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1.
Genes Immun ; 5(8): 631-40, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15526005

ABSTRACT

Tumour necrosis factor (TNF) is an important pro-inflammatory cytokine produced in sepsis. Studies examining the association of individual TNF single nucleotide polymorphisms with sepsis have produced conflicting results. This study investigated whether common polymorphisms of the TNF locus and the two receptor genes, TNFRSF1A and TNFRSF1B, influence circulating levels of encoded proteins, and whether individual polymorphisms or extended haplotypes of these genes are associated with susceptibility, severity of illness or outcome in adult patients with severe sepsis or septic shock. A total of 213 Caucasian patients were recruited from eight intensive care units (ICU) in the UK and Australia. Plasma levels of TNF (P = 0.02), sTNFRSF1A (P = 0.005) and sTNFRSF1B (P = 0.01) were significantly higher in those who died on ICU compared to those who survived. There was a positive correlation between increasing soluble receptor levels and organ dysfunction (increasing SOFA score) (sTNFRSF1A R = 0.51, P < 0.001; sTNFRSF1B R = 0.53, P < 0.001), and in particular with the degree of renal dysfunction. In this study, there were no significant associations between the selected candidate TNF or TNF receptor polymorphisms, or their haplotypes, and susceptibility to sepsis, illness severity or outcome. The influence of polymorphisms of the TNF locus on susceptibility to, and outcome from sepsis remains uncertain.


Subject(s)
Genetic Predisposition to Disease , Polymorphism, Genetic , Receptors, Tumor Necrosis Factor/genetics , Sepsis/genetics , Shock, Septic/genetics , Australia , DNA Primers , England , Female , Gene Frequency , Genotype , Haplotypes/genetics , Humans , Male , Prospective Studies , Receptors, Tumor Necrosis Factor/blood , Receptors, Tumor Necrosis Factor, Type I , Receptors, Tumor Necrosis Factor, Type II , Tumor Necrosis Factor Decoy Receptors , White People
3.
Genes Immun ; 5(4): 289-93, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15071491

ABSTRACT

We investigated the hypothesis that low-penetrance mutations in genes (TNFRSF1A, MEFV and NALP3/CIAS1) associated with hereditary periodic fever syndromes (HPFs) might be risk factors for AA amyloidosis among patients with chronic inflammatory disorders, including rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), Crohn's disease, undiagnosed recurrent fevers and HPFs themselves. Four of 67 patients with RA plus amyloidosis had MEFV variants compared with none of 34 RA patients without amyloid (P value=0.03). The E148Q variant of MEFV was present in two of the three patients with TNF receptor-associated periodic syndrome (TRAPS) complicated by amyloid in two separate multiplex TRAPS families containing 5 and 16 affected members respectively, and the single patient with Muckle-Wells syndrome who had amyloidosis was homozygous for this variant. The R92Q variant of TNFRSF1A was present in two of 61 JIA patients with amyloidosis, and none of 31 nonamyloidotic JIA patients. No HPF gene mutations were found in 130 healthy control subjects. Although allelic variants in HPFs genes are not major susceptibility factors for AA amyloidosis in chronic inflammatory disease, low-penetrance variants of MEFV and TNFRSF1A may have clinically significant proinflammatory effects.


Subject(s)
Amyloidosis/genetics , Familial Mediterranean Fever/genetics , Amino Acid Substitution , Amyloidosis/metabolism , Arthritis, Rheumatoid/genetics , Arthritis, Rheumatoid/metabolism , Carrier Proteins/genetics , Carrier Proteins/metabolism , Cytoskeletal Proteins , Familial Mediterranean Fever/metabolism , Female , Genetic Predisposition to Disease , Humans , Male , Mutation , NLR Family, Pyrin Domain-Containing 3 Protein , Pedigree , Proteins/genetics , Proteins/metabolism , Pyrin
5.
QJM ; 95(12): 787-96, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12454321

