Showing papers in "Genes and Immunity in 2003"
TL;DR: High-density oligonucleotide microarray has the potential to explore the mechanism of pathogenesis of systemic lupus erythematosus using TSA-1 antigens, which may represent an important alternative pathway for T-cell activation that may be involved in IFN-mediated immunomodulation.
Abstract: Epidemiologic studies suggest a strong genetic component for susceptibility to systemic lupus erythematosus (SLE) To investigate the genetic mechanism of pathogenesis of SLE, we studied the difference in gene expression of peripheral blood cells between 10 SLE patients and 18 healthy controls using oligonucleotide microarray When gene expression for patients was compared to the mean of normal controls, among the 3002 target genes, 61 genes were identified with greater than a two-fold change difference in expression level Of these genes, 24 were upregulated and 37 downregulated in at least half of the patients By the Welch's ANOVA/Welch's t-test, all these 61 genes were significantly different (P<005) between SLE patients and normal controls Among these genes with differential expression, IFN-omega and Ly6E (TSA-1/Sca-2) may play an important role in the mechanism of SLE pathogenesis TSA-1 antigens may represent an important alternative pathway for T-cell activation that may be involved in IFN-mediated immunomodulation Hierarchical clustering showed that patient samples were clearly separated from controls based on their gene expression profile These results demonstrate that high-density oligonucleotide microarray has the potential to explore the mechanism of pathogenesis of systemic lupus erythematosus
253 citations
TL;DR: A genome-wide linkage study has been performed to identify genes exerting a major effect on tuberculosis susceptibility in the general population and linkages were found to markers on chromosomes 15 and X.
Abstract: There is substantial evidence that host genetic factors are important in determining susceptibility to mycobacteria. Several different techniques have been used to identify the genes involved. Studies of an inbred strain of mice with increased susceptibility to mycobacteria, salmonella and leishmania infections led to the identification of the natural resistance-associated macrophage protein gene (Nramp1). Case-control studies have confirmed the importance of the human equivalent of this gene, NRAMP1, and have also suggested that the major histocompatibility complex and vitamin-D receptor genes may be involved in determining human susceptibility to mycobacteria. Studies of individuals with the rare condition of increased susceptibility to disseminated bacille Calmette-Guerin and other atypical mycobacterial infections have identified several abnormalities in the genes encoding the interferon gamma receptor (IFNgammaR) ligand binding chain, IFNgammaR signal transduction chain, IFNgamma signal transduction and activation of transcription-1, interleukin 12 receptor beta1 subunit and interleukin 12 p40 subunit. A genome-wide linkage study has been performed to identify genes exerting a major effect on tuberculosis susceptibility in the general population. Linkages were found to markers on chromosomes 15 and X. Studies to identify the genes responsible are in progress.
248 citations
TL;DR: Polymorphisms in the interferon-induced genes, MxA, OAS-1 and PKR appear thus associated with HCV outcome.
Abstract: Interferon stimulates the expression of a number of genes encoding enzymes with antiviral activities, including myxovirus resistance-1 (MxA), 2-5-oligoadenylate synthetase 1 (OAS-1) and double-stranded RNA-dependent protein kinase (PKR). We examined whether polymorphisms in these genes influenced the outcome of hepatitis C virus (HCV) infection. We observed a lower frequency of the GG genotype at position −88 in the MxA gene promoter in self-limiting HCV infection (OR=0.56; 95% CI: 0.35–0.8; P=0.010) and in nonresponders to therapy (OR=0.49; 95% CI: 0.25–0.95; P=0.020). This genotype predominantly influenced the outcome of treatment in patients with viral genotype 1 (OR=0.22 95% CI: 0.07–0.67; P=0.002). A polymorphism in the 3′-untranslated region of the OAS-1 gene was associated with outcome of infection (GG genotype less frequent in self-limiting infection: OR=0.43; 95% CI: 0.21–0.86; P=0.010). A polymorphism at position −168 in the promoter region of the PKR gene was associated with self-limiting infection (CT genotype: OR=2.75; 95% CI: 1.45–5.24; P=0.002). Further associations were found with a CGG trinucleotide repeat in the 5′UTR region of the PKR gene. Polymorphisms in the interferon-induced genes, MxA, OAS-1 and PKR appear thus associated with HCV outcome.
223 citations
TL;DR: The cDNA microarray technology used to subclassify RA patients and disclose disease pathways in rheumatoid synovium confirmed the heterogeneous nature of RA and suggested the existence of distinct pathogenic mechanisms that contribute to RA.
