Singapore - Medical genetics: Finding the elements of risk

Genome-wide association studies reveal risk factors that increase the susceptibility of children to certain diseases

Children are especially vulnerable to illness, but the deck may be further stacked against them by genomic mutations that increase disease susceptibility. For example, the onset of severe dengue shock syndrome (DSS) in response to dengue virus infection and Kawasaki disease, an inflammatory condition that causes cardiovascular damage, are likely to be associated with heritable risk factors.

“Both are severe diseases occurring in young children who are otherwise healthy, and we suspect that there is a genetic predisposition,” says Chiea Chuen Khor, a research scientist with Martin Hibberd’s group at the A*STAR Genome Institute of Singapore. Their team recently collaborated on two studies that confirm this hypothesis, zooming in on genetic risk factors that yield valuable clinical insights into both conditions1,2.

For each investigation, Khor and Hibberd joined forces with numerous other scientists to perform genome-wide association studies (GWAS). In a GWAS, researchers analyze genomic variations scattered throughout the genome in large numbers of healthy and disease-affected individuals, hoping to identify changes that show a robust statistical association with a given condition. Hibberd’s group has repeatedly demonstrated the power of such studies in the past. “These have resulted in the discovery of disease genes with unexpected functions that would never otherwise been picked up,” he says.

Kawasaki disease has been the target of GWAS before, but Khor and Hibberd partnered with several research consortia to perform an analysis of unprecedented scale, examining nearly half a million single-nucleotide polymorphisms (SNPs) in over 11,000 individuals1. Their study validated several genomic sites previously linked with disease risk, but also flagged a novel mutation in the FCGR2A gene. This change appears to modulate the extent to which the immune system can respond to certain molecules, including the intravenous immunoglobulin (IVIG) that is typically used to treat Kawasaki patients. “This could explain why up to 25% of children with Kawasaki are refractory to IVIG treatment,” says Khor.

Their investigation of DSS proved equally enlightening2. Based on analysis of 2,118 Vietnamese children affected by DSS versus an equivalent number of controls, they identified statistically strong disease associations for variations located near a pair of genes, PLCE1 and MICB. The latter is particularly interesting, as it encodes a protein that helps coordinate the immune antiviral response and is known to be strongly expressed in dengue-infected patients.

Khor and Hibberd will investigate the clinical ramifications of these findings more closely, but also plan in the near future to pursue higher-density searches for new risk factors using DNA sequencing-based approaches.

The A*STAR-affiliated researchers contributing to this research are from the Genome Institute of Singapore

References

1.     Khor, C. C. et al. Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease. Nature Genetics 43, 1241–1246 (2011). | article

2.     Khor, C. C. et al. Genome-wide association study identifies susceptibility loci for dengue shock syndrome atMICB and PLCE1. Nature Genetics 43, 1139–1141 (2011). | article