Genetic Polymorphisms, Gene–Gene Interactions and Neurologic Sequelae at Two Years Follow-Up in Newborns with Hypoxic-Ischemic Encephalopathy Treated with Hypothermia
Abstract
:1. Introduction
2. Subjects and Methods
2.1. Study Population
2.2. MR Scoring System
2.3. DNA Extraction and Genotyping
2.4. Statistical Analysis
3. Results
3.1. Association of Polymorphisms in Antioxidant and Inflammatory Pathways with Epilepsy and CP
3.2. Association of Gene-gene Interactions with Epilepsy and CP
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Lai, M.-C.; Yang, S.-N. Perinatal Hypoxic-Ischemic Encephalopathy. J. Biomed. Biotechnol. 2011, 2011, 609813. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Polin, R.A.; Randis, T.M.; Sahni, R. Systemic hypothermia to decrease morbidity of hypoxic-ischemic brain injury. J. Perinatol. 2007, 27, S47–S58. [Google Scholar] [CrossRef] [Green Version]
- Natarajan, G.; Pappas, A.; Shankaran, S. Outcomes in childhood following therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy (HIE). Semin. Perinatol. 2016, 40, 549–555. [Google Scholar] [CrossRef] [Green Version]
- Gano, D.; Orbach, S.A.; Bonifacio, S.L.; Glass, H.C. Neonatal seizures and therapeutic hypothermia for hypoxic-ischemic encephalopathy. Mol. Cell Epilepsy 2014, 1, e88. [Google Scholar] [CrossRef] [PubMed]
- Davidson, J.O.; Wassink, G.; van den Heuij, L.G.; Bennet, L.; Gunn, A.J. Therapeutic Hypothermia for Neonatal Hypoxic–Ischemic Encephalopathy – Where to from Here? Front. Neurol. 2015, 6, 198. [Google Scholar] [CrossRef] [Green Version]
- Robertson, C.M.; Perlman, M. Follow-up of the term infant after hypoxic-ischemic encephalopathy. Paediatr. Child Health 2006, 11, 278–282. [Google Scholar]
- McAdams, R.M.; Fleiss, B.; Traudt, C.; Schwendimann, L.; Snyder, J.M.; Haynes, R.L.; Natarajan, N.; Gressens, P.; Juul, S.E. Long-Term Neuropathological Changes Associated with Cerebral Palsy in a Nonhuman Primate Model of Hypoxic-Ischemic Encephalopathy. Dev. Neurosci. 2017, 39, 124–140. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Shankaran, S.; Laptook, A.R.; Ehrenkranz, R.A.; Tyson, J.E.; McDonald, S.A.; Donovan, E.F.; Fanaroff, A.A.; Poole, W.K.; Wright, L.L.; Higgins, R.D.; et al. Whole-Body Hypothermia for Neonates with Hypoxic–Ischemic Encephalopathy. N. Engl. J. Med. 2005, 353, 1574–1584. [Google Scholar] [CrossRef]
- Joy, R.; Pournami, F.; Bethou, A.; Bhat, V.B.; Bobby, Z. Effect of therapeutic hypothermia on oxidative stress and outcome in term neonates with perinatal asphyxia: A randomized controlled trial. J. Trop. Pediatr. 2013, 59, 17–22. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hakobyan, M.; Dijkman, K.P.; Laroche, S.; Naulaers, G.; Rijken, M.; Steiner, K.; van Straaten, H.L.M.; Swarte, R.M.C.; Ter Horst, H.J.; Zecic, A.; et al. Outcome of Infants with Therapeutic Hypothermia after Perinatal Asphyxia and Early-Onset Sepsis. Neonatology 2019, 115, 127–133. [Google Scholar] [CrossRef]
