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Genomics in the Journals : Apr 25, 2013

NEW YORK (GenomeWeb News) – In Nature Genetics, two teams described the immune region-focused, Immunochip array-based strategy that they used to find sites in the genome with ties to a serious liver disease called primary sclerosing cholangitis and to a form of childhood rheumatoid arthritis called juvenile idiopathic arthritis.

For the primary sclerosing cholangitis study, an international team led by investigators in Norway, the UK, and Germany compared genotyping data for 3,789 cases and nearly 25,100 controls in an effort to find new genetic contributors to the mysterious liver bile duct disease, which tends to appear in individuals also at risk of inflammatory bowel disease and other autoimmune conditions.

Using dense genotyping information covering 186 disease and/or immune-related areas of the genome targeted by the custom Illumina Immunochip, the researchers found a dozen primary sclerosing cholangitis-associated sites outside of human leukocyte antigen regions. Nine of the 12 loci had not been described in past studies of the disease. And half showed closer genetic ties to primary sclerosing cholangitis risk than to IBD, they noted, "suggesting overlapping yet distinct genetic architectures for these two diseases."

"Before our study, it was never quite clear whether PSC was a complication of IBD or a distinct disease in its own right," co-senior author Carl Anderson, with the Wellcome Trust Sanger Institute, said in a statement.

"We have proven it to be a unique disease," he added, "and hope that our results will inform the development of more effective treatments, designed to target the biological pathways involved in causing the disease."

Meanwhile, researchers from the UK, US, and Germany assessed 2,816 affected and 13,056 unaffected individuals for their study of juvenile idiopathic arthritis, another condition that seems to overlap genetically with autoimmune diseases.

Using Immunochip-based genotyping data for unaffected control individuals and for individuals with the two most common juvenile idiopathic arthritis sub-types, the team not only verified three known risk loci in the chronic rheumatic condition, but tracked down 14 more. Almost a dozen additional sites in the genome showed more tenuous ties to the disease, researchers noted.

The findings offer insight as to "where [juvenile idiopathic arthritis] fits within the spectrum of autoimmune diseases," the study's authors concluded, "and identifies a number of new genes and pathways as potential targets for future therapeutic intervention."

Influxes of individuals from Eurasia and Western Europe appear to have left their genetic mark on populations in central Germany, according to a new Nature Communications study.

Members of the Genographic Consortium — together with investigators from the University of Adelaide, the University of Huddersfield, and elsewhere — performed mitochondrial genome sequencing on DNA from more than three dozen ancient bone and tooth samples stretching back almost 5,500 years, focusing on the mitochondrial haplogroup H lineage that's currently common in Western Europe.

Results of the analysis revealed a shift in the haplogroup H lineage roughly 4,500 years ago during the middle of the Stone Age, researchers reported, when early agricultural populations interacted with other populations in the region. The mitochondrial lineage seems to have been subsequently influenced by expansions into the region by Eastern European populations as well as members of the so-called Bell Beaker culture, who appear to have migrated to the area from Iberia an estimated 2,800 years ago.

"We have established that the genetic foundations for modern Europe were only established in the Mid-Neolithic, after this major genetic transition around 4,000 years ago," co-first author Wolfgang Haak, a researcher with the Australian Centre for Ancient DNA at the University of Adelaide, said in a statement. "This genetic diversity was then modified further by a series of incoming and expanding cultures from Iberia and Eastern Europe through the Late Neolithic."

A Science study looks at the collection of proteins secreted by activated immune cells. Max Planck Institute of Biochemistry's Matthias Mann and colleagues came up with a sensitive, liquid chromatography mass spectrometric-centered strategy for profiling proteins secreted by immune cells and determining their levels under different conditions.

Using this approach, the team tallied up 775 proteins that are recurrently released by macrophages following the activation of a Toll-like receptor that's known for sensing lipopolysaccharide signals from certain bacteria.

Within so-called "secretome" sets generated over time and in different genetic backgrounds, investigators saw hundreds of proteins predicted or known to have extracellular functions. And consistent with the notion that the approach picked up authentic immune-related protein players, the reproducible secretome set included more than four-dozen known cytokine signaling proteins.

By folding in array-based gene expression data, meanwhile, the study's authors began teasing apart new details of the immune signaling process, illustrating that the enhanced secretion of certain proteins doesn't always coincide directly with a boost in transcription of that gene, for instance.

"From genetic models, we defined secretory profiles that depended on distinct intracellular signaling adaptors," they noted, "and showed that secretion of many pro-inflammatory proteins is safeguarded by redundant mechanisms, whereas signaling adaptor synergy promoted the release of anti-inflammatory proteins."

Genomics In The Journals is a weekly feature pointing readers to select, recently published articles involving genomics and related research.