Abstract: Rheumatoid arthritis (RA) is a heterogeneous disease. We used cDNA microarray technology to subclassify RA patients and disclose disease pathways in rheumatoid synovium. Hierarchical clustering of gene expression data identified two main groups of tissues (RA-I and RA-II). A total of 121 genes were significantly higher expressed in the RA-I tissues, whereas 39 genes were overexpressed in the RA-II tissues. Among the 121 genes overexpressed in RA-I tissues, a relative majority of nine genes are located on chromosome 6p21.3. An interpretation of biological processes that take place revealed that the gene expression profile in RA-I tissues is indicative for an adaptive immune response. The RA-II group showed expression of genes suggestive for fibroblast dedifferentiation. Within the RA-I group, two subgroups could be distinguished; the RA-Ia group showed predominantly immune-related gene activity, while the RA-Ib group showed an additional higher activity of genes indicative for the classical pathway of complement activation. All tissues except the RA-Ia subgroup showed elevated expression of genes involved in tissue remodeling. These results confirm the heterogeneous nature of RA and suggest the existence of distinct pathogenic mechanisms that contribute to RA. The differences in expression profiles provide opportunities to stratify patients based on molecular criteria.
151 citations
TL;DR: Experimental models of infection using TLR-deficient mice, as well as limited human studies, have clearly demonstrated the critical role of TLRs in host defense against most major groups of mammalian pathogens.
Abstract: Effective host defense against microbial infection depends upon prompt recognition of pathogens, activation of immediate containment measures, and ultimately the generation of a specific and definitive adaptive immune response. The innate immune system of the host is responsible for providing constant surveillance against infection; when confronted by pathogens it deploys a series of rapidly acting antimicrobial effectors while simultaneously instructing the adaptive immune system as to the nature and context of the infectious threat. Pathogen recognition and activation of innate immunity is mediated by members of the Toll-like receptor (TLR) family through detection of conserved microbial structures that are absent from the host. Experimental models of infection using TLR-deficient mice, as well as limited human studies, have clearly demonstrated the critical role of TLRs in host defense against most major groups of mammalian pathogens.
151 citations
TL;DR: The data suggest that the IL13Arg130Gln polymorphism and haplotypes consisting of IL13 Arg 130Gln and IL4 C−589 T were associated with the development of atopy and atopic dermatitis at 24 months of age.
Abstract: We studied a cohort containing 368 children at high risk of developing atopy and atopic disorders and 540 parents of those children to investigate whether the IL13 Arg130Gln and C-1112 T polymorphisms were associated with these outcomes. We also investigated whether haplotypes consisting of any two polymorphisms of IL13 Arg130Gln, IL13 C-1112 T and IL4 C-589 T were associated with these phenotypes. In 288 white children, the IL13 130Gln allele was associated with atopy (RR=1.9, P=0.047), and with atopic dermatitis (RR=2.5, P=0.014). The associations were confirmed using a family-based test of association (P=0.027 and 0.030, respectively) in all subjects. In white subjects there were associations of haplotypes consisting of IL13 Arg130Gln and IL4 C-589 T with atopic dermatitis (P=0.006) and with atopy (P=0.009). Our data suggest that the IL13 Arg130Gln polymorphism and haplotypes consisting of IL13 Arg130Gln and IL4 C-589 T were associated with the development of atopy and atopic dermatitis at 24 months of age.
140 citations
TL;DR: The disease, caused by mutations in AIRE, its function as a protein involved in transcription, and its restricted expression in cells important in negative selection, all together suggest that AIRE is a central protein in the maintenance of immune tolerance.
Abstract: The autoimmune regulator (AIRE) is a gene where mutations cause the recessively inherited disorder called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) or autoimmune polyendocrinopathy syndrome type 1 (APS1). Variable combinations of autoimmune endocrine diseases such as Addison's disease, hypoparathyroidism, and type 1 diabetes characterize APECED. The AIRE protein has several domains indicative of a transcriptional regulator. AIRE contains two PHD (plant homeodomain) type zinc fingers, four nuclear receptor binding LXXLL motifs, a putative DNA-binding domain named SAND and, in addition, a highly conserved N-terminal domain similar to the homogenously staining region domain of the Sp100 protein. At the subcellular level, AIRE is expressed in nuclear dots resembling promyelocytic leukemia nuclear bodies, which are associated with several transcriptionally active proteins. AIRE is primarily expressed in thymic medullary epithelial cells and monocyte-dendritic cells in the thymus but also in a rare subset of cells in the lymph nodes, spleen and fetal liver. The disease, caused by mutations in AIRE, its function as a protein involved in transcription, and its restricted expression in cells important in negative selection, all together suggest that AIRE is a central protein in the maintenance of immune tolerance. In this review of the recent literature we discuss the results of these studies with particular attention on the AIRE expression pattern and its function as a transcriptional regulator, as well as the effects of patient mutations on the molecular characteristics of the protein.
136 citations
TL;DR: Ttransmission disequilibrium tests revealed an association of SPINK5 polymorphisms with AD but not with asthma, suggesting the parent-of-origin effect for the development of atopic diseases in the SPink5 gene.
