CARD8 Rs2043211 Research Articles

Genetic Variability in Oxidative Stress, Inflammatory, and Neurodevelopmental Pathways: Impact on the Susceptibility and Course of Spinal Muscular Atrophy

The spinal muscular atrophy (SMA) phenotype strongly correlates with the SMN2 gene copy number. However, the severity and progression of the disease vary widely even among affected individuals with identical copy numbers. This study aimed to investigate the impact of genetic variability in oxidative stress, inflammatory, and neurodevelopmental pathways on SMA susceptibility and clinical progression. Genotyping for 31 genetic variants across 20 genes was conducted in 54 SMA patients and 163 healthy controls. Our results revealed associations between specific polymorphisms and SMA susceptibility, disease type, age at symptom onset, and motor and respiratory function. Notably, the TNF rs1800629 and BDNF rs6265 polymorphisms demonstrated a protective effect against SMA susceptibility, whereas the IL6 rs1800795 was associated with an increased risk. The polymorphisms CARD8 rs2043211 and BDNF rs6265 were associated with SMA type, while SOD2 rs4880, CAT rs1001179, and MIR146A rs2910164 were associated with age at onset of symptoms after adjustment for clinical parameters. In addition, GPX1 rs1050450 and HMOX1 rs2071747 were associated with motor function scores and lung function scores, while MIR146A rs2910164, NOTCH rs367398 SNPs, and GSTM1 deletion were associated with motor and upper limb function scores, and BDNF rs6265 was associated with lung function scores after adjustment. These findings emphasize the potential of genetic variability in oxidative stress, inflammatory processes, and neurodevelopmental pathways to elucidate the complex course of SMA. Further exploration of these pathways offers a promising avenue for developing personalized therapeutic strategies for SMA patients.

Association between NLRP3 rs10754558 and CARD8 rs2043211 Variants and Susceptibility to Chronic Kidney Disease.

Nod-like receptor protein 3 (NLRP3) is a multi-protein complex belonging to the innate immune system, whose activation by danger stimuli promotes inflammatory cell death. Evidence supports the crucial role of NLRP3 inflammasome activation in the transition of acute kidney injury to Chronic Kidney Disease (CKD), by promoting both inflammation and fibrotic processes. Variants of NLRP3 pathway-related genes, such as NLRP3 itself and CARD8, have been associated with susceptibility to different autoimmune and inflammatory diseases. In this study, we investigated for the first time the association of functional variants of NLRP3 pathway-related genes (NLRP3-rs10754558, CARD8-rs2043211), with a susceptibility to CKD. A cohort of kidney transplant recipients, dialysis and CKD stage 3-5 patients (303 cases) and a cohort of elderly controls (85 subjects) were genotyped for the variants of interest and compared by using logistic regression analyses. Our analysis showed a significantly higher G allele frequency of the NLRP3 variant (67.3%) and T allele of the CARD8 variant (70.8%) among cases, compared with the control sample (35.9 and 31.2%, respectively). Logistic regressions showed significant associations (p < 0.001) between NLRP3 and CARD8 variants and cases. Our results suggest that the NLRP3 rs10754558 and CARD8 rs2043211 variants could be associated with a susceptibility to CKD.

Inflammasome Genetic Variants Are Associated with Protection to Clinical Severity of COVID-19 among Patients from Rio de Janeiro, Brazil.

