Definition of polymorphisms and haplotypes in the interleukin-12B gene: association with IL-12 production but not with Crohn's disease (original) (raw)
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A TaqI polymorphism in the 3′UTR of the IL-12 p40 gene correlates with increased IL-12 secretion
Genes & Immunity, 2002
Interleukin-12 (IL-12) is a key cytokine for the induction of Th1 immune responses. We evaluated whether a TaqI polymorphism in the 3 0 UTR of the IL-12 p40 gene affects secretion of IL-12 in vitro, and whether this polymorphism is associated with susceptibility to Crohn's disease (CD). IL-12 p40 and p70 secretion by monocytes in relation to genotype was determined in 63 healthy donors. Genotype and allele frequencies of the TaqI polymorphism in 150 CD patients were compared with 145 ethnically matched healthy controls (HC). No significant association was found between genotype and IL-12 p40 secretion after stimulation of monocytes with SAC+IFNg. In contrast, increasing IL-12 p70 secretion was found across the categories of noncarriers, heterozygotes and homozygotes for the variant allele (median values 7 SEM: 147 7 27, 282 7 51 and 482 7 34 pg/ ml, respectively; Po0.005). The allele and genotype frequencies of this polymorphism in patients with CD did not differ statistically significantly from HC. The presence of a TaqI polymorphism in the IL12 p40 3 0 UTR correlates with increased in vitro IL-12 p70, but not p40 secretion. While this polymorphism does not appear to be correlated with susceptibility to CD in the limited population of patients tested here, it could influence the occurrence of the disease in certain subsets of patients.
Genetic analyses of chromosome 12 loci in Crohn's disease
Gut, 2000
Background and aims-Inflammatory bowel disease (IBD) includes ulcerative colitis and Crohn's disease, both of which are multifactorial diseases involving the interaction of genetic and environmental factors. A region on chromosome 12 centred around the marker locus D12S83 has previously been associated with IBD predisposition. The aim of the study was to investigate this genetic region in an independent panel of European families aVected by Crohn's disease. Methods-A sample of 95 families with two or more aVected relatives and 75 simplex nuclear families were genotyped for 19 microsatellite loci located on chromosome 12. A search for linkage and linkage disequilibrium was performed using nonparametric two point and multipoint analyses with the Analyze and Genehunter packages. Results-No evidence of linkage or linkage disequilibrium was observed for any of the marker loci, including D12S83 (p=0.35 for the two point linkage test). Multipoint linkage analysis also failed to reveal positive linkage on chromosome 12. Power calculations allowed us to reject the hypothesis that the genetic region of chromosome 12 centred on D12S83 contains a susceptibility locus with a relative risk ( s ) equal to or greater than 2.0 in these families. Conclusion-Failure to detect linkage or linkage disequilibrium in these families suggests that the chromosome 12 locus previously reported to be associated with genetic predisposition to IBD does not play a role in all European family samples. This observation is compatible with heterogeneity in the genetic basis of susceptibility to the disease and/or exposure to various environmental factors among Caucasian families. (Gut 2000;47:787-791)
Genetic polymorphism of IL-12 p40 gene in immune-mediated disease
Genes and Immunity, 2000
Understanding of the genetic basis of autoimmune diseases is currently incomplete. Cytokine gene polymorphisms warrant consideration as factors explaining variation in the human immune and inflammatory responses and as candidate susceptibility genes for related pathological states. Interleukin 12 (IL-12) is a key regulator of the polarisation of immune responses to T helper 1 or 2 categories and plays a role in autoimmune and infectious diseases. Using a bioinformatic strategy, we aligned cDNA and expressed sequence tag sequences to identify putative polymorphic regions of the IL-12 p40 gene. Position 1188 in the 3Ј untranslated region (UTR) was polymorphic with the frequency of the common allele around 80% in healthy UK Caucasoids. PCR genotyping of multiple Caucasoid groups and an African group showed significant population variation. In a case-control design, the polymorphism was not associated with rheumatoid arthritis, Felty's syndrome or large granular lymphocyte syndrome with arthritis or multiple sclerosis. A nonsignificant increase in the B allele frequency was observed in the rare large granular lymphocyte syndrome without arthritis (odds ratio 2.02 95% CI 0.95-4.3). This new genetic marker could be useful in anthropological studies and should be investigated in other autoimmune, allergic, inflammatory and infectious diseases. Genes and Immunity (2000) 1, 219-224.