- Sutcliffe, I.T.; Smith, H.A.; Stanimirovic, D.; Hutchison, J.S. Effects of moderate hypothermia on IL-1 beta-induced leukocyte rolling and adhesion in pial microcirculation of mice and on proinflammatory gene expression in human cerebral endothelial cells. J. Cereb. Blood Flow Metab. 2001, 21, 1310–1319. [Google Scholar] [CrossRef] [Green Version]
- Shi, J.; Dai, W.; Kloner, R.A. Therapeutic Hypothermia Reduces the Inflammatory Response Following Ischemia/Reperfusion Injury in Rat Hearts. Hypothermia Temp. Manag. 2017, 7, 162–170. [Google Scholar] [CrossRef]
- Del Arco, L.; Alonso-Alconada, D. Current Research in Neonatal Hypoxic-Ischemic Anti-Inflammatory Therapeutics. EC Paediatrics 2018, 73, 168–170. [Google Scholar]
- Nair, J.; Kumar, V.H.S. Current and Emerging Therapies in the Management of Hypoxic Ischemic Encephalopathy in Neonates. Children 2018, 5, 99. [Google Scholar] [CrossRef] [Green Version]
- Volpe, J.J. Volpe’s Neurology of the Newborn; Elsevier: Amsterdam, The Netherlands, 2018. [Google Scholar]
- Ghei, S.K.; Zan, E.; Nathan, J.E.; Choudhri, A.; Tekes, A.; Huisman, T.A.; Izbudak, I. MR imaging of hypoxic-ischemic injury in term neonates: Pearls and pitfalls. Radiographics 2014, 34, 1047–1061. [Google Scholar] [CrossRef]
- Millar, L.J.; Shi, L.; Hoerder-Suabedissen, A.; Molnár, Z. Neonatal Hypoxia Ischaemia: Mechanisms, Models, and Therapeutic Challenges. Front. Cell. Neurosci. 2017, 11, 78. [Google Scholar] [CrossRef] [Green Version]
- McDonough, T.L.; Paolicchi, J.M.; Heier, L.A.; Das, N.; Engel, M.; Perlman, J.M.; Grinspan, Z.M. Prediction of Future Epilepsy in Neonates With Hypoxic-Ischemic Encephalopathy Who Received Selective Head Cooling. J. Child Neurol. 2017, 32, 630–637. [Google Scholar] [CrossRef] [PubMed]
- Jung, D.E.; Ritacco, D.G.; Nordli, D.R.; Koh, S.; Venkatesan, C. Early Anatomical Injury Patterns Predict Epilepsy in Head Cooled Neonates With Hypoxic-Ischemic Encephalopathy. Pediatr. Neurol. 2015, 53, 135–140. [Google Scholar] [CrossRef] [Green Version]
- Martinez-Biarge, M.; Diez-Sebastian, J.; Kapellou, O.; Gindner, D.; Allsop, J.M.; Rutherford, M.A.; Cowan, F.M. Predicting motor outcome and death in term hypoxic-ischemic encephalopathy. Neurology 2011, 76, 2055–2061. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Forsberg, L.; Lyrenäs, L.; de Faire, U.; Morgenstern, R. A common functional C-T substitution polymorphism in the promoter region of the human catalase gene influences transcription factor binding, reporter gene transcription and is correlated to blood catalase levels. Free Radic Biol. Med. 2001, 30, 500–505. [Google Scholar] [CrossRef]
- Esih, K.; Goričar, K.; Dolžan, V.; Rener-Primec, Z. The association between antioxidant enzyme polymorphisms and cerebral palsy after perinatal hypoxic-ischaemic encephalopathy. Eur. J. Paediatr. Neurol. 2016, 20, 704–708. [Google Scholar] [CrossRef] [PubMed]