COVID-19 has a broad spectrum of clinical manifestations, from asymptomatic or mild/moderate symptoms to severe symptoms and death. The mechanisms underlying its clinical evolution are still unclear. Upon SARS-CoV-2 infection, host factors, such as the inflammasome system, are activated by the presence of the virus inside host cells. The search for COVID-19 risk factors is of relevance for clinical management. In this study, we investigated the impact of inflammasome single-nucleotide polymorphisms (SNPs) in SARS-CoV-2-infected individuals with distinct severity profiles at clinical presentation. Patients were divided into two groups according to disease severity at clinical presentation based on the WHO Clinical Progression Scale. Group 1 included patients with mild/moderate disease (WHO < 6; n = 76), and group 2 included patients with severe/critical COVID-19 (WHO ≥ 6; n = 357). Inpatients with moderate to severe/critical profiles were recruited and followed-up at Hospital Center for COVID-19 Pandemic – National Institute of Infectology (INI)/FIOCRUZ, RJ, Brazil, from June 2020 to March 2021. Patients with mild disease were recruited at Oswaldo Cruz Institute (IOC)/FIOCRUZ, RJ, Brazil, in August 2020. Genotyping of 11 inflammasome SNPs was determined by real-time PCR. Protection and risk estimation were performed using unconditional logistic regression models. Significant differences in NLRP3 rs1539019 and CARD8 rs2043211 were observed between the two groups. Protection against disease severity was associated with the A/A genotype (ORadj = 0.36; P = 0.032), allele A (ORadj = 0.93; P = 0.010), or carrier-A (ORadj = 0.45; P = 0.027) in the NLRP3 rs1539019 polymorphism; A/T genotype (ORadj = 0.5; P = 0.045), allele T (ORadj = 0.93; P = 0.018), or carrier-T (ORadj = 0.48; P = 0.029) in the CARD8 rs2043211 polymorphism; and the A-C-G-C-C (ORadj = 0.11; P = 0.018), A-C-G-C-G (ORadj = 0.23; P = 0.003), C-C-G-C-C (ORadj = 0.37; P = 0.021), and C-T-G-A-C (ORadj = 0.04; P = 0.0473) in NLRP3 genetic haplotype variants. No significant associations were observed for the other polymorphisms. To the best of our knowledge, this is the first study demonstrating an association between CARD8 and NLRP3 inflammasome genetic variants and protection against COVID-19 severity, contributing to the discussion of the impact of inflammasomes on COVID-19 outcomes.

Genetic Polymorphisms in NLRP3 Inflammasome-Associated Genes in Patients with B-Cell Non-Hodgkin's Lymphoma.

PurposeThe role of NLRP3 inflammasome in the progression of many diseases has been increasingly recognized. However, the function of this molecular assembly in the development and progression of B-cell non-Hodgkin’s lymphoma remains unclear.Patients and MethodsIn this study, we investigated the polymorphisms in the NLRP3 inflammasome associated genes in 281 patients with B-cell non-Hodgkin’s lymphoma and 385 age- and gender-matched healthy controls.ResultsWe found that IL-18 (rs1946518) and NFκB-94 ins/del (rs28362491) contributed to susceptibility to B-cell non-Hodgkin’s lymphoma. Specifically, the allele “G” in IL-18 (rs1946518) and allele “ins” in NFκB-94 ins/del (rs28362491) were significantly associated with the risk of disease. The AA genotype of CARD8 (rs2043211) and the higher level of serum lactate dehydrogenase (LDH) led to statistically poorer B-cell non-Hodgkin’s lymphoma survival. Less frequent genotype TT of CARD8 (rs2043211) was observed in patients with higher LDH level, clinical stages III–IV of disease, and IPI 3–5, although the relationship did not reach statistical significance. However, IPI is an independent prognostic factor for B-cell non-Hodgkin’s lymphoma.ConclusionIL-18 (rs1946518) and NFκB-94 ins/del (rs28362491) gene polymorphisms appear to be the factors influencing the risk of B-cell non-Hodgkin’s lymphoma. CARD8 (rs2043211) polymorphisms are important factors for the survival of patients with this disease.

Associations of NLRP3 and CARD8 gene polymorphisms with alcohol dependence and commonly related psychiatric disorders: a preliminary study.

We investigated two functional polymorphisms in NLRP3 inflammasome genes (NLRP3 rs35829419 and CARD8 rs2043211) and their association with alcohol dependence and related anxiety, depression, obsession-compulsion, or aggression in 88 hospitalised alcohol-dependent patients, 99 abstinent alcohol-dependent participants, and 94 controls, all male Caucasian. Alcohol dependence-related psychiatric disorders were assessed with the Zung Depression and Anxiety scale, Buss-Durkee Hostility Inventory, Alcohol Use Disorders Identification Test, Brief Social Phobia Scale, Obsessive Compulsive Drinking Scale, and Yale-Brown Obsessive-Compulsive Scale. For genotyping we used the allele-specific quantitative polymerase chain reaction-based methods. The three groups differed significantly in CARD8 rs2043211 distribution (P=0.049; chi-squared=9.557; df=4). The NLPR3 rs35829419 polymorphism was not significantly associated with alcohol dependence. In hospitalised alcohol-dependent patients the investigated polymorphisms were not associated with scores indicating alcohol consumption or comorbid symptoms. In abstinent alcohol-dependent subjects homozygotes for the polymorphic CARD8 allele presented with the highest scores on the Zung Anxiety Scale (p=0.048; df=2; F=3.140). Among controls, CARD8 genotype was associated with high scores on the Obsessive Compulsive Drinking Scale (P=0.027; df=2; F=3.744). In conclusion, our results reveal that CARD8 rs2043211 may play some role in susceptibility to alcohol dependence, expression of anxiety symptoms in abstinent alcohol-dependent subjects, and in obsessive compulsive drinking in healthy controls. However, further studies with larger cohorts are required to confirm these preliminary findings.

