| 1. |
- Abate Waktola, Ebba Abate, et al.
(författare)
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Polymorphisms in CARD8 and NLRP3 are associated with extrapulmonary TB and poor clinical outcome in active TB in Ethiopia
- 2019
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Innate immunity is a first line defense against Mycobacterium tuberculosis infection where inflammasome activation and secretion of the pro-inflammatory cytokine IL-1beta, plays a major role. Thus, genetic polymorphisms in innate immunity-related genes such as CARD8 and NLRP3 may contribute to the understanding of why most exposed individuals do not develop infection. Our aim was to investigate the association between polymorphisms in CARD8 and NLRP3 and active tuberculosis (TB) as well as their relationship to treatment outcome in a high-endemic setting for TB. Polymorphisms in CARD8 (C10X) and NLRP3 (Q705K) were analysed in 1190 TB patients and 1990 healthy donors (HD). There was a significant association between homozygotes in the CARD8 polymorphism and extrapulmonary TB (EPTB), which was not the case for pulmonary TB or HDs. Among TB-patients, there was an association between poor treatment outcome and the NLRP3 (Q705K) polymorphism. Our study shows that inflammasome polymorphisms are associated with EPTB and poor clinical outcome in active TB in Ethiopia. The practical implications and determining causal relationships on a mechanistic level needs further study.
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| 2. |
- Fransén, Karin, 1973-, et al.
(författare)
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Association between ulcerative growth and hypoxia inducible factor-1alpha polymorphisms in colorectal cancer patients
- 2006
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Ingår i: Molecular Carcinogenesis. - : John Wiley & Sons. - 0899-1987 .- 1098-2744. ; 45:11, s. 833-840
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Tidskriftsartikel (refereegranskat)abstract
- The hypoxia inducible factor-1alpha (HIF-1alpha) has been found to be involved in several different physiological mechanisms, such as blood-vessel formation, apoptosis, and erythropoiesis. HIF-1alpha is hydroxylated at normoxia and rapidly degraded via the von Hippel-Lindau (VHL)/ubiquitin-proteasome degradation system to prevent angiogenesis. In a previous study, the C1772T (P582S) and the G1790A (A588T) polymorphisms were identified in the human HIF-1alpha gene, which was shown to have a higher transactivating capability in vitro compared to the wild type allele. However, the role for these polymorphisms in vivo is still unclear. In the present investigation, we have therefore studied the role of the two polymorphic variants in the development of colorectal cancer (CRC) with PCR/RFLP (restriction fragment length polymorphism), single strand conformation analysis (SSCA), and immunohistochemistry (IHC). A significant higher-risk was identified between patients heterozygous for the C1772T polymorphism and the more severe ulcerative growth pattern compared to homozygous C1772C wild type tumors (RR = 5.2; 95% CI 1.26-21.6; P = 0.006). This was also verified on the allelic level (RR = 6.5; 95% CI 1.58-26.8; P = 0.001). In addition, patients carrying one or more polymorphic alleles in either the HIF-1alpha C1772T or the G1790A polymorphisms display significant higher risk for the development of ulcerative CRCs (RR = 4.17; 95% CI = 1.33-13.08; P = 0.004). These results suggest that the HIF-1alpha polymorpisms are an important factor for development of a subset of ulcerative intestinal tumors. Future screening of the polymorphic HIF-1alpha allele may therefore be of importance in the selection of treatment strategies of CRC.
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| 3. |
- Fransén, Karin, 1973-, et al.
(författare)
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Association between ulcerative growth and hypoxia inducible factor-1α polymorphisms in colorectal cancer patients
- 2006
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Ingår i: Molecular Carcinogenesis. - : Wiley. - 0899-1987 .- 1098-2744. ; 45:11, s. 833-840
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Tidskriftsartikel (refereegranskat)abstract
- The hypoxia inducible factor-1α (HIF-1α) has been found to be involved in several different physiological mechanisms, such as blood-vessel formation, apoptosis, and erythropoiesis. HIF-1α is hydroxylated at normoxia and rapidly degraded via the von Hippel–Lindau (VHL)/ubiquitin-proteasome degradation system to prevent angiogenesis. In a previous study, the C1772T (P582S) and the G1790A (A588T) polymorphisms were identified in the human HIF-1α gene, which was shown to have a higher transactivating capability in vitro compared to the wild type allele. However, the role for these polymorphisms in vivo is still unclear. In the present investigation, we have therefore studied the role of the two polymorphic variants in the development of colorectal cancer (CRC) with PCR/RFLP (restriction fragment length polymorphism), single strand conformation analysis (SSCA), and immunohistochemistry (IHC). A significant higher-risk was identified between patients heterozygous for the C1772T polymorphism and the more severe ulcerative growth pattern compared to homozygous C1772C wild type tumors (RR = 5.2; 95% CI 1.26–21.6; P = 0.006). This was also verified on the allelic level (RR = 6.5; 95% CI 1.58–26.8; P = 0.001). In addition, patients carrying one or more polymorphic alleles in either the HIF-1α C1772T or the G1790A polymorphisms display significant higher risk for the development of ulcerative CRCs (RR = 4.17; 95% CI = 1.33–13.08; P = 0.004). These results suggest that the HIF-1α polymorpisms are an important factor for development of a subset of ulcerative intestinal tumors. Future screening of the polymorphic HIF-1α allele may therefore be of importance in the selection of treatment strategies of CRC.