ABSTRACT

BACKGROUND: Vitamin-D deficiency and vitamin-D receptor genotype (VDR) are risk factors for several disorders with inflammatory components, including coronary heart disease (CHD) and diabetes, though the mechanisms involved are unclear. AIM: To examine the hypothesis that vitamin D status modulates the matrix metalloproteinase (MMP) system in a population with a high prevalence of vitamin D deficiency, a situation affecting susceptibility to CHD and diabetes. DESIGN: Prospective cross-sectional, interventional and embedded studies. METHODS: Circulating MMP2,9, the inhibitor TIMP-1 and C-reactive protein (CRP) were measured during studies of vitamin-D deficiency as a risk factor for type 2 diabetes and CHD in 171 healthy British Bangladeshi adults, free of known diabetes or major illness. Vitamin D status, VDR genotype, body-build, blood pressure, lipid and insulin profiles, glucose tolerance, fibrinogen, PAI-1, folate and homocysteine were measured. Vitamin-D-deficient subjects were re-assessed after 1 years' supplementation. MMP, TIMP-1 and CRP levels were measured in 41 subjects halfway through 5-year follow-up. Independent determinants of circulating concentrations of MMP9, TIMP-1 and CRP were assessed by multiple regression analysis. RESULTS: Vitamin D status was the sole determinant of circulating MMP9 (inversely) and an independent determinant of CRP (inversely). Determinants of TIMP-1 were MMP9, systolic blood-pressure (directly) and VDR genotype (TaqI). Significant reductions in MMP9 (-68%), TIMP-1 (-38%) and CRP (-23%) concentrations followed vitamin-D supplementation. DISCUSSION: Vitamin-D insufficiency is associated with increased circulating MMP2,9 and CRP, correctable by supplementation. This finding provides a possible mechanism for tissue damage in chronic inflammatory conditions, including CHD and diabetes.


Subject(s)
C-Reactive Protein/metabolism , Matrix Metalloproteinase 2/blood , Matrix Metalloproteinase 9/blood , Receptors, Calcitriol/genetics , Tissue Inhibitor of Metalloproteinase-1/blood , Vitamin D Deficiency/blood , Adult , Aged , Bangladesh/ethnology , Chronic Disease , Coronary Disease/blood , Coronary Disease/etiology , Cross-Sectional Studies , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/etiology , Humans , Middle Aged , Prospective Studies
6.
Clin Exp Immunol ; 130(3): 484-8, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12452839

ABSTRACT

Hereditary periodic fever syndromes comprise a group of distinct disease entities linked by the defining feature of recurrent febrile episodes. Hyper IgD with periodic fever syndrome (HIDS) is caused by mutations in the mevalonate kinase (MVK) gene. The mechanisms by which defects in the MVK gene cause febrile episodes are unclear and there is no uniformly effective treatment. Mutations of the TNFRSF1A gene may also cause periodic fever syndrome (TRAPS). Treatment with the TNFR-Fc fusion protein, etanercept, is effective in some patients with TRAPS, but its clinical usefulness in HIDS has not been reported. We describe a 3-year-old boy in whom genetic screening revealed a rare combination of two MVK mutations producing clinical HIDS as well as a TNFRSF1A P46L variant present in about 1% of the population. In vitro functional assays demonstrated reduced receptor shedding in proband's monocytes. The proband therefore appears to have a novel clinical entity combining Hyper IgD syndrome with defective TNFRSF1A homeostasis, which is partially responsive to etanercept.


