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Published on: November 20, 2015
The association between proinflammatory cytokine polymorphisms and cerebral palsy in very preterm infants
Helena Kapitanović Vidak1, Tina Catela Ivković, Mladen Jokić
1Special Hospital for Children with Neurodevelopmental and Motor Difficulties, Goljak 2, Zagreb, Croatia.
Insights
Certain gene variations in TNFα and IL1β are linked to an increased risk of cerebral palsy (CP) in very preterm infants, particularly those with cystic periventricular leukomalacia (cPVL). These genetic factors may contribute to white matter damage and CP development.
Area of Science:
- Genetics
- Neonatology
- Immunology
Background:
- Cerebral palsy (CP) is a nonprogressive motor disorder resulting from white matter damage in the developing brain, often associated with cognitive and sensory deficits.
- Infants born preterm face a higher risk of CP, with intrauterine infection/inflammation being a common cause of preterm delivery and subsequent brain injury.
- Elevated proinflammatory cytokines are implicated in preterm delivery, periventricular leukomalacia (PVL), and CP.
Purpose of the Study:
- To investigate the association between specific single nucleotide polymorphisms (SNPs) in TNFα, IL1β, and IL6 genes and the susceptibility to CP in very preterm infants.
- To explore potential links between these genetic variations and the risk of developing CP, especially in the context of cystic PVL (cPVL).
Main Methods:
- Genotyping of four TNFα promoter SNPs (-1031 T/C, -857 C/T, -308 G/A, -238 G/A), two IL1β SNPs (-511 C/T, +3954 C/T), and one IL6 SNP (-174 C/G).
- Statistical analysis to determine the association between these SNPs and the risk of CP in very preterm infants, including subgroup analysis for infants with cPVL.
Main Results:
- A significant association was observed between TNFα -1031 T/C high expression genotypes (TC, CC) and allele (C) and the risk of CP.
- Combined genotypes of TNFα (-1031/-857/-308/-238) and IL1β (-511/+3954) showed a statistically significant association with CP risk.
- In CP patients with cPVL, specific TNFα and IL1β high expression genotypes/alleles were significantly associated with increased CP risk, including combined genotype analyses.
Conclusions:
- The study suggests that polymorphisms in TNFα and IL1β genes, previously linked to higher cytokine levels, play a role in the genetic susceptibility to white matter damage and CP in very preterm infants.
- These findings highlight the potential contribution of specific genetic variations to the pathogenesis of CP, particularly in the context of inflammation and preterm birth.
Abstract:
Cerebral palsy (CP) is a nonprogressive motor disorder caused by white matter damage in the developing brain and is often accompanied with cognitive and sensory disabilities. The risk of CP is higher among infants born preterm than in more mature infants. Intrauterine infection/inflammation, activation of the cytokine network and elevated levels of proinflammatory cytokines in neonatal blood or in amniotic fluid to which the preterm infant is exposed, has been identified as the most common cause of preterm delivery, periventricular leukomalacia (PVL) and CP. The aim of our study was to evaluate the possible association of four TNFα promoter single nucleotide polymorphisms (SNPs) (-1031 T/C, -857 C/T, -308 G/A and -238 G/A), two IL1β SNPs (-511 C/T and +3954 C/T) and one IL6 (-174 C/G) polymorphism with susceptibility to CP in very preterm infants. Statistically significant association between TNFα -1031 T/C high expression genotypes (TC and CC) (OR, 2.339; p=0.016) as well as between TNFα -1031 C high expression allele (OR, 2.065; p=0.013) and risk of CP was observed. In addition, statistically significant association was found between TNFα TC, CC, GG, GG -1031/-857/-308/-238 genotypes combination (OR, 3.286; p=0.034) and risk of CP. Statistically significant association between IL1β TT, CC -511/+3954 genotypes combination and risk of CP (OR, 4.000; p=0.027) was also found. In CP patients with cystic PVL (cPVL) statistically significant association was found between TNFα -1031 T/C high expression genotypes (TC and CC) (OR, 2.361; p=0.038), IL1β -511 C/T high expression genotype TT (OR, 3.215; p=0.030) as well as IL1β -511 T high expression allele (OR, 1.956; p=0.019) and risk of CP. Statistically significant association was also found in patients with cPVL between TNFα TC, CC, GG, GG -1031/-857/-308/-238 genotypes combination (OR, 4.107; p=0.024), as well as IL1β TT, CC -511/+3954 genotypes combination (OR, 7.333; p=0.005) and risk of CP. Our results suggest the role of TNFα and IL1β polymorphisms which have previously been associated with higher circulating levels of these cytokines in genetic susceptibility to white matter damage and consequently CP in very preterm infants.
