Genome Studies Give Strong Clues to Origins of Lupus and Hand OA

Miner JJ and Diamond MS. News and Views: MDA5 and autoimmune diseaseNature Genetics (2014) 46:418–419 doi:10.1038/ng.2959 (April 28, 2014)

Rice GI, Duany YdT, Jenkinson EM, et al.Letter: Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signalingNature Genetics (2014) 46, 503–509 doi:10.1038/ng.2933 (March 30, 2014)

Styrkarsdottir U, Thorleifsson G, Helgadottir HT, et al. Letter: Severe osteoarthritis of the hand associates with common variants within the ALDH1A2 gene and with rare variants at 1p31.  Nature Genetics (2014) 46, 498–502 doi:10.1038/ng.2957 (April 13, 2014)

Researchers have discovered six rare variants in a gene associated with systemic lupus erythematosus (SLE), and also Aicardi-Goutières syndrome (AGS). The upregulation of type I interferon (IFN) is common to both diseases

The gene is IFIH1, which encodes the protein MDA5, part of the pathway that senses viral double-stranded RNA (dsRNA) and stimulates the IFN system in response. These variants are gain-of-function mutations, which enhance MDA5 binding to RNA and upregulate type I IFN. The paradigm is that aberrant pattern-recognition receptors interact with host or pathogen RNA, which results in sustained immune signaling and disease. This would explain how viral triggers cause disease in genetically susceptible subjects.

However, despite the association, most persons with the IFIH1 variants do not develop SLE, indicating a role for environmental factors in causing the disease.

This association between sensing viral dsRNA and autoimmune disease support the hypothesis that mutations in key regulatory or signaling genes could be selected during viral epidemics. Mutations in pathways sensing viral RNA and DNA could reduce susceptibility to the pathogens, with the adverse consequence of predisposing carriers to autoimmune disease.

Variations in the gene TREX1, which has a similar function to IFIH1, have also been associated with SLE and AGS.

The variations in IFIH1 were discovered by whole-exome sequencing of three individuals with AGS, an inflammatory disease that attacks the mylenated nerve fibers of the brain, with high death rate. Six other genes, also associated with the DNA or RNA virus response, were previously associated with AGS.

In another genome-wide association study, genomes of 623 Icelanders with severe osteoarthritis of the hand were screened and compared to those from the entire set of 2,230 Icelanders.

Two variants were found to be associated with osteoarthritis of the hand – one at 15q22 in the ALDH1A2 gene, and another at 1p31. ALDH1A2 was highly expressed in cartilage samples.

The ALDH1A2 gene encodes retinaldehyde dehydrogenase 2, an enzyme that catalyzes the synthesis of retinoic acid from retinaldehyde. Retinoic acid, an active derivative of vitamin A (retinol), is a hormone-signaling molecule with an essential role in embryonic development and in the maintenance of adult tissues, including cartilage and bone.