Functional genetic polymorphisms in interleukin-12B gene
2013
Genetic polymorphisms in cytokine genes, which influence gene expression, may have an important impact on SLE susceptibility and severity. The aim of this study was to examine the possible influence of two functional polymorphisms in cis-regulatory regions of IL12B gene in the susceptibility and clinical symptoms of SLE in Bulgarian patients. Female SLE patients (n = 141) and 124 healthy women were included in the study. Genotyping for the IL12B A/C polymorphism in 3 0 UTR was performed by restriction fragment length polymorphisms PCR assay and for the IL12Bpro polymorphism by allele-specific PCR. Genotype-22 of IL12Bpro polymorphism was overrepresented among women with SLE (28 vs. 17%; OR = 1.875; 95% CI: 1.037 7 3.390; P = 0.037). Respectively, a higher frequency of allele-2 was found in patients than in controls (51% vs. 40%; OR = 1.566; 95% CI: 1.110 7 2.210; P = 0.011). Also, we found significantly elevated frequency of genotype-22 of IL12Bpro polymorphism among SLE patients who were simultaneously carrier of genotype-AA of SNP in 3 0 UTR. Women with both homozygous genotypes, genotype-AA of SNP in 3 0 UTR and genotype-22 of IL12Bpro polymorphism, had a 2.1fold significantly elevated risk for SLE development. The carrying of genotype-11 of IL12Bpro polymorphism was positively associated with hematological and neuropsychiatric manifestations of SLE. We have provided evidence that the IL12Bpro polymorphism was associated with SLE development among Bulgarian women. Although a strong individual effect of SNP in 3 0 UTR of IL12B was not detected, we found that genotype-22 of IL12Bpro was predominantly combined with genotype-AA of SNP in 3 0 UTR among SLE patients and this combination elevates the risk of SLE.
Lack of Association between Interleukin 12 C(-1188)A Polymorphism and Irritable Bowel Syndrome
Avicenna journal of medical biotechnology, 2011
Irritable Bowel Syndrome (IBS) is a functional gastrointestinal disorder, characterized by recurrent abdominal pain and altered bowel habits. This study was performed to investigate the important role of interleukin-12 (IL-12) in intestinal inflammation. For this study seventy one patients with IBS and 140 controls were investigated. The allele and genotype frequencies of IL-12 C(-1188)A were determined using polymerase chain reaction with sequence-specific primers. The allele A was more common that the allele C in both groups of patients and controls. There was not any significant difference on IL-12 alleles and genotypes between patients and controls. The AA genotype was the most common genotypes, which was seen in 57.4% of the patients and 51.4% of the controls (p = 0.53). Although frequency of the CC genotype in the control group was lower than the patient group, this difference was not significant (5.7% vs. 11.5%, respectively, p = 0.16). Considering the lack of association bet...
Gastroenterology Research and Practice, 2010
DNA samples from 339 Crohn's disease (CD) and 407 randomly selected controls from the Auckland (New Zealand) IBD project, were genotyped for five common single nucleotide polymorphisms in IL-23R (rs11805303, rs7517847, rs1343151, rs11209026, and rs10889677) and two in IL-12B (rs1363670 and rs6887695). While the IL-12B variants did not show an overall association and other IL23R variants led to minor changes in the risk of CD, rs1343151 and/or rs7517847 variants in the IL-23R gene strongly reduced the risk of developing CD at both allelic and genotype levels. A significantly decreased risk of first diagnosis of childhood CD was observed in individuals carrying the A allele of rs1343151, or between 17-40 y in individuals carrying the G allele in rs7517847 of IL-23R. A significantly decreased risk of ileocolonic or structuring disease was observed in individuals carrying the A allele in either rs11209026 or rs1343151, or the G allele in rs7517847 of IL-23R, and when such individuals did develop the disease, they were unlikely to require a bowel resection. Certain haplotypes very strongly modified risk. There was evidence for interactions of IL-23R variants with the NOD2 wild-type (d/d) genotype. Down-regulating the function of the IL-23R gene may decrease CD risk in the normal population.