Subject(s)
Antigens, CD/genetics , Familial Mediterranean Fever/drug therapy , Immunoglobulin G/therapeutic use , Leukocytes, Mononuclear/metabolism , Mutation , Receptors, Tumor Necrosis Factor/antagonists & inhibitors , Receptors, Tumor Necrosis Factor/genetics , Receptors, Tumor Necrosis Factor/therapeutic use , Antigens, CD/blood , Child, Preschool , DNA Mutational Analysis , Etanercept , Familial Mediterranean Fever/genetics , Familial Mediterranean Fever/metabolism , Humans , Male , Mevalonic Acid/urine , Pedigree , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Receptors, Tumor Necrosis Factor/blood , Receptors, Tumor Necrosis Factor, Type I
7.
Genes Immun ; 3(1): 5-8, 2002 Feb.
Article in English | MEDLINE | ID: mdl-11857053

ABSTRACT

Fibrocalculous pancreatic diabetes (FCPD) is an uncommon cause of diabetes, seen mainly in developing countries. A family-based study was carried out in 67 Bangladeshi families, consisting of a proband with FCPD and both parents, to determine whether an association exists between FCPD susceptibility and either the major histocompatiblity complex (MHC) or insulin gene (INS) loci. HLA-DQB1 typing was done using allele-specific primers, and INS was typed using the restriction enzyme HphI. Three microsatellites (TNFa, TNFc and TNFd), from within and flanking the TNF-LT locus, were used for MHC Class IV typing and a PCR-RFLP assay was used to define the -308G/A TNF promoter polymorphism. The extended transmission disequilibrium test (ETDT) was used for statistical analysis. An overall association was observed between FCPD and HLA-DQB1 (P = 0.003), that was largely due to a positive association with HLA-DQB1*0302 and a negative association with HLA-DQB1*0202. Although no association was found between FCPD and TNF-LT microsatellite markers a trend was observed for TNFc (P = 0.037, Pc = 0.15). No association was found between FCPD and INS (P = 0.26). This study confirms an association between FCPD and the MHC using a family-based study design and the stringent ETDT analysis; a novel protective association was found with HLA-DQB1*0202 in Bangladeshi FCPD subjects. The genetic susceptibility to FCPD has features both similar and dissimilar to T1DM.


Subject(s)
Calculi/genetics , Diabetes Mellitus/genetics , Genetic Predisposition to Disease , Pancreatitis/genetics , Bangladesh , Female , HLA-DQ Antigens/genetics , HLA-DQ beta-Chains , Haplotypes , Histocompatibility Testing , Humans , Linkage Disequilibrium , Lymphotoxin-alpha/genetics , Major Histocompatibility Complex , Male , Microsatellite Repeats , Pedigree , Promoter Regions, Genetic , Tumor Necrosis Factor-alpha/genetics
8.
J Am Coll Cardiol ; 38(6): 1639-43, 2001 Nov 15.
Article in English | MEDLINE | ID: mdl-11704375

ABSTRACT

OBJECTIVES: The goal of this study was to determine the interaction between smoking and the glycoprotein IIIa P1(A2) polymorphism in patients admitted with non-ST-elevation acute coronary syndromes (ACS). BACKGROUND: An increased incidence of the P1(A2) polymorphism in smokers presenting with ST-elevation acute myocardial infarction (AMI) has recently been reported. We, therefore, postulated that, as a consequence of this interaction, fewer smokers with the P1(A2) polymorphism would present with non-ST-elevation ACS. METHODS: We performed a prospective cohort analysis of 220 white Caucasoid patients admitted with non-ST-elevation ACS fulfilling Braunwald class IIIb criteria for unstable angina who were stratified by smoking status. RESULTS: There were twice as many nonsmokers as smokers. Nonsmokers compared with smokers were older (mean [SD]; 63.9 [11.2] vs. 57.6 [10.3]; p < 0.0001), more likely to have had a previous admission with unstable angina (24.3% vs. 13.2%; p = 0.051) and AMI (45.8% vs. 30.3%; p < 0.026), more likely to have undergone revascularization (24.3% vs. 1.8%; p = 0.028) and were more likely to be on aspirin on admission (60.4% vs. 44.7%; p = 0.026). The proportion of nonsmokers positive for the P1(A2) polymorphism was equivalent to that expected for this population but was significantly reduced in smokers (28.7% vs. 10%; Pearson chi-square = 9.09, p = 0.0026). In a logistic regression model, the odds ratio (OR) for being positive for the P1(A2) polymorphism was significantly reduced by smoking (OR [interquartile range]: 0.26 [0.11 to 0.62]; p = 0.0026). CONCLUSIONS: There is a significant reduction in the P1(A2) polymorphism in smokers admitted with non-ST-elevation ACS compared with nonsmokers, which suggests an interaction between smoking and this polymorphism.


