Center for Genomics and Personalized Medicine Research

Wake Forest, NC, United States

Center for Genomics and Personalized Medicine Research

Wake Forest, NC, United States
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Palmer N.D.,Center for Genomics and Personalized Medicine Research | Freedman B.I.,Section on Nephrology
Current Diabetes Reports | Year: 2012

Diabetic nephropathy (DN) is a devastating complication of type 1 and type 2 diabetes and leads to increased morbidity and premature mortality. Susceptibility to DN has an inherent genetic basis as evidenced by familial aggregation and ethnic-specific prevalence rates. Progress in identifying the underlying genetic architecture has been arduous with the realization that a single locus of large effect does not exist, unlike in predisposition to non-diabetic nephropathy in individuals with African ancestry. Numerous risk variants have been identified, each with a nominal effect, and they collectively contribute to disease. These results have identified loci targeting novel pathways for disease susceptibility.With continued technological advances and development of new analytic methods, additional genetic variants and mechanisms (e.g., epigenetic variation) will be identified and help to elucidate the pathogenesis of DN. These advances will lead to early detection and development of novel therapeutic strategies to decrease the incidence of disease. © Springer Science+Business Media, LLC 2012.


Dillon L.W.,Medical Center Boulevard | Pierce L.C.T.,University of California at San Diego | Ng M.C.Y.,Center for Genomics and Personalized Medicine Research | Ng M.C.Y.,Center for Diabetes Research | Wang Y.-H.,Medical Center Boulevard
Human Molecular Genetics | Year: 2013

The formation of alternative DNA secondary structures can result in DNA breakage leading to cancer and other diseases. Chromosomal fragile sites, which are regions of the genome that exhibit chromosomal breakage under conditions of mild replication stress, are predicted to form stable DNA secondary structures. DNA breakage at fragile sites is associated with regions that are deleted, amplified or rearranged in cancer. Despite the correlation, unbiased examination of the ability to form secondary structures has not been evaluated in fragile sites. Here, using the Mfold program, we predict potential DNA secondary structure formation on the human chromosome 10 sequence, and utilize this analysis to compare fragile and non-fragile DNA. We found that aphidicolin (APH)-induced common fragile sites contain more sequence segments with potential high secondary structure-forming ability, and these segments clustered more densely than those in non-fragile DNA. Additionally, using a threshold of secondary structure-forming ability, we refined legitimate fragile sites within the cytogenetically defined boundaries, and identified potential fragile regions within non-fragile DNA. In vitro detection of alternative DNA structure formation and a DNA breakage cell assay were used to validate the computational predictions. Many of the regions identified by our analysis coincide with genes mutated in various diseases and regions of copy number alteration in cancer. This study supports the role of DNA secondary structures in common fragile site instability, provides a systematic method for their identification and suggests a mechanism by which DNA secondary structures can lead to human disease. © The Author 2013. Published by Oxford University Press.


Ortega V.E.,Center for Genomics and Personalized Medicine Research | Meyers D.A.,Center for Genomics and Personalized Medicine Research
Current Opinion in Allergy and Clinical Immunology | Year: 2014

Purpose of review: The frequency and severity of asthma differ between different racial and ethnic groups. An understanding of the genetic basis for these differences could constitute future genetic biomarker panels for predicting asthma risk and progression in individuals from different ethnic groups. Recent themes: The recent mixing of different ancestries during the European colonization of the Americas and the African slave trade has resulted in the complex population structures identified in different ethnic groups. These population structures represent varying degrees of genetic diversity which impacts the allele frequency of individual variants and, thus, how the gene variation is utilized in genetic association studies. In this review, we will discuss the basis for the complex population structures of modern human genomes and the impact of genetic diversity on genetic studies in different ethnic groups. We will also highlight the potential for admixture and rare variant-based genetic studies to identify novel genetic loci for asthma susceptibility and severity. Summary: The ability to account for the consequences of genetic diversity in different racial and ethnic groups will be critical in developing genetic profiles for personalized or precision medicine approaches tailored to asthmatic patients from different ethnic groups. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Meyers D.A.,Center for Genomics and Personalized Medicine Research | Bleecker E.R.,Center for Genomics and Personalized Medicine Research | Holloway J.W.,Center for Genomics and Personalized Medicine Research | Holgate S.T.,University of Southampton
The Lancet Respiratory Medicine | Year: 2014

Unbiased genetic approaches, especially genome-wide association studies, have identified novel genetic targets in the pathogenesis of asthma, but so far these targets account for only a small proportion of the heritability of asthma. Recognition of the importance of disease heterogeneity, the need for improved disease phenotyping, and the fact that genes involved in the inception of asthma are likely to be different from those involved in severity widens the scope of asthma genetics. The identification of genes implicated in several causal pathways suggests that genetic scores could be used to capture the effect of genetic variations on individuals. Gene-environment interaction adds another layer of complexity, which is being successfully explored by epigenetic approaches. Pharmacogenetics is one example of how gene-environment interactions are already being taken into account in the identification of drug responders and non-responders, and patients most susceptible to adverse effects. Such applications represent one component of personalised medicine, an approach that places the individual at the centre of health care. © 2014 Elsevier Ltd.


