N-acetyltransferase 2 slow acetylator genotype associated with adverse effects of sulphasalazine in the treatment of inflammatory bowel disease.

AIM: N-acetyltransferase 2 (NAT2) is an important enzyme catalyzing N-acetylation of sulfasalazine (SASP). The aim of the present study was to investigate associations of the genotypes of NAT2 with inflammatory bowel disease (IBD), and with adverse effects of SASP, which is used as the first-line treatment of IBD. PATIENTS AND METHODS: The wildtype allele (NAT2*4) and three variant alleles (NAT2*5B, NAT2*6A and NAT*7B) of the NAT2 gene were determined in 101 patients with IBD (84 patients with ulcerative colitis and 17 patients with Crohn's disease) and 109 healthy controls by the polymerase chain reaction-restriction fragment length polymorphism method. Sixty-eight patients with IBD treated with SASP were followed, and their adverse reactions were recorded. RESULTS: Eleven patients (16%) experienced adverse effects from SASP, including nine cases of sulfapyridine (SP) dose-related adverse effects and two cases of hypersensitivity (skin rash). Patients with the slow acetylator genotypes without the NAT2*4 allele experienced adverse effects more frequently (36%) than those with the fast acetylator genotypes with at least one NAT2*4 allele (11%), but the results were not significantly different (OR of 0.26, 95% CI 0.065 to 1.004; P=0.051). However, those with the slow acetylator genotypes experienced more SP dose-related adverse effects than those with the fast acetylator genotypes (36% versus 8%, OR of 0.17, 95% CI 0.039 to 0.749; P=0.019). CONCLUSIONS: The NAT2 gene polymorphism was not associated with susceptibility to IBD in Chinese populations, but the NAT2 slow acetylator genotypes were significantly associated with SP dose-related adverse effects of SASP in the treatment of IBD.     

Thiopurine metabolites variations during co-treatment with aminosalicylates for inflammatory bowel disease:Effect of N-acetyl transferase polymorphisms

AIM: To evaluate variation of the concentration of thiopurine metabolites after 5-aminosalicylate(5-ASA) interruption and the role of genetic polymorphisms of N-acetyl transferase(NAT) 1 and 2. METHODS: Concentrations of thioguanine nucleotides(TGN) and methymercaptopurine nucleotides(MMPN), metabolites of thiopurines, were measured by high performance liquid chromatography in 12 young patients(3 females and 9 males, median age 16 years) with inflammatory bowel disease(6 Crohn’s disease and 6 ulcerative colitis) treated with thiopurines(7 mercaptopurine and 5 azathioprine) and 5-ASA. Blood samples were collected one month before and one month after the interruption of 5-ASA. DNA was extracted and genotyping of NAT1, NAT2, inosine triphosphate pyrophosphatase(ITPA) and thiopurine methyl transferase(TPMT) genes was performed using PCR assays. RESULTS: Median TGN concentration before 5-ASA interruption was 270 pmol/8 x 108 erythrocytes(range: 145-750); after the interruption of the aminosalicylate, a 35% reduction in TGN mean concentrations(absolutemean reduction 109 pmol/8 × 108 erythrocytes) was observed(median 221 pmol/8 × 108 erythrocytes, range: 96-427, P value linear mixed effects model 0.0011). Demographic and clinical covariates were not related to thiopurine metabolites concentrations. All patients were wild-type for the most relevant ITPA and TPMT variants. For NAT1 genotyping, 7 subjects presented an allele combination corresponding to fast enzymatic activity and 5 to slow activity. NAT1 genotypes corresponding to fast enzymatic activity were associated with reduced TGN concentration(P value linear mixed effects model 0.033), putatively because of increased 5-ASA inactivation and consequent reduced inhibition of thiopurine metabolism. The effect of NAT1 status on TGN seems to be persistent even after one month since the interruption of the aminosalicylate. No effect of NAT1 genotypes was shown on MMPN concentrations. NAT2 genotyping revealed that 6 patients presented a genotype corresponding to fast enzymatic activity and 6 to slow activity; NAT2 genotypes were not related to thiopurine metabolites concentration in this study. CONCLUSION: NAT1 genotype affects TGN levels in patients treated with thiopurines and aminosalicylates and could therefore influence the toxicity and efficacy of these drugs; however the number of patients evaluated is limited and this has to be considered a pilot study.     