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| 4. |
- Lindh, Jonas, 1967-, et al.
(författare)
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Polymorphisms of GSTT1, GSTM1 and EPHX genotypes in patients with cryptogenic polyneuropathy: a case control study
- 2011
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Ingår i: Brain and Behavior. - Hoboken, New Jersey, USA : John Wiley & Sons, Inc. - 2162-3279 .- 2162-3279. ; 1:2, s. 135-141
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to analyze whether polymorphisms for the null alleles of Glutathione S-Transferase Mu-1 (GSTM1) and Theta-1 (GSTT1) and a low activity genetic variation of epoxide hydrolase exon three (EPHX*3) affect the risk of developing polyneuropathy. The enzymes of these genes are important in the metabolism of toxic compounds. 79 patients with cryptogenic polyneuropathy (equivalent to chronic idiopathic axonal neuropathy) and 398 controls were tested for the genetic polymorphism. Medical records were reviewed to collect data regarding clinical findings at diagnosis, and exposure data was collected via questionnaires. The odds ratios (OR) for the null forms of GSTM1 and GSTT1 and the normal activity YY form of EPHX*3 were close to one except GSTT1, which reached 1.86. The highest risk of polyneuropathy was found in smokers with GSTT1 null, who had a 3.7 times increased risk. Interactions between genes were analyzed and confirmed the increased odds ratio for GSTT1, which was strongest if the patients had the low activity HH form of EPHX*3 (OR 2.37). Our hypothesis is that the GSTT1 null polymorphism may be related to an impaired metabolism of toxic substances that could lead to nerve damage in the peripheral nervous system.
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| 5. |
- Pihl, Mikael, et al.
(författare)
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Polymorphisms in NALP3 inflammasome components NLRP3 and CARD8 affect C-peptide secretion in type 1 diabetes
- 2013
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Interleukin-1β has long been known to have potential roles in type 1 diabetes (T1D) pathogenesis. Production of active Iinterleukin-1β is dependent on the action of a caspase activating protein complex called NALP3 inflammasome. The NALP3 inflammasome is composed of NALP3/Cryopyrin, ASC and CARD8. Polymorphisms in the NLRP3 and CARD8 genes have been linked to several autoinflammatory diseases. The NALP3 inflammasome is crucial for adjuvanticity of aluminium hydroxide, which is used as adjuvant in clinical trials of glutamic acid decarboxylase (GAD)-alum in T1D. Our aim was to investigate the effect of common polymorphisms of NLRP3 on T1D susceptibility as well as on GAD-alum treatment efficacy. The single nucleotide polymorphisms NLRP3 Q705K, CARD8 C10X and an SNP downstream of the NLRP3 gene, rs10733113, were genotyped using a Taqman genotyping assay. The A allele of CARD8 C10X was associated with a lower stimulated insulin secretion 3 months after diagnosis in males. Patients with at least one G allele at rs10733113 were more likely to produce auto-antibodies against two or more of the islet antigens GAD, Insulin or IA-2. None of the genotyped SNPs had any significant influence on efficacy of GAD-alum treatment, but individuals with at least one rs10733113 G allele treated with placebo had lower residual insulin secretion than those with the AA genotype at 9, 15 and 21 months after start of treatment.
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| 6. |
- Schoultz, Ida, et al.
