Genetic risk factor for ALS

Scientists have identified a variant in the gene DPP6 that increases susceptibility to amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease) is an untreatable and fatal disorder caused by degeneration of motor neurons in the brain and spinal cord.

While mutations in genes have been found that cause rare cases of familial ALS, there has been much more limited success in identifying genetic influences on non-familial (sporadic) ALS, which accounts for more than 90% of cases.

Leonard van den Berg and colleagues carried out a genome-wide association study of more than 1,700 individuals with the disease and more than 1,900 healthy controls, sampled from three European populations, and including recently reported data from affected individuals in the United States. A single variant in DPP6 was associated with ALS in each population, increasing risk by approximately 30%. This is the first genetic risk factor identified for sporadic ALS in the context of a genome-wide study, and is the first to be found consistently in multiple populations. DPP6 encodes a dipeptidyl-peptidase-like protein, an enzyme found predominantly in the brain whose expression has been shown to be increased in rats in response to spinal cord injury.

Author contact:
Leonard van den Berg (University Medical Center, Utrecht, The Netherlands)
Tel: +31 302 506 506; E-mail: l.h.vandenberg@umcutrecht.nl



Genetic susceptibility to Kawasaki disease


A variant in a gene called ITPKC is associated with increased susceptibility to Kawasaki disease.Kawasaki disease is characterized by acute inflammation of the vascular system in infants and children, and if left untreated can lead to lethal coronary artery aneurysms.

Kawasaki disease tends to run in families, suggesting that there are genetic components to disease risk. It is also 10-20 times more common in Japan than in Western countries. Yoshihiro Onouchi and colleagues identified a region on chromosome 19 that was linked with the disease, and in particular a series of variants across four genes in the region were found more frequently in individuals with the disease than in healthy controls. The authors focused on one of these genes, ITPKC, which they regarded as the best candidate. ITPKC encodes an enzyme that is part of a signaling pathway with a critical role in certain cells of the immune system (T-cells). The authors went on to show that one of the risk variants reduces the expression of ITPKC, and that lower levels of ITPKC promote activation of T-cells. This is consistent with the marked activation of the immune system seen in Kawasaki disease.

Finally, the authors suggest that the association of ITPKC with Kawasaki disease may have immediate clinical implications. Approximately 10-20% of affected individuals are resistant to the standard treatment of intravenous immunoglobulins, but individuals with the ITPKC risk variant are 4-5 times more likely to fail to improve on the standard therapy. If these individuals could be identified with a genetic test, they could be offered alternative and more intensive therapies.

Author contact:
Yoshihiro Onouchi (SNP Research Center, RIKEN, Yokohama, Japan)
Tel: +81 45 503 9347; E-mail: onouchi@src.riken.jp