Difference in DRB1~* gene polymorphisms between Han and Uyghur ulcerative colitis patients in China

AIM:To evaluate the association between HLA-DRB1 alleles and Han and Uyghur ulcerative colitis (UC) patients residing in the Xinjiang Uyghur Autonomous Region of China. METHODS:In this study, 102 UC patients (53 Han including 22 men and 31 women, and 49 Uyghur patients including 25 men and 24 women; aged 48.07 ± 15.83 years) and 310 age- and sex-matched healthy controls were enrolled in the Department of Gastroenterology, Xinjiang People’s Hospital of China from January 2010 to May 2011. UC was diagnosed based on the clinical, endoscopic and histological findings following Lennard-Jones criteria. Blood samples were collected and genomic DNA was extracted by routine laboratory methods, and both polymerase chain reaction and gene sequencing were used to identify HLA-DRB1 allele variants. The potential association between genetic varia-tion and UC in Han and Uyghur patients was examined. There were no statistical differences in HLA-DRB1 allele frequencies in Han UC patients. RESULTS:There was no significant difference in the sex ratio between the controls and UC patients (P = 0.740). In Han patients with UC (n = 53), HLA-DRB1 *03 , *13 allele frequencies were lower than in healthy controls (n = 161), but not statistically significant, and HLA-DRB1*04*11*14 allele frequencies were higher than in healthy controls, but without statistical significance. Differences between Uyghur UC patients and the control group were observed for HLA-DRB1*04 and HLA-DRB1*13 , both showed a greater frequency in UC patients (10.21% vs 2.69%, P = 0.043; 14.29% vs 4.03%, P = 0.019). HLA-DRB1*14 also showed a greater frequency in UC patients (14.29% vs 2.69%, P = 0.006). The frequencies of DRB1*04 , *13*14 alleles were increased in Uyghur UC patients compared with normal controls. The frequency of DRB1 * 08 was decreased in Uyghur UC patients compared with normal controls. HLA-DRB1 alleles showed no association with UC in Han patients. There were no statistical differences in HLA-DRB1 allele frequencies in Han UC patients. The frequenci     

Thiopurine S-methyltransferase polymorphisms and the relationship between the mutant alleles and the adverse effects in systemic lupus erythematosus patients taking azathioprine

OBJECTIVE: The present study sought to elucidate the genetic basis of thiopurine methyltransferase (TPMT) polymorphism and subsequently to investigate the relationship between mutant TPMT and an adverse response observed in Korean patients with systemic lupus erythematosus (SLE) taking azathioprine (AZA). METHODS: The TPMT genotype of 342 patients with SLE was determined by MALDI-TOF mass spectrometry and correlated with the effects of clinical exposure to AZA. RESULTS: TPMT polymorphism was detected in 17 of the 342 study subjects (5.0%), 12 heterozygous for the TPMT*3C allele and 5 heterozygous for the TPMT*6 allele. Numerous patients taking AZA demonstrated adverse drug responses. Severe nausea occurred in 4 patients with the TPMT*3C allele, while 1 patient with the TPMT*6 allele suffered severe bone marrow toxicity. Leucopenia (n = 17), nausea (n = 4), and abnormal liver function (n = 1) were suspected in 23 of the 94 lupus patients taking AZA. AZA was relatively well tolerated by the remainder of the patients. The heterozygous genotype for the TPMT*3C and *6 alleles was frequently detected in Korean SLE patients. CONCLUSION: Contrary to previous hypotheses, this study identified no statistical correlation between TPMT genotype and AZA toxicity. We thus conclude that TMPT genotyping cannot replace regular blood monitoring in SLE patients receiving AZA treatment.     

