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Consortium IDs Variants Associated with Meningitis Susceptibility

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Members of the International Meningococcal Genetics Consortium, led by researchers at the Imperial College London and the Genome Institute of Singapore, have identified genetic variants linked to susceptibility to the meningitis bacteria Neisseria meningitidis.

Based on genome-wide association and replication studies involving more than 6,000 individuals, the team identified a locus tied to meningococcal disease susceptibility. Their results suggest variants in and around genes coding for components of the so-called complement immune system, which helps attack foreign interlopers in the body, are associated with disease risk. The team's findings appeared in the early, online edition of Nature Genetics yesterday.

"Our findings provide the strongest evidence so far that there are genetic factors that lead to people developing meningitis," co-corresponding author and project leader Michael Levin, pediatrics and international child health chair at Imperial College London, said in a statement.

Meningitis, inflammation of the membranes surrounding the brain and spinal cord, can quickly progress to death in some cases. A range of viral or bacterial infections can cause meningitis, with N. meningitidis being among the most common bacterial culprits.

While many people harbor N. meningitidis at some time during their lives, most individuals who carry the bug don't develop meningitis or related complications such as blood poisoning, known as septicemia. And studies suggest genetic variations may contribute to differences in susceptibility to meningococcal disease, researchers noted.

"Although most of us have carried the meningitis bacteria at some point, only around one in 40,000 people develop meningococcal meningitis," Levin noted. "Our study set out to understand what causes this small group of people to become very ill whilst others remain immune."

In an effort to find common genetic variants influencing susceptibility to meningococcal disease, the team used the Illumina HumanHap 610K chip to genotype 547 individuals with bacterial meningitis from the UK.

They then compared genetic patterns in these individuals with Illumina HumanHap 1.2 M chip genotype data for more than 5,000 unaffected controls assessed through phase 2 of the Wellcome Trust Case Control Consortium. After their quality control steps, the researchers were left with genotype data at more than half a million autosomal SNPs for 475 cases and 4,703 controls.

Of the 79 meningococcal disease-associated SNPs they decided to follow up on, the team found nine that also seemed to be associated in a validation cohort of 553 cases and 839 controls from western Europe.

Two SNPs — both in the complement factor H immune protein coding gene CFH — reached genome-wide significance in the first validation group. These CFH SNPs were also linked to meningococcal disease in a second replication study involving another 415 cases and 537 controls from southern Europe.

Meanwhile, the team's imputation analyses turned up even more meningococcal-related SNPs in and around CFH as well as CFHR3, which codes for a complement factor H-related protein. SNPs in a third gene, CFHR1, were associated in two of the three cohorts.

The findings are intriguing given that past studies indicate that meningococcal bacteria proteins can bind to complement factor H, impairing complement-mediated defense. Now, researchers have genetic evidence that changes to the complement factor H gene and genes coding for related proteins might influence susceptibility to the bug.

"Our study suggests that host genetic variation in these regulators of complement activation plays a role in determining the occurrence of invasive disease versus asymptomatic colonization by this pathogen," the researchers wrote.

Along with biological insights into meningococcal disease, those involved in the study are optimistic that the GWAS may lay the foundation for new and improved vaccines. Vaccines against meningococcal bacteria in the serogroup C are currently available in some areas, the researchers explained. But the development and distribution of vaccines targeting other serogroups has been less successful.

"Improving our understanding of why some people get the disease and not others will help to identify those at risk and develop better vaccines," co-lead author Victoria Wright, a pediatrics researcher at Imperial College London, said in a statement.

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