The association between proinflammatory cytokine polymorphisms and cerebral palsy in very preterm infants

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.