Abstract: Atopy, which is characterized by increased levels of immunoglobulin E (IgE) against common environmental allergens, is considered the strongest predisposing factor for asthma and atopic dermatitis (AD). Mutations in the gene encoding serine protease inhibitor Kazal-type 5 (SPINK5) are responsible for Netherton syndrome, a rare skin disorder characterized by greatly elevated IgE levels with atopic manifestations. A recent study of Caucasian AD families showed that maternally derived alleles of the SPINK5 gene are associated with development of AD and asthma, suggesting the parent-of-origin effect for the development of atopic diseases in the SPINK5 gene. We studied the possible association of the SPINK5 gene for the development of atopic diseases by determining the genotypes of five polymorphisms in a Japanese population. Ttransmission disequilibrium tests revealed an association of SPINK5 polymorphisms with AD but not with asthma. Our data indicate that the SPINK5 gene is associated with AD across ethnicities.
134 citations
TL;DR: The presence of − 1082A allele and in particular of −1082A/−819T/−592A haplotype, associated with a low production of anti-inflammatory cytokine IL-10, may be considered as an additive and independent genetic risk factor for AD.
Abstract: Proinflammatory cytokines and acute-phase proteins play an important role in Alzheimer's disease (AD) neurodegeneration, and common polymorphisms of genes controlling their high production have been shown to be associated with AD. Thus, AD patients display a proinflammatory genotype and the control of inflammation might play a protective role in AD development. By sequence-specific probes, we have evaluated the role of anti-inflammatory cytokine interleukin(IL)-10 in AD, by analysing in 132 AD patients and 213 healthy controls the prevalence of three different haplotypes, involving three single-nucleotide polymorphisms (SNPs) at −1082 (G→A), −819 (C→T) and −592 (C→A) nucleotides of IL-10 promoter, associated with different IL-10 production. The percentage of −1082A carrier subjects was significantly increased among AD patients, and this increase was mainly due to the increase of ATA haplotype. Analysing these results according to the well-known genetic risk factor APOE-e4 allele, no significant differences were observed in SNP IL-10 allele distribution between AD patients carrying the genotype or not. So we may conclude that the presence of −1082A allele and in particular of −1082A/−819T/−592A haplotype, associated with a low production of anti-inflammatory cytokine IL-10, may be considered as an additive and independent genetic risk factor for AD.
133 citations
TL;DR: Functional studies reveal that soluble CD8-GITRL prevents CD4+CD25+ regulatory T-cell-mediated suppressive activities and binds GITR expressed on HEK 293 cells and triggers NF-κB activation.
Abstract: The gene encoding the natural ligand of murine glucocorticoid-induced tumor necrosis factor receptor (GITR) was cloned and characterized. The putative GITR ligand (GITRL) is composed of 173 amino acids with features resembling those of type II membrane proteins and is 51% identical to the human activation-inducible TNF receptor (AITR) ligand, TL6. Expression of the GITRL is restricted to immature and mature splenic dendritic cells. GITRL binds GITR expressed on HEK 293 cells and triggers NF-kappaB activation. Functional studies reveal that soluble CD8-GITRL prevents CD4+CD25+ regulatory T-cell-mediated suppressive activities.
113 citations
TL;DR: A role for the type I interferon pathway in resistance to cerebral malaria is suggested in malaria pathogenesis and protection against severe malaria.
Abstract: The chromosome 21q22.11 cytokine receptor cluster contains four genes that encode subunits of the receptors for the cytokines interleukin-10 and interferon-alpha, -beta and -gamma that may have a role in malaria pathogenesis. A total of 15 polymorphic markers located within these genes were initially genotyped in 190 controls and 190 severe malaria cases from The Gambia. Two interferon-alpha receptor-1 (IFNAR1) gene SNPs (17470 and L168 V) showed evidence for an association with severe malaria phenotypes and were typed in a larger series of samples comprising 538 severe malaria cases, 338 mild malaria cases and 562 controls. Both the 17470-G/G and L168V-G/G genotypes were associated with protection against severe malaria, in general, and cerebral malaria, in particular (P=0.004 and 0.003, respectively). IFNAR1 diplotypes were then constructed for these two markers using the PHASE software package. The (17470-G L168V-G/17470-G L168V-G) diplotype was found to be associated with a reduced risk of cerebral malaria and the (17470-C L168V-C/17470-G L168V-G) diplotype with an increased risk of cerebral malaria (overall 3 x 2 chi(2)=12.8, d.f.=2, P=0.002 and 3 x 2 chi(2)=15.2, d.f.=2, P=0.0005, respectively). These data suggest a role for the type I interferon pathway in resistance to cerebral malaria.
TL;DR: In this article, the authors examined 59 multicase families of visceral leishmaniasis with/without post Kala-azar dermal leischmaniasis (PKDL) and found that polymorphisms at IL4/IL9 or IFNGR1 contribute to susceptibility.
