discovered that APOE epsilon3/epsilon4 genotype in men and APOE epsilon2/epsilon3 genotype in women are associated with increased risk of death from ischemic stroke (IS). One of the main physiological roles of apolipoprotein E is participation in cholesterol metabolism. A significant association of low serum cholesterol level with increased risk of death from stroke was documented. So, we aimed to establish if an association exists between APOE genotype, serum cholesterol and 1-month mortality in IS. METHODS: We studied 666 patients (330 men, 336 women) with a diagnosis of IS. Total serum cholesterol (TC) was measured with the method of Abbott Spectrum (USA). APOE genotyping was performed by PCR-RFLP method. RESULTS: The highest frequency of low serum TC was associated with APOE epsilon2/epsilon3 genotype (both in men and in women). Low serum TC was associated with increased mortality rate only in women; this effect was evident only in females not possessing APOE epsilon2/epsilon3. Female patients with APOE epsilon2/epsilon3 genotype had high 1-month mortality rate independently from serum TC. In multiple regression analyses APOE epsilon3/epsilon4 genotype in men and APOE epsilon2/epsilon3 genotype in women predicted risk of death independently from serum TC and also from other potential pre- and post-stroke prognostic factors. CONCLUSION: APOE epsilon3/epsilon4 genotype in men and APOE epsilon2/epsilon3 in women are associated with increased 30-day mortality in stroke. This effect seems be independent from serum cholesterol.

Aged↗
PubMedDate not supplied

[Role of various virus genotypes in progression of chronic hepatitis C].

The relation between HCV genotypes and the progression of chronic hepatitis is still unknown. Some studies implied more pathogenic effect of genotype 1b for the severity of liver inflammation. However, other studies did not show the association between HCV genotype 1b and the severe outcome of HCV infection. The aim of this study was to determine the most frequent genotypes in this environment and their influence on hepatitis C severity. The investigation included 34 patients with histologically confirmed chronic hepatitis C, aged 20-65 (mean 35.0 years). On the basis of pathohistological findings, applying the modern classification, the disease activity was graded as: minimal (A1) moderate (A2) and severe (A3). The extent of fibrosis was marked as: absent (F0), mild (F1), moderate (F2) and severe (F3). Genotyping was performed by nested PCR with type-specific primers and LIPA test and verified by sequencing. The most prevailing genotype in our group of patients was 1b (44.1%), followed by genotype 3a (26.4%), genotype 1a (11.7%) and 2a (2.8%). Five patients had mixed genotypes (four 3a/1b, and one 1a/1b). The severity of liver cell necrosis, measured by alanintransferase (ALT) levels in serum was not related to any of HCV genotypes. There was no statistically significant difference between histological disease activity in relation to HCV genotypes. Stage of the disease was not significantly related to the HCV genotypes. There was a strong association between the degree of fibrosis and the age of patients (p < 0.01). These results could indicate that the determination of HCV genotypes was not useful in the estimation of disease severity and that liver biopsy was the most important for the prognosis of the disease.

Adult↗
PubMed1975

H-2-associated quantitative traits; statistical analysis of the relative contributions of the H-2 linked genes and the residual genotype.

Several associations have been recently reported of the kind that a certain H-2 haplotype tends to be accompanied by a low value and another H-2 haplotype by a high value of some quantitative traits. This includes also the weights of lymphoid and reproductive organs. In order to throw more light on the seeming clustering within the H-2 gene complex of the genetic determinants of such traits, statistical analysis of the relative contributions of the H-2 and the total residual genotypes to the variations in the weight of the thymus, spleen, lymph nodes, testes, seminal vesicles and ovaries was performed. Ten genotypically uniform populations of 2-month-old mice, each consisting of 31 males and 31 females, were analyzed using two different statistical procedures. Four of them were mice of the inbred strains A (H-2a), B10 (H-2b), A.BY (H-2b) and B10.A (H-2a) and six were various F1 hybrids derived from these four strains. The conclusion based on both approaches was that the relative contribution to the variations in the weight of the tested organs from the H-2 haplotype is much smaller or maximally not greater than the contribution from the total residual genotype.

Animals↗
PubMed2006

Serotonin transporter polymorphism in Croatian patients with major depressive disorder.