- Esih, K.; Goričar, K.; Dolžan, V.; Rener-Primec, Z. Antioxidant polymorphisms do not influence the risk of epilepsy or its drug resistance after neonatal hypoxic-ischemic brain injury. Seizure 2017, 46, 38–42. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sun, L.; Xia, L.; Wang, M.; Zhu, D.; Wang, Y.; Bi, D.; Song, J.; Ma, C.; Gao, C.; Zhang, X.; et al. Variants of the OLIG2 Gene are Associated with Cerebral Palsy in Chinese Han Infants with Hypoxic-Ischemic Encephalopathy. Neuromolecular Med. 2019, 21, 75–84. [Google Scholar] [CrossRef] [PubMed]
- Wang, H.; Xu, Y.; Chen, M.; Shang, Q.; Sun, Y.; Zhu, D.; Wang, L.; Huang, Z.; Ma, C.; Li, T.; et al. Genetic association study of adaptor protein complex 4 with cerebral palsy in a Han Chinese population. Mol. Biol. Rep. 2013, 40, 6459–6467. [Google Scholar] [CrossRef]
- Torres-Merino, S.; Moreno-Sandoval, H.N.; Thompson-Bonilla, M.D.R.; Leon, J.A.O.; Gomez-Conde, E.; Leon-Chavez, B.A.; Martinez-Fong, D.; Gonzalez-Barrios, J.A. Association Between rs3833912/rs16944 SNPs and Risk for Cerebral Palsy in Mexican Children. Mol. Neurobiol. 2019, 56, 1800–1811. [Google Scholar] [CrossRef] [Green Version]
- Weeke, L.C.; Groenendaal, F.; Mudigonda, K.; Blennow, M.; Lequin, M.H.; Meiners, L.C.; van Haastert, I.C.; Benders, M.J.; Hallberg, B.; de Vries, L.S. A Novel Magnetic Resonance Imaging Score Predicts Neurodevelopmental Outcome After Perinatal Asphyxia and Therapeutic Hypothermia. J. Pediatr. 2018, 192, 33–40. [Google Scholar] [CrossRef] [Green Version]
- Sarnat, H.B.; Sarnat, M.S. Neonatal Encephalopathy Following Fetal Distress: A Clinical and Electroencephalographic Study. Arch. Neurol. 1976, 33, 696–705. [Google Scholar] [CrossRef]
- Fisher, R.S.; Acevedo, C.; Arzimanoglou, A.; Bogacz, A.; Cross, J.H.; Elger, C.E.; Engel, J., Jr.; Forsgren, L.; French, J.A.; Glynn, M.; et al. ILAE official report: A practical clinical definition of epilepsy. Epilepsia 2014, 55, 475–482. [Google Scholar] [CrossRef] [Green Version]
- Bax, M.; Goldstein, M.; Rosenbaum, P.; Leviton, A.; Paneth, N.; Dan, B.; Jacobsson, B.; Damiano, D. Proposed definition and classification of cerebral palsy, April 2005. Dev. Med. Child Neurol. 2005, 47, 571–576. [Google Scholar] [CrossRef]
- Cans, C. Surveillance of cerebral palsy in Europe: A collaboration of cerebral palsy surveys and registers. Dev. Med. Child Neurol. 2000, 42, 816–824. [Google Scholar] [CrossRef]
- Esih, K.; Goričar, K.; Rener-Primec, Z.; Dolžan, V.; Soltirovska-Šalamon, A. CARD8 and IL1B Polymorphisms Influence MRI Brain Patterns in Newborns with Hypoxic-Ischemic Encephalopathy Treated with Hypothermia. Antioxidants 2021, 10, 96. [Google Scholar] [CrossRef]