Subject(s)
Angina, Unstable/genetics , Myocardial Infarction/genetics , Platelet Glycoprotein GPIIb-IIIa Complex/genetics , Polymorphism, Genetic , Smoking/adverse effects , Acute Disease , Angina, Unstable/blood , Chi-Square Distribution , Female , Genotype , Humans , Logistic Models , Male , Middle Aged , Myocardial Infarction/blood , Prospective Studies , Statistics, Nonparametric , Syndrome , White People
9.
Eur J Hum Genet ; 9(1): 63-6, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11175303

ABSTRACT

Mutations of the tumor necrosis factor receptor 1 (TNFRSF1A) gene underly susceptibility to a subset of autosomal dominant recurrent fevers (ADRFs). We report on a two-generation six-member Dutch family in which a novel R92P mutation and reduced plasma TNFRSF1A levels were found in all the children, including two who are unaffected. However, only the daughter proband and father exhibited a typical TNF-receptor associated periodic syndrome (TRAPS) phenotype. PCR-RFLP analysis revealed that the mutation was not present in 120 control chromosomes from unaffected Dutch individuals. As this R92P mutation is present in two unaffected carriers it appears to be less penetrant than previously reported TNFRSF1A mutations involving cysteine residues in the extracellular domains.


Subject(s)
Antigens, CD/genetics , Fever of Unknown Origin/genetics , Receptors, Tumor Necrosis Factor/genetics , Antigens, CD/blood , DNA/chemistry , DNA/genetics , DNA Mutational Analysis , Family Health , Female , Fever of Unknown Origin/pathology , Humans , Male , Microsatellite Repeats , Mutation , Netherlands , Pedigree , Penetrance , Phenotype , Point Mutation , Polymorphism, Restriction Fragment Length , Receptors, Tumor Necrosis Factor/blood , Receptors, Tumor Necrosis Factor, Type I
10.
Diabetes Metab Res Rev ; 16(6): 454-57, 2000.
Article in English | MEDLINE | ID: mdl-11114105

ABSTRACT

BACKGROUND: A distinct type of pancreatitis associated with diabetes, termed fibrocalculous pancreatic diabetes (FCPD), has been reported in tropical developing countries including Bangladesh. The molecular basis for autosomal dominant hereditary pancreatitis (HP) has recently been attributed to mutations in exons 2 and 3 of the trypsinogen gene. We have investigated the hypothesis that mutations in the aforementioned exons of this gene might also predispose to FCPD. METHODS: Seventy Bangladeshi and 50 South Indian unrelated FCPD patients and seven South Indian families with FCPD probands were studied. Pancreatic calcification was confirmed by abdominal X-ray, ultrasound and/or ERCP. Established mutations of exons 2 and 3 of the trypsinogen gene were studied in these subjects by PCR-RFLP analysis and DNA sequencing. RESULTS: The mutations found in hereditary pancreatitis were not observed in this collection of FCPD subjects, and complete DNA sequencing of exons 2 and 3 of the fourth cationic trypsinogen gene also excluded any new mutations. CONCLUSIONS: These results indicate that chronic pancreatitis of FCPD is unlikely to be caused by common mutations in the trypsinogen gene.