Are polymorphisms of N-acetyltransferase genes susceptible to primary liver cancer in Luoyang, China？

AIM: To identify whether the polymorphisms of the N-acetyltransferase (NAT) genes are susceptible to primary liver cancer (PLC) in Luoyang, a PLC low-incidence area of China. METHODS: The NAT1 and NAT2 genotypes of 96 PLC cases and 173 controls were determined by PCR-RFLP. Both interaction between NAT1 or NAT2 and environmental risk factors were analyzed based on case control study. RESULTS: Compared to the control group, the frequencies of alleles NAT1*3, NAT1*4, NAT1*10, NAT1*14B and alleles NAT2*4, NAT2*6, NAT2*7 in PLC group showed no statistically significant difference (x2= 2.61 and 4.16, respectively, both P>0.05). The frequencies of NAT1 genotypes NAT1*3/*3, NAT1*3/*4, NAT1*3/*10, NAT1*3/*14B, NAT1*4/*4, NAT1*4/*10, NAT1*4/*14B, NAT1*10/*10, NAT1*10/*14B, and NAT2 genotypes NAT2*4/*4, NAT2*4/*6, NAT2*4/*7, NAT2*6/*6, NAT2*6/*7 and NAT2*7/*7 also had no statistically significant difference between the two groups (x2= 11.86 and 2.94 respectively both, P>0.05). Neither the frequencies of rapid and slow NAT1 acetylators nor the frequencies of rapid and slow NAT2 acetylators were significantly different between the two groups (x2 = 0.598 and 0.44, respectively, both P>0.05). The interaction between NAT1*10 and occupational exposures was found significant with an odds ratio of 3.40 (x2=8.42, P=0.004, OR 95%CI:1.03-11.22). But no interaction was found between NAT2 and any environmental risk factors. CONCLUSION: The polymorphisms of NAT1 and NAT2 are not susceptible to PLC in Luoyang. Allele NAT1*10 interacts with occupational exposures.     

Genetic polymorphisms of cytochrome P450 in patients with hepatitis C virus-associated hepatocellular carcinoma

BACKGROUND: The carcinogenic process can be modulated by exposure to endogenous or environmental substance(s) acting as carcinogens or protocarcinogens. Polymorphic enzymes of cytochrome P450 (CYP) that play a role in detoxication/toxication of such substances via metabolization may account for the interpatient variability of clinical course in cancers such as hepatocellular carcinoma (HCC). Many CYP genetic polymorphisms, which may change enzyme activity, are known to exist in Japanese. The aim of the present study was to compare the frequencies of CYP polymorphisms between hepatitis C virus (HCV)-related HCC patients and healthy subjects. METHODS: Seven mutant alleles and related genotypes of CYP in 44 HCV-positive HCC patients were chosen as follows: *1C heterozygous, *1C homozygous and *1F homozygous for CYP1A2, *4A homozygous for CYP2A6, *2A or *3 heterozygous, *2A or *3 homozygous and *2A and *3 heterozygous for CYP2C19, and *10/*5 homozygous for CYP2D6. These mutant alleles have been reported to change the CYP enzyme activity in Japanese. The frequencies of the mutant alleles and genotypes were then compared with those reported in healthy Japanese. RESULTS AND CONCLUSION: There is no statistically significant difference in genetic mutant alleles between the two groups, except for the genotype of CYP2A6*4A homozygous. The frequency of this genotype in the HCC patients (0.144) is significantly higher than that in healthy Japanese (0.034; P < 0.05; odds ratio 3.36). The clinical significance related to HCC is unknown. Further evaluation of CYP2A6*4A (deletion type) in HCV-related HCC patients is required.     

Long-term intermittent treatment with low-dose 5-aminosalicylic enemas is efficacious for remission maintenance in ulcerative colitis

BACKGROUND: The standard remission maintenance treatment for ulcerative colitis (UC) is 5-amino-salicylic acid (5-ASA), given orally and topically and in different doses, with various frequencies and duration of administration. Both the efficacy of long-term intermittent therapy with low-dose 5-ASA enemas in preventing UC relapses and its economic implications were evaluated. METHODS: In accordance with a prospective case control study, 42 adult UC outpatients (29 M and 13 F) were treated with 5-ASA tablets (1.6 g/day) and 5-ASA enemas (2 g/50 mL) twice weekly, and 42 concurrent UC outpatients, matched for sex, age, extension and duration of disease, received only the oral therapy; the median treatment period was 6 years. RESULTS: There was a significant reduction in the number (42%: P = 0.034) and incidence of relapses (43%: P = 0.022) in the patients receiving combined oral + topical 5-ASA, who also had a significantly higher cumulative probability of not experiencing a first relapse (P = 0.001). There were no dropouts or side effects. Local therapy increased drug costs, but decreased the costs of relapses by 48% and completely precluded hospitalization costs. CONCLUSIONS: The scheduled oral + topical 5-ASA treatment, at the lowest cumulative topical dosage tested over the longest known observation period, is efficacious in improving clinical outcome and decreasing overall costs in UC patients.     