Abstract: Longitudinal studies in Sudan show ethnic differences in incidence and clinical phenotypes associated with Leishmania donovani. Immunologically, bias in type 1 vs type 2 cytokine responses is important. To determine whether polymorphisms at IL4/IL9 or IFNGR1 contribute to susceptibility, we examined 59 multicase families of visceral leishmaniasis (VL) with/without post Kala-azar dermal leishmaniasis (PKDL). Multipoint nonparametric analysis (Allegro) linked IL4/IL9 to VL per se (P=0.002). Transmission disequilibrium testing with robust variance estimates confirmed association in the presence of linkage between VL per se and IL4 (P=0.008) but not IL9. Stepwise logistic regression analysis showed both IL4RP2 and IL4RP1 markers contributed significantly to the association, suggesting a common disease-associated haplotype. In contrast, IFNGR1 was linked (P=0.031) and associated (P=0.007) to PKDL but not VL or VL per se. Hence, polymorphism in a type 2 cytokine gene influences underlying susceptibility to VL, whereas IFNGR1 is specifically related to susceptibility to PKDL.
TL;DR: The present study suggests that the disappearance of parasitic diseases and the improved environmental conditions may have ensued the occurrence of a high percentage of 24-bp mutation in Sicily, in Sardinia and in other Mediterranean countries, whereas in the sub-Saharan regions (Benin and Burkina Faso), the widespread parasitic Diseases and the poor social status have contributed to maintenance of the wild-type Chit gene.
Abstract: Human chitotriosidase (Chit) is a member of the chitinase family and it is synthesized by activated macrophages. Recently, a genetic polymorphism was found to be responsible for the common deficiency in Chit activity, frequently encountered in different populations. We analyzed the Chit gene in some ethnic groups from the Mediterranean and African areas, to evaluate whether the Chit gene polymorphism correlates with the changes in environmental features and the disappearance of parasitic diseases. We found a heterozygote frequency for the duplication of 24 bp in exon 10 of 44% in Sicily and 32.71% in Sardinia, whereas those homozygous Chit deficient were 5.45 and 3.73%, respectively. In contrast, in Benin and Burkina Faso, both mesoendemic regions for Plasmodium falciparum malaria and other infections due to intestinal parasites, a low incidence of Chit mutation was found (heterozygous 0 and 2%, respectively) and no subject was homozygous for Chit deficiency. Our results provide evidence of the fact that the low frequency or the absence of mutant Chit gene may represent a protective factor in the population still living in disadvantaged environmental conditions. The present study suggests that the disappearance of parasitic diseases and the improved environmental conditions may have ensued the occurrence of a high percentage of 24-bp mutation in Sicily, in Sardinia and in other Mediterranean countries, whereas in the sub-Saharan regions (Benin and Burkina Faso), the widespread parasitic diseases and the poor social status have contributed to maintenance of the wild-type Chit gene.
TL;DR: Researchers studied 37 families with at least two affected sibs living in a village in eastern Sudan, where an outbreak of visceral leishmaniasis occurred between 1995 and 2000, to seek genetic loci involved in the control of susceptibility to visceral disease caused by L. donovani in humans.
Abstract: There is some evidence showing that genetic factors are involved in human susceptibility to parasitic diseases such as schistosomiasis and malaria. Studies have shown that the Nramp1 and H-2 genes are implicated in the control of Leishmania donovani infection in mice. We sought genetic loci involved in the control of susceptibility to visceral disease caused by L. donovani in humans. We studied 37 families with at least two affected sibs living in a village in eastern Sudan, where an outbreak of visceral leishmaniasis occurred between 1995 and 2000. The genetic markers located in five chromosomal regions containing candidate genes were typed: 2q35 (NRAMP1), 5q31-q33 (Th2 cytokine cluster), 6p21 (HLA/TNF-alpha), 6q23 (INFGRI) and 12q15 (INF-gamma). Linkage (multipoint lod-score=1.08; P=0.01) was observed for the 5'(CA) repeat polymorphism in the NRAMP1 promoter. This suggests that genetic variations of this gene affect susceptibility to visceral leishmaniasis in this population.
TL;DR: The present results reveal the importance of polymorphisms in the CTLA4 promoter region, their probable role in gene expression and, ultimately, their relation to the etiology of type 1 diabetes.
Abstract: The contribution of the candidate gene CTLA4 to type 1 diabetes is not well established. Although several polymorphisms have been repeatedly associated to the disease, several studies have not confirmed the association. The joint analysis of three SNPs in the CTLA4 promoter region (� 1722, � 1661, and � 319), one SNP in the first exon (+49), and one dinucleotide repeat in the 3 0 untranslated region, in a case–control study in a North African population, shows a strong association of the CTLA4 region with the disease. The � 1661G allele showed a significant association with an odds ratio of 2.13. Moreover, the internal structure of the dinucleotide repeat has been deeply analyzed. The present results reveal the importance of polymorphisms in the CTLA4 promoter region, their probable role in gene expression and, ultimately, their relation to the etiology of type 1 diabetes. Previous contradictory association studies might be due to the effect of linkage disequilibrium between the polymorphism analyzed and the alteration within the CTLA4 region. This alteration may be different depending on the genetic background of the population. The present work stresses the need to perform exhaustive analysis of the promoter region polymorphisms in order to detect association with the disease. Genes and Immunity (2003) 4, 132–137. doi:10.1038/sj.gene.6363933
TL;DR: MIF is a susceptibility gene for the development of IP, and the same alleles previously reported to be associated with susceptibility to juvenile idiopathic arthritis account for the increased risk.