OBJECTIVES: Differences in serotonin transporter (SERT) expression and function produced by gene polymorphisms are associated with several behavioral and psychiatric traits. Two polymorphic regions of SERT gene: a 44-base-pair (bp) insertion / deletion polymorphism in the promoter region (SERTPR), and variable number of tandem repeats (VNTR) in second intron (SERT-in2) have been characterized. In this study we investigated the frequency distribution of polymorphic variants of short (S, s) and long (L, l) alleles, genotypes and haplotypes of SERTPR, and SERTin2, in patients with major depressive disorder (MDD) and compared it with results obtained from the Croatian healthy population. SUBJECTS AND METHODS: one hundred and fourteen patients who fulfilled DSM-IV criteria for a diagnosis of MDD were included in the study. Comparisons were made with the results obtained for 120 healthy volunteers representing a mixed Croatian population. SERT genotyping was performed by the PCR (polymerase-chain reaction) method. RESULTS: The frequency distribution of L and S alleles and genotypes of SERTPR was not statistically different between MDD patients and control participants. The proportion of SERT-in2 short (s) alleles was significantly higher among MDD patients in comparison to healthy subjects (p = 0.04). CONCLUSION: "s" allele variant in the intron 2 of SERT gene could be associated with susceptibility to MDD.

Adult↗
PubMed1996

Analysis of p53, K-ras-2, and C-raf-1 in pulmonary neuroendocrine tumors. Correlation with histological subtype and clinical outcome.

Neuroendocrine tumors of lung, including typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell lung carcinoma (SCLC) constitute a spectrum of malignancies in which the pathologist at times has difficulty in discerning tumor subtype and aggressiveness in a reproducible fashion. Therefore, 59 primary neuroendocrine lung tumors including 10 TCs, 26 ACs, 15 LCNECs, and 8 SCLCs were selected from cases collected from 1976 to 1988 and immunostained for p53 protein. All of these tumors were also genotyped for specific point mutational damage affecting p53 (exons 5, 7, and 8; with ACs additionally sequenced for p53 exon 6); 13 tumors for K-ras-2 (exon 1); and 31 tumors for c-raf-1 (exon 15) growth-regulatory genes. Genotyping was performed on topographically selected, minute tumor samples removed from unstained formalin-fixed, paraffin-embedded tissue sections (topographic genotyping) using polymerase chain reaction and direct sequencing. The distribution of p53 immunohistochemical staining had four patterns: negative in TCs, one-half of ACs, 3 of 15 LCNECs, and 1 of 8 SCLCs; less than 10% but more than five tumor cells per 10 high power fields (focal) in a subset (7 of 26) of aggressive ACs; 10 to 49% of tumor cells (patchy) in a subset (6 of 26) of ACs with a higher grade of aggressiveness; and 50 to 100% of tumor cells (diffuse), exclusively seen in LCNECs (12 of 15) and SCLCs (7 of 8). Three patterns of immunohistochemical staining intensity of p53 protein were seen: negative, weak or mild, and moderate to marked. SCLCs and LCNECs accounted for cases of moderate to marked staining and were the only ones to have mutations in p53 exons 5, 7, or 8. No mutations were found in AC and TC, showing absent to weak staining and no staining, respectively. The difference in distribution and staining intensities between LCNEC and SCLC compared with AC and TC was statistically significant (P < 0.001). Patients having AC with patchy p53 immunostaining usually had survival limited to 3 years, whereas those having AC with focal p53 immunostaining subsequently developed metastatic or recurrence of AC disease (P < 0.05). The absence of point mutations in cases with patchy or focal immunostaining suggests increased expression of wild-type p53 tumor suppressor protein likely in response to growth deregulation in a more aggressive subtype of AC. A novel hypothesis is presented in regard to these findings. K-ras-2 and c-raf-1 gene sequence analysis showed no evidence of point mutational change in any of the tumors studied. The TC and AC categories are therefore genetically distinct from the higher grade neuroendocrine SCLC and LCNEC. Immunohistochemistry for p53 on AC lung tumors may be helpful to delineate cases at higher risk for aggressive behavior. Additionally, although LCNEC is categorized as a non-small-cell carcinoma, it is more akin genetically and immunohistochemically to SCLC.