(författare)
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Combined polymorphisms in genes encoding the inflammasome components NALP3 and CARD8 confer susceptibility to Crohn's disease in Swedish men
- 2009
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Ingår i: American Journal of Gastroenterology. - : Wolters Kluwer. - 0002-9270 .- 1572-0241. ; 104:5, s. 1180-1188
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Crohn's disease (CD) is characterized by overproduction of proinflammatory cytokines like interleukin (IL)-1beta. Production of mature IL-1beta is dependent on a caspase-1-activating protein complex called the NALP3 inflammasome, composed of NALP3, ASC, and CARD8. NALP3 shares structural similarities with Nod2, and both of these proteins are required for bacteria-induced IL-1beta secretion. The combination of the polymorphisms CARD8 (C10X)and NALP3 (Q705K) was recently shown to be associated with rheumatoid arthritis.Our aim was to investigate whether these combined polymorphisms play a role in the susceptibility to CD. METHODS: The study included 498 CD patients in two cohorts from different regions and 742 control individuals from a Swedish population. DNA was isolated from whole blood. Polymorphisms of (Q705K) NALP3 and (C10X) CARD8, as well as the Nod2 variants, R702W and G908R, were genotyped using the Taqman single nucleotide polymorphism assay. The Nod2 frameshift mutation, L1007fs, was detected by Megabace SNuPe genotyping. RESULTS: Our results show that men who have both the C10X and Q705K alleles in CARD8 and NALP3, and who express wild-type alleles of Nod2 are at an increased risk of developing CD (odds ratio, OR: 3.40 range: 1.32-8.76); P = 0.011). No association with these polymorphisms was found in women (OR: 0.89 (range: 0.44-1.77); P = 0.74). CONCLUSIONS: We suggest a role for combined polymorphisms in CARD8 and NALP3 in the development of CD in men, with obvious sex differences in the genetic susceptibility pattern. These findings give further support to the importance of innate immune responses in CD.
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| 7. |
- Ungerbäck, Jonas, et al.
(författare)
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Genetic variation and alterations of genes involved in NFκB/TNFAIP3- and NLRP3-inflammasome signaling affect susceptibility and outcome of colorectal cancer
- 2012
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Ingår i: Carcinogenesis. - Oxford, United kingdom : Oxford University Press. - 0143-3334 .- 1460-2180. ; 33:11, s. 2126-2134
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal tumors are continuously exposed to an inflammatory environment, which together with mitogenic signals sustain several cancer hallmarks. Nuclear factor-kappa B (NFκB) is a major regulator of inflammation and variation in NFκB-associated genes could potentially be used as biomarkers to identify patients with increased risk of colorectal cancer (CRC) development, and/or a rapidly progressing disease. In this study, 348 CRC cases and 806 randomly selected healthy individuals from southeastern Sweden were examined with regard to seven polymorphisms in NFκB pathway-associated genes. Log-rank-tests and Cox proportional hazard regression analysis examined the association between the polymorphisms and CRC-specific survival, whereas chi-square tests and logistic regression analysis were used to test for associations between the polymorphisms and CRC susceptibility. Gene expression and loss of heterozygosity analyses of TNFAIP3 were carried out in a subset of tumors to assess its role as a tumor suppressor in CRC. Heterozygous and polymorphic TNFAIP3 (rs6920220), heterozygous NLRP3 (Q705K) and polymorphic NFκB -94 ATTG ins/del genotypes were found to be associated with poorer survival in patients diagnosed with invasive CRC (aHR = 5.2, 95% CI: 2.5-10.9, P < 0.001). TNFAIP3 mRNA levels were significantly decreased in tumors compared with adjacent non-neoplastic mucosa (P < 0.0001) and loss of heterozygosity of 6q23.3 (TNFAIP3) was detected in 17% of cases, whereas only 2.5% of the investigated specimens displayed TNFAIP3 gene mutations. We propose that TNFAIP3 (rs6920220), NLRP3 (Q705K) and NFκB -94 ATTG ins/del polymorphisms are associated with poor survival in patients with advanced CRC and may be used as prognostic markers. Experimental results indicate that TNFAIP3 may act as a tumor suppressor in CRC.
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| 8. |
- Ungerbäck, Jonas, et al.