- Rutherford, M.; Ramenghi, L.A.; Edwards, A.D.; Brocklehurst, P.; Halliday, H.; Levene, M.; Strohm, B.; Thoresen, M.; Whitelaw, A.; Azzopardi, D. Assessment of brain tissue injury after moderate hypothermia in neonates with hypoxic-ischaemic encephalopathy: A nested substudy of a randomised controlled trial. Lancet Neurol. 2010, 9, 39–45. [Google Scholar] [CrossRef] [Green Version]
- Procianoy, R.S.; Corso, A.L.; Longo, M.G.; Vedolin, L.; Silveira, R.C. Therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy: Magnetic resonance imaging findings and neurological outcomes in a Brazilian cohort. J. Matern. Fetal Neonatal. Med. 2019, 32, 2727–2734. [Google Scholar] [CrossRef]
- Martinez-Biarge, M.; Diez-Sebastian, J.; Rutherford, M.A.; Cowan, F.M. Outcomes after central grey matter injury in term perinatal hypoxic-ischaemic encephalopathy. Early Hum. Dev. 2010, 86, 675–682. [Google Scholar] [CrossRef] [PubMed]
- Trivedi, S.B.; Vesoulis, Z.A.; Rao, R.; Liao, S.M.; Shimony, J.S.; McKinstry, R.C.; Mathur, A.M. A validated clinical MRI injury scoring system in neonatal hypoxic-ischemic encephalopathy. Pediatr. Radiol. 2017, 47, 1491–1499. [Google Scholar] [CrossRef] [PubMed]
- Tregouet, D.A.; Garelle, V. A new JAVA interface implementation of THESIAS: Testing haplotype effects in association studies. Bioinformatics 2007, 23, 1038–1039. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dupont, W.D.; Plummer, W.D., Jr. Power and sample size calculations. A review and computer program. Control Clin. Trials 1990, 11, 116–128. [Google Scholar] [CrossRef]
- Jacobs, S.E.; Berg, M.; Hunt, R.; Tarnow-Mordi, W.O.; Inder, T.E.; Davis, P.G. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst. Rev. 2013, 2013, CD003311. [Google Scholar] [CrossRef] [PubMed]
- Pisani, F.; Piccolo, B.; Cantalupo, G.; Copioli, C.; Fusco, C.; Pelosi, A.; Tassinari, C.A.; Seri, S. Neonatal seizures and postneonatal epilepsy: A 7-y follow-up study. Pediatric Res. 2012, 72, 186–193. [Google Scholar] [CrossRef] [Green Version]
- Lin, Y.-K.; Hwang-Bo, S.; Seo, Y.-M.; Youn, Y.-A. Clinical seizures and unfavorable brain MRI patterns in neonates with hypoxic ischemic encephalopathy. Medicine 2021, 100, e25118. [Google Scholar] [CrossRef] [PubMed]
- Nanavati, T.; Seemaladinne, N.; Regier, M.; Yossuck, P.; Pergami, P. Can We Predict Functional Outcome in Neonates with Hypoxic Ischemic Encephalopathy by the Combination of Neuroimaging and Electroencephalography? Pediatr. Neonatol. 2015, 56, 307–316. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bai, Y.; Nie, S.; Jiang, G.; Zhou, Y.; Zhou, M.; Zhao, Y.; Li, S.; Wang, F.; Lv, Q.; Huang, Y.; et al. Regulation of CARD8 expression by ANRIL and association of CARD8 single nucleotide polymorphism rs2043211 (p.C10X) with ischemic stroke. Stroke 2014, 45, 383–388. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bagnall, R.D.; Roberts, R.G.; Mirza, M.M.; Torigoe, T.; Prescott, N.J.; Mathew, C.G. Novel isoforms of the CARD8 (TUCAN) gene evade a nonsense mutation. Eur. J. Hum. Genet. 2008, 16, 619–625. [Google Scholar] [CrossRef]
