Fig. 1: Scanning electron microscopy image of the interaction between host cells and N. meningitides 48 hours after infection.
Micrograph courtesy of Ariann Hey, Imperial College London, UK
Meningococcal disease is a life-threatening and debilitating illness that affects people of all ages, but infants and children under five years of age are most at risk. It often begins with flu-like symptoms, such as fever, headache and stiff neck, but can quickly progress into meningitis — inflammation in the lining of the brain and spinal cord — and even septicemia (blood poisoning) and death.
Meningococcal disease is caused by the bacterium Neisseria meningitides (Fig. 1). Four serogroups of N. meningitides, namely serogroups B, C, Y and W135, are responsible for most of the cases of meningococcal disease in the developed world, while serogroup A strains cause devastating epidemics in sub-Saharan Africa. Currently, vaccines are available for all serogroups except for serogroup B, which remains a health threat in many developed countries.
Family studies have shown that host genetic factors are important in determining the susceptibility and clinical outcomes of diseases, but scientists have yet to find the genetic factors that contribute to a higher risk of meningococcal disease. Sonia Davila at the A*STAR Genome Institute of Singapore and co-workers have now conducted a genome-wide association study in Europe and identified two genetic variants — or single-nucleotide polymorphisms (SNPs) — that increase the risk of developing meningococcal disease.
The researchers recruited 475 people with meningococcal disease and 4,703 people without from the UK for initial screening. They sampled over half a million common SNPs and identified an initial set of 79 of interest in connection with meningococcal disease.
To remove false positives, the researchers further performed two replication studies that helped pinpoint two SNPs, rs1065489 on the gene CFH and rs426736 on CFHR3, that are highly associated with susceptibility to meningococcal disease.
CFH is an important regulator of the alternative complement pathway, an innate component of the immune system’s natural defense against pathogens, and N. meningitides is known to evade the host immune system by binding itself to CFH. The discovery of the two SNPs suggests that genetic variations on the CFH-related pathway may increase susceptibility to meningococcal disease. The finding could have implications for both vaccine development and potential new therapies.
“Genome-wide association studies allow us to interrogate the whole genome in an unbiased fashion and identify genes, as well as genetic variants, involved in human diseases. With advances in the development of next-generation sequencing technologies, we should be able to sequence the complete human genome at a reasonable financial cost in the very near future,” says Davila.
The A*STAR-affiliated researchers contributing to this research are from the Genome Institute of Singapore.