N-acetyl transferase genotypes in relation to risk of developing systemic lupus erythematosus

OBJECTIVE: To examine the association between N-acetyl transferase (NAT) genotype (NAT1 and NAT2) and risk of developing systemic lupus erythematosus (SLE). METHODS: DNA samples were collected from 243 recently diagnosed cases and 298 controls enrolled in a population based case-control study conducted in 60 counties in North Carolina and South Carolina, USA. RESULTS: There was no association between SLE and NAT1 genotype (OR 0.96, 95% CI 0.65, 1.4 for the presence of a *10 allele) or NAT2 genotype (OR 1.1, 95% CI 0.73, 1.6 for the slow- compared with fast-acetylation genotype). We saw some evidence of interaction between NAT genotypes and use of hair dyes (a source of arylamines), with higher risk seen among hair dye users who had both the *10 NAT1 allele and the NAT2 slow-acetylation genotype (OR 2.9, 95% CI 1.2, 6.9 in this subgroup compared with all others). CONCLUSION: Our results suggest that although there is little overall association between NAT genotypes and risk of developing SLE, the interaction between NAT1 and NAT2 and specific exposures such as hair dyes may be important. This finding highlights the need to consider exposure when assessing genetic susceptibility.     

丙型肝炎病毒基因型及患者人类白细胞抗原对其抗病毒疗效的影响

目的 探讨不同基因型丙型肝炎病毒(HCV)及人类白细胞抗原(HLA)-DRB等位基因多态性对慢性丙型肝炎(简称丙肝)患者干扰素联合利巴韦林治疗应答率的影响。 方法 对113例接受干扰素联合利巴韦林治疗的丙肝患者进行基因型调查,采用基因芯片技术对其中25例患者的HLA-DRB基因型进行分析,探讨病毒基因型及宿主HLA等位基因对丙肝患者抗病毒治疗反应性的影响。 结果 不同基因型HCV感染对干扰素联合利巴韦林治疗的应答率不同,其中HCV-Ⅳ/2b型应答率最高,为57.7 8％,I/la型和Ⅲ/2a型次之,分别为46.15％和47.62％,Ⅱ/1 b型应答率最低,仅为11.76％。HLA-DRBl*07阳性者对干扰素联合利巴韦林治疗的应答率较高,而DRB1*04阳性者应答率较低。患者性别、HCV基因型、宿主HLA-DRB等位基因三种因素均与抗病毒疗效密切相关,女性、Ⅳ型HCV感染以及携带HLA-DRB1*07等位基因的患者多表现为完全应答,而男性、Ⅱ型HCV感染以及携带HLA-DRB1*04等位基因的患者多表现对干扰素联合利巴韦林治疗无应答。其中DRB1*07等位基因及Ⅳ型HCV感染对抗病毒疗效的影响最大。 结论 病毒与宿主在影响抗病毒治疗应答状况方面具有同等重要的地位,丙肝的治疗方案不应单纯只针对抗病毒一个方面.还应着眼于宿主本身,通过多种方式调节机体的免疫状态以增强宿     

Polymorphisms in tumour necrosis factor and adhesion molecule genes in patients with inflammatory bowel disease: associations with HLA-DR and -DQ alleles and subclinical markers

