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Genomics In The Journals: Sep 13, 2012

NEW YORK (GenomeWeb News) – A fine-mapping study in Nature Genetics reveals three new loci linked to a liver autoimmune disease known as primary biliary cirrhosis, or PBC.

For the analysis, a UK-led team that included representatives from the UK PBC Consortium and the Wellcome Trust Case Control Consortium 3 genotyped 2,861 individuals with and 8,514 individuals without PBC using an Immunochip array targeting variants at 186 sites in the genome that have been implicated in autoimmunity. The search helped to verify and expand researchers' understanding of some known PBC risk loci. It also revealed new variants with significant ties to PBC at loci on chromosomes 12, 17, and 19 — bringing the tally of loci associated with the condition up to 25.

"[B]y comparing our results with similar studies of other autoimmune diseases, we hope to further characterize the genetic relationship between this group of clinically diverse but biologically related disorders," Cambridge University medical genetics researcher Richard Sandford, a co-senior author on the study, said in a statement.

The work follows from a large GWAS of primary biliary cirrhosis that was conducted by some of the same researchers and published in Nature Genetics last year. That analysis uncovered more than a dozen primary biliary cirrhosis-linked loci and confirmed several sites found in even earlier studies.


Also in Nature Genetics, members of the Wellcome Trust Case Control Consortium and the Esophageal Adenocarcinoma Genetics Consortium report on two Barrett's esophagus-associated loci that they tracked down through a genome-wide association study involving thousands of individuals with the condition, which involves stomach acid-related damage to the lining of the esophagus.

After identifying suspicious SNPs during a discovery GWAS based on 1,852 cases and 5,172 controls from the UK, the team verified associations for variants at two loci through multi-stage validation testing on nearly 19,000 more individuals of European descent. One of the risk loci fell within the immune-related major histocompatability complex region on chromosome 6, while the other turned up in a region near the chromosome 16 gene FOXF1, believed to influence gastrointestinal tract development. The analysis also sussed out several variants with small affects individually that appear to combine to increase Barrett's esophagus risk. Among them: variants with previous ties to obesity.

"Given that [Barrett's esophagus] is known to be a precursor to esophageal cancer, it is quite possible that these genetic variations could also be risk factors for developing the cancer and they may give us clues as to the biological mechanisms involved," co-corresponding author Janusz Jankowski, a researcher affiliated with Queen Mary University of London and the University of Oxford, said in a statement.


Different members of the microbial communities living in the sinus cavity can contribute to — or help protect against — a type of sinus infection called chronic rhinosinusitis, according to a Science Translational Medicine study.

California researchers used array-based 16S ribosomal gene profiling to identify microbiome members in sinus samples from 10 individuals with chronic rhinosinusitis, a bacterial infection characterized by mucus membrane inflammation in the sinuses. When they compared sinus microbe community profiles in these patients with those found in sinus samples from 10 unaffected control individuals, the investigators saw a dip in bacterial diversity in the patient microbiomes. In particular, sinus microbiomes from individuals with chronic rhinosinusitis contained fewer lactic acid-producing bacteria, the team noted, but showed an uptick in the levels of Corynebacterium tuberculostearicum, a bacterial species suspected of spurring on chronic rhinosinusitis infection. A series of follow-up experiments in mice supported that notion, while at once pointing to a protective role for at least one lactic acid-producing species, Lactobacillus sakei.

"These studies demonstrate that sinus mucosal health is highly dependent on the composition of the resident microbiota," University of California at San Francisco biologist Susan Lynch, the study's senior author, and her colleagues wrote, "as well as identify both a new sino-pathogen and a strong bacterial candidate for therapeutic intervention."


Researchers from Washington University School of Medicine, the Medical College of Wisconsin, and the MD Anderson Cancer Center compared mutation profiles in non-small cell lung carcinoma tumors from smokers and never-smokers in a Cell study.

The investigators found more than 3,700 point mutations and dozens of small insertions and deletions when they scoured genome and transcriptome sequences for NSCLC tumors from 17 individuals — a dozen smokers and five never-smokers — and compared them to matched normal tissue adjacent to the tumors. But the team saw far more somatic mutations in tumors from those with a history of smoking tobacco: there, the mutation frequency was 10 times higher, on average. When they looked at alterations present across all of the NSCLC tumors, the researchers found mutations affecting several known lung cancer genes, new candidate genes (including genes from chromatin and DNA repair-related pathways), and dozens of potentially druggable genes.

"Whether these drugs will actually work in patients with these DNA alterations still needs to be studied," co-first author Ramaswamy Govindan, an oncologist with Washington University's Siteman Cancer Center, said in a statement. "[W]e need to drill deeper and do studies to understand how these mutations cause and promote cancer, and how they can be targeted for therapy."

In a second Cell study, an international team led by investigators at the Broad Institute, Harvard Medical School, and the Dana Farber Cancer Institute looked into mutation patterns that characterize another lung cancer sub-type: lung adenocarcinoma.

That group did exome sequencing on DNA from 182 matched tumor-normal samples sets. Almost two-dozen of these were also assessed by whole-genome sequencing, as was one tumor-normal pair that had not been subjected to exome sequencing. When they began sifting through the sequence data, researchers saw 12 somatic mutations for every million bases of coding sequence, on average, and uncovered mutational signatures that seemed to distinguish smoker from non-smoker tumors. In addition, by focusing in on some of the recurrently mutated and rearranged genes in the tumors, the team found what it believes may be promising targets for treating lung adenocarcinoma.


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

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