Published online October 1, 2004
PEDIATRICS Vol. 114 No. 4 October 2004, pp. 941-947 (doi:10.1542/peds.2003-0494-F)
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Does Interleukin-6 Genotype Influence Cerebral Injury or Developmental Progress After Preterm Birth?

David R. Harding, PhD*, Sukbhir Dhamrait, MD{ddagger}, Andrew Whitelaw, MD§, Steve E. Humphries, PhD{ddagger}, Neil Marlow, MD|| and Hugh E. Montgomery, MD{ddagger}

* Department of Child Health, University of Bristol, Bristol, United Kingdom
{ddagger} Cardiovascular Genetics, University College London, London, United Kingdom
§ Neonatal Intensive Care Unit, University of Bristol Medical School, Southmead Hospital, Bristol, United Kingdom
|| School of Human Development, University of Nottingham, Nottingham, United Kingdom

Objective. The severity of the proinflammatory response may determine outcome in the critically ill. Genetic variation in the promoter region of the gene encoding the proinflammatory cytokine interleukin-6 (IL-6; –174 CC genotype) may encode enhanced production of IL-6. Our objective was to determine whether the CC genotype is associated with worse early illness severity, neurologic injury, and lower developmental scores among surviving preterm children.

Methods. Genotype was determined from dried blood spots that were taken for neonatal screening tests 7 days or more after birth; outcome was independently assessed as part of a longitudinal study of children of ≤32 weeks’ gestational age.

Results. CC genotype was associated with worse intensive care indices. Significant hemorrhagic brain injuries occurred in 5 (19%) of 27 children with CC genotype compared with 7 (6%) of 121 children with GC or GG genotype, and images consistent with white matter damage (ventriculomegaly or cystic periventricular leukomalacia) occurred in 9 (26%) of CC patients compared with 9 (7%) in GC/GG children. Disability occurred significantly more often in CC children: 8 (31%) compared with 16 (13%). A similar trend was also noted in children with cerebral palsy (15% compared with 7%, respectively). Developmental, cognitive, and motor scores at 2 years and 5.5 years were independent of genotype among children with or without disability.

Conclusions. In a population of surviving children who were born at ≤32 weeks’ gestational age, variation of the gene that may increase IL-6 synthesis is associated with disabling brain injury but not cognitive development despite association with worse early critical care indices.

Key Words: interleukin-6 • polymorphism • infant premature • neurodevelopment

Abbreviations: PVL, periventricular leukomalacia • CP, cerebral palsy • IL-6, interleukin-6 • WMD, white matter damage • IVH, intraventricular hemorrhage • APIP, Avon Premature Infant Project • BAS-II, British Ability Scales, Second Edition • OR, odds ratio • CI, confidence interval

Accepted Apr 1, 2004.




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