BACKGROUND: When investigating susceptibility to inflammatory bowel disease (IBD), a multifactorial disorder with a genetic predisposition, polymorphisms of molecules with immunoregulatory function are of potential interest. This is the first time that the polymorphisms of HLA-DR and -DQ, tumour necrosis factor (TNF), E-selectin (CD62E), L-selectin (CD62L), and intercellular adhesion molecule 1 (ICAM-1, CD54) were determined in Estonians, a population with a low IBD incidence rate, and their occurrence investigated in subgroups of a total of 53 IBD patients. METHODS: The reverse hybridization principle and sequence specific primers were used for HLA genotyping. To analyse the TNF and adhesion molecule polymorphisms, the polymerase chain reaction with subsequent restriction fragment length polymorphism or single-strand conformation polymorphism method was used. RESULTS: In the subgroup of antineutrophil cytoplasmic antibody (ANCA)-positive ulcerative colitis (UC) patients we found a higher frequency of the TNF2 (20.8% versus 0.0% in ANCA-negative UC patients, P = 0.051) and HLA-DRB1*15 allele (35.4% versus 15.7% in controls; P = 0.004). Of ANCA-positive UC patients 87.5% were carriers of one of these alleles (22.2% among ANCA-negative UC patients (P<0.001, Pc = 0.039) and 51.4% among controls (P = 0.002). Specific typing of HLA-DRB1*15 alleles showed that the HLA-DRB1*1501 allele was responsible for the HLA-DRB1*15 association with ANCA-positive UC. Associations of ICAM-1, E-selectin, or L-selectin polymorphisms with IBD were not found. CONCLUSIONS: TNF2 and HLA-DRB1*15 alleles were associated with ANCA-positive UC in the investigated population. ANCA might be a useful marker, at least in some ethnic groups, for dividing IBD patients into genetically more homogeneous subgroups.     

Effect of weekend 5-aminosalicylic acid (mesalazine) enema as maintenance therapy for ulcerative colitis: results from a randomized controlled study

BACKGROUND: 5-aminosalicylic acid (5-ASA) is known to be effective in the treatment of active ulcerative colitis (UC). The aim of the current study was to investigate the effect of 5-ASA enemas, as a maintenance therapy for UC, when administered twice weekly as a weekend treatment regimen, compared to daily oral 5-ASA alone. We hypothesized that the weekend enema therapy would be better tolerated by patients who worked or attended school. METHODS: Between January 2004 and August 2005, patients with UC, in whom remission of the condition had just been induced, were randomly assigned to either: the weekend 5-ASA enema group (n=11), who received 1 g 5-ASA enemas twice a week on Saturday and Sunday plus oral 5-ASA 3 g/day for 7 days, or to the daily oral 5-ASA use only group (n=13), who received only oral 5-ASA 3 g/day for 7 days. The primary endpoint of the study was defined as the incidence of relapse. The study was stopped after 24 patients had been enrolled because an interim analysis showed a significant benefit of the weekend 5-ASA enema group. RESULTS: In the weekend enema group, 2 patients (18.2%) had relapses compared with 10 (76.9%) in the oral 5-ASA only group. The multivariate hazard ratio of relapse associated with weekend 5-ASA enema, relative to the oral alone group, was 0.19 (95% confidence interval, 0.04-0.94). CONCLUSIONS: This study demonstrated the beneficial effects of adding weekend 1 g 5-ASA enema to daily 3 g oral 5-ASA as maintenance therapy for UC.     

Association of the HLA-DRB1＊0701 allele with perinuclear anti-neutrophil cytoplasmatic antibodies in Mexican patients with severe ulcerative colitis

AIM: To determine the association between the HLADRB1 alleles and perinuclear anti-neutrophil cytoplasmatic antibodies (p-ANCA) positive in Mexican patients with ulcerative colitis (DC). METHODS: Ninety Mexican mestizo patients (45 females) with DC, confirmed by biopsy, were studied. High resolution HLA typing was performed by PCR-SSO reverse dot blot and PCR-SSP. Molecular typing techniques were applied to define HLA-DRB1 alleles. Enzyme-linked immunosorbent assay and immunofluorescence techniques were used to detect p-ANCA. RESULTS: Forty-eight (53%) UC patients were positive for p-ANCA by ELISA and IF. We found that p-ANCA-positive UC patients had a significantly increased frequency of HLA-DR7 compared with p-ANCA-negative controls (22% vs 5.1%; pC = 0.02, OR = 5.2, CI 95%: 1.06-37.82). Disease activity was scored as severe in 20 patients, moderate in 8, mild in 14 and no activity in the remaining 38 patients according to the Truelove and Witts criteria. Subgroup analysis showed a significantly increased frequency of the HLA-DRB1*07 allele in 15 of 20 UC patients with severe activity of UC and p-ANCA positivity [100% vs 0%; pC = 0.0000001; OR = 35]. No significant differences were found between p-ANCA positive patients, HLA-DR alleles and other clinical features such as extraintestinal manifestations, proctocolectomy and extension. CONCLUSION: The HLA-DRB1*07 is associated with p-ANCA positive UC Mexican patients.     