Subject(s)
Calcinosis/genetics , Diabetes Mellitus/genetics , Mutation , Pancreatitis/genetics , Trypsinogen/genetics , Adult , Bangladesh , Calcinosis/complications , Chronic Disease , Diabetes Mellitus/etiology , Diabetes Mellitus, Type 2/genetics , Female , Humans , Male , Pancreatitis/complications , Pedigree , Polymerase Chain Reaction , Polymorphism, Restriction Fragment Length , Tropical Climate
11.
Arthritis Rheum ; 43(9): 2034-40, 2000 Sep.
Article in English | MEDLINE | ID: mdl-11014353

ABSTRACT

OBJECTIVE: To investigate genetic susceptibility in the first Indian family identified as having an autosomal dominantly inherited periodic fever syndrome. The inflammatory disease was characterized chiefly by arthralgia, skin rashes, and AA amyloidosis. METHODS: Markers from known periodic fever susceptibility loci were investigated in 7 affected and 11 healthy members of a north Indian family. These included the TNFRSF1A locus (formerly known as TNFRI), which is involved in autosomal dominant tumor necrosis factor receptor-associated periodic syndrome on chromosome 12p13, the familial Mediterranean fever locus (MEFV) on chromosome 16p13, the hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) locus on chromosome 12q24, and the Muckle-Wells syndrome/familial cold urticaria (MWS/FCU) locus on distal chromosome 1q44. RESULTS: Linkage to both TNFRSF1A and MEFV was definitively excluded, and DNA sequencing of these genes revealed no mutations. Furthermore, there was no evidence of linkage to the HIDS locus. In contrast, significant logarithm of odds scores for 5 markers from the MWS/FCU region were obtained in this family, and the disease segregated with the same haplotype in all affected members. CONCLUSION: We have identified an inherited inflammatory disease in a north Indian family with clinical features overlapping some of those of MWS and FCU. The susceptibility gene maps to distal chromosome 1q44, a region already implicated in both MWS and FCU. Different mutations in the same (or a closely related) gene may be responsible for an inflammatory disease with a broad phenotype among diverse ethnic populations.


Subject(s)
Amyloidosis/genetics , Chromosomes, Human, Pair 1 , Familial Mediterranean Fever/complications , Familial Mediterranean Fever/genetics , Serum Amyloid A Protein/metabolism , Adult , Chromosome Mapping , Female , Genetic Markers , Genetic Predisposition to Disease , Humans , India/epidemiology , Lod Score , Male , Pedigree
13.
Diabetologia ; 40(8): 971-5, 1997 Aug.
Article in English | MEDLINE | ID: mdl-9267994

ABSTRACT

Vitamin D has important immunomodulatory properties and prevents development of diabetes mellitus in an animal model of insulin-dependent diabetes (IDDM). We have studied the vitamin D receptor locus as a candidate for genetic susceptibility to IDDM in Southern Indian families. We found evidence for an association of one particular vitamin D receptor allele with IDDM susceptibility in this community. Ninety-three South Indian families consisting of available parents and an affected offspring were genotyped for three vitamin D receptor polymorphisms using the restriction enzymes TaqI, ApaI and BsmI as well as an adjacent microsatellite located to 12q14 (D12S85). Transmission disequilibrium testing analysis was used to assess preferential transmission of polymorphic markers and haplotypes with IDDM. There was significant excess transmission of vitamin D receptor alleles containing the BsmI restriction site to affected offspring in these families (p = 0.016). No association was found between D12S85 and IDDM. This study suggests that a polymorphism within or close to the vitamin D receptor gene may modify susceptibility to IDDM in this ethnic group.


Subject(s)
Chromosomes, Human, Pair 12 , Diabetes Mellitus, Type 1/genetics , Linkage Disequilibrium/genetics , Receptors, Calcitriol/genetics , Adolescent , Adult , Age of Onset , Alleles , Child , Child, Preschool , Disease Susceptibility , Family , Female , Genotype , Haplotypes , Humans , India , Infant , Male , Polymerase Chain Reaction , Polymorphism, Restriction Fragment Length
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