A Genetic Polymorphism Increases the Risk for Cerebral Palsy

LOUISVILLE—A functional polymorphism in the interleukin-6 (IL-6) gene is a risk factor for cerebral palsy in term and near-term infants, Yvonne W. Wu, MD, MPH, Associate Professor of Neurology and Pediatrics, University of California, San Francisco, reported at the 38th National Meeting of the Child Neurology Society.

“This association suggests that the elevation of IL-6 that we see in some patients with cerebral palsy plays a causative role in the disease,” she said. Studies have linked IL-6 levels in newborn blood samples to cerebral palsy. However it is possible that IL-6 elevation occurs merely as a response to hypoxic-ischemic brain injury and other factors, Dr. Wu explained.

“We reasoned that if a gene that modulates this fetal inflammatory response is associated with risk of cerebral palsy, then the IL-6 elevation may in fact represent an important pathogenetic factor and not just a downstream result of brain injury and maternal infection.”

In a population-based, case-control study of infants born between 1991 and 2002 in northern California—where the prevalence of cerebral palsy among term and near-term infants is one in 1,500—Dr. Wu’s group identified 250 patients with cerebral palsy and 305 randomly selected controls. Using neonatal blood spot specimens retrieved within the first 24 hours of life, the researchers found that the IL-6 gene promoter region polymorphism at position –174 G/C correlated with an increased risk of cerebral palsy.

Dr. Wu and colleagues found that the C allele, which is the less common allele, was seen more frequently in whites than in Hispanics, blacks, or Asians. The CC genotype was more common in patients with cerebral palsy (17.4%) than in controls (8.1%). “In all genetic studies, we need to be careful about racial heterogeneity,” Dr. Wu commented. “After restricting our analysis to whites only, the CC genotype was still more common in cases (21%) than in controls (12%), and this is a statistically significant difference.”

Serum IL-6 Levels

Serum IL-6 protein levels were higher in cases than in controls; however, 89% of samples did not have detectable levels of IL-6, according to Dr. Wu. When the data were dichotomized into detectable versus nondetectable IL-6 levels, cases were more likely to have detectable levels (25.2%) than were controls (11.1%).

Among those with detectable levels, mean IL-6 levels were higher among cases than in control infants (64.5 µm vs 7.4 µm), and the five infants with the highest serum IL-6 levels all had cerebral palsy.

Based on genotypes, about half of patients with the CC genotype had detectable IL-6 levels, whereas only 19% of those with the more common GG genotype had detectable IL-6 levels. Similarly, in controls, more subjects with the CC genotype than the GG genotype (28% vs 12%) had detectable IL-6 levels. However, these were not statistically significant, because the numbers of subjects in these analyses were small, Dr. Wu explained.

When the data were further stratified and controlled for race, the CC genotype was associated with a fourfold increased risk of quadraparetic cerebral palsy and a threefold increased risk of hemiparetic cerebral palsy.

Preventive Treatments on the Horizon?

In multivariate analysis controlling for race, independent risk factors for cerebral palsy included CC genotype compared with GG (OR, 2.4), clinical chorioamnionitis (OR, 4.6), advanced maternal age (OR, 2.6), and male gender (OR, 1.6).

“We do not know how to prevent the vast majority of cases of cerebral palsy, and this is because we have a poor understanding of the underlying cause of brain injury in most cases,” Dr. Wu told Neurology Reviews. “Our finding supports the notion that underlying inflammatory processes play a role in newborn brain injury leading to cerebral palsy. If we can better identify the risk factors, both genetic and environmental, that place a particular baby at high risk for cerebral palsy, we may be able to devise new preventive and treatment strategies. Our finding, that a functional polymorphism in the IL-6 gene confers increased risk of cerebral palsy, is a first step in elucidating the complex gene-environment interactions that lead to cerebral palsy.”

Suggested Reading
Wu YW, Croen LA, Torres AR, et al. Interleukin-6 genotype and risk for cerebral palsy in term and near-term infants. Ann Neurol. 2009;66(5):663-670.