Glenn S. Gerhard

Risk factors for drug dependence among out-patients on opioid therapy in a large US health-care system

AIMS Our study sought to assess the prevalence of and risk factors for opioid drug dependence among out-patients on long-term opioid therapy in a large health-care system. METHODS Using electronic health records, we identified out-patients receiving 4+ physician orders for opioid therapy in the past 12 months for non-cancer pain within a large US health-care system. We completed diagnostic interviews with 705 of these patients to identify opioid use disorders and assess risk factors. RESULTS Preliminary analyses suggested that current opioid dependence might be as high as 26% [95% confidence interval (CI) = 22.0-29.9] among the patients studied. Logistic regressions indicated that current dependence was associated with variables often in the medical record, including age <65 [odds ratio (OR) = 2.33, P = 0.001], opioid abuse history (OR = 3.81, P < 0.001), high dependence severity (OR = 1.85, P = 0.001), major depression (OR = 1.29, P = 0.022) and psychotropic medication use (OR = 1.73, P = 0.006). Four variables combined (age, depression, psychotropic medications and pain impairment) predicted increased risk for current dependence, compared to those without these factors (OR = 8.01, P < 0.001). Knowing that the patient also had a history of severe dependence and opioid abuse increased this risk substantially (OR = 56.36, P < 0.001). CONCLUSION Opioid misuse and dependence among prescription opioid patients in the United States may be higher than expected. A small number of factors, many documented in the medical record, predicted opioid dependence among the out-patients studied. These preliminary findings should be useful in future research efforts.

IL-4-induced Stat6 activities affect apoptosis and gene expression in breast cancer cells

IL-4-induced Stat6 signaling is active in a variety of cell types, including immune cells and cancer cells, and plays an important role in the regulation of gene expression. Using EMSA gel shift assay and an antibody to Stat6, we phenotyped two breast cancer cell lines, ZR-75-1 being active Stat6(high) phenotype and BT-20 being defective Stat6(null) phenotype, respectively. Breast cancer cells carrying Stat6(null) phenotype exhibited increased spontaneous apoptosis compared with those carrying Stat6(high) phenotype. Expression microarray analyses demonstrated that IL-4 upregulated CCL26, SOCS1, CISH, EGLN3, and SIDT1, and downregulated DUSP1, FOS, and FOSB, respectively, in these breast cancer cells. Among those genes, CCL26 and SOCS1 were known genes regulated by IL-4/Stat6 pathway, but CISH, EGLN3, SIDT1, DUSP1, FOS, and FOSB were novel genes demonstrated to be IL-4 responsive for the first time. IL-4 also upregulated 38 genes unique to Stat6(null) BT-20 cells and 23 genes unique to Stat6(high) ZR-75-1 cells, respectively. Furthermore, Stat6(high) and Stat6(null) cells showed very different profiles of constitutively expressed genes relevant to apoptosis and metastasis among others, which serve as a valuable expression database and warrant for detailed studies of IL-4/Stat6 pathway in breast cancer.

Electronic Health Records in Genomic Medicine

The Electronic Health Record (EHR) is an electronic compilation of longitudinal data related to the complete healthcare of an individual, a potentially ideal platform for genomic and personalized medicine. However, the integration of genomic data with EHRs is at its early stages. The ongoing efforts of end-users and commercial EHR vendors, coupled with substantive policy initiatives by the federal government, will likely accelerate progress. We describe the current landscape of EHRs in genomic medicine, how federal policies may impact implementation, and how the special cases of newborn screening, family history, and pharmacogenomics may be accommodated. As a case study of EHR genomic medicine, we present a number of applications at the Geisinger Clinic. EHRs provide the ideal environment for genomic medicine to flourish but are still in a nascent phase.

Angptl8 antisense oligonucleotide improves adipose lipid metabolism and prevents diet-induced NAFLD and hepatic insulin resistance in rodents