Abstract: The aim of the study was to investigate whether polymorphisms of macrophage migration inhibitory factor (MIF) determine susceptibility to or severity of inflammatory polyarthritis (IP). Genotypes for a single-nucleotide polymorphism (MIF-173*G/C) and a tetranucleotide (CATT)(n) repeat mapping to the promoter region of the MIF gene were compared between UK Caucasian IP cases (n=438) and controls (n=343). Both polymorphisms were also investigated for association with features of disease activity and severity at baseline and by 5 years. The MIF-173*C allele (OR 1.7, 95% CI 1.3-2.4, P=1.8 x 10(-4)) and the CATT(7) allele (OR 1.5, 95% CI 1.0-2.1, P=0.02) were found to be associated with increased susceptibility to IP. Furthermore, presence of the haplotype containing both associated polymorphisms was associated with a three-fold increase risk of developing IP. No association with disease severity or activity either at baseline or by 5 years was detected for either of the promoter polymorphisms studied. In conclusion, MIF is a susceptibility gene for the development of IP. The same alleles previously reported to be associated with susceptibility to juvenile idiopathic arthritis account for the increased risk. The promoter polymorphisms of MIF, investigated in this study, do not influence the severity of disease outcome by 5 years.
TL;DR: The AITD gene in the 2q33 locus is the CTLA-4 gene and not the CD28 or ICOS genes; and the G allele is associated with decreased function of CTLA -4.
Abstract: The cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene on 2q33 is associated with autoimmune thyroid diseases (AITDs). Our earlier study in 56 families showed linkage of 2q33 to the presence of thyroid antibodies (TAbs). The goals of this study were to confirm the linkage of the 2q33 region to TAbs, to fine map this region, and study the ICOS gene. We performed a linkage study in an expanded data set of 99 multiplex AITD-TAb families (529 individuals). The highest two-point LOD score of 2.9 was obtained for marker D2S325 on 2q33. To fine map this locus, we genotyped 238 Caucasian AITD patients and 137 controls for five additional markers in the linked locus, which contained the CTLA-4, CD28, and ICOS genes. The A/G single-nucleotide polymorphism at position 49 of CTLA-4 was associated with AITD (P=0.01, OR=1.5), while markers inside CD28 and ICOS were not. Functional studies have shown that the G allele was associated with reduced inhibition of T-cell proliferation by CTLA-4. We concluded that: (1) the AITD gene in the 2q33 locus is the CTLA-4 gene and not the CD28 or ICOS genes; and (2) the G allele is associated with decreased function of CTLA-4.
TL;DR: It is concluded that genetic variability in the IL-6, IL-10, and IL-1RN genes is associated with a poor outcome in meningococcal disease.
Abstract: Patients with meningococcal disease have increased plasma levels of proinflammatory cytokines IL-6, IL-1b, and TNF-a, with higher levels associated with fatal outcome. This study investigated whether polymorphisms in genes encoding these cytokines, and in those encoding anti-inflammatory IL-10 and IL-1Ra, are associated with the outcome in patients with meningococcal disease. Seven polymorphisms were genotyped in 183 meningococcal disease patients and 389 controls. The IL-6 � 174 G/G and IL-10 � 1082 A/A genotypes were more frequent in nonsurvivors compared with survivors (P¼0.023 IL-6, 0.25 IL-10), and in patients with severe disease compared to those with mild disease (P¼0.037 IL-6, 0.0078 IL-10). An association was also found between meningococcal disease and the IL-1RN VNTR polymorphism, but no association was observed with the LTA þ 252, TNF � 308, IL-10 � 592, or IL-1B þ 3953 polymorphisms. We conclude that genetic variability in the IL-6, IL-10, and IL-1RN genes is associated with a poor outcome in meningococcal disease. Genes and Immunity (2003) 4, 533–540. doi:10.1038/sj.gene.6364020
TL;DR: MIL-22BP binds to mouse and human IL-22 and neutralizes STAT3 activation induced by both cytokines in human and rat hepatoma cell lines, and could be upregulated by LPS stimulation in mouse monocytes.
