By Carol Cruzan Morton
2 September 2020
Researchers in Iceland have discovered a variant in the FLT3 gene that increases the risk of autoimmune thyroid disease more than any sequence variant previously linked to the disease. The same genetic variant also bumps up the odds of three other autoimmune diseases, as well as doubling the risk for a type of leukemia.
The key to the discovery was the combination of very large data sets of different types of molecular information.
Autoimmune thyroid disease is the most common autoimmune disease, affecting about 5 percent of the population. It is more common in women and it often co-occurs with other autoimmune diseases. The disease is usually diagnosed after the immune attack has destroyed thyroid hormone production and is then treated with hormone replacement.
The study, which appears in the 27 August 2020 issue of Nature, began with a genome-wide association study of 30,000 patients with autoimmune thyroid disease from Iceland and patients in the UK Biobank.
This phase identified 99 gene variants associated with the disease, 84 of which were newly discovered.
“One was particularly interesting for several reasons,” said Saedis Saevarsdottir, a scientist at deCODE genetics and a professor of precision medicine at the University of Iceland, in a video accompanying the deCODE press release. “[The variant in FLT3] increased the risk of autoimmune thyroid disease by 46 percent. And because autoimmune diseases have quite a lot in common, we also looked at this variant in other autoimmune diseases, and found that it increased the risk of some of those even more.”
The risk of systemic lupus erythematosus was nearly doubled, and the increased risk of rheumatoid arthritis and celiac disease was comparable to that of autoimmune thyroid disease.
The team deployed three large data sets to trace the risky variant—in a gene called FLT3—from its genome (DNA) sequence to its molecular mechanism on the transcriptome (RNA) and proteome (protein) levels, and finally to its clinical consequences.
“The combination of these three omics in a hypothesis independent manner yields a remarkably powerful approach to the study of human disease,” said Kari Stefansson, CEO of deCODE genetics and senior author on the paper, in the press release.
Among doctors and researchers, FLT3 is better known as a gene that becomes more active through somatic mutations found in about one-third of people with a blood cancer known as acute myeloid leukemia (AML), and relate to worse outcome. FLT3 codes for a receptor on blood and immune cells. Saevarsdottir and her colleagues found the new variant almost doubled the risk of AML, but not of cancers overall.
The code stops here!
This was puzzling, because a transcriptome analysis showed that the FLT3 variant introduces a premature stop-codon in the non-coding section. A stop-codon is a traffic signal along the genetic code that tells the cellular machinery that it can ignore the next section of code as it prepares to make new proteins. The resulting truncated receptor is missing a key signaling connection point.
A proteome analysis of 5,000 Icelanders provided more clues to the mystery.
“This intron variant introduces a stop-codon despite being in a non-coding region and yields a shorter transcript that would result in a truncated FLT3 receptor that lacks the kinase part,” wrote Saevarsdottir in an email to NSHG-PM. “The proteome-wide analyses then showed that it almost doubles the levels of its ligand in carriers, but this molecular couple, FLT3 and the FLT3 ligand, has a key role in cells that are important in both autoimmune processes and AML.”
Other authors on the paper include scientists at deCODE genetics, a subsidiary of Amgen, and their collaborators from the Icelandic healthcare system, the University of Iceland and the Karolinska Institute in Sweden.
Saevarsdottir S, Olafsdottir TA, Ivarsdottir EV, Halldorsson GH, Gunnarsdottir K, Sigurdsson A, Johannesson A, Sigurdsson JK, Juliusdottir T, Lund SH, Arnthorsson AO, Styrmisdottir EL, Gudmundsson J, Grondal GM, Steinsson K, Alfredsson L, Askling J, Benediktsson R, Bjarnason R, Geirsson AJ, Gudbjornsson B, Gudjonsson H, Hjaltason H, Hreidarsson AB, Klareskog L, Kockum I, Kristjansdottir H, Love TJ, Ludviksson BR, Olsson T, Onundarson PT, Orvar KB, Padyukov L, Sigurgeirsson B, Tragante V, Bjarnadottir K, Rafnar T, Masson G, Sulem P, Gudbjartsson DF, Melsted P, Thorleifsson G, Norddahl GL, Thorsteinsdottir U, Jonsdottir I, Stefansson K. FLT3 stop mutation increases FLT3 ligand level and risk of autoimmune thyroid disease.
Nature. 2020 Aug;584(7822):619-623. doi: 10.1038/s41586-020-2436-0. Epub 2020 Jun 24. PMID: 32581359