Genetic variants in CC2D2B gene may affect HAE disease severity

Novel gene variant ID'd in study may play a role in HAE types 1 and 2

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Genetic variants in the CC2D2B gene may affect disease severity in hereditary angioedema (HAE) types 1 and 2, according to a new study.

“We demonstrated, on a large cohort of [people with HAE types 1 and 2], the importance of the CC2D2B gene as a disease-modifying factor,” the researchers wrote.

These findings highlight the need for further investigation into the potential role of these and other genetic variants in modulating HAE disease severity, the team noted.

More knowledge regarding these associations “will contribute to a better understanding of the pathophysiology [disease mechanisms] of [HAE types 1 and 2], improve clinical management, and possibly help us develop novel personalized therapies for patients,” they wrote

The study, “The CC2D2B is a novel genetic modifier of the clinical phenotype in patients with hereditary angioedema due to C1 inhibitor deficiency,” was published in the journal Gene.

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12 new SERPING1 gene mutations tied to HAE discovered in Slovakia

Researchers looking for genetic variants that may impact disease severity

HAE types 1 and 2 are caused by mutations in the SERPING1 gene, which provides instructions for making a protein called C1-inhibitor, or C1-INH. In HAE types 1 and 2 — sometimes also referred to as HAE-C1-INH — the lack or dysfunction of the C1-INH protein leads to the overproduction of a signaling molecule called bradykinin, which drives swelling in HAE.

For most people with HAE, the condition is marked by swelling attacks, but the severity of the disease varies widely from person to person. Indeed, studies estimate that as many as 1 in every 7 individuals who carry an HAE-causing mutation in the SERPING1 gene do not experience any HAE symptoms over the course of their lifetimes.

The reasons for this variation are poorly understood. One possibility is that mutations in other genes besides SERPING1 may influence the severity of the disease. Yet, actually pinpointing other genetic variants that may modulate HAE disease severity has proven difficult.

In the first part of this study, an international team led by scientists in Slovenia conducted extensive genetic sequencing on three pairs of HAE patients. Each pair consisted of two people from the same biological family, both of whom carried an identical HAE-causing mutation in the SERPING1 gene. But within each pair, one person had experienced symptoms, while the other was entirely asymptomatic.

The researchers specifically looked for genetic variants that were found in asymptomatic patients but were not present in any of the individuals who had experienced HAE symptoms. Following this approach, they identified a total of 39 potential genetic variants in 23 different genes.

Two of the identified genes, CC2D2B and PLCL1, had previously been reported to affect bradykinin signaling, so researchers decided to zero in on both of them for further analysis.

The genetic sequence of both CC2D2B and PLCL1 were analyzed in a larger group of 88 people with HAE-carrying SERPING1 mutations. Nine of these individuals were asymptomatic, and the rest had experienced symptoms.

Statistical tests demonstrated that a specific genetic variant in CC2D2B, dubbed c.190A>G or rs17383738, was significantly more common among asymptomatic patients: More than half of asymptomatic patients (56%) carried this mutation, while less than 1 in 4 individuals (23%) who had symptoms did.

Variants in the PLCL1 gene, however, were not significantly more common among asymptomatic patients in the larger patient population.

“Our study identified novel genetic factors that modify the clinical variability of HAE-C1-INH,” the researchers wrote, adding that these genetic variants “may have the potential as genetic biomarkers to differentiate asymptomatic from symptomatic patients.”

More research is needed, the team concluded.