Genetics in autoimmune hepatitis.

Current hypotheses suggest that autoimmune hepatitis (AIH) is triggered by an environmental factor in a genetically susceptible host. Multiple genes may interact to produce a "permissive gene pool" that determines both disease risk and phenotype. Studies of type 1 AIH have focused on the major histocompatibility complex (MHC), mapping susceptibility to the DRB1 region.

Genetic bases of autoimmune hepatitis.

Our goal was to review the hypotheses in evolution that promise to elucidate the genetic bases of autoimmune hepatitis. DRB1*0301 and DRB1*0401 are the principal risk factors in Britain and the United States. Other susceptibility alleles in different ethnic groups commonly share the same or a similar motif at the critical DRbeta71 position of the HLA class II molecule.

Interleukin-1, interleukin-10 and tumour necrosis factor-alpha gene polymorphisms in hepatitis C virus infection: an investigation of the relationships with spontaneous viral clearance and response to alpha-interferon therapy.

Background/aims: Though there is a consensus that the HLA DQB1*0301 allele is important in untreated HCV clearance, this association is not universal and a number of genes outside the major histocompatibility complex may also play a role in host responses to HCV infection. Prime candidates, at present, are the genes encoding pro-inflammatory and immuno-regulatory cytokines. The aim of this study was to investigate the relationship between a number of these candidate genes and both spontaneous and treatment related clearance of hepatitis C virus infection.

Genetic effects on susceptibility, clinical expression, and treatment outcome of type 1 autoimmune hepatitis.

Currently, three genetic factors have been short-listed as possible modulators of susceptibility and severity in type 1 AIH. They are female sex, HLA DRB alleles encoding lysine at position DR beta 71, and the CTLA4*G allele. The fourth association (i.

Molecular identification of P-glycoprotein: a role in lens circulation?

Purpose: To determine whether P-glycoprotein is expressed in the rat lens and to assess what type of damage occurs when P-glycoprotein inhibitors are applied to organ-cultured lenses.

Methods: An initial screening for the P-glycoprotein isoforms multidrug resistance (mdr)1a, mdr1b, and mdr2 was performed by RT-PCR on RNA extracted from rat lens fiber cells. Northern blot analysis was used to determine whether transcript levels detected by RT-PCR were significant.

Gender effects and synergisms with histocompatibility leukocyte antigens in type 1 autoimmune hepatitis.

Objectives: Our goals were to determine the effect of gender on the clinical features and treatment outcome of type 1 autoimmune hepatitis, and to assess synergisms with the known genetic risk factors.

Methods: Clinical findings and treatment outcomes were compared in 144 women and 41 men who were also assessed for HLA DR3, HLA DR4, HLA DR3 and DR4 alleles, and the DRB1*1501-DQA1*102 haplotype by polymerase chain reaction. A total of 102 healthy men and women were similarly typed.

Clinical distinctions and pathogenic implications of type 1 autoimmune hepatitis in Brazil and the United States.

Background/aims: Type 1 autoimmune hepatitis has a strong genetic predisposition that varies among different ethnic groups. Our aims were to determine if the clinical manifestations differed between patients with type 1 autoimmune hepatitis from Brazil and the United States and if classical disease could be associated with region-specific susceptibility markers.

Methods: The clinical manifestations and genetic risk factors of 161 patients from the United States were compared to those of 115 patients from Brazil.

Molecular profiling and cellular localization of connexin isoforms in the rat ciliary epithelium.

The functionally distinct epithelial layers of the ciliary body act as a syncitium to produce the aqueous humour. Ultrastructural studies have shown that the pigmented (PE) and non-pigmented (NPE) cell layers of the ciliary epithelium are connected by gap junctions. However the molecular composition of gap junctions both between and within the two cell layers has not been comprehensively studied.

The elimination of contraceptive acceptor targets and the evolution of population policy in India.

In 1966 the government of India announced a new national population policy that eliminated numerical targets for new contraceptive acceptors. This paper examines the history of target setting in India and factors that led to the elimination of targets. The analysis is based on published and unpublished reports on India's population policy and the family planning programme and interviews with senior Indian and foreign officials and population specialists.

HLA and cytokine gene polymorphisms in biliary atresia.

Background/aims: Extrahepatic biliary atresia remains one of the major hepatic causes of death in early childhood. Though a number of hypotheses have been developed to account for this disease, its aetiopathogenesis is poorly understood. One possibility is that this is an immune mediated disease which occurs following either toxic or infectious insult in a genetically susceptible host.

Pacemaker-mediated tachycardia: management by pacemaker interrogation/reprogramming in the ED.

We report a case of a patient with symptomatic pacemaker-mediated tachycardia (PMT). PMT should be suspected when asynchronous pacing induced by magnet application causes temporary resolution of an unknown tachycardia in a patient with a pacemaker. The underlying mechanism of PMT is either reentrant tachycardia or atrial triggering.

Polymorphisms in immunoregulatory genes: towards individualized immunosuppressive therapy?

In organ transplantation, successful immunosuppression requires that both rejection and infection episodes be minimized. Unfortunately it is currently impossible to predict individual dose requirement for immunosuppressive drugs, but a number of studies of various immune response genes are now being performed with a view to identifying genotypes associated with rejection and/or infection. The key role of cytokines in the immune response and other processes, including fibrosis, has concentrated most of this attention on polymorphisms in cytokine genes.

