Researchers Find Gene Mutation That Makes Japanese More Susceptible to AAV

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by Alice Melão |

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AAV and gene variants

A mutation of the ETS1 gene increases the risk of Japanese developing an inflamed blood vessel condition known as granulomatosis with polyangiitis, a study shows.

Granulomatosis with polyangiitis is one of three versions of ANCA-associated vasculitis.

The ETS1 mutation, which leads to lower levels of the ETS1 protein, is common in people with ANCA-associated vasculitis stemming from a protein called the proteinase 3 enzyme. The full scientific name of ANCA-associated vasculitis is anti-neutrophil cytoplasmic antibody-associated vasculitis, or AAV.

Researchers published their study in the Journal of Human Genetics. Its title is  “Association of ETS1 polymorphism with granulomatosis with polyangiitis and proteinase 3-anti-neutrophil cytoplasmic antibody positive vasculitis in a Japanese population.

AAV is a group of autoimmune diseases whose hallmark is inflammation that damages small blood vessels. Depending on the symptoms, doctors classify the disease as microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), or eosinophilic granulomatosis with polyangiitis (EGPA). An autoimmune disease is one in which the immune system attacks healthy tissue or organs instead of invaders.

Scientists say AAV occurs when patients produce antibodies against a type of immune cell called a neutrophil. The key proteins that the antibodies target are proteinase 3, or PR3, and myeloperoxidase, MPO.

The type of AAV that a person has varies between European and Japanese populations. GPA and PR3 cases account for most AAV in Europe, while MPA and MPO cases predominate in Japan.

“Such epidemiological differences may partly be caused by differences in the genetic background between the populations of European and Asian ancestries,” the researchers explained.

Studies have shown that autoimmune diseases share a number of gene mutations. This prompted Japanese researchers to wonder whether the EST1 mutation, which makes people susceptible to lupus, increases people’s susceptibility to AAV as well.

A previous study showed that a single letter change — from a G to an A — in the coding of EST1‘s DNA sequencing increased the risk that an ethnic Chinese would develop lupus. Scientists have dubbed the abnormality the rs1128334A mutation.

EST1 helps prevent the development of immune B-cells, which produce antibodies — proteins that fight invaders. The gene also controls the activity of immune T-cells.

“Based on the functional relevance of ETS1 in AAV, and previous reports of association with multiple rheumatic disease, especially in the Asian populations, we considered ETS1 as a candidate gene for AAV,” the researchers wrote.  Rheumatic diseases affect the joints.

The researchers examined 466 Japanese with AAV and 1,099 healthy controls to try to determine how EST1 mutations influence the disease.

Two hundred eight-five of the participants had MPA, 92 GPA, 56 EGPA, and 33 an AAV that doctors had been unable to classify. In addition, 376 patients had MPO autoantibodies, and 62 PR3 autoantibodies.

A key finding was that patients with GPA were significantly more likely than healthy controls to have the  rs1128334A mutation. In contrast, neither MPA nor EGPA patients were likely to have such an association.

Another finding was that the rs1128334A mutation showed up much more frequently in AAV patients with PR3 autoantibodies. This was consistent with previous findings that PR3 autoantibodies are much more likely to be found in GPA patients.

Together with previous observations of ETS1 activity, the “findings suggest that genetically determined reduced expression of ETS1 may result in T-cell and B-cell abnormalities, which eventually play a role in AAV,” the researchers said.

The team called for studies in larger groups to confirm the roles that EST1 and the rs1128334A mutation play in Asians developing AAV.