- Wang, Y.; Xu, Y.; Fan, Y.; Bi, D.; Song, J.; Xia, L.; Shang, Q.; Gao, C.; Zhang, X.; Zhu, D.; et al. The Association Study of IL-23R Polymorphisms With Cerebral Palsy in Chinese Population. Front. Neurosci. 2020, 14, 590098. [Google Scholar] [CrossRef]
- Herman, R.; Jensterle, M.; Janez, A.; Goricar, K.; Dolzan, V. Genetic Variability in Antioxidative and Inflammatory Pathways Modifies the Risk for PCOS and Influences Metabolic Profile of the Syndrome. Metabolites 2020, 10, 439. [Google Scholar] [CrossRef]
- McGovern, D.P.; Butler, H.; Ahmad, T.; Paolucci, M.; van Heel, D.A.; Negoro, K.; Hysi, P.; Ragoussis, J.; Travis, S.P.; Cardon, L.R.; et al. TUCAN (CARD8) genetic variants and inflammatory bowel disease. Gastroenterology 2006, 131, 1190–1196. [Google Scholar] [CrossRef]
- Lv, J.; Jiang, X.; Zhang, J.; Peng, X.; Lin, H. Combined polymorphisms in genes encoding the inflammasome components NLRP3 and CARD8 confer risk of ischemic stroke in men. J. Stroke Cereb. Dis. 2020, 29, 104874. [Google Scholar] [CrossRef] [PubMed]
- Roberts, R.L.; Topless, R.K.; Phipps-Green, A.J.; Gearry, R.B.; Barclay, M.L.; Merriman, T.R. Evidence of interaction of CARD8 rs2043211 with NALP3 rs35829419 in Crohn’s disease. Genes Immun. 2010, 11, 351–356. [Google Scholar] [CrossRef]
- Fontalba, A.; Gutiérrez, O.; Llorca, J.; Mateo, I.; Berciano, J.; Fernández-Luna, J.L.; Combarros, O. Deficiency of CARD8 Is Associated with Increased Alzheimer’s Disease Risk in Women. Dement. Geriatr. Cogn. Disord. 2008, 26, 247–250. [Google Scholar] [CrossRef]
- Chen, Y.; Ren, X.; Li, C.; Xing, S.; Fu, Z.; Yuan, Y.; Wang, R.; Wang, Y.; Lv, W. CARD8 rs2043211 Polymorphism is Associated with Gout in a Chinese Male Population. Cell. Physiol. Biochem. 2015, 35, 1394–1400. [Google Scholar] [CrossRef]
- Mao, L.; Kitani, A.; Similuk, M.; Oler, A.J.; Albenberg, L.; Kelsen, J.; Aktay, A.; Quezado, M.; Yao, M.; Montgomery-Recht, K.; et al. Loss-of-function CARD8 mutation causes NLRP3 inflammasome activation and Crohn’s disease. J. Clin. Investig. 2018, 128, 1793–1806. [Google Scholar] [CrossRef]
- Kanemoto, K.; Kawasaki, J.; Miyamoto, T.; Obayashi, H.; Nishimura, M. Interleukin (IL)1beta, IL-1alpha, and IL-1 receptor antagonist gene polymorphisms in patients with temporal lobe epilepsy. Ann. Neurol. 2000, 47, 571–574. [Google Scholar] [CrossRef]
- Papiol, S.; Molina, V.; Rosa, A.; Sanz, J.; Palomo, T.; Fañanás, L. Effect of interleukin-1beta gene functional polymorphism on dorsolateral prefrontal cortex activity in schizophrenic patients. Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007, 144B, 1090–1093. [Google Scholar] [CrossRef]
