Genome study finds new genetic risk factors predicting IgG4-RD
Researchers in Japan say they're 'closer to understanding genetic architecture'
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Researchers in Japan studying genetic data from hundreds of patients confirmed several genetic variations and identified new ones as genetic risk factors of IgG4-related disease (IgG4-RD).
Two variations were associated with an increased susceptibility to IgG4-related dacryoadenitis and sialadenitis (Mikulicz’s disease), a form of IgG4-RD marked by inflammation of the tear and salivary glands.
“These findings take us a step closer to understanding the genetic architecture underlying IgG4-related disease” and “provide a foundation for future [multi-ethnic] comparative studies and subtype-specific therapeutic strategies,” the researchers wrote.
The study, “IgG4-related disease in the Japanese population: a whole-genome sequencing study,” was published in The Lancet Rheumatology.
IgG4-RD is a rare immune disorder marked by abnormal clumps of immune cells, particularly those producing the antibody IgG4. These clumps can form in organs throughout the body, resulting in a wide array of symptoms and clinical profiles.
Whole-genome sequencing
The causes of IgG4-RD aren’t fully understood, but genetic variations are believed to play a role in determining disease susceptibility.
Previous studies have shown that mutations in certain genes, such as FCGR2B and HLA-DRB1, are associated with an increased risk of IgG4-RD. But these studies have generally been done using microarray data. With a microarray, researchers test a person’s DNA for common genetic variants. By design, this approach makes it impossible to assess whether other types of mutations might also affect disease risk.
Aiming to get a more comprehensive understanding of how genetics influences IgG4-RD susceptibility, the team of scientists in Japan conducted a comprehensive analysis of genetic data from more than 800 IgG4-RD patients, as well as more than 2,000 people without the disease. All participants were of Hondo Japanese ancestry.
Instead of microarrays, the researchers used whole-genome sequencing, which screens a person’s entire genetic code and uses powerful computer-based analyses to identify potential disease-associated genetic variations.
The results validated previous research that had found a significant association between FCGR2B gene mutations and an increased risk of IgG4-RD.
In addition to the HLA-DRB1 gene, the researchers identified IgG4-RD-associated variants in two other HLA genes, HLA-DQ and HLA-A. HLA comprises a family of genes that play key roles in helping the immune system distinguish between the body’s own healthy cells and foreign threats.
When looking at potential risk factors of specific IgG4-RD clinical profiles, the researchers found that specific variants in two DNA regions, one near the PTCH1 gene and the other near the LOC102724227 gene, were significantly linked to an increased risk of Mikulicz’s disease.
The team also assessed copy number variations, a phenomenon in which some individuals have more or fewer copies of a given gene.
This analysis specifically focused on the complement C4 gene, which codes for a protein involved in the immune system, and whose copy number variations have also been implicated in other autoimmune diseases.
There are two common versions of the C4 gene, dubbed C4A and C4B. The researchers’ analysis indicated that having more C4A copies was significantly associated with a reduced risk of IgG4-RD, while having more copies of the C4B variant was linked to a higher risk.
The scientists emphasized that further research is necessary to comprehend the biological function of these genes in disease development, which could inform personalized care for patients.
“Further studies exploring the molecular mechanisms underlying these associations could improve the understanding of immune dysregulation across subtypes and refine the classification of IgG4-related disease,” they wrote.
A pair of researchers in Italy who were not involved in the study wrote a comment published alongside it.
“Studies on larger IgG4-related disease [patient groups] are likely to unravel other associations with disease [clinical profiles]; given that IgG4-related disease comprises such a [wide] disease spectrum, it is reasonable to think that different genetic variants are linked to specific disease subsets,” they wrote.
Because genetics and other disease risk factors can vary across ethnic groups, the study’s authors emphasized a need to validate the findings in more diverse populations.
The researchers in Italy agreed, noting that “as for other autoimmune diseases, ethnicity represents an important risk factor; as a result, it is important to consider the future possibility to extend these studies to other ethnicities.”