Carcinoid Tumor↗
PubMed2001

Analysis for a limited number of gene codons can predict drug resistance of Mycobacterium tuberculosis in a high-incidence community.

Correct and rapid diagnosis is essential in the management of multidrug-resistant tuberculosis (MDR-TB). In this population-based study of 61 patients with drug-resistant tuberculosis, we evaluated the frequency of mutations and compared the performance of genotypic (mutation analysis by dot blot hybridization) and phenotypic (indirect proportion method) drug resistance tests. Three selected codons (rpoB531, rpoB526, and katG315) allowed identification of 90% of MDR-TB cases. Ninety percent of rifampin, streptomycin, and ethambutol resistance and 75% of isoniazid resistance were detected by screening for six codons: rpoB531, rpoB526, rrs-513, rpsL43, embB306, and katG315. The performance (reproducibility, sensitivity, and specificity) of the genotypic method was superior to that of the routine phenotypic method, with the exception of sensitivity for isoniazid resistance. A commercialized molecular genetic test for a limited number of target loci might be a good alternative for a drug resistance screening test in the context of an MDR "DOTS-plus" strategy.

Bacterial Proteins↗
PubMed2006

Genetic analyses of non-small cell lung cancer in Jewish Israeli patients.

BACKGROUND: The contribution of the abnormal DNA mismatch repair system to non-small cell lung cancer tumorigenesis is controversial and has not been reported in Jewish Israeli patients. Similarly, the involvement of 3p deletions in NSCLC in the same population has not been assessed. OBJECTIVES: To assess the contribution of the DNA-MMR system to NSCLC pathogenesis by analyzing microsatellite instability, and evaluate loss of heterozygosity at 3p rates in Israeli NSCLC patients. METHODS: Paired DNA from tumorous and non-tumorous tissue was extracted, and genotyping for MSI determination was carded out using the five Bethesda markers and for determining LOH two 3p markers were used. Genotyping was performed using polymerase chain reaction amplification and size separation on an ABI semiautomatic DNA sequencer, and the allelic patterns of tumorous and non-tumorous tissue were compared. RESULTS: Forty-four NSCLCs from 35 smokers and 9 non-smokers were analyzed, with 26 of the 44 (59%) at stage I disease. Using five microsatellite markers (D17S250, D5S346, D2S123, BAT-25, BAT-26) (known as Bethesda markers) for MSI determination, 6 of the 44 tumors (13.6%) exhibited MSI in at least one marker. Similarly, genotyping for LOH at chromosome 3p was performed using two markers (D3S4103, D3S1234) located at 3p14.2 I. With D3S4103, 33 of the 44 patients successfully analyzed were homozygous and therefore non-informative with respect to LOH. Using D3S1234, 33 of 36 patients (91.7%) were heterozygous, and 23 of these individuals' tumors (69.7%) displayed LOH. Unexpectedly, 4 of 33 tumors (12.1%) genotyped by D3S4103, and 16 of 36 tumors (44.5%) genotyped by D3S1234 showed a pattern of MSI, even though only one of these tumors showed a similar pattern when genotyped with the five consensus markers. Overall, 23 of 44 tumors (52.3%) demonstrated MSI on at least one marker, and 5 of these 23 tumors (21.7%) had MSI on two or more markers. CONCLUSIONS: MSI using 3p markers and not the Bethesda markers occurs at a high rate and in early stages in Jewish NSCLC patients.

Aged↗
PubMed2004

Cytokine gene polymorphisms in hemodialysis patients: association with comorbidity, functionality, and serum albumin.