Slager R.E.,Center for Genomics and Personalized Medicine Research | Otulana B.A.,Aerovance | Hawkins G.A.,Center for Genomics and Personalized Medicine Research | Yen Y.P.,Aerovance | And 4 more authors.
Journal of Allergy and Clinical Immunology | Year: 2012

Background: This is the first large pharmacogenetic investigation of the inflammatory IL-4/IL-13 pathway in patients with moderate-to-severe asthma. We analyzed genomic DNA from participants in a 12-week placebo-controlled efficacy trial of pitrakinra (1, 3, or 10 mg twice daily), a novel IL-4/IL-13 pathway antagonist (Clinicaltrials.gov NCT00801853). Objectives: The primary hypothesis for this analysis is that amino acid changes in the 3′ end of the IL-4 receptor α gene (IL4RA) or closely proximal variants would predict reductions in asthma exacerbations for subjects randomized to pitrakinra therapy. Methods: Nineteen IL4RA single nucleotide polymorphisms (SNPs) were tested in 407 non-Hispanic white subjects for association with the primary clinical end point of asthma exacerbations and changes in secondary end points for asthma symptom scores. Results: The most consistent pharmacogenetic associations were observed for the correlated tagging SNPs rs8832 and rs1029489 in the IL4RA 3′ untranslated and proximal regions, respectively. Subjects homozygous for the rs8832 common G allele randomized to pitrakinra (placebo group nonsignificant) had decreased asthma exacerbations and decreased nocturnal awakenings and activities limited by asthma. There was also a significant pitrakinra dose-response relationship (placebo/1 mg/3 mg/10 mg) for exacerbations in subjects homozygous for the common allele in rs1029489 (P =.005) and rs8832 (P =.009) and the intronic SNPs rs3024585, rs3024622, and rs4787956 (P =.03). Conclusion: This study demonstrates a significant pharmacogenetic interaction between anti-IL-4 receptor α therapy and IL4RA gene variation, identifying an asthma subgroup that is more responsive to therapy with this antagonist. © 2012 American Academy of Allergy, Asthma & Immunology.


Rank M.A.,Mayo Medical School | Peters S.P.,Center for Genomics and Personalized Medicine Research
Journal of Allergy and Clinical Immunology: In Practice | Year: 2014

Stepwise adjustments have been suggested as a framework to manage chronic asthma over time. In this framework, individuals with good asthma control and a low risk for future asthma exacerbations may be considered for a reduction or "step down" of their chronic asthma medications. In this article, we discuss how patients may benefit or be harmed by stepping down asthma medications. Based on the literature presented in this article, we recommend that clinicians discuss the option of stepping down with patients when symptoms are stable, lung function is near normal, and biomarkers (if measured) are near normal. Other factors that should be considered in the decision to step down include the length of asthma stability, age of the patient, time of year, and patient preferences. Reducing the dose of inhaled corticosteroid by 25% to 50% appears to be the safest method of stepping down. A clear plan of care and follow-up is needed when stepping down asthma medications because many patients are likely to have recurrent exacerbations. © 2014 American Academy of Allergy, Asthma & Immunology.


Traister R.S.,University of Pittsburgh | Uvalle C.E.,University of Pittsburgh | Hawkins G.A.,Center for Genomics and Personalized Medicine Research | Meyers D.A.,Center for Genomics and Personalized Medicine Research | And 2 more authors.
Journal of Allergy and Clinical Immunology | Year: 2015

Background Severe asthma remains poorly characterized, although it likely consists of at least 1 phenotype with features of TH2-like inflammation. IL1RL1, encoding both the IL-33 receptor, ST2L, and decoy receptor, sST2, has been genetically associated with asthma, though the mechanism for susceptibility remains unknown.Objective Given previous data supporting a role for IL1RL1 in TH2 inflammation, we hypothesized that ST2L expression might be increased in TH2-like asthma and that expression levels would be associated with single nucleotide polymorphisms in IL1RL1, possibly explaining its genetic relationship with asthma. We also sought to evaluate the regulation of ST2L and sST2 in vitro.Methods Endobronchial brushings and biopsies were obtained and expression of ST2L compared by severity levels, as well as by TH2-like biomarkers. Subjects were genotyped and the relationship of dichotomous expression of ST2L and sST2 to single nucleotide polymorphisms in IL1RL1 were determined. Epithelial cells were grown in air-liquid interface culture, and ST2L and sST2 responses to IFN-γ and IL-13 were evaluated.Results ST2L expression was increased in severe asthma (P =.02) and associated with multiple indicators of TH2-like inflammation, including blood eosinophils (P =.001), exhaled nitric oxide (P =.003), and epithelial CLCA1 (P <.0001) and eotaxin-3 (P =.001) mRNA expression. Multiple single nucleotide polymorphisms in IL1RL1 were found in relation to dichotomous expression of both ST2L and sST2. sST2 expression was associated with IFN-γ expression in bronchoalveolar lavage, while inducing its expression in vitro in primary human epithelial cells.Conclusion Both pathologic and genetic approaches support a role for IL1RL1 in severe asthma, as well as TH2-lke asthma, suggesting that targeting this pathway may have therapeutic benefits. © 2014 American Academy of Allergy, Asthma & Immunology.


