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Archive - Oct 27, 2013


Scientists ID Novel Mutation That Causes Aortic Aneurysms and Acute Aortic Dissection

Ascending thoracic aortic aneurysms can lead to life-threatening acute aortic dissections (TAADs). An example of this is the sudden death of popular actor John Ritter, who died from this problem. Subsequent examination of his brother Tommy showed that he had a dangerously large aortic aneurysm that was treated surgically to reduce his risk (see John Ritter’s father, Tex Ritter, known as the “Singing Cowboy,” had died suddenly while clutching his chest and is thus presumed to have died from the same problem as his son John. It is known that gene mutations that lead to decreased contraction of vascular smooth-muscle cells (SMCs) can cause inherited thoracic aortic aneurysms and aortic dissections. Using exome sequencing of distant relatives affected by thoracic aortic disease, followed by Sanger sequencing of additional probands with familial thoracic aortic disease, a research group presenting their results on Friday, October 25, at the American Society of Human Genetics (ASHG) 2013 annual meeting in Boston, reported identifying the same rare variant (c.530G>A) (p.Arg177Gln) in the gene PRKG1 in four families. This mutation segregated with aortic disease in the four families, with the majority (63%) of affected individuals presenting with acute aortic dissections at relatively young ages (mean 31 years, range 17-51 years). The PKRG1 gene encodes a type I cGMP-dependent protein kinase (PKG-1) that is activated upon binding of cGMP and controls SMC relaxation. Although the p.Arg177Gln alteration disrupts binding to the high-affinity cGMP binding site within the regulatory domain, the altered PKG-1 is constitutively activated even in the absence of cGMP.

Multiple, Distinct Y Chromosomes Associated with Significant Excess Risk of Prostate Cancer

An analysis of the genealogical and medical records of males in Utah's multi-generational families strongly supports the case that inherited variations in the Y chromosome, the male sex chromosome, play a role in the development of prostate cancer, according to a study presented on Friday, October 25, at the American Society of Human Genetics (ASHG) 2013 meeting in Boston. The study identified multiple, distinct Y chromosomes associated with a significant excess risk of prostate cancer, said Lisa Cannon-Albright, Ph.D., Professor and Chief of the Division of Genetic Epidemiology at the University of Utah School of Medicine. Dr. Cannon-Albright, who headed the study and presented the results, said that her lab plans to search these Y chromosomes for the genetic mutations that can predispose a man to develop prostate cancer, the second most frequently diagnosed cancer in the U.S. Because most of the Y chromosome does not recombine during cell division, it is passed virtually unchanged from father to son. “As a result, each male resident of Utah shares the Y chromosome of his father and his father’s father and so on,” she said. “This provided the ability to estimate the risk for prostate cancer in independent Y chromosomes represented in Utah.” The study relied upon the Utah Population Data Base (UPDB), which identifies over 6.5 million individuals, including many of the Utah pioneers in the 1800s. The pioneer genealogies in the UPDB are typically large, spanning 15 generations. The Utah population represented in the UPDB is genetically representative of Northern Europe. The database was created in the 1970s to define familial clustering and identify evidence for heritable contribution to cancer.

DNA Variants May Influence Response to Inhaled Bronchodilators by Patients with COPD

Several novel gene variants may help explain the response of patients with chronic obstructive pulmonary disease (COPD) to inhaled bronchodilators, according to a meta-analysis reported on Friday, October 25, at the American Society of Human Genetics (ASHG) 2013 meeting in Boston. The meta-analysis used statistical methods to combine results from four individual studies with a total of 6,500 Caucasian patients with moderate to severe COPD. Over 6.3 million unique single nucleotide polymorphisms (SNPs) were identified in the genotypes of the patients with COPD, which is a progressive breathing disorder that limits airflow in the lungs. The genotypes of over 800 African Americans with COPD were also analyzed. “Identifying single nucleotide polymorphisms associated with bronchodilator responsiveness may reveal genetic pathways associated with the pathogenesis of COPD and may identify novel treatment methods,” said Megan Hardin, M.D., Instructor of Medicine at Harvard Medical School and researcher in the Channing Division of Network Medicine at Brigham and Women's Hospital, Boston. Dr. Hardin, who presented the research, added that multiple genetic determinants likely influence bronchodilator responsiveness. Functional analysis of the SNPs will be conducted, she added. “As we continue to analyze the data, we expect to identify other important SNPs,” said Craig P. Hersh, M.D., who headed the study and is Assistant Professor, Harvard Medical School, and faculty member in the Channing Division of Network Medicine at Brigham and Women’s Hospital. All of the subjects studied had significant histories of smoking, with most (4,561), having smoking histories of over 10 pack-years (i.e., 10 years of smoking a smoking one pack of cigarettes per day.