An international team led by investigators at the National Human Genome Research Institute and Istanbul University has uncovered new loci linked to Behçet's disease, a blood vessel condition characterized by bouts of inflammation and ulcers affecting the skin, eyes, and other tissues, and which sometimes leading to vision loss. As they reported in Nature Genetics, the researchers genotyped around 800,000 SNPs in 1,209 individuals from Turkey with Behçet's disease. By comparing the variant patterns with those found in 1,278 unaffected people from the same population, investigators unearthed new disease-associated SNPs in and around four genes with suspected immune functions — results that they verified in another 1,468 Turkish cases and controls as well as in samples from almost 1,400 Japanese individuals. One of the genes, ERAP1, contained two variants that bump up Behçet's disease risk when inherited recessively. That gene apparently shares epistatic interactions with the human leukocyte antigen gene HLA-B*51, a known Behçet's disease-related gene. And as a set, the variants identified in the GWAS indicate overlap between Behçet's disease and other inflammatory conditions, particularly psoriasis and a form of arthritis known as ankylosing spondylitis.
"These newly discovered genetic associations provide a link between Behçet's disease and other more common illnesses, and thereby suggest new therapies for Behçet's disease," said co-senior author Dan Kastner, scientific director of NHGRI's intramural research program, in a statement.
Also in Nature Genetics, researchers from the National Institutes of Health and elsewhere reported on findings from a study suggesting natural clearance of hepatitis C virus is compromised in individuals with the frame-shift variant ss469415590, which falls upstream of the interleukin-28-coding gene IFNL3 (also called IL28B). The group detected the suspicious variant through RNA sequencing and 5' rapid amplification of cDNA ends, or RACE, experiments on human liver cells challenged with a synthetic compound that mimics HCV. The cell line was developed using samples from an uninfected individual who was heterozygous for rs12979860, an IFNL3/IL28B SNP tied to HCV clearance in past studies. Together, results of these and other analyses suggested that ss469415590 — which is found in linkage disequilibrium with rs12979860 — alters IFNL3/IL28B in ways that produce a substitute protein-coding gene called IFNL4. And though that protein appears to trigger some antiviral pathways in the cell, investigators said, it also coincides with an overall dip in HCV clearance.
Over at BMC Medicine, meanwhile, an independent team from Spain's National Center for Microbiology verified ties between spontaneous HCV clearance and several different IL28B variants through a meta-analysis that brought together data from past studies involving up to 23,500 people. But the impact of the pro-clearance SNPs varied somewhat depending on the population considered and the HCV genotype involved, the researchers noted. Results of that study also suggested that SNPs in IL28B may help in predicting who will respond most favorably to pegylated interferon-alpha plus ribavirin treatments for HCV infection. If such findings hold, study authors said that it eventually may be possible to guide HCV treatments in a more targeted manner, siphoning individuals with IL28B variants linked to poor PEG-IFN/RBV response off into alternative treatment strategy pools.
"Treatment with PEG-IFN/RBV is costly and can have side effects which prevent patient compliance," study leaders María Ángeles Jiménez-Sousa, Amanda Fernández-Rodríguez, and Salvador Resino said in a statement.
"Consequently knowing a patient's IL28B status will help target interferon treatment to those who will benefit most," they added, "and play a substantial role in the selection of candidates for standard treatment versus triple therapy with direct-acting antivirals."
Somatic mutation patterns in tumor cells can serve as a source of information on the processes that have gone awry in cancers and, in some cases, the environmental exposures to blame for these genetic glitches. Until now, though, routinely finding such mutational signatures has been tricky, researchers from the Wellcome Trust Sanger Institute, Addenbrooke's Hospital, and the University of Cambridge said in a new Cell Reports paper. In that study, the Sanger Institute's Michael Stratton and colleagues presented their computational strategy for sifting through the sets of base substitutions, insertions and deletions, rearrangements, and copy-number shifts found within the growing collection of cancer genome sequences to identify potentially informative mutational signatures. After applying this approach to simulated cancer sequence data, the researchers demonstrated its feasibility for finding mutational signatures in breast cancer using data from whole-genome and exome sequencing studies of the disease.
"Our approach provides a basis for characterizing mutational signatures from cancer-derived somatic mutation catalogs," the study's authors explained, "paving the way to insights into the pathogenetic mechanisms underlying all cancers."
Genomics In The Journals is a weekly feature pointing readers to select, recently published articles involving genomics and related research.