Aims/hypothesisTargeting regulators of adipose tissue lipoprotein lipase could enhance adipose lipid clearance, prevent ectopic lipid accumulation and consequently ameliorate insulin resistance and type 2 diabetes. Angiopoietin-like 8 (ANGPTL8) is an insulin-regulated lipoprotein lipase inhibitor strongly expressed in murine adipose tissue. However, Angptl8 knockout mice do not have improved insulin resistance. We hypothesised that pharmacological inhibition, using a second-generation antisense oligonucleotide (ASO) against Angptl8 in adult high-fat-fed rodents, would prevent ectopic lipid accumulation and insulin resistance by promoting adipose lipid uptake.MethodsANGPTL8 expression was assessed by quantitative PCR in omental adipose tissue of bariatric surgery patients. High-fat-fed Sprague Dawley rats and C57BL/6 mice were treated with ASO against Angptl8 and insulin sensitivity was assessed by hyperinsulinaemic–euglycaemic clamps in rats and glucose tolerance tests in mice. Factors mediating lipid-induced hepatic insulin resistance were assessed, including lipid content, protein kinase Cε (PKCε) activation and insulin-stimulated Akt phosphorylation. Rat adipose lipid uptake was assessed by mixed meal tolerance tests. Murine energy balance was assessed by indirect calorimetry.ResultsOmental fat ANGPTL8 mRNA expression is higher in obese individuals with fatty liver and insulin resistance compared with BMI-matched insulin-sensitive individuals. Angptl8 ASO prevented hepatic steatosis, PKCε activation and hepatic insulin resistance in high-fat-fed rats. Postprandial triacylglycerol uptake in white adipose tissue was increased in Angptl8 ASO-treated rats. Angptl8 ASO protected high-fat-fed mice from glucose intolerance. Although there was no change in net energy balance, Angptl8 ASO increased fat mass in high-fat-fed mice.Conclusions/interpretationDisinhibition of adipose tissue lipoprotein lipase is a novel therapeutic modality to enhance adipose lipid uptake and treat non-alcoholic fatty liver disease and insulin resistance. In line with this, adipose ANGPTL8 is a candidate therapeutic target for these conditions.

Electronic Medical Records in Genomic Medicine Practice and Research

Publisher Summary The disciplines of medical informatics and biological informatics have both evolved to address the needs of genomic medicine practice and research. This chapter discusses the role of electronic medical records (EMRs) in the practice of genomic medicine and their use for genomic research. The need of digital approaches to storing, processing, and using information is driven by the growing density of genomic data, whether derived from gene expression profiling, single nucleotide polymorphism genotyping, or DNA sequencing, and from the pace of discovery. Differences between the two communities have resulted in an attempt to integrate the approaches. The complexity of clinical decision-making changes as genetic data relevant to diagnosis and therapeutic interventions increases. The large health systems that are adopting EMRs are becoming increasingly integrated, especially in adopting and implementing practice standards. The major factors driving the development of EMRs, such as quality measures, efficiency, and reimbursement, are not directly related to genomic medicine. Thus, health care organizations should be more proactive in collaborating with other public and private sector organizations in the development of an EMR containing both clinical and genomic data.

Abstract A82: The FTO obesity gene and the risk of postmenopausal breast cancer among the medically underserved population in rural Pennsylvania

Purpose: Among all the established risk factors for postmenopausal breast cancer (PMBC), obesity, with 21 % risk, accounts for the largest share of potentially modifiable population attributable risk (PAR). The risk of PMBC from obesity is multifactorial and includes genetic, behavioral and environmental influences. Of all the genes associated with obesity, FTO has the highest risk (RR=1.67) and greatest PAR (> 20%), in the white European population. The risk of human adiposity has been associated with allele A (Adenine) in SNP rs9939609, and G (Guanine) in SNP rs1477196 and T(Thymidine) in SNP rs1861868. Central and northeastern counties in Pennsylvania (PA), of which 75% has been designates as medically underserved, is home to a relatively homogenous population of white European ancestry. This region experiences significantly above the national average age-adjusted breast cancer incidence and high prevalence of obesity. Elimination of health disparities across different segments of population is one of the objectives of the Healthy People of 2010. The notion of health disparities implies that the disease-specific risk for different sub-populations should be identified and resources should be allocated accordingly. Research on the genetic susceptibility of PMBC from obesity has been inconclusive. Therefore, we conducted a retrospective study with the primary objective of assessing prevalence of three SNPs [rs9939609, rs1861868, and rs1477196] of the FTO gene in group of women diagnosed with invasive breast cancer and their age-matched controls. Methods: The study benefits from an ongoing population-based biobanking project entitled “MyCode” at the GHS. A total of 201 women diagnosed with invasive breast cancer have donated blood samples to the project constitute the cases. Controls were 603 women with no medical history of breast cancer, who have also participated in the biobanking. SNPs have been genotyped using ABI TaqMan assays. Clinical and demographic data have been retrieved from medical records. Measures of associations were estimated using non-parametric statistics. All statistical analyses were performed using SAS v. 9.1 (SAS Institute, Cary, NC). Results: So far genotyping has been completed for a total of 50 cases and 99 controls with the mean age of 66 (±12) and 64 (±11) (P=.49) years, respectively. The difference in mean BMI between cases (32.23 ±7.23) and controls (33.52 ± 8.80) did not reach the level of statistical significance. Of the three SNPs, the SNP rs9939609 yielded a potential association with PMBC (OR= 2.04,95% CI .96-4.34, P=.0653). Conclusions: Preliminary findings suggest that one of the SNPs of FTO might increase the risk of PMBC. The FTO gene, in addition to its role in human adiposity, has been reported to encode a protein that is a member of the non-heme dioxygenase super family, involved in DNA repair pathway by reversing of alkylated damages to DNA and RNA. Discerning the association between the common SNPs of the FTO gene and PMBC offers the potential to identify at risk women that could benefit from targeted intervention strategies to reduce their risk of PMBC. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):A82.