C3 glomerulopathy (C3G), a type of primary membranoproliferative glomerulonephritis (MPGN), is generally thought to result from mutations in complement genes. However, a new study suggests that autoimmunity rather than a genetic complement disorder is the key mechanism in the majority of patients.

To investigate genetic causes of primary MPGN and C3G in the UK population, Daniel Gale and colleagues analysed whole-genome sequence data from 146 patients and 6,442 control individuals. “Unexpectedly, we found that rare genetic variants in complement genes were not over-represented in the patients, occurring in around 6% of individuals in both groups,” says Gale. “The frequency of rare variants in all other genes was also similar in patients and controls, suggesting that in the UK population, primary MPGN and C3G are seldom explained by a single gene defect.”

The researchers did, however, identify a strong association between common variants at the HLA locus and primary MPGN. “One particular HLA type — DQA1*05:01, DQB1*02:01 and DRB1*03:01 — was significantly more common in patients with primary MPGN and C3G than controls,” explains Gale. “This HLA type is also associated with autoimmune diseases such as type 1 diabetes mellitus (T1DM), which probably explains why people with C3G are more likely to have a family history of T1DM than the general population.” The researchers confirmed their finding by analysing the HLA serotypes of 338 patients with primary or secondary MPGN and 15,614 control individuals.

“Our results suggest that complement gene sequencing in individuals with primary MPGN or C3G is less helpful than previously thought,” says Gale. “They may also explain anecdotal reports of patients responding well to immunosuppression and suggest that this is a logical therapeutic strategy.”