BACKGROUND: Cytokine-orchestrated chronic inflammation plays a major role in long-term morbidity and mortality in patients with end-stage renal disease (ESRD) on hemodialysis (HD). In this cross-sectional study, we evaluated the association between specific alleles/genotypes and combinations of genotypes of interleukin (IL)-6, tumor necrosis factor-alpha (TNF-alpha), and IL-10 with indices of comorbidity, functional status, and other biological markers in a cohort of 183 ESRD patients recruited to the Hemodialysis (HEMO) Study from two Boston centers. METHODS: Genotyping was performed for single nucleotide polymorphisms in the promoter region of IL-6 (-174 G-->C), TNF-alpha (-308 G-->A), and IL-10 (-1082 G-->A). The relationship of specific genotypes to the index of coexistent disease (ICED) score (an index of comorbidity), Karnofsky Index (a measure of functional status), serum albumin, and nutritional indices (anthropometric measurements, body mass index, normalized protein catabolic ratio) were studied. Plasma IL-6 levels, as well as TNF-alpha and IL-10 production by endotoxin-stimulated peripheral blood mononuclear cells (PBMC), were also measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Patients with the high producer genotypes for the proinflammatory cytokines IL-6 (G/G and G/C) and TNF-alpha (G/A and A/A) had significantly higher comorbidity (ICED scores of > or =2) and lower functional scores (Karnofsky Index) compared with patients with the low producer genotypes for these cytokines (C/C and G/G, respectively). In contrast, patients with the high and intermediate producer genotypes (G/G and G/A) for the anti-inflammatory cytokine IL-10 had a higher Karnofsky Index compared with those with the low producer genotype (A/A). Serum albumin levels were lower in patients with the TNF-alpha high producer genotype (G/A and A/A) compared with those with the low producer genotype (G/A and A/A). On multivariate analysis, the IL-6 high producer genotypes were associated with an odds ratio (OR) of 4.87 for higher comorbidity (ICED scores > or =2) (P= 0.02), and 4.9 for lower Karnofsky Index (lower functional status) (P= 0.04) compared with patients with the low IL-6 producer genotypes. Similarly, the TNF-alpha high producer genotype was associated with increased odds for a higher ICED score, lower Karnofsky Index, and lower serum albumin compared with patients with the low producer genotype for this cytokine. In contrast, the IL-10 high/intermediate producer genotype was associated with increased odds for a higher Karnofsky Index (P= 0.05). Cytokine genotype combinations-the TNF-alpha high producer and IL-6 high producer genotype combination, and the IL-6 high producer and IL-10 low producer genotype combination-were independently associated with a higher ICED score. These genotype combinations, as well as the TNF-alpha high producer and IL-10 low producer genotype combination, were also associated with a lower Karnofsky Index. CONCLUSION: In ESRD patients on long-term HD, single nucleotide polymorphisms in the promoter region of the proinflammatory cytokines IL-6 and TNF-alpha, and the regulatory monokine IL-10, show a strong association with indices of comorbidity and function, and biological and nutritional markers.

Aged↗
PubMed2005

Analysis of TGF-beta(1) gene polymorphisms in Hong Kong Chinese patients with asthma.

BACKGROUND: The C-509T polymorphism of TGF-beta(1) gene has been associated with asthma and atopy in white populations. OBJECTIVE: We investigated the association between asthma and previously identified polymorphisms at C-509T and T869C of the TGF-beta(1) gene among 250 Chinese patients with asthma and 308 healthy controls in Hong Kong. METHODS: Genotyping was performed on peripheral blood genomic DNA by using PCR-RFLP. RESULTS: There were no differences in the frequencies of genotypes and alleles between patients and controls. The C-509T and T869C polymorphisms were in tight linkage disequilibrium (P < .01). Among atopic subjects, significant differences were found in genotype and allele frequencies for T869C polymorphism between patients and controls (P = .014 and P = .019, respectively), and individuals bearing the CC genotype were associated with increased risk for the development of asthma (odds ratio, 2.58; 95% CI, 1.17-5.66; P = .018) after adjusting for age, sex, and smoking status. Individuals with asthma bearing the CT genotype of the C-509T polymorphism had significantly increased risk for severe airflow obstruction compared with individuals who had mild obstruction (odds ratio, 4.00; 95% CI, 1.06-15.08; P = .035). CONCLUSION: Our results indicate that the polymorphisms at C-509T and T869C of the TGF-beta(1) gene are associated with asthma susceptibility in atopic subjects of the Hong Kong Chinese population, and the C-509T polymorphism may play a role in the pathogenesis of airflow obstruction.

Adult↗
PubMed2002

Eotaxin gene single nucleotide polymorphisms in the promoter and exon regions are not associated with susceptibility to atopic dermatitis, but two of them in the promoter region are associated with serum IgE levels in patients with atopic dermatitis.