Cytochrome P450 pharmacogenetics as a predictor of toxicity and clinical response to pulse cyclophosphamide in lupus nephritis

OBJECTIVE: Pulse cyclophosphamide is the treatment of choice for severe lupus nephritis. However, not all patients respond to this therapy, and gonadal toxicity is of particular concern. Cyclophosphamide is a prodrug that requires activation by cytochrome P450 (CYP) enzymes. We conducted a retrospective cohort study to test whether genetic polymorphisms of these enzymes are associated with the toxicity of, and clinical response to, cyclophosphamide in patients with lupus nephritis. METHODS: Sixty-two patients with proliferative lupus nephritis treated with cyclophosphamide were genotyped for common variant alleles of CYP2B6, 2C19, 2C9, and 3A5. We examined the association between these genotypes and the following clinical end points: development of premature ovarian failure, end-stage renal disease (ESRD), doubling of serum creatinine level, and achievement of complete renal response. RESULTS: The observed frequencies of the variant alleles CYP2B6*5, CYP2C19*2, CYP2C9*2, and CYP3A5*3 were 12.1%, 25.0%, 4.0%, and 75.8%, respectively. Patients who were either heterozygous or homozygous for CYP2C19*2 had a significantly lower risk of developing premature ovarian failure (relative risk 0.10; 95% confidence interval 0.02-0.52), after adjustment for age and total number of cyclophosphamide pulses received. In a survival analysis, patients homozygous for CYP2B6*5 (n = 3) or CYP2C19*2 (n = 4) had a higher probability of reaching ESRD (P = 0.0005) and of doubling the creatinine level (P = 0.0005) as well as a trend toward a lower probability of achieving a complete renal response (P = 0.051). CONCLUSION: Determination of selected cytochrome P450 enzyme genotypes may be valuable for predicting the risk of premature ovarian failure in lupus nephritis patients treated with cyclophosphamide. The association of these genotypes with renal response needs further validation.     

Tnfluence of HLA-DRB1 alleles and HBV genotypes on interferon-α therapy for chronic hepatitis B

AIM: To investigate the influence of HLA-DRB1 alleles and HBV genotypes on interferon-α therapy for chronic hepatitis B.METHODS: HLA-DRB1*03, *07, *09, *12, *15 alleles were determined using polymerase chain reaction/sequence specific primer (PCR/SSP) technique in 126 patients with chronic hepatitis B and 76 normal control subjects in Shandong Province, and HBV genotypes were determined by nested-PCR analysis using type-specific primers in 126 patients.RESULTS: The positivity of HLA-DRB1*07 allele in chronic hepatitis B group was significantly higher than that in normal control group (x2 = 6.33, P<0.025, RR = 2.37). Among the 126 patients, genotype B was found in 38 (30.2%), genotype C in 69 (54.8%), and mixed genotype (B+C) in 19 (15.0%),genotypes D-F were not found. Among the 46 DRB1*07(+)patients, 7 were responders and 39 were non-responders among them (x2 = 6.71, P<0.05). The positivity of HLADRB1*07 and prevalence of HBV genotype C were significantly higher in non-responders than in responders.CONCLUSION: High positivities of HLA-DRB1 *07 allele and HBV genotype C are closely associated with the lower response to interferon-α therapy for chronic hepatitis B.     

