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Genomics in the Journals: 2013.07.03

NEW YORK (GenomeWeb News) - In Lancet Respiratory Medicine, an international team led by investigators at the Duke University Medical Center described findings from a prospective study looking at asthma-related information that can be gleaned from apparent asthma risk variants identified in past genome-wide association studies.

By following nearly 900 individuals of European ancestry from the age of nine-years old until they reached 38-years old, the group was able to track a range of asthma-related diagnostic information, traits, and behaviors in relation to each individual's polygenic risk score for asthma.

For instance, the researchers found that those with more asthma risk variants tended to be diagnosed with asthma at younger ages than those in the low-risk group and had more asthma-related complications. Likewise, asthma often stuck around throughout the lives of individuals who had the riskier polygenic profile and developed asthma when they were relatively young.

Based on their findings, the study's authors argued that "[g]enetic risk assessments might be able to predict which childhood-onset asthma cases remit and which become life-course-persistent, who might develop impaired lung function, and the burden of asthma in terms of missed school and work and hospital admissions, although these predictions are not sufficiently sensitive or specific to support immediate clinical translation."

Loci on chromosomes 4, 6, and 17 can contribute to the risk of cervical cancer in women from the Han Chinese population who are infected with human papillomavirus, according to a GWAS appearing online in Nature Genetics.

Researchers based at several centers in China initially compared genotyping patterns in 1,364 Han Chinese women with cervical cancer to more than 3,000 unaffected individuals from the same population. That analysis — and an analysis based on a smaller set of closely matched cases and controls — helped them narrow in on almost two dozen suspicious SNPs for additional testing.

After a pair of follow-up studies involving thousands more cases and controls, the team verified associations at two new loci: a chromosome 4 site in an intron of an exocytosis-related gene called EXOC1 and a chromosome 17 variant downstream of a gene called GSDMB, which has been shown to have higher-than-usual expression in other cancer types. The group's data also supported a cervical cancer association at a chromosome 6 locus that contains the human leukocyte antigen genes HLA-DPB1 and HLA-DPB2.

The same three sites showed ties to the development of a pre-cancerous condition known as cervical intraepithelial neoplasia, too, the study's authors found when they looked at genotype profiles for hundreds more women with CIN alone or CIN plus cervical cancer.

"The identification of susceptibility loci in the EXOC1 and GSDMB regions, as well as in the HLA-DP alleles, suggests an essential role for T cell-mediated immune responses or tumor proliferation," study authors wrote, "strengthening the hypothesis that inherited immunological and carcinogenic factors are prominent in determining the risk for cervical cancer, probably by affecting the mechanisms involved in the persistent infection and integration of HPV."

For two other Nature Genetics studies, independent research teams looked at genetic contributors to allergy risk using GWAS and GWAS meta-analysis approaches.

For the first of these, members of the Early Genetics and Lifecourse Epidemiology consortium focused on finding variants associated with allergic sensitization, which involves the production of immunoglobulin E molecules that recognizes a given allergen.

After identifying candidate SNPs in the discovery stage of the study, which included 5,789 allergy sensitized individuals and 10,056 unaffected controls, the team took variants at 26 loci forward for testing in a validation cohort comprised of thousands more cases and controls. All told, the search unearthed seven new loci, along with three loci implicated in allergic sensitization previously.

For their own allergy GWAS meta-analysis, meanwhile, researchers from 23andMe and the University of Bristol brought together genotyping data for 53,862 individuals from 23andMe's pool of study participants and from mothers enrolled through the Avon Longitudinal Study of Parents and Children, dubbed ALSPAC. Each of the participants had provided information about their susceptibility to cat, dust-mite, and pollen allergies.

Using analytical approaches aimed at finding shared and distinct genetic contributors for each of the allergy types, the group found eight known loci showing significant ties to allergy in general, along with eight not described in the past. That set included loci implicated in other allergic conditions such as asthma and allergic rhinitis in the team's own analysis and/or through past studies. Another locus, located in a class II human leukocyte antigen region of chromosome 6, was specifically associated with allergy to cats.

A team reporting in Science Translational Medicine has detected signs of selection in the genomes of individuals living in Bangladesh that appear to correspond to long-term cholera exposure in that population.

Using the latest iteration of the composite of multiple signals, or CMS, method, the team looked for cholera-related selection signatures in the genomes of 126 individuals of Bengali descent from a Bangladeshi population in the Ganges River Delta, where cholera is endemic and exposure to the Vibrio cholerae bacteria that causes it is widespread.

With array-based genotyping profiles for 108 of the individuals — representing three-dozen parent-child trios — the researchers saw more than 300 candidate sites of selection. From there, they narrowed in on cholera-associated sites of selection in and around genes involved in everything from NF-kappa B signaling (part of the innate immune system) and inflammation to potassium channel function.

The regions implicated in that analysis appear to coincide with cholera sensitivity and resistance, too, the group found: an association study of hundreds of V. cholerae-exposed individuals who did or did not develop cholera unearthed cholera risk SNPs that fell in at least some of the same parts of the genome identified in the natural selection-centered analysis.

"We're not only able to detect the footprint of natural selection in the genome, but also pinpoint its source, where the forces of natural section are exerting their effects," co-senior author Pardis Sabeti, a researcher affiliated with the Broad Institute, Harvard University's Center for Systems Biology, and the Harvard School of Public Health, said in a statement.

"This disease is ancient, widespread, and applies high selective pressure," she added, noting that "[w]e should also be able to apply CMS to other diseases with these characteristics — including malaria and tuberculosis, and perhaps Lassa fever and Ebola as well."

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