Genetic Polymorphisms, Gene–Gene Interactions and Neurologic Sequelae at Two Years Follow-Up in Newborns with Hypoxic-Ischemic Encephalopathy Treated with Hypothermia

Inflammation and oxidative stress after hypoxic-ischemic brain injury may be modified by genetic variability in addition to therapeutic hypothermia. The aim of our study was to evaluate the association between the polymorphisms in genes of antioxidant and inflammatory pathways in newborns treated with therapeutic hypothermia and the development of epilepsy or CP at two years follow-up. The DNA of 55 subjects was isolated from buccal swabs. Genotyping using competitive allele-specific PCR was performed for polymorphisms in antioxidant (SOD2 rs4880, CAT rs1001179, GPX1 rs1050450) and inflammatory (NLRP3 rs35829419, CARD8 rs2043211, IL1B rs1143623, IL1B rs16944, IL1B rs10716 76, TNF rs1800629) pathways. Polymorphic CARD8 rs2043211 T allele was less frequent in patients with epilepsy, but the association was not statistically significant. The interaction between CARD8 rs2043211 and IL1B rs16944 was associated with epilepsy after HIE: CARD8 rs2043211 was associated with lower epilepsy risk, but only in carriers of two normal IL1B rs16944 alleles (ORadj = 0.03 95% CI = 0.00–0.55; padj = 0.019). Additionally, IL1B rs16944 was associated with higher epilepsy risk only in carriers of at least one polymorphic CARD8 rs2043211 (ORadj = 13.33 95% CI = 1.07–166.37; padj = 0.044). Our results suggest that gene–gene interaction in inflammation pathways might contribute to the severity of brain injury in newborns with HIE treated with therapeutic hypothermia.

The current role of NLRP3 inflammasome polymorphism in gout susceptibility.

The NLR family pyrin domain containing 3 (NLRP3) signaling pathway has an important role in inflammation mediated by monosodium urate crystals in gout, and the characterization of single nucleotide polymorphisms (SNPs) have helped to recognize disease susceptibility. The aim of this review is to provide an overview of the potential role of the inflammasome gene SNPs as a susceptibility factor for gout, discussing the current evidence available. This review analyzes the relevant literature in the field of inflammasome SNPs and gout published in the last 10years. The systematic research was performed in 16 articles, including both the SNPs associated and those not associated with gout, with the goal to have a complete overview. Sixty-nine SNPs from 10 different genes have been reported in the literature. Of these, 13 SNPs present association with gout susceptibility in different populations, while 56 have been established as not being associated with the disease. This review is a summary of the potential role of inflammasome gene SNPs and their association with gout risk, all of them related with NLRP3 inflammasome signaling, suggesting these polymorphisms are susceptibility candidates and genetic markers for gout. From the 69 SNPs analyzed in the literature, 13 of them have been associated with gout as follows: NLRP3 (rs3806268 and rs10754558), CARD8 (rs2043211), TLR4 (rs2149356), CD14 (rs2569190), IL-1β (rs1143623), P2RX7 (rs2230911, rs1653624, rs7958316 and rs17525809) and PPARGC1B (rs45520937, rs10491360 and rs7712296) in different populations.

Genetic Polymorphisms of NLRP3 (rs4612666) and CARD8 (rs2043211) in Periodontitis and Cardiovascular Diseases.

