AAV genetic risk factors may differ according to sex: Study

Gene mutation was linked to almost 5X higher chance of MPO-AAV in women

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Women carrying a genetic mutation dubbed rs9274619 have a significantly higher risk of ANCA-associated vasculitis (AAV) associated with antibodies against myeloperoxidase (MPO) than men, a new study shows.

Among MPO-AAV patients, this mutation was linked to a greater likelihood of eye involvement and a lower risk of lung involvement.

The results “raise the hypothesis that an association of rs9274619 with both sex and organ involvement may manifest in differential clinical presentation of disease in males and females,” the researchers wrote in “Stratified Genetic Analysis Reveals Sex Differences In MPO-ANCA-associated Vasculitis,” which was published in Rheumatology.

AAV is caused by inflammation that damages the body’s small blood vessels. This inflammation is driven by self-reactive antibodies, called anti-neutrophil cytoplasmic autoantibodies, or ANCAs, that give the disease its name. The most common targets of ANCAs are the MPO enzyme or the proteinase 3 (PR3) enzyme.

Research has linked certain genetic mutations to an increased risk of developing AAV. Most of these mutations affect genes important for regulating immune function. Several have been associated with a higher risk of AAV marked by ANCAs that target either PR3 or MPO.

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Mutations with higher AAV risk for women

Scientists analyzed genetic data from 1,088 adults with AAV and 1,589 adults without the disease to explore how biological sex affects the impact of these genetic risk factors. Patients were recruited through centers in Sweden, Norway, and Denmark, while healthy controls were from Sweden or Norway.

In prior studies, the rs9274619 mutation, located between the HLA-DQB1 and HLA-DQA2 genes, showed the strongest association with a higher risk of AAV positive for anti-MPO ANCAs (MPO-AAV).

In this analysis, carrying the rs9274619 mutation was linked to a nearly five times higher chance of developing MPO-AAV in women, but a less than twofold increased risk in men. This means women with the genetic variant were more than two times more likely to develop MPO-AAV than men carrying the mutation.

“Our findings suggest a differential impact of genetic variation on disease risk in males and females with [MPO-ANCA-positive] AAV,” the researchers wrote.

MPO-AAV patients carrying the rs9274619 mutation were about 11 times more likely for the disease to affect their eyes than those who didn’t have the same risk factor, additional analyses showed. Meanwhile, the risk of lung involvement was about 48% lower in MPO-AAV patients carrying this mutation.

“The distribution of eye and pulmonary involvement in regard to rs9274619 was similar in females and males,” the team wrote.

Since this mutation was linked with differences in clinical manifestations and differences in risk according to sex, the findings may help explain how AAV tends to affect male and female patients differently, the researchers said, noting further research to verify the results and test this idea was needed.

Also, rs1042335 and rs9277341, two mutations in the region of the HLA-DPB1/DPA1 genes that’ve been strongly associated with PR3-ANCA-associated AAV, showed a similarly strong link to disease risk in both sexes.

The rs1042335 mutation showed a link with a significantly increased risk of ANCAs targeting both PR3 and MPO. This suggests these “double ANCA-positive AAV cases are genetically similar to PR3-ANCA-positive cases, providing clues to the clinical follow-up and treatment of these patients,” the team wrote.

The findings “suggest sex-dependent genetically distinct subgroups of patients within [MPO-ANCA-positive] AAV,” and also suggest “patients positive for both PR3- and MPO-ANCA are more likely to share characteristics with ]PR3-ANCA-positive] patients,” the researchers said.