Several rheumatic autoimmune diseases have strong genetic associations with the MHC locus; however, although definite links have been identified between these genetic associations and HLA molecules in rheumatoid arthritis, such clear links have not yet been identified for systemic lupus erythematosus (SLE) or primary Sjögren syndrome (pSS). The results of a study published in Nature suggest that the genetic association between the MHC locus and SLE and pSS could instead be due to the complement protein C4, which is encoded at the same locus.

C4 is encoded as two separate genes, C4A and C4B, which are present at different copy numbers in different individuals. The copy numbers of C4 genes can be imputed from combinations of specific single nucleotide polymorphisms, which enabled the authors of the new study to investigate the copy numbers of C4A to C4B in individuals with different diseases.

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“Our lab’s prior work on the association between copy number variation of the [C4 genes] and schizophrenia motivated us to see if this source of genetic variation could possibly explain other signals of common, heritable risk at the MHC locus of the human genome,” explains corresponding author Nolan Kamitaki. “In particular, though previously attributed to various combinations of HLA class I and class II alleles, the associations for [SLE] and [pSS] risk in this region seemed to have a similar pattern of linkage disequilibrium as seen with C4 variation itself.”

Kamitaki and colleagues found that variation in the copy number of C4A and C4B was associated with a sevenfold difference in risk for SLE and a 16-fold difference in risk for pSS. For both diseases, an increased copy number of C4A was strongly protective, and an increased copy number of C4B was moderately protective. The researchers also investigated HLA-DRB1*03:01, which had been thought to account for the association between the C4 copy number and SLE, and found no consistent effect on SLE risk once C4 variation was accounted for.

“Resolving the genetic association in [the MHC locus] to copy number variation of the C4 gene[s] heavily suggests that the complement pathway is a fundamental contributor to the development of these autoimmune disorders rather than an observed outcome,” states Kamitaki.

Interestingly, the protective effects of C4A in SLE and pSS are reversed in schizophrenia. As SLE and pSS are more common in women and schizophrenia is more common in men, the researchers investigated whether the effects of C4 variation had a sex bias. They found that C4 genes are associated with larger effects in all three diseases in men than in women.

“Although the expression of C4 at the RNA level does not appear to differ between men and women, we saw that men had more C4 protein in both cerebrospinal fluid and blood plasma, suggesting that this [difference] may explain the greater genetic association in men,” says Kamitaki. “This result suggests a molecular pathway contributing to the sex-bias in disease incidence”.