Simple SummaryResearchers have been studying the relationship between gum disease and cardiac health for decades. Gum disease develops when a sticky bacterial biofilm known as plaque forms around the teeth. The bacterial plaque and its toxic byproducts sometimes migrate inside the blood vessels and get lodged in the arterial wall known as atheroma which is found to be a leading cause for heart disease. Various host products are seen to be elevated in the human body as the result of the inflammation. We focused on the relationship between the two biomolecules namely NLRP3 (rs4612666) and CARD8 (rs2043211) with gum and heart disease. Seventy patients were selected for the study and were divided into two groups. Group I consisted of patients with gum diseases only and Group 2 consisted of patients with both gum and heart disease. On analysis, certain factors such as age, cholesterol levels and poor oral health were observed to be higher in patients with both gum and heart disease. The dental plaque from the teeth and the blood drawn from these patients were collected for the testing of the above biomolecules. These were found to be higher in patients with both gum and the heart diseases. Thus, the higher levels of the above biomolecules indicated that patients with severe gum disease and poor oral health may develop a risk to develop heart problems in the future. Thus, early prevention of the oral diseases and gum ailments might reduce the risk of the future heart diseases.Background: The existing data show that inflammasomes play a role in periodontal disease pathogenesis. However, their role in the pathogenesis of periodontitis and coronary heart disease remains unclear. This study had the objective of assessing NLRP3 (rs4612666) and CARD8 (rs2043211) gene polymorphisms in dental plaque and blood of generalized chronic periodontitis (CP) patients in the presence and absence of coronary heart disease (CHD). Methods: A total of 70 subjects were divided into two groups, including CP and CP + CHD subjects. Demographic variables, periodontal, and cardiac parameters were recorded from both groups. Subgingival plaque and blood samples were obtained from both groups and were subjected to further molecular analysis for NLRP3 (rs4612666) and CARD8 (rs2043211) expression and allele change using conventional polymerase chain reaction (PCR) and gene sequencing (Sanger’s method). Results: Amongst the demographic variables, age, and monthly income were statistically significant between the two groups. Plaque index (PI), clinical attachment level (CAL), high-density lipoprotein (HDL), and low density-lipoprotein (LDL) exhibited statistically significant levels between the two groups. NLRP3 (rs4612666) and CARD8 (rs2043211) genes showed a statistically significant association of allele change (frequency) among the groups. In general, when all of the parameters were compared to the allele change of the genes, statistically significant relationships were found between the two groups. Conclusions: The present study expressed an allele change of the investigated genes which could profoundly affect the pathobiology of the two diseases under investigation.

CARD8 and IL1B Polymorphisms Influence MRI Brain Patterns in Newborns with Hypoxic-Ischemic Encephalopathy Treated with Hypothermia.

Inflammation and oxidative stress are recognized as important contributors of brain injury in newborns due to a perinatal hypoxic-ischemic (HI) insult. Genetic variability in these pathways could influence the response to HI and the outcome of brain injury. The aim of our study was to evaluate the impact of common single-nucleotide polymorphisms in the genes involved in inflammation and response to oxidative stress on brain injury in newborns after perinatal HI insult based on the severity and pattern of magnetic resonance imaging (MRI) findings. The DNA of 44 subjects was isolated from buccal swabs. Genotyping was performed for NLRP3 rs35829419, CARD8 rs2043211, IL1B rs16944, IL1B rs1143623, IL1B rs1071676, TNF rs1800629, CAT rs1001179, SOD2 rs4880, and GPX1 rs1050450. Polymorphism in CARD8 was found to be protective against HI brain injury detected by MRI overall findings. Polymorphisms in IL1B were associated with posterior limb of internal capsule, basal ganglia, and white matter brain patterns determined by MRI. Our results suggest a possible association between genetic variability in inflammation- and antioxidant-related pathways and the severity of brain injury after HI insult in newborns.

Genetic Variability in Antioxidative and Inflammatory Pathways Modifies the Risk for PCOS and Influences Metabolic Profile of the Syndrome.

Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder of multifactorial etiopathology likely to involve the interactions between genetics and lifestyle. Chronic inflammation and oxidative stress (OS) may participate in the pathophysiology of the syndrome. The question of the extent to which OS and inflammation are causally related to the development of the syndrome and metabolic complications remains unanswered. By our knowledge, the role of the NLR family pyrin domain containing 3 (NLRP3) inflammasome as an important trigger of inflammatory pathways and NLRP3 and CARD8 polymorphisms has never been addressed in PCOS yet. We conducted a case-control study conducting of total 169 Slovenian PCOS patients and 83 healthy blood donors. They were genotyped for polymorphisms in antioxidative (SOD2 rs4880, CAT rs1001179, PON1 rs854560, and rs662) and inflammatory pathways genes (NLRP3 rs35829419, CARD8 rs2043211, TNF rs1800629, IL1B rs1143623, and rs16944, IL6 rs1800795) using competitive allele-specific polymerase chain reaction (PCR). Logistic regression and the Mann–Whitney test were used in the statistical analysis. SOD2 rs4880, CARD8 rs2043211, and IL1B rs16944 were associated with the risk of developing PCOS. Furthermore, the interactions between CARD8 rs2043211 and IL6 rs1800795 and between IL1B rs1143623 and IL6 rs1800795 also significantly affected the risk for PCOS. With regard to glucose homeostasis, CAT rs1001179, SOD2 rs4880, PON1 rs854560, NLRP3 rs35829419, and TNF rs1800629 were significantly associated with response to the glycemic load. Our data indicate that the genetic variability in the antioxidative and inflammatory pathways influences the development of PCOS and glucose homeostasis in PCOS patients.

