Deborah Meyers

Atopy is generally considered to be caused by interaction of genetic and environmental factors. Recently, an association of a C-to-T transition in the promoter region of the CD14 gene on chromosome 5q31.1 and atopic phenotypes was reported in a population study of school children in the United States. The aim of the present study was to investigate the association of the C allele of the CD14/-159 with phenotypes of atopy and asthma in an adult Dutch population in which linkage of total serum IgE and bronchial hyperresponsiveness to chromosome 5q31-33 is present. We studied 159 probands with asthma and 158 spouses as controls. Phenotypes for asthma (e.g., bronchial hyperresponsiveness, physician's diagnosis) and for atopy (e.g., total serum IgE level, intracutaneous skin test, allergic rhinitis) were studied. In this population, homozygotes for the C allele had a higher number of positive skin tests and higher total serum IgE levels (in skin test-positive individuals) and subsequently, more self-reported allergic symptoms including rhinitis and hay fever, compared with subjects with CT and TT alleles. We conclude that the -159 C-to-T promoter polymorphism in the CD14 gene may result in expression of a more severe allergic phenotype.

To characterize the extent and impact of ancestry-related biases in precision genomic medicine, we use 642 whole-genome sequences from the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) project to evaluate typical filters and databases. We find significant correlations between estimated African ancestry proportions and the number of variants per individual in all variant classification sets but one. The source of these correlations is highlighted in more detail by looking at the interaction between filtering criteria and the ClinVar and Human Gene Mutation databases. ClinVar's correlation, representing African ancestry-related bias, has changed over time amidst monthly updates, with the most extreme switch happening between March and April of 2014 (r=0.733 to r=-0.683). We identify 68 SNPs as the major drivers of this change in correlation. As long as ancestry-related bias when using these clinical databases is minimally recognized, the genetics community will face challenges with implementation, interpretation and cost-effectiveness when treating minority populations.

To investigate the genetic susceptibility to asthma, we developed an algorithm to classify the phenotype of each family member enrolled in a family study on the genetics of asthma. This algorithm was applied to 92, two- and three-generation families, identified through a subject (proband) with asthma first diagnosed 25 yr previously. The algorithm consisted of five classes based on the presence or absence of bronchial hyperresponsiveness (BHR), respiratory symptoms, smoking, airways obstruction, and bronchodilator reversibility. All family members were classified as: (1) definite asthma; (2) probable asthma; (3) unclassifiable airway disease; (4) chronic obstructive pulmonary disease (COPD); (5) unaffected (without clinical evidence of asthma and COPD). Thirteen of the 92 probands (14%) could not be classified as asthmatic when retested 25 yr later because of loss of BHR, loss of bronchodilator reversibility, or a current history of cigarette smoking. Of the 265 first-degree offspring, 49 (18%) were classified as having definite asthma (Class 1), and 22 (8%) as probable asthma (Class 2). A large number of offspring with clinical evidence of asthma did not have a prior physician's diagnosis of asthma, and offspring in Class 1 (definite asthma), with and without a physician's diagnosis, had similar clinical and physiologic characteristics. These results support the usefulness of this approach to classify subjects with asthma for genetic epidemiologic studies and show that reliance on a prior physician's diagnosis may result in misclassification or underdiagnosis. Characterization of the offspring in this family study showed that there is familial clustering, which supports the presence of a hereditary component in asthma.