Cytokine gene polymorphisms in inflammatory bowel disease
Gut, 1996
Background-Concordance rates in siblings and twins provide strong evidence that genetic susceptibility is important in the pathogenesis of inflammatory bowel disease. The number and identity of susceptibility genes is largely uncertain. Cytokine genes are attractive candidate loci. Aims-To study allelic frequencies of polymorphisms of the interleukin-1 receptor antagonist (IL-1RA) gene and the tumour necrosis factor ae gene in patients with inflammatory bowel disease. Subjects-One hundred and twenty nine North European caucasoid patients with ulcerative colitis, 120 patients with Crohn's disease, and 89 healthy controls. Methods-Genotyping was performed by polymerase chain reaction. A variable number of tandem repeats (VNTR) in the IL-1RA gene and a single base pair polymorphism in the TNFa gene promoter region (TNF-308) were analysed. Results-No significant differences in IL-1RA VNTR allelic frequencies were noted between Crohn's disease (allele 1: 72.6%, allele 2: 24.7%, allele 3: 2.6%), ulcerative colitis (72.6%, 24.3%, 3.1%, respectively), and controls (76.9%, 20.8% and 2.3%). Some 42.4% of patients with ulcerative colitis and 43.4% patients with Crohn's disease were carriers of allele 2, compared with 34.8% healthy subjects. The TNF2 allele was modestly reduced in Crohn's disease (13.2%), compared with healthy subjects (21.3%; p=0.04), and ulcerative colitis (21.6%). Conclusions-The associations demonstrated are modest: these polymorphisms are unlikely to be important determinants of overall disease susceptbility.
The Egyptian journal of immunology, 2020
Rheumatoid arthritis (RA) is one of the common autoimmune diseases, which affected by genetic and environmental factors. IL-12 is important cytokine that play an effective role in the inflammatory reaction of RA. It regulates the balance between Th1 and Th2 cells. Gene polymorphism of cytokines may predispose to susceptibility and severity of RA. To assess the association between single nucleotide polymorphism (SNP) in IL-12B gene (rs3212227 A/C) and serum level of IL-12 with the development and or activity of RA disease in Egyptian population. Sixty RA patients and thirty healthy individuals were studied for IL-12B gene (rs3212227 A/C) polymorphism using PCR-RFLP. Serum level of IL-12 was measured by ELISA. The frequency of genotype AC, CC, AC+CC and C allele were significantly higher in patients compared to control group (P < 0.02, 0.007, 0.02) respectively. Serum level of IL-12 was significantly higher in patients compared to control (P < 0.000). Patients who carry AC+CC ge...
Linkage and Association between Inflammatory Bowel Disease and a Locus on Chromosome 12
The American Journal of Human Genetics, 1998
Genetic epidemiological studies have shown that genetic factors are important in the pathogenesis of the idiopathic inflammatory bowel diseases (IBD), Crohn disease (CD), and ulcerative colitis (UC). A genome screen in the United Kingdom found linkage of IBD to a 41-cM region of chromosome 12, surrounding D12S83. We aimed to replicate this linkage and to narrow the region of interest. Nonparametric linkage analyses at microsatellites surrounding D12S83 were performed in 122 North American Caucasian families containing 208 genotyped IBD-affected relative pairs. Transmission/disequilibrium tests (TDTs) were also performed. We confirmed that IBD is linked to chromosome 12 (peak GENEHUNTER-PLUS LOD* score 2.76 [P ϭ .00016] between D12S1724 and D12S90). The evidence for linkage is contributed by both the group of CD-affected relative pairs (peak GENEHUNTER-PLUS LOD* score 1.79 [P ϭ .0021] between D12S1724 and D12S90) and the group of UC-affected relative pairs (peak GENE-HUNTER-PLUS LOD* score 1.82 [P ϭ .0019] at D12S335). The TDT is positive at the D12S83 locus (global x 2 ϭ 16.41, 6 df, P ϭ .012). In conclusion, we have independently confirmed linkage of IBD to the chromosome 12 region that we investigated. A positive TDT at D12S83 suggests that we have greatly narrowed the chromosome 12 region that contains an IBD locus.
IL23R and IL12B polymorphisms in spanish IBD patients: No evidence of interaction
Inflammatory Bowel Diseases, 2008
Background: Recent genomic surveys have identified IL23R and IL12B as susceptibility loci for inflammatory bowel disease (IBD). Our aim in the present study was to ascertain whether the IL23R and IL12B associations with IBD are also observed in our population, and to analyze possible genetic interactions between polymorphisms at IL12B and IL23R, ligand and receptor, respectively.