Genetic polymorphisms and expression of NLRP3 inflammasome-related genes are associated with Philadelphia chromosome-negative myeloproliferative neoplasms

Inflammation plays a crucial role in the initiation, progression and prognosis of Philadelphia chromosome-negative myeloproliferative neoplasms (MPN), which could be clinically subdivided into polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Nucleotide binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasomes affect inflammatory diseases and carcinomas by excessive production of cytokines. To investigate a possible association of NLRP3 inflammasome signaling with MPN, we investigated the expression of selected inflammasome-related genes from bone marrow cells of 67 MPN patients as well as gene polymorphisms in NLRP3 (rs35829419), NF-κB1 (rs28362491), CARD8 (rs2043211), IL-1β (rs16944), and IL-18 (rs1946518). It showed that inflammasome-related genes (NLRP3, NF-κB1, CARD8, IL-1β, and IL-18) were highly expressed in BM cells from MPN patients and the increased expression was associated with JAK2V617F mutation, white blood cell counts and splenomegaly. Analysis of genetic polymorphisms in 269 MPN patients and 291 healthy controls demonstrated that NF-κB1 (rs28362491) was associated with MPN and increased expression of NF-κB1, NLRP3 and IL-1β. This research provided novel biomarkers and potential targets for MPN.

Association of NLRP3 and CARD8 Inflammasome Polymorphisms With Aseptic Loosening After Primary Total Hip Arthroplasty.

Our aim was to investigate the association of inflammasome polymorphisms NLRP3 rs35829419 (p. Q705K) and CARD8 rs2043211 (p. C10X) with aseptic loosening of total hip endoprostheses. We asked whether patients with the loosening of total hip arthroplasty earlier than 15 years after primary implantation had a higher proportion of the polymorphisms Q705K and C10X in comparison to subjects without loosening. A retrospective case-control study compared 36 patients with total hip endoprosthesis loosening earlier than 15 years after primary implantation and 51 control subjects with unloosened total hip endoprostheses, matched for gender, age, and follow-up period. Buccal mucosa samples were used for genomic DNA analysis and genotyped for NLRP3 rs35829419 and CARD8 rs2043211 using a fluorescence-based competitive allele-specific real-time polymerase chain reaction. The proportion of subjects with both wild-type NLRP3 and CARD8 (i.e., without Q705K or C10X) was considerably higher in the control group when compared with patients with early total hip arthroplasty loosening (49% vs. 28%; p = 0.05). After adjustment for gender, age, and follow-up, patients with combined wild type of both NLRP3 and CARD8 had significantly smaller odds for early implant loosening (odds ratio 0.33, p = 0.02). Investigated polymorphisms may influence several inflammatory pathways and contribute to the loosening of artificial implants with potential clinical significance for the appropriate selection of patients and endoprostheses when planning elective total hip arthroplasty. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:417-421, 2020.

Investigation of NF-κB-94ins/del ATTG and CARD8 (rs2043211) Gene Polymorphism in Acute Lymphoblastic Leukemia

NLRP3 inflammasome has been widely implicated in the development and progression of various hematological diseases. However, how NLRP3 inflammasome contributes to the pathogenesis and clinical features of acute lymphoblastic leukemia (ALL) is still unknown. Here, in ALL patients' bone marrow, we investigated the single-nucleotide polymorphisms (SNPs) and expression of NLRP3 inflammasome related genes, NF-κB, NLRP3, IL-1β, IL-18, Caspase-1, and ASC. A total of 308 ALL patients and 300 healthy participants were included in this study. D allele and DD genotype under codominant model of NF-κB-94ins/del ATTG were showed as a protective factor in susceptibility of ALL. As for CARD8 (rs2043211), AT/TT genotype under dominant model and TT genotype under codominant model greatly increased the ALL susceptibility. We further studied the relationship between NLRP3 inflammasome genetic polymorphisms and clinical relevance. The results showed that DD genotype of NF-κB-94 ins/del ATTG and AT/TT genotype of CARD8 (rs2043211) contributed to lower WBC count and T-cell immunophenotype, respectively. Moreover, we also found that AT and TT genotypes of CARD8 (rs2043211), GT and TT genotypes of IL-1β (rs16944), and TT genotype of IL-18 (rs1946518) were associated with higher mRNA expression of NLRP3 inflammasome related genes and secretion of downstream cytokines. In conclusion, NF-κB-94 ins/del ATTG and CARD8 (rs2043211) genotypes might serve as novel biomarkers and potential targets for ALL.