Abstract: Interleukin-22 (IL-22), a member of IL-10 family, plays some important roles in immune response through activation of the STAT 3 signal transduction pathway. Two types of IL-22-binding receptor have been discovered, a membrane-bound receptor and a soluble receptor, both encoded by different genes. IL-22 may be involved in inflammatory processes specifically regulated by soluble receptors. By screening a mouse genomic library for a human IL-22 binding protein homologue, we identified the mouse genomic clone of IL-22 binding protein. Its coding sequence was verified and isolated by RT–PCR. The gene encodes a protein of 230 amino acids that share 67.1% amino-acid sequence identity with human IL-22 binding protein. We designated this receptor ‘mouse IL-22 binding protein’ (mIL-22BP). mIL-22BP could be upregulated by LPS stimulation in mouse monocytes. mIL-22BP binds to mouse and human IL-22 and neutralizes STAT3 activation induced by both cytokines in human and rat hepatoma cell lines. Treating B cells with mouse IL-22 induces production of reactive oxygen species, which mIL-22BP blocks.
TL;DR: Tests of the pharmacogenomic effects of eight polymorphisms in the interferon receptor genes in a group of 147 patients undergoing open-label IFNβ therapy found no significant differences in the distribution of responders and nonresponders, classified based on prospectively acquired primary and secondary clinical end points.
Abstract: Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system characterized by progressive neurological dysfunction. No curative therapy is currently available, and approximately 80-90% of afflicted individuals are ultimately disabled. Interferon beta (IFNbeta) has been shown to decrease clinical relapses, reduce brain disease activity, and possibly slow progression of disability. However, the overall effect of treatment is partial and a substantial number of patients are considered poor or nonresponders. For this report, we tested the pharmacogenomic effects of eight polymorphisms in the interferon receptor genes (IFNAR1 and IFNAR2) in a group of 147 patients undergoing open-label IFNbeta therapy. Overall, no significant differences in the distribution of responders and nonresponders, classified based on prospectively acquired primary and secondary clinical end points, were observed when stratified by any of the studied IFNAR gene polymorphisms. A trend detected with a single nucleotide polymorphism SNP 16469 (A/T) located at the third intron of the IFNAR1 gene, suggesting modest association with relapse-free status, will require confirmation in an independent data set. In addition, no significant association was observed of any of the IFNAR gene polymorphisms with susceptibility to MS, as studied by a family-based association analysis.
TL;DR: An extensive genetic analysis of IL2, IL4, IL6, IL10, IL12p35 and p40, IL13 and IFNγ genes found no relation with variants of other genes and will facilitate further genetic investigations of Th1–Th2 cytokines in AIDS and other immune-related disorders.
Abstract: Polymorphisms of Th1–Th2 cytokine genes have previously been implicated in the rate of progression to AIDS in seropositive patients. To evaluate further the impact of these genes in the development of AIDS, we have performed an extensive genetic analysis of IL2, IL4, IL6, IL10, IL12p35 and p40, IL13 and IFNγ. The coding regions and promoters of these genes were sequenced in a Caucasian cohort of 337 HIV-1 seropositive extreme patients (the GRIV cohort) consisting of patients with slow progression and rapid progression, and up to 470 healthy controls. In all, 64 single nucleotide polymorphisms (SNPs) and four deleterious polymorphisms with frequency >1% were identified and evaluated for their association with disease. Statistically significant associations were observed with haplotypes of the IL4 and IL10 genes, but no relation was found with variants of other genes. The catalogue of SNP and haplotypes presented here will facilitate further genetic investigations of Th1–Th2 cytokines in AIDS and other immune-related disorders.
TL;DR: It is shown that markers in the HLA class II, III and centromeric class I regions contribute to the DQ2-DR3 associated risk of T1D, independently of linkage disequilibrium (LD) with both the D Q/DR genes and the D6S2223 associated gene.
Abstract: Susceptibility to, and protection against development of type 1 diabetes (T1D) are primarily associated with the highly polymorphic exon 2 sequences of the HLA class II genes: DQB1, DQA1 and DRB1. However, several studies have also suggested that additional genes in the HLA complex influence T1D risk, albeit to a lesser degree than the class II genes. We have previously shown that allele 3 of microsatellite marker D6S2223, 4.9 Mb telomeric of DQ in the extended class I region, is associated with a reduction in risk conferred by the DQ2-DR3 haplotype. Here we replicate this finding in two populations from Sweden and France. We also show that markers in the HLA class II, III and centromeric class I regions contribute to the DQ2-DR3 associated risk of T1D, independently of linkage disequilibrium (LD) with both the DQ/DR genes and the D6S2223 associated gene. The associated marker alleles are carried on the DQ2-DR3-B18 haplotype in a region of strong LD. By haplotype mapping, we have located the most likely location for this second DQ2-DR3 haplotype-modifying locus to the 2.35 Mb region between HLA-DOB and marker D6S2702, located 970 kb telomeric of HLA-B.
TL;DR: In conclusion, non-Asheknazi MS patients carrying one mutated MEFV gene, particularly M694V, expressed rapid progression to disability, and the expressed mutation may increase inflammatory damage inflicted by autoimmune responses.