Tnfluence of HLA-DRB1 alleles and HBV genotypes on interferon-α therapy for chronic hepatitis B

AIM: To investigate the influence of HLA-DRB1 alleles and HBV genotypes on interferon-α therapy for chronic hepatitis B.METHODS: HLA-DRB1*03, *07, *09, *12, *15 alleles were determined using polymerase chain reaction/sequence specific primer (PCR/SSP) technique in 126 patients with chronic hepatitis B and 76 normal control subjects in Shandong Province, and HBV genotypes were determined by nested-PCR analysis using type-specific primers in 126 patients.RESULTS: The positivity of HLA-DRB1*07 allele in chronic hepatitis B group was significantly higher than that in normal control group (x2 = 6.33, P<0.025, RR = 2.37). Among the 126 patients, genotype B was found in 38 (30.2%), genotype C in 69 (54.8%), and mixed genotype (B+C) in 19 (15.0%),genotypes D-F were not found. Among the 46 DRB1*07(+)patients, 7 were responders and 39 were non-responders among them (x2 = 6.71, P<0.05). The positivity of HLADRB1*07 and prevalence of HBV genotype C were significantly higher in non-responders than in responders.CONCLUSION: High positivities of HLA-DRB1 *07 allele and HBV genotype C are closely associated with the lower response to interferon-α therapy for chronic hepatitis B.     

lnfluence of HLA-DRB1 alleles and HBV genotypes on interferon-α therapy for chronic hepatitis B

AIM: To investigate the influence of HLA-DRB(1) alleles and HBV genotypes on interferon-alpha therapy for chronic hepatitis B. METHODS: HLA-DRB1*03, *07, *09, *12, *15 alleles were determined using polymerase chain reaction/sequence specific primer (PCR/SSP) technique in 126 patients with chronic hepatitis B and 76 normal control subjects in Shandong Province, and HBV genotypes were determined by nested-PCR analysis using type-specific primers in 126 patients. RESULTS: The positivity of HLA-DRB1*07 allele in chronic hepatitis B group was significantly higher than that in normal control group (chi(2) = 6.33, P<0.025, RR = 2.37). Among the 126 patients, genotype B was found in 38 (30.2%), genotype C in 69 (54.8%), and mixed genotype (B+C) in 19 (15.0%), genotypes D-F were not found. Among the 46 DRB1*07(+) patients, 7 were responders and 39 were non-responders among them (chi(2) = 6.71, P<0.05). The positivity of HLA-DRB1*07 and prevalence of HBV genotype C were significantly higher in non-responders than in responders. CONCLUSION: High positivities of HLA-DRB1 *07 allele and HBV genotype C are closely associated with the lower response to interferon-alpha therapy for chronic hepatitis B.     

Slow N-acetyltransferase 2 genotype affects the incidence of isoniazid and rifampicin-induced hepatotoxicity.

SETTING: Japanese in-patients with pulmonary tuberculosis and normal liver function receiving treatment with isoniazid and rifampicin (INH + RMP). OBJECTIVE: To elucidate the relationship between N-acetyltransferase 2 (NAT2) genotype and the incidence of isoniazid + rifampicin-induced hepatotoxicity. DESIGN: Prospective study. After NAT2* genotyping, 77 patients were classified into three groups according to their NAT2* genotypes: rapid-type (a homozygote of NAT2*4), intermediate-type (a heterozygote of NAT2*4 and mutant alleles) and slow-type (a combination of mutant alleles). Their biochemical profiles of liver function test were investigated for 3 months to assess the development of serum aminotransferase elevation. RESULT: Of the 77 patients, 18.2% developed adverse hepatic reaction within the first month of INH + RMP treatment. A significant association was observed between hepatotoxicity and NAT2* genotype: compared with rapid-type, the relative risk was 4.0 (95% CI 1.94-6.06) for intermediate-type and 28.0 (95%CI 26.0-30.0) for slow-type. Especially in slow-type, the incidence of hepatotoxicity and serum aminotransferase elevation was significantly higher than in the other two types. CONCLUSION: Slow NAT2* genotype significantly affected the development of INH + RMP-induced hepatotoxicity. This suggests the possibility that NAT2* genotyping prior to medication may be useful in evaluating patients with high risk for INH + RMP-induced hepatotoxicity.     

