The NLRP3 Genetic Variant (rs10754555) Reduces the Risk of Adverse Outcome in Middle-Aged Patients with Chronic Coronary Syndrome
Background. Inflammation is central in development of cardiovascular disease (CVD). Aberrant function of the Nod-Like Receptor Protein 3 (NLRP3) inflammasome, a central mediator in the proinflammatory response, has been associated with atherosclerosis. The influence of genetic determinants on this i...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Hindawi Limited
2022-01-01
|
| Series: | Journal of Immunology Research |
| Online Access: | http://dx.doi.org/10.1155/2022/2366695 |
| _version_ | 1797972551070121984 |
|---|---|
| author | Trine B. Opstad Jostein Nordeng Alf-Aage R. Pettersen Sissel Åkra Vibeke Bratseth Hani Zaidi Ragnhild Helseth Svein Solheim Ingebjørg Seljeflot |
| author_facet | Trine B. Opstad Jostein Nordeng Alf-Aage R. Pettersen Sissel Åkra Vibeke Bratseth Hani Zaidi Ragnhild Helseth Svein Solheim Ingebjørg Seljeflot |
| author_sort | Trine B. Opstad |
| collection | DOAJ |
| description | Background. Inflammation is central in development of cardiovascular disease (CVD). Aberrant function of the Nod-Like Receptor Protein 3 (NLRP3) inflammasome, a central mediator in the proinflammatory response, has been associated with atherosclerosis. The influence of genetic determinants on this inflammatory pathway and its downstream effects is less known. We aimed to investigate the frequency of a single NLRP3 gene variant according to clinical outcome in CVD and its influence on NLRP3-related markers. Methods. In this observational study, we included 1001 patients with chronic coronary syndrome. Blood samples were drawn at inclusion, including whole-blood and PAXgene tubes for DNA and RNA isolation, respectively. Allelic discrimination of the NLRP3 single nucleotide polymorphism rs10754555 was performed; and gene expression of NLRP3, Toll-Like Receptor 4, Interleukin- (IL-) 1β, and IL-18 was relatively quantified, both methods by RT-PCR. Circulating IL-6, high-sensitivity (hs) C-reactive protein, IL-18, and IL-12 were measured by enzyme-like immunosorbent assays. Clinical endpoints during 2 years (n=106) were a composite of unstable angina pectoris, myocardial infarction, nonhemorrhagic stroke, and death. Results. Minor allele frequency of the NLRP3 variant was 0.36. In all, no association of the NLRP3 variant with clinical subgroups or outcome was found, neither any significant influence on the genes’ mRNA expression or circulating protein. However, in subjects<56 years (25 percentile), the variant G-allele is associated with significant lower risk of suffering a composite event (OR=0.43 (95% CI 0.19, 0.97), p=0.043, adjusted). In the same age group, the NLRP3 gene was accordingly downregulated in G-allele carriers vs. noncarriers, and circulating IL12 was significantly reduced (p<0.05, both). In subjects>56 years, no significant effect of the variant was observed. Conclusion. The age-related reduced risk of composite endpoint in rs10754555 G-allele carriers accompanied by diminished NLRP3 mRNA expression is hypothesis generating and needs to be further explored. The study is registered at http://www.clinicaltrials.gov, with identification number NCT00222261. |
| first_indexed | 2024-04-11T03:50:15Z |
| format | Article |
| id | doaj.art-ed8375e724c34be2a4e71ac48214a653 |
| institution | Directory Open Access Journal |
| issn | 2314-7156 |
| language | English |
| last_indexed | 2024-04-11T03:50:15Z |
| publishDate | 2022-01-01 |
| publisher | Hindawi Limited |
| record_format | Article |
| series | Journal of Immunology Research |
| spelling | doaj.art-ed8375e724c34be2a4e71ac48214a6532023-01-02T02:12:47ZengHindawi LimitedJournal of Immunology Research2314-71562022-01-01202210.1155/2022/2366695The NLRP3 Genetic Variant (rs10754555) Reduces the Risk of Adverse Outcome in Middle-Aged Patients with Chronic Coronary SyndromeTrine B. Opstad0Jostein Nordeng1Alf-Aage R. Pettersen2Sissel Åkra3Vibeke Bratseth4Hani Zaidi5Ragnhild Helseth6Svein Solheim7Ingebjørg Seljeflot8Center for Clinical Heart ResearchCenter for Clinical Heart ResearchCenter for Clinical Heart ResearchCenter for Clinical Heart ResearchCenter for Clinical Heart ResearchCenter for Clinical Heart ResearchCenter for Clinical Heart ResearchCenter for Clinical Heart ResearchCenter for Clinical Heart ResearchBackground. Inflammation is central in development of cardiovascular disease (CVD). Aberrant function of the Nod-Like Receptor Protein 3 (NLRP3) inflammasome, a central mediator in the proinflammatory response, has been associated with atherosclerosis. The influence of genetic determinants on this inflammatory pathway and its downstream effects is less known. We aimed to investigate the frequency of a single NLRP3 gene variant according to clinical outcome in CVD and its influence on NLRP3-related markers. Methods. In this observational study, we included 1001 patients with chronic coronary syndrome. Blood samples were drawn at inclusion, including whole-blood and PAXgene tubes for DNA and RNA