Abstract: Ancient founder mutations in the Mediterranean fever gene, MEFV, are associated with familial Mediterranean fever, a recessive, episodic, inflammatory disease. Since these mutations are reported to express with above normal levels of acute phase reactants in healthy heterozygotes we postulated that the heterozygous phenotype could aggravate the clinical expression of ongoing autoimmune diseases. This study evaluated progression to disability in relapsing-remitting multiple sclerosis (RR-MS) patients of non-Ashkenazi and Ashkenazi origin carrying an MEFV mutation, particularly the detrimental M694V, using the expanded disability status scale (EDSS). In the non-Ashkenazi patients group (n=48), carriers (n=17) presented with a two-fold higher fraction which reached EDSS=3.0 and 6.0 compared to noncarriers (n=31) despite a comparable mean of MS duration. The median time to reach EDSS=3.0 was 2 years in the carriers vs 10 years in noncarriers (P=0.007); The median time to reach EDSS=6.0 was 6 years vs 23 years, respectively (P=0.003). M694V heterozygous patients reached both EDSS milestones earlier than other patients. Progression to disability was not enhanced in Ashkenazi RR-MS carriers (n=12, noncarriers n=59). In conclusion, non-Asheknazi MS patients carrying one mutated MEFV gene, particularly M694V, expressed rapid progression to disability. The expressed mutation may increase inflammatory damage inflicted by autoimmune responses.
TL;DR: The genetic association of the tyrosine phosphatase CD45 and autoimmune hepatitis is analyzed to identify CD45 as a gene associated with AIH, and substantiates the hypothesis that CD45 represents a modifier gene of human autoimmunity.
Abstract: Autoimmune hepatitis is a chronic immune-mediated disease characterized by a loss of tolerance against liver resident antigens. The genetic background of autoimmune hepatitis is considered to be polygenic. Here we analyzed the genetic association of the tyrosine phosphatase CD45 and autoimmune hepatitis. CD45 plays an important role in normal antigen receptor mediated signaling in T and B cells. A point mutation at nucleotide position 77 of the CD45 gene results in abnormal CD45 splicing. In this study a significantly higher frequency of the 77 C/G genotype was observed in 190 autoimmune hepatitis patients when compared to 210 healthy blood donors. Our data identify CD45 as a gene associated with AIH, and further substantiates the hypothesis that CD45 represents a modifier gene of human autoimmunity.
TL;DR: Low MBL-producing genotypes were associated with more frequent admissions to hospital with respiratory infection, suggesting that the MBL2 gene is disease-modifying in COPD.
Abstract: Infection frequently causes exacerbations of chronic obstructive pulmonary disease (COPD) Mannose-binding lectin (MBL) is a pattern-recognition receptor that assists in clearing microorganisms Polymorphisms in the MBL2 gene reduce serum MBL levels and are associated with risk of infection We studied whether the MBL2 codon 54 B allele affected serum MBL levels, admissions for infective exacerbation in COPD and disease susceptibility Polymorphism frequency was determined by PCR-RFLP in 200 COPD patients and 104 smokers with normal lung function Serum MBL was measured as mannan-binding activity in a subgroup of 82 stable COPD patients Frequency of COPD admissions for infective exacerbation was ascertained for a 2-year period The MBL2 codon 54 B allele reduced serum MBL in COPD patients In keeping, patients carrying the low MBL-producing B allele had increased risk of admission for infective exacerbation (OR 49, P(corrected)=0011) No association of MBL2 genotype with susceptibility to COPD was detected In COPD, serum MBL is regulated by polymorphism at codon 54 in its encoding gene Low MBL-producing genotypes were associated with more frequent admissions to hospital with respiratory infection, suggesting that the MBL2 gene is disease-modifying in COPD MBL2 genotype should be explored prospectively as a prognostic marker for infection risk in COPD
TL;DR: The findings suggest that Sl 2 and McCb have arisen to confer a selective advantage against infectious disease that, in view of these case–control study data, was not solely Plasmodium falciparum malaria.
Abstract: The Knops blood group antigen erythrocyte polymorphisms have been associated with reduced falciparum malaria-based in vitro rosette formation (putative malaria virulence factor). Having previously identified single-nucleotide polymorphisms (SNPs) in the human complement receptor 1 (CR1/CD35) gene underlying the Knops antithetical antigens Sl1/Sl2 and McCa/McCb, we have now performed genotype comparisons to test associations between these two molecular variants and severe malaria in West African children living in the Gambia. While SNPs associated with Sl:2 and McC(b+) were equally distributed among malaria-infected children with severe malaria and control children not infected with malaria parasites, high allele frequencies for Sl 2 (0.800, 1365/1706) and McCb (0.385, 658/1706) were observed. Further, when compared to the Sl 1/McCa allele observed in all populations, the African Sl 2/McCb allele appears to have evolved as a result of positive selection (modified Nei–Gojobori test Ka−Ks/s.e.=1.77, P-value <0.05). Given the role of CR1 in host defense, our findings suggest that Sl 2 and McCb have arisen to confer a selective advantage against infectious disease that, in view of these case–control study data, was not solely Plasmodium falciparum malaria. Factors underlying the lack of association between Sl 2 and McCb with severe malaria may involve variation in CR1 expression levels.
