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Danish GWAS Yields Genetic Risk Loci for Vaccine-related Febrile Seizures

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NEW YORK (GenomeWeb) — A series of GWAS taking advantage of Denmark's national population and health registries has identified two genetic loci associated with febrile seizures in children after receiving the measles, mumps, and rubella (MMR) vaccine.

The study, published this week in Nature Genetics also discovered four additional loci associated with elevated risk of febrile seizures in general, regardless of vaccination. Because the general risk loci also appeared linked to higher seizure risk in those patients who specifically experienced vaccine-associated seizures, the researchers hypothesize that both types of variants — vaccine-specific and general — may contribute to risk for these seizures.

According to the authors, though the discoveries are only a first step, follow-up research might some day lead to improved future vaccine design or more personalized vaccination strategies.

Bjarke Feenstra, the study's first author and a member of the department of epidemiology research at the Statens Serum Institut in Copenhagen, told PGx Reporter this week that he and his colleagues set out to try to better understand the biology and underlying genetic causes of one of the only well-documented adverse events associated with vaccines, an approximately tripled risk for fever-induced seizures during the second week after vaccination.

Feenstra's colleagues have previously used Denmark's population registries to study suspected side effects or adverse events associated with vaccines, using essentially the entire Danish population as a cohort. "For the majority of adverse effects, for example, autism, there hasn't been any evidence that they are caused by vaccines, but one example where there is a well-documented increased risk [are these] febrile seizures in the second week after vaccination," Feenstra said.

Overall, febrile seizures occur in about two to five percent of children of European descent, often due to viral infection. MMR vaccination is associated with an additional three to 16 cases of these seizures per 10,000 vaccinated children, according to the study authors. In their GWAS, the researchers hoped to identify genetic variants that might explain why this small proportion of children suffers these events.

"Vaccination programs are such an important part of public health," Feenstra said. "We think as researchers it's important to do these studies to establish whether there is a risk, and in the case where there is a risk, to look into these questions and try to find the underlying causes."

Overall, the group conducted four separate GWAS using three cohorts they derived from Denmark's vaccine registry, which contains a record of all childhood vaccinations in the country including the time and date on which they were given, and a national patient registry, which stores data on outcomes such as febrile seizures.

Combining these two datasets, the group could identify cases of febrile seizures that occurred specifically within two weeks of MMR vaccinations. They then collected genotype data for this group, as well for a separate cohort of febrile seizure cases that were not vaccine-associated, and a control group. In total, the study included approximately 1,300 children who experienced MMR-induced febrile seizures, 2,000 children with febrile seizures unrelated to the MMR vaccine, and 5,800 children with no history of seizures.

The team performed four different GWAS analyses, first comparing vaccine-associated seizure cases to controls, then to non vaccine-associated cases, then comparing non vaccine-associated cases to the control group, and finally combining the two seizure cohorts and comparing that whole group to the controls. This allowed them to narrow significant loci to either the vaccine-associated or non-vaccine-associated seizure populations.

Based on this, the team group identified two loci that reached genome-wide significance specifically for vaccine-associated febrile seizures — one in the gene IFI44L and the other in the gene CD46.

According to the authors, the two implicated genes are both involved in the innate immune response. IFI44L has been shown in previous research to increase its expression after measles infection, while CD46 has been linked to the biological MMR vaccine immune response.

The study also identified four loci that reached genome-wide significance for febrile seizures regardless of vaccination. Two, in the genes SCN1A and SCN2A, had some strong functional evidence behind their influence on febrile seizure, the authors wrote, because variants in these genes have been linked to a range of epilepsy syndromes.

A third loci in the gene ANO3 and a fourth in an intergenic region where reported SNPs have been previously associated with serum magnesium levels also open future avenues of research, the authors wrote.

Feenstra said that an important next step for the researchers will be fine mapping the identified loci, as well as investigating the pathways by which the important variants actually influence the immune response and contribute to the development of febrile seizures specifically after MMR vaccination.

The hope is that future efforts could eventually elucidate alternative vaccine designs or personalized vaccination strategies that predicts individuals' risk of seizures and avoids this complication.

However, Feenstra said, whether this is possible will depend on whether the group can identify additional loci in larger studies, since the newly identified loci account for only a small part of the variation in risk among individuals.

According to Feenstra, the study was not able to answer whether the impact of variants at the loci for vaccine-associated and non-vaccine-associated seizures might be contributing to elevated risk of adverse events in different ways, by first increasing risk of fever and then also increasing risk of seizures during fever. "In other words, children who experience post-vaccination seizures might be genetically susceptible perhaps to increased fever after vaccination due to one set of variants and to increased risk of febrile seizures in general due to another set," Feenstra said.

"We think it is plausible because we see the same effects for the general seizure variants in both groups," he added.

To better address this question would require detailed data on patients who had fever following a vaccination, which is not available in the Danish system, Feenstra said. It is however something that was collected during the clinical trials of MMR vaccines. The researchers are working to try to negotiate access to that data, he said.

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