- Hall, S.K.; Perregaux, D.G.; Gabel, C.A.; Woodworth, T.; Durham, L.K.; Huizinga, T.W.; Breedveld, F.C.; Seymour, A.B. Correlation of polymorphic variation in the promoter region of the interleukin-1 beta gene with secretion of interleukin-1 beta protein. Arthritis Rheum. 2004, 50, 1976–1983. [Google Scholar] [CrossRef] [PubMed]
- Wang, J.; Shi, Y.; Wang, G.; Dong, S.; Yang, D.; Zuo, X. The association between interleukin-1 polymorphisms and their protein expression in Chinese Han patients with breast cancer. Mol. Genet. Genom. Med. 2019, 7, e804. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tiwari, P.; Dwivedi, R.; Mansoori, N.; Alam, R.; Chauhan, U.K.; Tripathi, M.; Mukhopadhyay, A.K. Do gene polymorphism in IL-1β, TNF-α and IL-6 influence therapeutic response in patients with drug refractory epilepsy? Epilepsy Res. 2012, 101, 261–267. [Google Scholar] [CrossRef]
- Fan, X.; Chen, Y.; Li, W.; Xia, H.; Liu, B.; Guo, H.; Yang, Y.; Xu, C.; Xie, S.; Xu, X. Genetic Polymorphism of ADORA2A Is Associated With the Risk of Epilepsy and Predisposition to Neurologic Comorbidity in Chinese Southern Children. Front. Neurosci. 2020, 14, 590605. [Google Scholar] [CrossRef] [PubMed]
- Kukec, E.; Goričar, K.; Dolžan, V.; Rener-Primec, Z. HIF1A polymorphisms do not modify the risk of epilepsy nor cerebral palsy after neonatal hypoxic-ischemic encephalopathy. Brain Res. 2021, 1757, 147281. [Google Scholar] [CrossRef] [PubMed]
Clinical Characteristic | Category | N (%) |
---|---|---|
Sex | Male | 33 (60.0) |
Mode of delivery | Vaginal | 16 (31.4) [4] |
Caesarean section | 31 (60.8) | |
Vacuum extraction | 4 (7.8) | |
Apgar score in 5 min | ≤5 | 40 (81.6) [6] |
>5 | 9 (18.4) | |
Apgar score in 10 min | ≤5 | 21 (46.7) [10] |
>5 | 24 (53.3) | |
Sarnat and Sarnat score | 2 | 25 (48.1) [3] |
3 | 27 (51.9) | |
Neonatal convulsions | No | 23 (43.4) [2] |
Yes | 30 (55.6) | |
Epilepsy | No | 39 (70.9) |
Yes | 16 (29.1) | |
Cerebral palsy | No | 40 (72.7) |
Yes | 15 (27.3) | |
GMCSF (1–5) | 1 | 1 (7.1) [1] |
2 | 1 (7.1) | |
3 | 2 (14.3) | |
4 | 2 (14.3) | |
5 | 8 (57.1) | |
Cerebral palsy type | Spastic | 11 (73.3) |
Dystonic | 2 (13.3) | |
Spastic-dystonic | 2 (13.3) | |
Clinical Characteristic | Unit | Median (25–75%) |
Gestational age | weeks | 39 (38–40) [2] |
Birthweight | g | 3300 (2793–3500) [5] |
Head circumference | cm | 34.8 (33–35.5) [11] |
Characteristic | Epilepsy N (%) | OR (95% CI) | p-Value | CP N (%) | OR (95% CI) | p-Value | |
---|---|---|---|---|---|---|---|
Gender | Male | 10 (30.3) | Ref. | 9 (27.3) | Ref. | ||
Female | 6 (27.3) | 0.86 (0.26–2.85) | 0.809 | 6 (27.3) | 1.00 (0.30–3.36) | 1.000 | |
Mode of delivery | Vaginal/vacuum | 9 (45.0) | Ref. | 7 (35.0) | Ref. | ||
Caesarean section | 6 (19.4) | 0.29 (0.08–1.03) | 0.055 | 6 (19.4) | 0.45 (0.12–1.60) | 0.216 | |
Apgar score in 5 min | >5 | 3 (33.3) | Ref. | 2 (22.2) | Ref. | ||
≤5 | 12 (30.0) | 0.86 (0.18–4.01) | 0.845 | 12 (30.0) | 1.50 (0.27–8.30) | 0.642 | |