NLRP3 and CARD8 polymorphisms influence risk for asbestos-related diseases.

This study aimed to investigate the association between NLRP3 rs35829419 and CARD8 rs2043211 polymorphisms and the risk of developing pleural plaques, asbestosis, and malignant mesothelioma (MM), and to study the influence of the interactions between polymorphisms and asbestos exposure on the risk of developing these diseases. The case-control study included 416 subjects with pleural plaques, 160 patients with asbestosis, 154 subjects with MM and 149 subjects with no asbestos disease. The NLRP3 rs35829419 and CARD8 rs2043211 polymorphisms were determined using real-time PCR-based methods. In the statistical analysis, standard descriptive statistics was followed by univariate and multivariate logistic regression modelling. Asbestos exposure (medium and high vs low) was associated with the risk for each studied asbestos-related disease. An increased risk of pleural plaques was found for CARD8 rs2043211 at + TT genotypes (OR = 1.48, 95% CI 1.01-2.16, p = 0.042). When the analysis was performed for MM patients as cases, and pleural plaques patients as controls, a decreased MM risk was observed for carriers of CARD8 rs2043211 TT genotype (OR = 0.52, 95% CI 0.27-1.00, p = 0.049). The interactions between NLRP3 rs35829419 and CARD8 rs2043211 genotypes did not influence the risk of any asbestos-related disease. However, when testing interactions with asbestos exposure, a decreased risk of asbestosis was found for NLRP3 CA+AA genotypes (OR = 0.09, 95% CI 0.01-0.60, p = 0.014). The results of our study suggest that NLRP3 and CARD8 polymorphisms could affect the risk of asbestos-related diseases.

Genetic variability of inflammation and oxidative stress genes does not play a major role in the occurrence of adverse events of dopaminergic treatment in Parkinson\u2019s disease

BackgroundInflammation and oxidative stress are recognized as important contributors to Parkinson’s disease pathogenesis. As such, genetic variability in these pathways could have a role in susceptibility for the disease as well as in the treatment outcome. Dopaminergic treatment is effective in management of motor symptoms, but poses a risk for motor and non-motor adverse events. Our aim was to evaluate the impact of selected single-nucleotide polymorphisms in genes involved in inflammation and oxidative stress on Parkinson’s disease susceptibility and the occurrence of adverse events of dopaminergic treatment.MethodsIn total, 224 patients were enrolled, and their demographic and clinical data on the disease course were collected. Furthermore, a control group of 146 healthy Slovenian blood donors were included for Parkinson’s disease’ risk evaluation. Peripheral blood was obtained for DNA isolation. Genotyping was performed for NLRP3 rs35829419, CARD8 rs2043211, IL1β rs16944, IL1β rs1143623, IL6 rs1800795, CAT rs1001179, CAT rs10836235, SOD2 rs4880, NOS1 rs2293054, NOS1 rs2682826, TNF-α rs1800629, and GPX1 rs1050450. Logistic regression was used for analysis of possible associations.ResultsWe observed a nominally significant association of the IL1β rs1143623 C allele with the risk for Parkinson’s disease (OR = 0.59; 95%CI = 0.38–0.92, p = 0.021). CAT rs1001179 A allele was significantly associated with peripheral edema (OR = 0.32; 95%CI = 0.15–0.68; p = 0.003). Other associations observed were only nominally significant after adjustments: NOS1 rs2682826 A allele and excessive daytime sleepiness and sleep attacks (OR = 1.75; 95%CI = 1.00–3.06, p = 0.048), SOD2 rs4880 T allele and nausea/vomiting (OR = 0.49, 95%CI = 0.25–0.94; p = 0.031), IL1β rs1143623 C allele and orthostatic hypotension (OR = 0.57, 95%CI = 0.32–1.00, p = 0.050), and NOS1 rs2682826 A allele and impulse control disorders (OR = 2.59; 95%CI = 1.09–6.19; p = 0.032). We did not find any associations between selected polymorphisms and motor adverse events.ConclusionsApart from some nominally significant associations, one significant association between CAT genetic variability and peripheral edema was observed as well. Therefore, the results of our study suggest some links between genetic variability in inflammation- and oxidative stress-related pathways and non-motor adverse events of dopaminergic treatment. However, the investigated polymorphisms do not play a major role in the occurrence of the disease and the adverse events of dopaminergic treatment.