N-乙酰化转移酶1基因多态性与老年人胃肠腺癌易感性的关系

目的　探讨N 乙酰化转移酶 1(NAT1)基因多态性与老年人胃肠腺癌易感性的关系。　方法　应用PCR 限制性片段长度多态性分析 (RFLP)及多重PCR技术检测NAT1基因多态性 ,14 C尿素呼气试验和外周血ELISA法检测幽门螺杆菌 (HP)感染情况。　结果　老年胃腺癌组与老年对照组含NAT1 10的基因型频率分别为 4 2 0 %、2 8 6 % ,其差异无显著性 ,胃腺癌组不同分化程度、部位及临床分期分别与老年对照组比较 ,含NAT1 10的基因型的频率差异均无显著性。含NAT1 10的基因型在HP阳性胃腺癌组中的频率 (4 5 7% )显著高于HP阳性对照组 (2 6 1% ,P <0 0 5 ) ;在大肠腺癌组、老年人远端大肠腺癌及中分化腺癌中的频率分别为 4 3 2 %、4 6 9%及 4 8 4 % ,均显著高于老年对照组 (P <0 0 5 )。　结论　含NAT1 10的基因型与老年人胃腺癌的易感性无关 ,与肿瘤发生部位、临床分期及分化程度等均无关联 ,与老年大肠腺癌的易感性有关 ,肿瘤多位于大肠远端 ,以中分化腺癌多见。含NAT1 10的基因型可提高HP感染的老年人患胃腺癌的危险性。     

Medical treatment: does it influence the natural course of inflammatory bowel disease?

It is difficult to predict the clinical course of inflammatory bowel disease (IBD). Moderately sick Crohn's disease (CD) patients and patients with distal ulcerative colitis (UC) may get better even without medical or surgical treatment. Once better, they may continue in remission even without treatment. If they are not treated, there are several factors that predict whether they will maintain remission. Most patients will probably alternate between remission and relapse, with 10% having a relapse-free course after 10 years, and only 1% having a continuously active course. Frequent relapses initially are associated with active disease later on, but the disease activity course is independent of the response to the initial medical treatment. There is a cumulative frequency of operation of 50-80% and of reoperation of 33% in CD, which suggests that CD has a more serious course than UC. In UC, the overall probability of surgery is 33% for pancolitis and 10% for proctitis within 5 years of diagnosis, and the majority of patients are operated on within the first few years. Maintenance treatment with sulphasalazine (SASP) and 5-aminosalicylic acid (5-ASA) in UC has reduced relapse rates to about half over a 1-year follow-up period. The use of 5-ASA for maintenance of CD has been shown to result in only a modest therapeutic gain, while azathioprine and 6-mercaptopurine (6-MP) improve the relapse frequency for at least 3 years whilst on treatment. Changes in disease distribution in UC are part of the natural course of the disease, which should have implications for medical treatment strategies, and affects the risk of colectomy and colonic cancer. Certain enviromental factors are thought to determine disease activity and disease outcome in UC and CD. Patient compliance with prescribed medication and clinical check-ups must be considered another non-specific variable affecting the clinical outcome. IBD frequently requires potent medication with side effects that limit patients' acceptance. Such patients often resort to medicinal herbs, acupuncture, and homeopathy, which may alter the expected course.     

5-氨基水杨酸维持治疗溃疡性结肠炎114例

目的:评估5-氨基水杨酸(5-ASA)对溃疡性结肠炎(UC)缓解期患者维持治疗及影响UC复发的相关因素.方法:回顾性分析2004-01/2010-08在北京大学第一医院消化内科就诊的114例缓解期UC患者的临床资料,纳入分析病例114例.其中,男64例,女50例,年龄16-76岁.结果:选择应用5-ASA诱导缓解治疗病例75例(65.8%).结果显示:(1)UC复发与性别无关;(2)病程>5年的UC患者复发率显著高于病程≤5年的UC患者(62.1%vs35.7%,P>0.05);(3)轻度UC患者5-ASA维持治疗剂量>2g/d者复发率显著低于≤2g/d者(10%vs33.3%,P<0.05);(4)轻度UC患者复发率显著低于中度和重度患者(24.6%vs83.3%,80.6%,P<0.05);(5)直肠型UC患者复发率(19.2%)较低;(6)诱导缓解治疗达到黏膜愈合患者的复发率显著低于未达到黏膜愈合的患者(4.8%vs89.6%,P<0.05);(7)UC患者诱导缓解后第2年始复发率随时间逐年上升.结论:黏膜愈合及疾病活动程度是影响UC复发率的重要因素,5-ASA是轻-中度UC维持缓解治疗的首选药物,5-...