Eotaxin is believed to play an important role in atopic dermatitis (AD) as a potent chemoattractant and activator of eosinophils and Th2 lymphocytes. The eotaxin gene is located at chromosome 17q21.1-q21.2, and linkage findings of AD on chromosome 17 were reported. Recently we have identified single nucleotide polymorphisms (SNPs) of eotaxin gene (-426C > T, -384A > G, 67G > A). To learn whether eotaxin gene SNPs are associated with susceptibility to AD or phenotypes of AD, we investigated the genotype frequencies at each SNP of the gene in AD patients and in controls. We examined 140 Japanese AD patients and 140 healthy Japanese individuals. Genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism method. No significant difference was observed in allele or genotype frequencies of any SNP between AD patients and controls. Serum immunoglobulin E (IgE) levels were significantly lower in CT and TT genotype than in CC (P = 0.038) in -426C > T SNP, and lower in GG than in AA and AG with borderline significance (P = 0.053) in -384A > G SNP in AD patients. Eotaxin gene SNPs in the promoter and exon regions are not associated with susceptibility to AD, but two of them in the promoter region are associated with phenotype of AD.

Adolescent↗
PubMed2001

CMV gB genotypes and outcome of vertical transmission: study on dried blood spots of congenitally infected babies.

BACKGROUND: The role of the virulence of the infecting cytomegalovirus (CMV) strain in the transmission of the virus from mother to fetus and the outcome of the fetal infection has not received much attention yet. Molecular analysis of the gene coding for the surface glycoprotein B (gB) has been used to investigate the relationship between genotype and virulence in groups of immunosuppressed patients. OBJECTIVES: (1) to assess the prevalence of different gB genotypes in babies with congenital CMV infection; (2) to investigate the possible relationship between genotype and severity of congenital CMV disease; (3) to evaluate the possibility of using dried blood on Guthrie cards (DBS) for genotyping. STUDY DESIGN: CMV DNA was extracted from DBS and from urine/saliva samples collected in the first two weeks of life of 98 congenitally infected babies, half of which were symptomatic at birth. Genotyping was performed through RFLP analysis of the region corresponding to the cleavage site of the gB protein. RESULTS: The most prevalent genotype was gB1 (42%) followed by gB3 (26%), gB2 (19%) and gB4 (13%). Rates of disease and CNS damages were higher among children infected by gB1 (35%, 17%) and gB3 (31%, 28%) than in those infected by gB2 and gB4 (20%, 17% and 13%, 15%, respectively). These differences however did not reach the statistical significance. The parallel typing of DBS and urine/saliva strains gave a full concordance of results. CONCLUSIONS: All four major CMV gB genotypes (gB1-4) can cause a congenital infection but none seems to be associated to the development and the severity of disease. The possibility of using the neonatal DBS for genotyping opens a way to the examination of large numbers of cases of congenital CMV infection.

Blood Specimen Collection↗
PubMedDate not supplied

Association between HLA-DQB1 and cervical dysplasia in Vietnamese women.

Host genetic background seems to play a key role in cervical carcinogenesis as only a small subset of women infected with high-risk human papillomaviruses (HPVs) develop cervical cancer. The rate of cervical cancer in Vietnamese women is notably high. To explore the association of human leukocyte antigen (HLA)-DQB1 alleles, HPV infection, and cervical dysplasia in this population, cervical smears were obtained from 101 women attending the obstetrics and gynecology clinic of Da Nang General Hospital in Vietnam. Besides the Papanicolaou test, HPV and HLA-DQB1 genotyping were performed using cervical smear DNA. Additionally, a subset of 30 blood samples was used as the gold standard for HLA genotyping. HLA-DQB1 alleles showed no association with HPV infection status. However, a positive association with cervical dysplasia was found for HLA-DQB1*0302 (P= 0.0229, relative risk (RR) = 4.737) and HLA-DQB1*0601 (P= 0.0370, RR = 4.038), whereas HLA-DQB1*0301 (P= 0.0152, RR = 0.221) was found negatively associated. The low diversity of HLA-DQB1 alleles, wide spectrum of HPV genotypes, and high prevalence of HPV 16 and HPV 18 observed in the study population suggest a permissive/susceptible genetic background that deserves further research. Total concordance of HLA-DQB1 genotyping results between blood and cervical cells confirms the potential value of cervical smears as an effective tool for the development of cervical cancer biomarkers.

Adult↗
PubMed2006

No correlation of five gene polymorphisms with periodontal conditions in a Greek population.