Inflammasome Genes' Polymorphisms in Egyptian Chronic Hepatitis C Patients: Influence on Vulnerability to Infection and Response to Treatment.

Chronic inflammation is a pivotal contributor to the liver damage mediated by hepatitis C virus (HCV). The NOD-like receptor, pyrin domain-containing 3 (NLRP3) inflammasome is activated by HCV in both hepatocytes and Kupffer cells. The aim of our study was to investigate the association of nine single-nucleotide polymorphisms in four inflammasome genes (NLRP3, CARD8, IL-1β, and IL-18) with the susceptibility to HCV infection and outcome of interferon treatment in 201 Egyptian chronic hepatitis C patients and 95 healthy controls. The genotyping was conducted using TaqMan predesigned SNP assay. In the comparative analysis, the CC genotype of the NLRP3 rs1539019 was found to be associated with the lower risk to chronic HCV infection (OR: 0.33, 95% CI: 0.17-0.62). This association was also found for the CA genotype and the A allele of the NLRP3 rs35829419 (OR: 0.18 and 0.22, respectively), in addition to the GG genotype and G allele of IL-18 rs1946518 (OR: 0.55 and 0.61, respectively). In contrast, the AA genotype of the IL-1β rs1143629 was significantly more frequent in HCV patients (OR: 1.7, 95% CI: 1-2.86). Notably, the frequency of the AA genotype of NLRP3 rs1539019 was significantly higher in patients with lack of response (NR) to the interferon treatment (OR: 1.95, 95% CI: 1-3.7). A similar association was found for both the CC genotype and C allele of the NLRP3 rs35829419 (OR: 2.78 and 2.73, respectively) and for the TT genotype and T allele of CARD8 rs2043211 (OR: 2.64 and 1.54, respectively). Yet, the IL-1β (rs1143629, rs1143634) and IL-18 (rs187238, rs1946518) polymorphisms did not show any significant association with response to interferon treatment. In conclusion, this study reports, for the first time, the association of genetic variations in NLRP3 with hepatitis C susceptibility and response to treatment in Egyptian patients. However, further large-scale studies are recommended to confirm our findings.

ANRIL as a genetic marker for cardiovascular events in renal transplant patients - an observational follow-up cohort study.

Cardiovascular disease is the leading cause of morbidity and mortality in kidney transplant recipients. Several single-nucleotide polymorphisms (SNPs) in the ANRIL gene pathway have been associated with cardiovascular events (CE). The main objective was to ascertain whether ANRIL (rs10757278) and CARD8 (rs2043211) SNPs could mediate susceptibility to CE. This was an observational follow-up cohort study of renal transplant recipients at Bellvitge University Hospital (Barcelona) from 2000 to 2014. A total of 505 recipients were followed up until achievement of a CE. Patients who did not achieve the endpoint were followed up until graft loss, lost to follow-up or death. Survival analysis was used to ascertain association between genetic markers, clinical data, and outcome. Fifty-three patients suffered a CE after renal transplantation. Results showed a significant association between ANRIL SNP and CE. Homozygous GG for the risk allele showed higher risk for CE than A carriers for the protective allele [HR = 2.93(1.69-5.11), P < 0.0001]. This effect was maintained when it was analyzed in combination with CARD8, suggesting that CARD8 SNP could play a role in the ANRIL mechanism. However, our study does not clarify the molecular mechanism for the CARD8 SNP regulation by ANRIL. ANRIL SNP may predispose to the development of CE after successful kidney transplantation.