TL;DR: The results confirm the importance of chromosome 5q31–q33 in the genetic control of PFBI levels and detect allelic association in the presence of linkage between blood infection levels and D5S487.
Abstract: Linkage and association between Plasmodium falciparum blood infection levels and chromosome 5q31–q33
TL;DR: Results of association analysis with protein motifs composed of polymorphic amino-acid residues do not add much to comprehension of the molecular basis of the HLA-DRB1/EPF associations, and interactions between susceptible, protective and neutral alleles clearly deviate from the codominant model.
Abstract: Endemic pemphigus foliaceus (EPF) is a blistering skin disease characterized by autoantibodies against the desmosomal protein desmoglein 1. Genetic and environmental factors influence its pathogenesis. A total of 128 patients and 402 controls from an ethnically admixed Brazilian population were analyzed for associations by allele and genotype with HLA-DRB1. The alleles DRB1(*)0101, (*)0102, (*)0103, (*)0404, (*)0406, (*)0410, (*)1406 and (*)1601 are significantly more frequent among patients, while DRB1(*)0301, (*)0701, (*)0801, (*)1101, (*)1104 and (*)1402 are negatively associated to EPF. Results of association analysis with protein motifs composed of polymorphic amino-acid residues do not add much to comprehension of the molecular basis of the HLA-DRB1/EPF associations. Interactions between susceptible (SU), protective (PR) and neutral (NE) alleles clearly deviate from the codominant model. Protection is dominant, since the PR/NE and PR/PR genotypes are both equally (P=0.95) and strongly protective (odds ratio OR=0.07 and 0.05, respectively; P<10(-6) for both). The SU/SU genotype confers a higher (P=0.012) risk than genotype SU/NE (OR=8.7 and 4.0; P<10(-6) for both), an evidence of a semi-dominant effect of SU alleles relative to NE alleles. The OR for the SU/PR genotype (statistically close to 1) is consistent with semi-dominance between PR and SU alleles. Knowledge of these allelic interactions is relevant for understanding the mechanisms underlying autoimmune disease pathogenesis.
TL;DR: The results of this study demonstrate that the IL-10 haplotype has a role in determining severity and course of plaque type of psoriasis.
Abstract: We analyzed three single-nucleotide polymorphisms (SNPs) at the interleukin-10 (IL-10) 5′ flanking region (positions −1082 A/G, −819 C/T and −592 C/A) in an association case–control study involving 248 patients with plaque type of psoriasis and 148 unrelated healthy volunteers using ARMS (amplification refractory mutation system)-PCR (Polymerase Chain Reaction) method. No difference was found in the frequencies of haplotype distribution between healthy controls and patients with psoriasis. There were no significant differences in the IL-10 haplotype distribution depending on the age of onset and family history of psoriasis. However, the results of our study demonstrate that the IL-10 haplotype has a role in determining severity and course of plaque type of psoriasis. IL-10 ACC haplotype (P<0.05) is likely to be defining lower activity of disease (PASI≤20; extent≤10%) and ATA haplotype is likely to be associated with persistent eruption (P<0.01). As ACC haplotype is suggested to be associated with high IL-10 secretion and ATA is related to low IL-10 secretion, potential differences in the IL-10 secretion levels might contribute the differences in the clinical course of psoriasis.
TL;DR: Data do not support the hypothesis that the FPR1 SNPs c.329T>C and c.378C>G play an etiologic role in aggressive periodontitis, but do suggest that SNPs in the second extracellular loop may be etiologically important.
Abstract: Polymorphonuclear neutrophils (PMNs) are attracted to sites of infection by N-formylpeptide (fMLP) chemoattractants. The high-affinity fMLP receptor (FPR1) of phagocytic cells interacts with bacterial fMLP and mediates chemotaxis, degranulation, and superoxide production. These cellular functions are disrupted in PMN from aggressive periodontitis (AP) patients. Two FPR1 gene single nucleotide polymorphisms (SNPs), c.329T>C and c.378C>G, have been associated with a localized form of AP in African-American patients. To evaluate the generality of these SNPs in AP patients, we sequenced a 363 bp interval of the FPR1 gene in an ethnically diverse group of patients (n=111) and controls (n=115). Neither c.329T>C nor c.378C>G were detected in the 452 alleles sequenced. Six SNPs were identified including two located in the FPR1 second extracellular loop that were significantly associated with the AP phenotype in African-American patients (p.R190W, P=0.0033; and p.N192K, P=0.0018). These two SNPs show three predominant haplotypes, each associated with a different disease risk in African-Americans. These data do not support the hypothesis that the FPR1 SNPs c.329T>C and c.378C>G play an etiologic role in aggressive periodontitis, but do suggest that SNPs in the second extracellular loop may be etiologically important.