Elvin Price

Gene Expression Variability in Human Hepatic Drug Metabolizing Enzymes and Transporters

Interindividual variability in the expression of drug-metabolizing enzymes and transporters (DMETs) in human liver may contribute to interindividual differences in drug efficacy and adverse reactions. Published studies that analyzed variability in the expression of DMET genes were limited by sample sizes and the number of genes profiled. We systematically analyzed the expression of 374 DMETs from a microarray data set consisting of gene expression profiles derived from 427 human liver samples. The standard deviation of interindividual expression for DMET genes was much higher than that for non-DMET genes. The 20 DMET genes with the largest variability in the expression provided examples of the interindividual variation. Gene expression data were also analyzed using network analysis methods, which delineates the similarities of biological functionalities and regulation mechanisms for these highly variable DMET genes. Expression variability of human hepatic DMET genes may affect drug-gene interactions and disease susceptibility, with concomitant clinical implications.

Liver X receptor α gene polymorphisms and variable cardiovascular outcomes in patients treated with antihypertensive therapy: results from the INVEST-GENES study.

Background/aims Liver X receptor-&agr; (LXRA) is a nuclear receptor that regulates genes important in cholesterol homeostasis and inflammation. Several single nucleotide polymorphisms (SNPs) in the LXRA gene (NR1H3) have been earlier associated with metabolic phenotypes (dyslipidemia and elevated body mass index). Metabolic dysregulation is a major contributor to coronary disease; therefore, we assessed LXRA in International Verapamil Sustained Release SR Trandolapril Study Genetic Substudy (INVEST-GENES), a genetic-substudy of a large clinical trial in patients with hypertension and coronary artery disease. Methods Seven tag SNPs in the LXRA gene region (NR1H3) were selected for study: rs11039149, rs12221497, rs2279238, rs7120118, rs326213, rs11039159, and rs10501321. One thousand fifty-nine patients were genotyped from the INVEST-GENES case–control set (verapamil-sustained release-based or atenolol-based treatment strategies) that comprised of 297 cases frequency matched (approximately 2.5:1) with that of event-free controls by sex and race. The primary outcome was defined as first occurrence of all-cause death, nonfatal myocardial infarction, or nonfatal stroke. Adjusted odds ratios (ORs) were calculated using logistic regression. Results Three of the seven SNPs were associated with significant effects on the primary outcome in nonBlacks. The variant G allele of rs11039149 and the variant A allele of rs12221497 were associated with reduced risk of experiencing the primary outcome [OR: 0.62, confidence interval (CI): 0.45–0.85, P=0.003 and OR: 0.60, CI: 0.39–0.91, P=0.016, respectively]. The rs2279238 genotype was associated with a significant increase in risk for the primary outcome (OR: 1.42, CI: 1.03–1.95, P=0.03). Furthermore, there was a significant genotype–treatment strategy interaction for carriers of the variant T allele of rs2279238 (OR for verapamil-sustained release strategy compared with atenolol strategy: 2.86, CI: 1.50–5.46, P=0.0015). Diplotype analyses showed that the SNPs are rarely coinherited and support the directionally opposite effects of the SNPs on the primary outcome. Conclusion LXRA genotypes were associated with variable risk for cardiovascular outcomes and pharmacogenetic effect in INVEST-GENES. These novel findings suggest that LXRA is a genetic/pharmacogenetic target that should be further explored.

The Blood Neutrophil to Lymphocyte Ratio Correlates with Clinical Status in Children with Cystic Fibrosis: A Retrospective Study

Purpose The blood neutrophil to lymphocyte ratio (NLR) has been identified as a potentially useful marker of clinical outcome in disease states with an inflammatory component. The objective of this study was to evaluate the relationship between NLR and clinical status in children with cystic fibrosis. Methods This was a retrospective chart review. Data collected included NLR, body mass index, and forced expiratory volume in 1 second (FEV1) while asymptomatic, and during hospitalizations for pulmonary exacerbation. An NLR breakpoint of 3 was used for comparisons of body mass index and FEV1. Results A total of 159 charts were reviewed. An NLR ≥ 3 was significantly associated with lower body mass index and lower FEV1. NLR during hospitalization was significantly higher than NLR while asymptomatic. NLR measured during the first 3 months of life was negatively correlated with FEV1 at age 12. Conclusion NLR correlates with clinical status in children with cystic fibrosis and may be a useful biomarker in this population.

Perceptions of family history and genetic testing and feasibility of pedigree development among African Americans with hypertension.

Background: Pedigree development, family history, and genetic testing are thought to be useful in improving outcomes of chronic illnesses such as hypertension (HTN). However, the clinical utility of pedigree development is still unknown. Further, little is known about the perceptions of African Americans (AAs) of family history and genetic testing. Aims: This study examined the feasibility of developing pedigrees for AAs with HTN and explored perceptions of family history and genetic research among AAs with HTN. Methods: The US Surgeon General’s My Family Health Portrait was administered, and 30–60 min in-person individual interviews were conducted. Descriptive statistics were used to analyze pedigree data. Interview transcripts were analyzed with content analysis and constant comparison. Results: Twenty-nine AAs with HTN were recruited from one free clinic (15 women, 14 men; mean age 49 years, standard deviation (SD) 9.6). Twenty-six (90%) reported their family history in sufficient detail to develop a pedigree. Perceptions of family history included knowledge of HTN in the family, culturally influenced family teaching about HTN, and response to family history of HTN. Most participants agreed to future genetic testing and DNA collection because they wanted to help others; some said they needed more information and others expressed a concern for privacy. Conclusion: The majority of AAs in this sample possessed extensive knowledge of HTN within their family and were able to develop a three-generation pedigree with assistance. The majority were willing to participate in future genetic research.