Apgar score in 10 min | >5 | 4 (16.7) | Ref. | 4 (16.7) | Ref. | ||
≤5 | 8 (38.1) | 3.08 (0.77–12.34) | 0.113 | 8 (38.1) | 3.08 (0.77–12.34) | 0.113 | |
Sarnat and Sarnat grading | 2 | 7 (28.0) | Ref. | 5 (20.0) | Ref. | ||
3 | 9 (33.3) | 1.29 (0.39–4.20) | 0.677 | 10 (37.0) | 2.35 (0.67–8.24) | 0.181 | |
Neonatal convulsions | No, N (%) | 2 (8.7) | Ref. | 2 (8.7) | Ref. | ||
Yes, N (%) | 14 (46.7) | 9.19 (1.82–46.34) | 0.007 | 13 (43.3) | 8.03 (1.59–40.58) | 0.012 |
MRI Brain Pattern Overall Assessment | Without Epilepsy N (%) | With Epilepsy N (%) | OR (95% CI) | p-Value | without CP N (%) | with CP N (%) | p-Value |
---|---|---|---|---|---|---|---|
Normal + mild | 25 (96.2) | 1 (3.8) | Ref. | 26 (100.0) | 0 (0.0) | ||
Moderate + severe | 6 (35.3) | 11 (64.7) | 45.83 (4.92–427.36) | 0.001 | 8 (47.1) | 9 (52.9) | <0.001 * |
SNP | Genotype | without Epilepsy N (%) | with Epilepsy N (%) | OR (95% CI) | p | OR (95% CI) Adj | Padj |
---|---|---|---|---|---|---|---|
SOD2 rs4880 | CC | 12 (70.6) | 5 (29.4) | Ref. | Ref. | ||
CT + TT | 27 (71.1) | 11 (28.9) | 0.98 (0.28–3.44) | 0.972 | 1.1 (0.27–4.4) | 0.894 | |
CAT rs1001179 | CC | 24 (64.9) | 13 (35.1) | Ref. | Ref. | ||
CT + TT | 15 (83.3) | 3 (16.7) | 0.37 (0.09–1.51) | 0.166 | 0.36 (0.08–1.65) | 0.187 | |
GPX1 rs1050450 | CC | 17 (68) | 8 (32) | Ref. | Ref. | ||
CT + TT | 22 (73.3) | 8 (26.7) | 0.77 (0.24–2.48) | 0.665 | 1.07 (0.29–3.95) | 0.914 | |
NLRP3 rs35829419 | CC | 34 (72.3) | 13 (27.7) | Ref. | Ref. | ||
CA | 5 (62.5) | 3 (37.5) | 1.57 (0.33–7.52) | 0.573 | 1.38 (0.24–7.76) | 0.717 | |
CARD8 rs2043211 | AA | 17 (63) | 10 (37) | Ref. | Ref. | ||
AT + TT | 22 (78.6) | 6 (21.4) | 0.46 (0.14–1.53) | 0.207 | 0.27 (0.07–1.11) | 0.070 | |
IL1B rs1143623 | GG | 21 (75) | 7 (25) | Ref. | Ref. | ||
GC + CC | 18 (66.7) | 9 (33.3) | 1.50 (0.46–4.84) | 0.497 | 1.86 (0.5–6.92) | 0.352 | |
IL1B rs16944 | CC | 21 (77.8) | 6 (22.2) | Ref. | Ref. | ||
TC + TT | 18 (64.3) | 10 (35.7) | 1.94 (0.59–6.40) | 0.274 | 1.99 (0.54–7.42) | 0.303 | |
IL1B rs1071676 | GG | 14 (63.6) | 8 (36.4) | Ref. | Ref. | ||
GC + CC | 25 (75.8) | 8 (24.2) | 0.56 (0.17–1.82) | 0.335 | 0.58 (0.16–2.13) | 0.411 | |
TNF rs1800629 | GG | 27 (73) | 10 (27) | Ref. | Ref. | ||
GA + AA | 12 (66.7) | 6 (33.3) | 1.35 (0.40–4.57) | 0.630 | 1.18 (0.31–4.54) | 0.811 |
SNP | Genotype | without CP N (%) | with CP N (%) | OR (95% CI) | p | OR (95% CI) Adj | Padj |
---|---|---|---|---|---|---|---|
SOD2 rs4880 | CC | 11 (64.7) | 6 (35.3) | Ref. | Ref. | ||
CT + TT | 29 (76.3) | 9 (23.7) | 0.57 (0.16–1.97) | 0.374 | 0.57 (0.14–2.24) | 0.419 | |
CAT rs1001179 | CC | 25 (67.6) | 12 (32.4) | Ref. | Ref. | ||
CT + TT | 15 (83.3) | 3 (16.7) | 0.42 (0.10–1.72) | 0.226 | 0.42 (0.09–1.91) | 0.262 | |
GPX1 rs1050450 | CC | 18 (72) | 7 (28) | Ref. | Ref. | ||
CT + TT | 22 (73.3) | 8 (26.7) | 0.94 (0.28–3.07) | 0.912 | 1.33 (0.35–4.96) | 0.675 | |