The genetic polymorphism and expression profiles of NLRP3 inflammasome in patients with chronic myeloid leukemia

NLRP3 inflammasome has been recently reported as an important risk factor in the development of cancer. But the relationship between polymorphisms of NLRP3 inflammasome related genes and chronic myeloid leukemia (CML) is rarely reported. Therefore, the aim of the present study was to investigate the association of five genetic polymorphisms (NLRP3, IL-1β, IL-18, CARD8 and NF-κB) in 267 CML patients and 344 healthy controls. We found that the AT genotype of CARD8 (rs2043211) was significantly higher compared to TT genotype in high and intermediate risk CML patients. IL-1β (rs16944) polymorphism in early molecular response at 6 months was marginally different, with more GG and less AA genotype in BCR-ABLIS >1% group. IL-18 (rs1946518) polymorphism was significantly different with more GG genotype in BCR-ABLIS >1% group at 6 months. We also demonstrated that WBC count of newly diagnosed patients carrying AG genotype was significantly higher than that of GG or AA genotype of IL-1β (rs16944). The onset age of patients carrying ins/ins genotype of NF-κB (rs28362491) was significantly older than that of ins/del and del/del genotype. Moreover, IL-1β or NLRP3 mRNA expression was decreased and IL-18 mRNA expression was increased significantly in CML patients compared with controls. In conclusion, the genetic polymorphisms of NLRP3 inflammasome may be served as potential predictors for CML.

The Association between Polymorphism of CARD8 rs2043211 and Susceptibility to Arteriosclerosis Obliterans in Chinese Han Male Population

Background and aims: Cholesterol crystals have been shown to cause inflammation. As a response to cholesterol crystal accumulation, the NLRP3 inflammasome is activated to produce IL-1β which eventually leads to atherosclerotic lesions. As a part of innate immunity, CARD8 is involved in the modulation of above mentioned inflammatory activities. The primary objective of this study was to investigate the association between polymorphism of CARD8 rs2043211 and susceptibility to arteriosclerosis obliterans (ASO) in Chinese Han male population. Methods: 758 male arteriosclerosis obliterans patients and 793 male controls were genotyped for rs2043211 with the TaqMan allele assays. Fasting blood-glucose (FBG), total cholesterol (TC), triglycerides (TG), urea nitrogen, creatinine, Serum uric acid, high density lipoprotein, low density lipoprotein, ALT, AST, and IL-1β in the blood were detected for all subjects. Clinical data were recorded to analyze the genotype-phenotype. Independent samples t-test was used to perform the comparisons between two groups. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to measure the strength of relationship in the genotype distribution and allele frequencies between patients and controls. The analysis of variance was used for a genotype-phenotype analysis of the ASO patients. Results: The genotypic and allelic frequencies in the ASO group were significantly different from that in the control group (P = 0.014 by genotype, P = 0.003 by allele). Those carrying the genotype TT had a higher risk for ASO than those carrying the genotype AA (OR = 1.494, 95%CI1.131-1.974, P = 0.005).The difference was also significant after the adjustment for the history of smoking, TC, LDL, fasting blood glucose, systolic blood pressure and BMI(OR = 1.525, 95%CI1.158-2.009, P = 0.003). Conclusion: Our finding suggests that the polymorphism of CARD8 rs2043211 is probably associated with the development of ASO in Chinese Han male population.

Genetic polymorphisms of IL-18 rs1946518 and IL-1β rs16944 are associated with prognosis and survival of acute myeloid leukemia.

Though the pathogenesis of AML is still unknown, accumulating evidence revealed that immune response plays a vital part in it. NLRP3 inflammasome as a component of immune system has been found related to several cancers. The single nucleotide polymorphisms (SNPs) of NLRP3 inflammasome genes may be related to pathogenesis and prognosis of AML. We determined polymorphisms of NLRP3 (rs35829419), CARD8 (rs2043211), IL-1β (rs16944), IL-18 (rs1946518) and NF-κB -94 ins/del ATTG in de novo AML patients to find out whether they play roles in the susceptibility and severity of AML. In our study, 383 AML cases and 300 randomly selected healthy individuals were examined for the polymorphisms and expression of NLRP3 genes. IL-1β (rs16944) polymorphism in different risk AML subgroups was found statistically different, with more GA genotype in favorable-risk cytogenetics group. We also demonstrated that the bone marrow blasts of patients carrying IL-18 (rs1946518) GG or GT genotype were higher than patients of TT genotype. IL-18 plasma level of patients with IL-18 (rs1946518) GT or TT genotype was higher than GG genotype. Moreover, the GT genotype of IL-18 (rs1946518) led to statistically poorer AML-specific survival. IL-1β (rs16944) and IL-18 (rs1946518) may be served as potential predictors for AML.