(författare)
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Genetic variation in NFκB signaling pathway genes in colorectal cancer susceptibility and survival
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- PURPOSE: Variations in genes orchestrating inflammatory responses, such as those being connected with NFκB and NLRP3 inflammasome signaling, are associated with chronic inflammatory bowel diseases, which are well-known risk factors for colorectal cancer (CRC). The purpose of this study was to investigate the association between genetic variation and alterations in genes involved in NFκB and NLRP3 inflammasome signaling and their possible influence on susceptibility and clinical outcome of colorectal cancer. EXPERIMENTAL DESIGN: 344 CRC cases and 793 randomly selected healthy individuals from southeastern Sweden were examined with regard to seven polymorphisms in NFκB, TNFAIP3, NLRP3, CARD8 and TLR4 genes. Chi-square tests and multiple logistic regression analysis were used to test for associations between the SNPs and CRC susceptibility, while log-rank tests and Cox proportional hazard regression analysis were used to examine the association between the SNPs and CRC-specific survival. Gene expression assay and loss of heterozygosity analyzes of TNFAIP3 were carried out in a subset of tumors to assess its role as a potential tumor suppressor in CRC. RESULTS: Adjusted for age, gender and polypoid/ulcerative CRC phenotype, a panel of heterozygous and mutant TNFAIP3 (rs6920220), mutant NFκB -94 ATTG ins/del and heterozygous NLRP3 (Q705K) genotypes were found to be associated with poorer survival in patients diagnosed with invasive CRC (aHR = 5.2 95% CI 2.5-10.9, P < 0.001). TNFAIP3 mRNA levels were significantly decreased in tumors compared to adjacent non-neoplastic mucosa (P < 0.0001) and LOH of 6q23.3, (TNFAIP3), was detected in 17% of cases, while only 2.5% of the investigated specimens displayed TNFAIP3 gene mutations. CONCLUSIONS: A panel of the TNFAIP3 (rs6920220), NFκB -94 ATTG ins/del and NLRP3 (Q705K) polymorphisms are associated with poor survival in patients with advanced CRC and may be used as a prognostic marker. Experimental results indicate that TNFAIP3 may act as a tumor suppressor in CRC.
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| 9. |
- Verma, Deepti, et al.
(författare)
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Inflammasome polymorphisms confer susceptibility to sporadic malignant melanoma
- 2012
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Ingår i: Pigment Cell & Melanoma Research. - : Blackwell Publishing. - 1755-1471 .- 1755-148X. ; 25:4, s. 506-513
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants of NLRP3 and NLRP1 are known to modulate levels of pro-inflammatory cytokine interleukin (IL)-1 beta. The purpose of this study was to investigate the association of NLRP3/NLRP1 polymorphisms with susceptibility and clinical features of malignant melanoma in a Swedish casecontrol study. Common variants in NLRP3/NLRP1 were investigated in sporadic malignant melanoma patients and healthy controls followed by analysis using logistic regression. NLRP3 variant (rs35829419) was significantly more common in male patients than in controls (OR, 2.22; CI, 1.273.86). Upon stratification, significant association with nodular melanoma was observed (OR, 2.89; CI, 1.336.30), which intensified in male patients (OR 4.03, CI 1.4011.59). The NLRP1 variant (rs12150220) was significantly more common in fair-skinned female patients (OR, 1.85; CI, 1.043.33) and showed strong associations with nodular melanoma (OR, 6.03; CI, 1.3325). Our data suggest that NLRP3/NLRP1 polymorphisms are associated with melanoma susceptibility; these findings warrant validation in other independent populations.
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| 10. |
- Willander, Kerstin, et al.
(författare)
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MDM2 SNP309 promoter polymorphism, an independent prognostic factor in chronic lymphocytic leukemia
- 2010
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Ingår i: European Journal of Haematology. - : Wiley. - 1600-0609 .- 0902-4441. ; 85:3, s. 251-256
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Tidskriftsartikel (refereegranskat)abstract
- Background: The single nucleotide polymorphism SNP309 with a change from T to G in the promoter region of the MDM2 gene is shown to increase the MDM2 protein levels and attenuate the p53 levels and associates with disease progression in several tumors. Objective: In this study, the role of the polymorphism was investigated with regard to the clinical outcome in B-cell chronic lymphocytic leukemia (B-CLL). Patients: A total of 210 patients with B-CLL were followed for up to 19 yr. Results: The overall survival (OS) of patients with at least one G-allele was significantly shorter when compared with those with two T-alleles (P = 0.024) with a more pronounced difference in patients below the median age. Age at onset of B-CLL was similar irrespective of MDM2 status. The presence of a G-allele in combination with TP53 mutations or unmutated IgVH gene status resulted in an additive risk of death. Conclusion: In this report, with a high proportion of B-CLL patients with an advanced Binet stage and with an unmutated IgVH gene, MDM2 SNP309 was found to be independently associated with OS. The survival difference was more pronounced in younger patients.
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