Study Identifies AAV-associated Genetic Variants in Chinese Population

Variants in immune-related genes may make certain people more or less susceptible to anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV), a new study suggests.

The study, “Risk HLA class II alleles and amino acid residues in myeloperoxidase–ANCA-associated vasculitis,” was published in the journal Kidney International. 

The fact that AAV can run in families suggests that there are inheritable genetic factors that make some people more likely to develop it. Previous studies in European populations have suggested that variants in human leukocyte antigen (HLA) genes may be one of these factors.

HLA, sometimes also called major histocompatibility complex (MHC), is a system that cells use to present cellular components — mostly proteins — to the immune system. Basically, it’s a way for the immune system to “see what’s going on inside a cell.” For example, a cell that consumes an invading bacteria can “show” bits of the bacteria to the immune system, prompting an immune response against the invaders.

In this study, researchers examined the frequency of variations in HLA genes among Chinese people with AAV characterized by antibodies against myeloperoxidase (MPO). This variation is more common in people who are ethnically Chinese, whereas AAV associated with antibodies against proteinase 3 [PR3] is more common in Caucasian people.

The researchers evaluated the sequence of HLA genes in 258 people with AAV from Northern China and 97 people with AAV from Southern China. The geographical distinction is needed because the frequency of some HLA genes is known to differ by region in China, so the researchers wanted to control for that variable.

For comparison, the researchers sequenced HLA genes from 597 people without AAV from Northern China, and 107 people from Southern China who don’t have the disease. The control groups were “ethnically and geographically matched” with the cases of those with AAV, though not matched by other demographic features, specifically age and sex.

The researchers found that two HLA variants were significantly more common among people with AAV than those without: DQA1*0302 (20.9% vs. 10.3% in the Northern group; 31.6% vs. 8.0% in the Southern group) and DQB1*0303 (23.9% and 14.4% Northern; 33.7% vs. 13.0% Southern). Those findings suggest that these variants confer a higher risk of AAV.

In contrast, two variants were less common in people with AAV: DQB1*0201 (3.6% vs. 11.0% Northern; 2.6% vs. 9.0% Southern) and DQA1*0501 (2.8% vs. 8.9% Northern; 2.6% vs. 9.5% Southern).

While this suggests that these variants might protect against AAV, the data was not as strong — the difference did not reach statistical significance in the Southern Cohort, the investigators found. More research with larger sample sizes will be needed to clarify this finding, and to validate the above results, the team said.

The researchers also modeled the expected protein-level changes caused by these variations. This may be valuable for researchers in future studies trying to untangle exactly why these variants make people more or less likely to develop AAV.

Interestingly, the team found that some of the variants weren’t in the part of the protein that’s involved directly in presentation. Instead, these variants were in parts of the protein that serve more structural roles. This highlights the need to examine the whole HLA complex in future studies, since all parts may play a role in human disease.

“In conclusion,” the researchers said, “this study identified 2 strong-linked risk HLA alleles, DQA1*0302 and DQB1*0303, for MPO-[associated] AAV in the Chinese Han population.”