BACKGROUND: Various studies have examined possible correlations between a number of cytokine gene polymorphisms and periodontal disease in populations of different origins. The present study sought the correlation between four single-nucleotide polymorphisms (IL1A+3954, IL1B+4845, TNFA-308, COL1A1 Sp1), a variable number of tandem repeats polymorphism (IL1RN intron 2) and periodontal conditions in subjects of Greek origin. METHODS: One hundred and ninety-two healthy subjects, stratified as non-periodontitis and periodontitis (chronic and aggressive) cases, participated in the present study. Genotyping was performed by polymerase chain reaction-based techniques using the primers and conditions described in the literature. The frequencies of genotypes between study groups were compared using Genepop v3.3 genetic software and Instat statistical package. RESULTS: No differences were observed among the groups concerning the distributions of genotypes under investigation. CONCLUSIONS: Carriage rates of the polymorphisms under investigation in systemically healthy subjects of Greek origin are well within the range reported for Caucasians but these polymorphisms cannot discriminate between non-periodontitis and periodontitis (chronic or aggressive) cases.

Adult↗
PubMed1995

Clinical and prognostic evaluation of familial hypertrophic cardiomyopathy in two South African families with different cardiac beta myosin heavy chain gene mutations.

BACKGROUND: Familial hypertrophic cardiomyopathy is the most common inherited cardiac disorder, with sudden cardiac death at a young age the most frequent cause of death in affected individuals. Some cases of familial hypertrophic cardiomyopathy are caused by missense mutations of the beta myosin heavy chain (beta MHC) gene on chromosome 14 and at least 17 such mutations have been described. Recent reports suggest that a correlation exists between a specific beta MHC gene mutation and prognosis in familial hypertrophic cardiomyopathy. This premise is currently being used as a basis to provide counselling for affected families. This mutation/prognosis association, however, has not been widely assessed as yet. The clinical and prognostic features of two South African families of mixed racial descent, in which different beta MHC gene mutations were segregating, were studied to evaluate this correlation. The results were compared with those of previously published reports of European families carrying the same mutations. METHODS: The beta MHC gene missense mutations in two affected families were identified by single strand conformation polymorphism analysis and sequencing (pedigree 106: Arg403Trp; pedigree 108: Arg249Gln). All family members were subjected to genotypic analysis using polymerase chain reaction amplification and restriction enzyme based mutation detection techniques. Clinical, electrocardiographic, and echocardiographic studies were performed on genotypically affected individuals in these two kindreds. RESULTS: The number of individuals identified in pedigree 106 with the Arg403Trp mutation was 32.10 individuals bore the Arg249Gln mutation in pedigree 108. The penetrance rate in adults (equal to or greater than 16 years), using the strict echocardiographic criterion of maximum left ventricular wall thickness > or = 13 mm, was 25% for pedigree 106 and 33% for pedigree 108. Familial hypertrophic cardiomyopathy compatible electrocardiographic and echocardiographic abnormalities were seen in 60% of genotypically positive individuals aged > or = 16 years in pedigree 106 and 80% in pedigree 108. The prognosis was uniformly benign in the two families. For pedigree 106 this corresponded to a report of no early sudden cardiac deaths in a French family with the Arg403Trp mutation. For pedigree 108 the absence of such deaths was in apparent contrast to the four cases reported in 24 genotypically affected individuals in a study of a kindred of European ancestry bearing the Arg249Gln mutation. CONCLUSION: This study of a large South African kindred confirmed the benign nature of the Arg403Trp mutation suggested in a previous report. The number and the relatively young age of affected individuals in a second South African family must be considered when comparing the absence of familial hypertrophic cardiomyopathy associated deaths with the intermediate survival reported for the Arg249Gln mutation in a European family. This investigation lends support to current evidence relating specific beta MHC gene mutations to prognosis, which may be used as a basis to provide counselling for affected families.

Adolescent↗
PubMed2005

[Durability of HBeAg seroconversion in lamivudine treatment of chronic hepatitis B patients].

