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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. Source

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. Source

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. Source

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. Source

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. Source

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