isolation, respectively. Allelic discrimination of the NLRP3 single nucleotide polymorphism rs10754555 was performed; and gene expression of NLRP3, Toll-Like Receptor 4, Interleukin- (IL-) 1β, and IL-18 was relatively quantified, both methods by RT-PCR. Circulating IL-6, high-sensitivity (hs) C-reactive protein, IL-18, and IL-12 were measured by enzyme-like immunosorbent assays. Clinical endpoints during 2 years (n=106) were a composite of unstable angina pectoris, myocardial infarction, nonhemorrhagic stroke, and death. Results. Minor allele frequency of the NLRP3 variant was 0.36. In all, no association of the NLRP3 variant with clinical subgroups or outcome was found, neither any significant influence on the genes’ mRNA expression or circulating protein. However, in subjects<56 years (25 percentile), the variant G-allele is associated with significant lower risk of suffering a composite event (OR=0.43 (95% CI 0.19, 0.97), p=0.043, adjusted). In the same age group, the NLRP3 gene was accordingly downregulated in G-allele carriers vs. noncarriers, and circulating IL12 was significantly reduced (p<0.05, both). In subjects>56 years, no significant effect of the variant was observed. Conclusion. The age-related reduced risk of composite endpoint in rs10754555 G-allele carriers accompanied by diminished NLRP3 mRNA expression is hypothesis generating and needs to be further explored. The study is registered at http://www.clinicaltrials.gov, with identification number NCT00222261.http://dx.doi.org/10.1155/2022/2366695 |
| spellingShingle | Trine B. Opstad Jostein Nordeng Alf-Aage R. Pettersen Sissel Åkra Vibeke Bratseth Hani Zaidi Ragnhild Helseth Svein Solheim Ingebjørg Seljeflot The NLRP3 Genetic Variant (rs10754555) Reduces the Risk of Adverse Outcome in Middle-Aged Patients with Chronic Coronary Syndrome Journal of Immunology Research |
| title | The NLRP3 Genetic Variant (rs10754555) Reduces the Risk of Adverse Outcome in Middle-Aged Patients with Chronic Coronary Syndrome |
| title_full | The NLRP3 Genetic Variant (rs10754555) Reduces the Risk of Adverse Outcome in Middle-Aged Patients with Chronic Coronary Syndrome |
| title_fullStr | The NLRP3 Genetic Variant (rs10754555) Reduces the Risk of Adverse Outcome in Middle-Aged Patients with Chronic Coronary Syndrome |
| title_full_unstemmed | The NLRP3 Genetic Variant (rs10754555) Reduces the Risk of Adverse Outcome in Middle-Aged Patients with Chronic Coronary Syndrome |
| title_short | The NLRP3 Genetic Variant (rs10754555) Reduces the Risk of Adverse Outcome in Middle-Aged Patients with Chronic Coronary Syndrome |
| title_sort | nlrp3 genetic variant rs10754555 reduces the risk of adverse outcome in middle aged patients with chronic coronary syndrome |
| url | http://dx.doi.org/10.1155/2022/2366695 |
| work_keys_str_mv | AT trinebopstad thenlrp3geneticvariantrs10754555reducestheriskofadverseoutcomeinmiddleagedpatientswithchroniccoronarysyndrome AT josteinnordeng thenlrp3geneticvariantrs10754555reducestheriskofadverseoutcomeinmiddleagedpatientswithchroniccoronarysyndrome AT alfaagerpettersen thenlrp3geneticvariantrs10754555reducestheriskofadverseoutcomeinmiddleagedpatientswithchroniccoronarysyndrome AT sisselakra thenlrp3geneticvariantrs10754555reducestheriskofadverseoutcomeinmiddleagedpatientswithchroniccoronarysyndrome AT vibekebratseth thenlrp3geneticvariantrs10754555reducestheriskofadverseoutcomeinmiddleagedpatientswithchroniccoronarysyndrome AT hanizaidi thenlrp3geneticvariantrs10754555reducestheriskofadverseoutcomeinmiddleagedpatientswithchroniccoronarysyndrome AT ragnhildhelseth thenlrp3geneticvariantrs10754555reducestheriskofadverseoutcomeinmiddleagedpatientswithchroniccoronarysyndrome AT sveinsolheim thenlrp3geneticvariantrs10754555reducestheriskofadverseoutcomeinmiddleagedpatientswithchroniccoronarysyndrome AT ingebjørgseljeflot thenlrp3geneticvariantrs10754555reducestheriskofadverseoutcomeinmiddleagedpatientswithchroniccoronarysyndrome AT trinebopstad nlrp3geneticvariantrs10754555reducestheriskofadverseoutcomeinmiddleagedpatientswithchroniccoronarysyndrome AT josteinnordeng nlrp3geneticvariantrs10754555reducestheriskofadverseoutcomeinmiddleagedpatientswithchroniccoronarysyndrome AT alfaagerpettersen nlrp3geneticvariantrs10754555reducestheriskofadverseoutcomeinmiddleagedpatientswithchroniccoronarysyndrome AT sisselakra nlrp3geneticvariantrs10754555reducestheriskofadverseoutcomeinmiddleagedpatientswithchroniccoronarysyndrome AT vibekebratseth nlrp3geneticvariantrs10754555reducestheriskofadverseoutcomeinmiddleagedpatientswithchroniccoronarysyndrome AT hanizaidi nlrp3geneticvariantrs10754555reducestheriskofadverseoutcomeinmiddleagedpatientswithchroniccoronarysyndrome AT ragnhildhelseth nlrp3geneticvariantrs10754555reducestheriskofadverseoutcomeinmiddleagedpatientswithchroniccoronarysyndrome AT sveinsolheim nlrp3geneticvariantrs10754555reducestheriskofadverseoutcomeinmiddleagedpatientswithchroniccoronarysyndrome AT ingebjørgseljeflot nlrp3geneticvariantrs10754555reducestheriskofadverseoutcomeinmiddleagedpatientswithchroniccoronarysyndrome |