NLRP3 rs35829419 | CC | 34 (72.3) | 13 (27.7) | Ref. | Ref. | ||
CA | 6 (75) | 2 (25) | 0.87 (0.16–4.88) | 0.876 | 0.7 (0.11–4.39) | 0.701 | |
CARD8 rs2043211 | AA | 18 (66.7) | 9 (33.3) | Ref. | Ref. | ||
AT + TT | 22 (78.6) | 6 (21.4) | 0.55 (0.16–1.82) | 0.325 | 0.36 (0.09–1.41) | 0.143 | |
IL1B rs1143623 | GG | 22 (78.6) | 6 (21.4) | Ref. | Ref. | ||
GC + CC | 18 (66.7) | 9 (33.3) | 1.83 (0.55–6.13) | 0.325 | 2.32 (0.61–8.84) | 0.216 | |
IL1B rs16944 | CC | 22 (81.5) | 5 (18.5) | Ref. | Ref. | ||
TC + TT | 18 (64.3) | 10 (35.7) | 2.44 (0.71–8.46) | 0.158 | 2.58 (0.67–9.94) | 0.169 | |
IL1B rs1071676 | GG | 15 (68.2) | 7 (31.8) | Ref. | Ref. | ||
GC + CC | 25 (75.8) | 8 (24.2) | 0.69 (0.21–2.28) | 0.538 | 0.74 (0.2–2.74) | 0.653 | |
TNF rs1800629 | GG | 29 (78.4) | 8 (21.6) | Ref. | Ref. | ||
GA + AA | 11 (61.1) | 7 (38.9) | 2.31 (0.67–7.88) | 0.183 | 2.25 (0.58–8.7) | 0.238 |
Epilepsy | CP | |||||||
---|---|---|---|---|---|---|---|---|
Interaction | OR (95% CI) | p | OR (95% CI) adj | Padj | OR (95% CI) | p | OR (95% CI) adj | Padj |
CARD8 rs2043211 & IL1B rs1143623 | 5.00 (0.42–59.16) | 0.202 | 20.20 (0.99–412.40) | 0.051 | 3.50 (0.29–42.46) | 0.325 | 9.93 (0.56–175.78) | 0.117 |
CARD8 rs2043211 & IL1B rs16944 | 12.50 (0.76–205.33) | 0.077 | 32.91 (1.33–811.49) | 0.033 | 8.75 (0.52–146.93) | 0.132 | 16.96 (0.77–375.99) | 0.073 |
CARD8 rs2043211 & IL1B rs1071676 | 0.90 (0.07–11.43) | 0.937 | 0.47 (0.03–8.21) | 0.608 | 2.80 (0.23–33.93) | 0.419 | 1.85 (0.12–28.78) | 0.660 |
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Esih, K.; Goričar, K.; Soltirovska-Šalamon, A.; Dolžan, V.; Rener-Primec, Z. Genetic Polymorphisms, Gene–Gene Interactions and Neurologic Sequelae at Two Years Follow-Up in Newborns with Hypoxic-Ischemic Encephalopathy Treated with Hypothermia. Antioxidants 2021, 10, 1495. https://doi.org/10.3390/antiox10091495
Esih K, Goričar K, Soltirovska-Šalamon A, Dolžan V, Rener-Primec Z. Genetic Polymorphisms, Gene–Gene Interactions and Neurologic Sequelae at Two Years Follow-Up in Newborns with Hypoxic-Ischemic Encephalopathy Treated with Hypothermia. Antioxidants. 2021; 10(9):1495. https://doi.org/10.3390/antiox10091495
Chicago/Turabian StyleEsih, Katarina, Katja Goričar, Aneta Soltirovska-Šalamon, Vita Dolžan, and Zvonka Rener-Primec. 2021. "Genetic Polymorphisms, Gene–Gene Interactions and Neurologic Sequelae at Two Years Follow-Up in Newborns with Hypoxic-Ischemic Encephalopathy Treated with Hypothermia" Antioxidants 10, no. 9: 1495. https://doi.org/10.3390/antiox10091495
APA StyleEsih, K., Goričar, K., Soltirovska-Šalamon, A., Dolžan, V., & Rener-Primec, Z. (2021). Genetic Polymorphisms, Gene–Gene Interactions and Neurologic Sequelae at Two Years Follow-Up in Newborns with Hypoxic-Ischemic Encephalopathy Treated with Hypothermia. Antioxidants, 10(9), 1495. https://doi.org/10.3390/antiox10091495