Quantifying changes in gap junction structure as a function of lens fiber cell differentiation.

The ocular lens is an ideal model system for studying gap junction structure-function relationships. Here we apply novel methods to quantitatively compare connexin expression over macroscopic distances while simultaneously resolving the intracellular distribution of gap junctions in sub-micron detail. Our approach has identified three distinct zones of connexin density and allowed changes in gap junction plaque size, number and dispersion to be quantified.

Antibodies to soluble liver antigen/liver pancreas and HLA risk factors for type 1 autoimmune hepatitis.

Objective: Antibodies to soluble liver antigen/liver-pancreas are highly specific markers of type 1 autoimmune hepatitis that have been associated with relapse. Our aim was to determine if these antibodies are reflective of a genetic predisposition for recrudescent disease.

Methods: One hundred forty-four white North American patients were evaluated by an enzyme immunoassay and by Western blot using recombinant soluble liver antigen/liver-pancreas; 122 were assessed for class II human leukocyte antigens (HLAs).

Absence of a genetic association between IL-1RN and IL-1B gene polymorphisms in ulcerative colitis and Crohn disease in multiple populations from northeast England.

Background: Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal tract of unknown aetiology, phenotypically categorized into ulcerative colitis (UC) and Crohn disease (CD). Genetic factors are of considerable importance in both. The genetic relationship between IBD and the interleukin-1 receptor antagonist and interleukin-1beta genes (IL-1RN, and IL-1B, respectively) has been extensively studied.

MP20, the second most abundant lens membrane protein and member of the tetraspanin superfamily, joins the list of ligands of galectin-3.

Background: Although MP20 is the second most highly expressed membrane protein in the lens its function remains an enigma. Putative functions for MP20 have recently been inferred from its assignment to the tetraspanin superfamily of integral membrane proteins. Members of this family have been shown to be involved in cellular proliferation, differentiation, migration, and adhesion.

Immunogenetics in PSC.

Primary sclerosing cholangitis (PSC) does not exhibit simple Mendelian inheritance attributable to a single gene locus and our knowledge of the genetics of this complex disease is based entirely on case-control studies of candidate genes. The prime candidates in PSC are inherited variation (polymorphism) in the genes that regulate the immune response, especially the genes of the major histocompatability complex (MHC). Thus far, five different human leukocyte antigen (HLA) haplotypes have been associated with PSC: three with increased risk of disease and two with reduced risk.

Molecular solutions to mammalian lens transparency.

The mammalian lens generates an internal microcirculation that maintains transparency in the avascular lens. Significant progress has been made in characterizing the membrane transport proteins associated with this circulation. By combining physiological and molecular evidence, a more comprehensive understanding of normal lens function and cataractogenesis is emerging.

A functional polymorphism of the stromelysin gene (MMP-3) influences susceptibility to primary sclerosing cholangitis.

Background And Aims: We have investigated the influence of a biallelic polymorphism of the promoter region of stromelysin (matrix metalloproteinase 3) on susceptibility to primary sclerosing cholangitis (PSC). The 5A allele is associated with increased transcription, compared with wild-type (6A).

Methods: An allelic association study was performed: in stage 1, 52 PSC patients (43 with inflammatory bowel disease [IBD]) and 99 healthy subjects (HS) were genotyped.

The CC chemokine receptor 5 delta32 mutation is not associated with inflammatory bowel disease (IBD) in NE England.

Inflammatory bowel disease (IBD) is a group of chronic inflammatory diseases of the gastrointestinal tract of unknown aetiology. Evidence of abnormalities in immune regulation and cytokine production in patients with IBD has led to investigations of various immuno-regulatory genes as potential candidate susceptibility loci. Studies using whole genome scanning have highlighted chromosomes 3, 7, 12 and 16.

Transmission disequilibrium analysis of HLA class II DRB1, DQA1, DQB1 and DPB1 polymorphisms in schizophrenia using family trios from a Han Chinese population.

Our goal was to evaluate the role of HLA in the risk of developing schizophrenia, in a Han Chinese population. In several Japanese studies, there is evidence of association with DR1 and schizophrenia. A variety of other associations have been reported in other populations, including negative associations with DQbeta(*)0602 and positive associations with DR1(*)0101.

HLA class II alleles in Chinese patients with hepatocellular carcinoma.

Background/aims: Recent reports of an association between human leucocyte antigens (HLA) and persistence of hepatitis B virus infection, and the familial clustering of hepatocellular carcinoma raise the question of genetic susceptibility. Previous studies have been limited to serological phenotyping of HLA B and DR antigens. The aim of this study was to use molecular genotyping to investigate HLA class II as a risk factor for the development of hepatocellular carcinoma in Hong Kong Chinese.

Mapping MHC-encoded susceptibility and resistance in primary sclerosing cholangitis: the role of MICA polymorphism.

Background & Aims: Recent studies suggest that major histocompatibility complex-encoded susceptibility to primary sclerosing cholangitis (PSC) maps to the HLA B-TNFA region on chromosome 6p21.3.

Methods: The present study uses a standard polymerase chain reaction protocol to investigate the 16 common alleles of the MICA locus as candidates in 2 patient populations (King's College Hospital, London, and John Radcliffe Hospital, Oxford).