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Genomics in the Journals Jun 19, 2014

NEW YORK (GenomeWeb) – In Nature Genetics, an international team led by investigators in the US, UK, Netherlands, and Belgium described half a dozen new loci linked to the lung volume-related trait called forced vital capacity (FVC) that's sometimes used as a metric for detecting lung disease and following its progression.

Through a meta-analysis of existing data for 52,253 individuals evaluated in past genome-wide association studies of FVC, the researchers focused in on seven suspicious variants, verifying associations for SNPs at six sites through follow-up testing on almost 33,000 more individuals of European descent.

The analysis also highlighted potential contributions to FVC by two more variants in and around genes previously implicated in related lung traits such as forced expiratory volume.

Through additional experiments and analyses on data for African-American, Korean, Chinese, and Hispanic individuals, the researchers explored potential lung-related roles for the FVC loci and looked at alternative alleles with potential ties to this process in non-European populations.

"Our findings point to previously unexplored pathways and mechanisms underlying lung function," the study's authors concluded. "Improvement of the understanding of the role that these genes have in normal lung development and pathogenesis could lead to the identification of novel therapeutic targets for lung diseases."


A University of Michigan-led team used 16S ribosomal RNA gene sequencing as part of their look at the gut microbial community changes in Clostridium difficile patients treated with fecal transplants.

As they reported in mBio, the researchers did 16S sequencing on samples from 14 individuals afflicted with recurrent C. difficile infections, using the sequence data to assess gut microbiome composition and predicted functional properties before and after fecal microbiota transplantation.

The most pronounced shifts in the treated individuals' gut microbial communities were a rise in Bacteroidetes pylum bacteria, they reported, and a dip in representation by bugs from another phylum known as Proteobacteria.

The investigators also saw a general increase in microbial diversity. And in the 10 cases where they directly compared transplant recipient and donor microbe sequence data, they determined that patient gut microbiomes tended to become more similar to those of their healthy donors with time.

The group's efforts to predict functional consequences of the fecal transplants with imputed metagenomic information, meanwhile, suggested fecal transplant may dial down representation by bacterial genes involved in amino acid transport.

"The bottom line is fecal transplants work, and not by just supplying a missing bug but a missing function being carried out by multiple organisms in the transplanted feces," senior author Vincent Young, an infectious disease researcher at the University of Michigan, said in a statement. "By restoring this function, C. difficile isn't allowed to grow unchecked, and the whole ecosystem is able to recover."


A Genes & Development study by researchers at the University of Pennsylvania and the Children's Hospital of Philadelphia described long non-coding RNAs (lncRNAs) with apparent roles in regulating the aspects of lung development.

Through RNA sequencing on developing mouse embryos and lung tissue from adult mice, the team tracked down more than 350 lncRNAs in endoderm tissue from the mouse lung and foregut.

These non-coding RNAs appeared to be positioned in ways that corresponded to regulatory transcription factors in the genome, the study's authors noted. And follow-up experiments confirmed a role for at least two of the lncRNAs — dubbed NANCI and LL34 — in the development of endoderm tissue in the lung via interactions with signaling pathways and transcription factors.

"We are hopeful that these new data provide the foundation for a better understanding of how the non-coding transcriptome regulates tissue development and also maintenance of adult tissues," the study's corresponding author Edward Morrisey, scientific director of the University of Pennsylvania's Penn Institute for Regenerative Medicine, said in a statement.


A pair of studies in the New England Journal of Medicine suggest that rare, triglyceride-lowering mutations may help in diminishing heart disease risk.

With the help of protein-coding sequence data generated for 3,734 participants in National Heart, Lung, and Blood Institute Exome Sequencing Project (ESP), members of the ESP's triglycerides and high-density lipoprotein working group searched for rare mutations with ties to plasma triglyceride levels.

Amongst the variants identified were three loss-of-function mutations and one missense mutation in the apolipoprotein C3 gene APOC3, each coinciding with lower-than-usual triglyceride levels.

In the heterozygous carriers of such alterations — about one in every 150 individuals tested in the study — the team saw triglyceride levels that were more than one-third lower than those measured in non-APOC3 mutation carriers. Carriers also had 46 percent lower circulating apolipoprotein C3 levels.

After tracking down potential contributors to triglyceride levels, the team went on to look at whether any of these alterations associated with coronary heart disease risk in another 110,970 individuals. The nearly 500 APOC3 rare mutation carriers in the group had a 40 percent lower risk of coronary heart disease than their rare APOC3 mutation-free counterparts.

"Based on our findings, we predict that lowering triglycerides specifically through inhibition of APOC3 would have a beneficial effect by lowering disease risk," co-senior author Alex Reiner, a public health researcher affiliated with the Fred Hutchinson Cancer Research Center and the University of Washington, said in a statement.

Copenhagen researchers presented their own evidence in favor of a protective role for rare APOC3 mutations in heart disease in another NEJM study.

By bringing together data for more than 75,700 individuals tested through past population studies in Denmark, that team looked at the general relationships between non-fasting triglyceride levels and heart/vascular disease risk. It also considered the impact that loss-of-function APOC3 mutations have on both triglyceride levels and heart/vascular disease risk.

Again, the findings pointed to ties between loss-of-function glitches in APOC3 and lower-than-usual triglyceride levels. Although 10,797 participants in that study ultimately developed ischemic vascular disease (including 7,557 who progressed further to ischemic heart disease), these conditions were less common in the APOC3 mutation carriers.

Heterozygous APOC3 loss-of-function mutation carriers had a 41 percent lower risk of developing ischemic vascular disease and a 36 percent drop in ischemic heart disease risk, according to authors of that study.

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