OBJECTIVE: To investigate the factors which may affect the rate of HBeAg seroconversion and its durability after long-term lamivudine therapy in chronic hepatitis B patients. METHODS: 81 patients were treated in a phase III clinical trial with lamivudine 100 mg daily for up to 5 years. The mean period of treatment was (48.84+/-10.52) months (range: 16 approximately 60 months). When HBeAg seroconversion occurred in the patients, which was defined as loss of HBeAg and detection of anti-HBe antibody, HBV DNA level less than 10 mEq/ml more than two times (once every 3 months), the lamivudine treatment was stopped and they were followed-up for another 6 approximately 12 months. The HBV DNA level was detected using Branched DNA assay (Chiron). The HBV markers were detected using IMX assay (Abbott). HBV genotyping was performed using type-specific PCR. The data were analyzed using logistic multivariant analysis. RESULTS: (1) The distribution of HBV genotypes was as follows: type B, 17 (20.97%), type C, 62 (76.54%), and type B+C, 2 (2.47%). (2) 26 patients achieved HBeAg seroconversion (32.10%). The annual seroconversion rates were 16.05% (13/81) in the 1st year, 19.75% (16/81) in the 2nd, 27.16 % (22/81) in the 3rd, 28.40% (23/81) in the 4th and 32.10% (26/81) in the 5th year. Four patients had a reappearance of HBeAg and an elevation of HBV DNA. Therefore the stability ratio was 84.62% (22/26). The mean baseline ALT and HBV DNA levels in those who were seroconvered were (104.8+/-86.3) U/L and (940.1+/-1123.7) mEq/ml, respectively. Mean baseline ALT and HBV DNA of non-seroconverters were (48.3+/-46.9) U/L and (2152.3+/-3063.5) mEq/ml. There was a significant difference between the two groups shown by Kruskal-Wallis Test (P < 0.05). Analysis by logistic multivariate analysis showed that the rate of HBeAg seroconversion and its durability rate correlated with a high baseline ALT. In contrast, a relatively low seroconversion rate and durability rate was observed in patients with high baseline HBV DNA. The durability rate also correlated with additional lamivudine treatment after HBeAg seroconversion. CONCLUSION: Continuation of lamivudine therapy for more than 6 months after HBeAg seroconversion might increase the durability of response.

Adult↗
PubMed2005

Correlation of rheumatoid arthritis severity with the genetic functional variants and circulating levels of macrophage migration inhibitory factor.

OBJECTIVE: To study whether genetic variants of macrophage migration inhibitory factor (MIF), the MIF -173G>C and CATT(5-8) alleles, are associated with disease severity and levels of circulating MIF in patients with rheumatoid arthritis (RA). METHODS: Genotyping was performed in patients with early RA and in healthy controls. Demographic data, disease activity, and outcome measurements were compared between patients with and without the MIF variants. MIF -173G>C and CATT(5-8) polymorphisms were genotyped, and a newly developed enzyme-linked immunosorbent assay for human MIF was used. Allele and genotype distributions of the MIF -173G>C and CATT(5-8) polymorphisms were compared between patients and controls by chi-square test. Multiple regression analysis was performed to assess the independence of the MIF functional genetic variants as risk factors for radiologic joint damage. RESULTS: Genotyping of the -173G>C and CATT(5-8) polymorphisms of MIF in RA patients and healthy individuals (n = 277 each) revealed similar frequencies of genotypes and haplotypes in both groups. No significant differences in demographic or clinical features were observed between RA patients carrying the MIF -173C allele or the MIF CATT7 allele or both and non-carrier RA patients. Radiologic joint damage was significantly higher in patients carrying risk alleles of the MIF -173G>C or the MIF CATT(5-8) functional variants. No synergistic effects between both genetic variants were observed. Multivariate regression analysis revealed that presence of the MIF -173C/C and MIF CATT(7/7) genotypes and having 1 MIF -173C allele were independent prognostic variables. Carriership of the MIF -173C allele (P = 0.002) or MIF CATT7 allele (P = 0.004) was associated with significantly higher circulating MIF levels compared with those in subjects having none of the risk-conferring alleles, and greater circulating MIF levels correlated with more severe radiologic joint damage (r = 0.64, P = 0.001). CONCLUSION: The MIF polymorphisms are not associated with RA susceptibility but are associated with high levels of radiologic joint damage. High circulating MIF levels were shown to correlate strongly with radiologic joint damage, suggesting that MIF expression is genetically determined and can be used as a novel prognostic tool in RA.

Adult↗