No evidence of large genetic effects on steroid response in asthma patients.

BACKGROUND: Inhaled corticosteroids (ICSs) are considered the most effective anti-inflammatory therapy for asthma control and management; however, there is substantial treatment response variability. OBJECTIVE: We sought to identify genetic markers of ICS response by conducting the largest pharmacogenetic investigation to date in 2672 ICS-treated patients with asthma. METHODS: Genotyping and imputation was performed in fluticasone furoate (FF) or fluticasone propionate-treated patients with asthma from 3 phase IIB and 4 phase IIIA randomized, double-blind, placebo-controlled, parallel group, multicenter studies. The primary end point analyzed was change in trough FEV1 (ΔFEV1) from baseline to 8 to 12 weeks of treatment. RESULTS: More than 9.8 million common genetic variants (minor allele frequency ≥ 1%) were analyzed to test for association with ΔFEV1. No genetic variant met the prespecified threshold for statistical significance. CONCLUSIONS: This study provides no evidence to confirm previously reported associations between candidate genetic variants and ICS response (ΔFEV1) in patients with asthma. In addition, no variant satisfied the criterion for genome-wide significance in our study. Common genetic variants are therefore unlikely to prove useful as predictive biomarkers of ICS response in patients with asthma.

Accurate interrogation of FCGR3A rs396991 in European and Asian populations using a widely available TaqMan genotyping method.

A polymorphism in the receptor for the Fc region of IgG, Fc γ-receptor IIIa (FcγRIIIa, FCGR3A rs396991), has been inconsistently shown in the literature to have an effect on response to monoclonal antibody therapy in several indications. The rs396991 (T/G) polymorphism leads to an F176V substitution and increased affinity for IgG. This variant has proven difficult to genotype accurately, primarily because of extensive homology between the FCGR3A and FCGR3B genes. We have shown that rs396991 can be genotyped by PCR amplification, followed by direct Sanger sequencing of the product, without coamplification of FCGR3B, and that the rs396991 TaqMan assay (C__25815666_10) agrees with Sanger sequencing results in 100% of European and Asian samples tested, but it has a small error rate in African and American populations. C__25815666_10 is therefore suitable to interrogate rs396991 in studies involving Europeans and Asians; however for other populations, the default genotyping method should be PCR followed by Sanger sequencing.

Guidelines for evaluation of patients at risk for inherited breast and ovarian cancer: recommendations of the Department of Defense Familial Breast/Ovarian Cancer Research Project.

Patients at high risk for inherited breast and/or ovarian cancer are frequently encountered in all medical specialties. Department of Defense, Health Affairs funding as part of the Breast Cancer Education and Awareness Program was used to develop a comprehensive program for the identification, counseling, genetic testing, and long-term follow-up of such high-risk patients. This article reports the recommendations for high-risk patient management based on 4 years of evaluation and care, including discussions of the approach to counseling, indications for genetic testing, post-testing counseling, patient surveillance with examination, imagining, and laboratory testing, and suggested options for surgical and chemoprophylaxis as well as lifestyle modifications.

Diagnostic criteria for testing for BRCA1 and BRCA2: the experience of the Department of Defense Familial Breast/Ovarian Cancer Research Project.

The Department of Defense Familial Breast/Ovarian Cancer Research Project has offered genetic counseling and testing for BRCA1 and BRCA2 on a research basis to patients meeting specific diagnostic criteria, with risk for BRCA1 and BRCA2 mutations calculated based on the Couch model. In 2.5 years, 250 patients were evaluated and 101 patients met criteria requirements, including 33 who met criteria in more than one category. Ninety patients elected to undergo DNA testing. In this group of 90 patients, 14 mutations (15.5%) and 16 unclassified variants (17.7%) were identified. The most common inclusion criteria were onset of breast/ovarian cancer before age 45 years (n = 32) and onset of breast/ovarian cancer before age 45 years with strong family history (n = 21). However, when number of mutations and unclassified variants found were compared separately across all diagnostic criteria (including those of more than one capacity) using the chi 2 statistic, no significant differences were seen among the categories to suggest that one criterion was more predictive of mutations or variants than another. Couch risk values for patients with mutations showed a mean of 14% and ranged from 3.2 to 43.5% (range for all patients, 1.2-69.7%). These findings emphasize the importance of using multiple diagnostic criteria and suggest that a Couch risk value of > 3% may be useful in selecting patients for testing. The data also underscore the necessity of genetic counseling in the testing process, particularly given the large number of unclassified variants diagnosed and their uncertain status for disease predisposition.