Scientists at deCODE genetics have together with their Nordic collaborators published the largest genome-wide association study to date on rheumatoid arthritis (RA), including over thirty thousand cases and one million controls.
The study is based on an extensive collaboration between researchers in six northwestern European countries and includes information on not only RA overall but also the disease subsets, defined by serology (rheumatoid factor/anti-CCP antibodies). A total of 64 million sequence variants were investigated, based on whole-genome sequencing of a large number of individuals from these countries. It was determined thereafter whether sequence variants that associate with RA or its subsets affect protein coding, gene expression and/or levels of five thousand other proteins in plasma.
Previously unreported sequence variants were found to have large effect on the risk of seropositive RA
Several previously unreported sequence variants were found to have large effect on the risk of seropositive RA, while associations with seronegative RA were scarce. Through sequential application of genomics, transcriptomics and proteomics, causal genes were identified for most signals and the majority of those that associate with seropositive RA encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. This includes a missense variant in the STAT4 gene that confers 2.27-fold risk, larger than previously reported signals, and it leads to a replacement of hydrophilic glutamic acid with hydrophobic valine in a conserved, surface-exposed loop of the STAT4 protein. Furthermore, a stop-mutation in the FLT3 gene increases seropositive RA risk 35%, while three missense variants in the TYK2 gene confer 15-59% reduced risk and affect levels of the interferon-alpha/beta receptor 1 (IFNAR1).
These findings highlight how a multiomics approach can reveal causal genes. Furthermore, they support treatment of seropositive RA with the already registered JAK and IL-6R inhibitors as well as CTLA4-Ig, but also open for repurposing of other drugs that target proteins in the JAK/STAT-pathway, including inhibitors of FLT3, TYK2 and IFNAR1, that are currently used or under development for other diseases.
Photo: deCODE genetics