Fenofibrate Attenuates Neutrophilic Inflammation in Airway Epithelia: Potential Drug Repurposing for Cystic Fibrosis

A hallmark of cystic fibrosis (CF) lung disease is neutrophilic airway inflammation. Elevated neutrophil counts have been associated with decreased forced expiratory volume in 1 second and poor clinical measures in patients with CF. Interleukin 8 (IL‐8), epithelial neutrophil activating protein 78 (ENA‐78), tumor necrosis factor alpha (TNF‐α), granulocyte macrophage colony‐stimulating factor (GM‐CSF), and granulocyte colony‐stimulating factor (G‐CSF) contribute to neutrophil activation and disease pathogenesis in the airways of patients with CF. Drugs that modify the production of these chemokines in the airways could potentially benefit CF patients. Thus, we determined the effects of fenofibrate on their production in cell populations obtained from the airways. Human small airway epithelial cells and CF bronchial epithelial cells were treated with IL‐1β to induce inflammation. We cotreated the cells with fenofibrate at concentrations ranging from 10 to 50 μM to determine if this drug could attenuate the inflammation. IL‐8, ENA‐78, TNF‐α, GM‐CSF, and G‐CSF production were measured from the cell culture supernates by ELISA. ANOVA statistical testing was conducted using SPSS 17.0. IL‐1β increased the production of each of the chemokines by several fold. Fenofibrate reduced IL‐1β induced production of each of these neutrophilic chemokines at the concentrations used. IL‐1β increases the production of neutrophilic chemokines in airway epithelial cells. Cotreatment with fenofibrate blunts these processes. Fenofibrate should be explored as a therapeutic option to modulate the abundant neutrophilic inflammation observed in CF.

African Americans’ Perceptions of Adherence to Medications and Lifestyle Changes Prescribed to Treat Hypertension

More than 80 million Americans have hypertension (HTN), and African Americans (AAs) are disproportionately affected. AAs also have lower rates of adherence to HTN treatment. It is important to understand AAs’ perceptions of adherence to develop effective interventions. The aim of this study is to examine AAs’ perceptions of adherence to medications and lifestyle changes prescribed to treat HTN. In this qualitative study, we used purposive sampling to recruit Southern AAs with HTN aged 21 and older from a free, faith-based clinic. We recorded individual, in-person interviews about perceptions related to adherence to treatment of HTN and analyzed verbatim transcripts using content analysis and constant comparison. We also conducted medical record audits. Twenty-nine AAs participated (52% female, 38% were <50 years of age, 52% had taken anti-HTN medications for ≥5 years). Audits indicated that 65% had uncontrolled HTN during the previous year. Two main themes included causes of HTN and ways to improve blood pressure. Perceived causes of HTN included diet, stress, unhealthy actions, genes, and obesity. Ways to improve HTN included using cultural treatments “passed down,” increasing exercise, reducing stress, and losing weight. Many reported using home remedies to control HTN, including drinking pickle juice. More than half of this sample had uncontrolled HTN. They identified influences of culture on perceptions of adherence including causes and treatment of HTN, and possibly detrimental home remedies. It is imperative that clinicians identify culturally appropriate interventions for this high-risk group.

Warfarin pharmacogenomics and African ancestry.

In this issue of Blood, Limdi and coauthors demonstrate that racially informed warfarin pharmacogenetic algorithms perform better than traditional algorithms, which previously excluded genetic variants that are unique to patients with African ancestry.

Reverse Translational Study of Fenofibrate's Observed Effects in Diabetes‐Associated Retinopathy

Clinical trials suggest that fenofibrate reduces the progression of retinopathies in patients with type 2 diabetes. Furthermore, patients with retinopathies have elevated levels of inflammatory chemokines and dysfunctional retinal angiogenesis. Therefore, we investigated the effects of fenofibrate on the production of inflammatory chemokines and genes associated with angiogenesis. Retinal pigment epithelial cells (RPECs) were cultured with IL‐1β and fenofibrate ranging from 1–50 μM. ENA‐78, IL‐8, and RANTES were measured in cell culture by ELISA. ENA‐78, ABCA1, and ABCG1 gene expression were tested by RT‐PCR. IL‐1β significantly induced the production of ENA‐78, IL‐8, and RANTES. Fenofibrate at concentrations of 25–50 uM blunted the IL‐1β induced production of ENA‐78 (p < 0.05) with no significant effects on RANTES and IL‐8. Fenofibrate also reduced the expression of the ENA‐78 gene as well as ABCA1 and ABCG1, which are genes involved in angiogenesis. Fenofibrate decreases ENA‐78 production and ABCA1/ABCG1 gene expression in RPECs.

iHeart nano: A sweet cure

Sugar-based nanoparticles prevent foam cell formation and limit atherogenesis.

SORTing out lipid handling in atherosclerosis

Sortilin mediates LDL uptake into macrophages, which contributes to foam cell formation and atherogenesis.