Peters S.P.,Center for Genomics and Personalized Medicine Research
Journal of Allergy and Clinical Immunology: In Practice | Year: 2013

Dyspnea, "a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity," is an important and challenging complaint associated with a wide variety of adverse clinical outcomes, including hospitalizations for chronic obstructive pulmonary disease and cardiac mortality. Although up to 85% of cases are caused by asthma, chronic obstructive pulmonary disease, interstitial lung disease, pneumonia, cardiac ischemia, congestive heart failure, or psychogenic disorders, a systematic approach can help to identity uncommon, but important, causes of dyspnea. In this review that includes clinical examples as well as a didactic review of currently available information, we suggest a step-wise approach to the evaluation of the adult patient with dyspnea. It is also important to avoid 3 possible pitfalls: accepting a cause for dyspnea in which the element identified is only part of a syndrome which includes that element; accepting a single cause for dyspnea when the cause is multifactorial; and failing to recognize a diagnosis and cause of dyspnea is incorrect and has been assumed without rigorous confirmation, when a patient with a specific diagnosis is referred for "failing to respond to treatment." © 2013 American Academy of Allergy, Asthma & Immunology.


Moore W.C.,Center for Genomics and Personalized Medicine Research | Hastie A.T.,Center for Genomics and Personalized Medicine Research | Li X.,Center for Genomics and Personalized Medicine Research | Li H.,Center for Genomics and Personalized Medicine Research | And 6 more authors.
Journal of Allergy and Clinical Immunology | Year: 2014

Background Clinical cluster analysis from the Severe Asthma Research Program (SARP) identified 5 asthma subphenotypes that represent the severity spectrum of early-onset allergic asthma, late-onset severe asthma, and severe asthma with chronic obstructive pulmonary disease characteristics. Analysis of induced sputum from a subset of SARP subjects showed 4 sputum inflammatory cellular patterns. Subjects with concurrent increases in eosinophil (≥2%) and neutrophil (≥40%) percentages had characteristics of very severe asthma. Objective To better understand interactions between inflammation and clinical subphenotypes, we integrated inflammatory cellular measures and clinical variables in a new cluster analysis. Methods Participants in SARP who underwent sputum induction at 3 clinical sites were included in this analysis (n = 423). Fifteen variables, including clinical characteristics and blood and sputum inflammatory cell assessments, were selected using factor analysis for unsupervised cluster analysis. Results Four phenotypic clusters were identified. Cluster A (n = 132) and B (n = 127) subjects had mild-to-moderate early-onset allergic asthma with paucigranulocytic or eosinophilic sputum inflammatory cell patterns. In contrast, these inflammatory patterns were present in only 7% of cluster C (n = 117) and D (n = 47) subjects who had moderate-to-severe asthma with frequent health care use despite treatment with high doses of inhaled or oral corticosteroids and, in cluster D, reduced lung function. The majority of these subjects (>83%) had sputum neutrophilia either alone or with concurrent sputum eosinophilia. Baseline lung function and sputum neutrophil percentages were the most important variables determining cluster assignment. Conclusion This multivariate approach identified 4 asthma subphenotypes representing the severity spectrum from mild-to-moderate allergic asthma with minimal or eosinophil-predominant sputum inflammation to moderate-to-severe asthma with neutrophil-predominant or mixed granulocytic inflammation. © 2014 American Academy of Allergy, Asthma & Immunology.


Ortega V.E.,Center for Genomics and Personalized Medicine Research | Wechsler M.E.,National Jewish Health
Current Opinion in Allergy and Clinical Immunology | Year: 2013

PURPOSE OF REVIEW: Asthma is a chronic, complex disease that is treated with a combination of different therapies. However, interindividual variability in clinical responses to different therapies complicates asthma management. A personalized approach to asthma management could identify appropriate responders to specific agents or those that might be at an increased risk for adverse responses. RECENT FINDINGS: Pharmacogenetic studies of genes from the leukotriene, glucocorticoid, and beta2-Adrenergic receptor pathways have improved our understanding of how gene variation determines therapeutic responses to different classes of antiasthma therapies. Such studies have previously been limited to retrospective analyses of candidate genes in the leukotriene, glucocorticoid, and beta2-Adrenergic receptor pathways in trial cohorts. However, prospective genotype-stratified trials in asthma have recently been done and recent genome-wide association studies have identified novel pharmacogenetic loci. SUMMARY: It will be important to replicate previous genotypic associations in large clinical trial cohorts as future pharmacogenetic studies continue to focus on genome-wide approaches and the study of novel therapeutic pathways. This review of the pharmacogenetics of asthma highlights the contributions of genomics research to the future of personalized medicine in asthma and draws attention to the role of genetic biomarkers in predicting clinical responses to specific therapies. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

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