Date Published: March 30, 2017
Publisher: Public Library of Science
Author(s): Hsiang-Wei Kuo, Chia-Lung Shih, Jieh-Hen Tsung, Sheng-Wen Liu, Shih-Kai Chu, Hsin-Chou Yang, Hsiao-Hui Tsou, Zih-Hsiang Wang, Andrew C. H. Chen, Yu-Li Liu, Sunil K Ahuja.
Heroin dependent patients have a high incidence of HIV infection. In contrast to the gene expression method, we developed a systemic correlation analysis method built upon the results of pharmacogenomics study in a methadone maintenance treatment (MMT) cohort consisting of 344 Taiwanese heroin dependent patients. We identified genetic variants and their encoding proteins that may be involved with HIV infection and MMT treatment outcome. Cadherin 2 (CDH2) genetic determinants were identified through the genome-wide pharmacogenomic study. We found significant correlations among HIV infection status, plasma levels of CDH2, cytokine IL-7, ADAM10, and the treatment responses to methadone. Two single nucleotide polymorphisms located within CDH2 gene showed associations with blood pressure and plasma CDH2 concentration. Plasma concentration of CDH2 showed correlations with the level of cytokine IL-7, status of HIV infection, and urine morphine test result. Plasma level of IL-7 was correlated with corrected QT interval (QTc) and gooseflesh skin withdrawal symptom score, while level of ADAM10 was correlated with plasma concentrations of vitamin D metabolite, nicotine metabolite, and R-methadone. The results suggest a novel network involving HIV infection and methadone treatment outcome.
Pharmacogenomics study has recently received recognition for its potential application in personalized medicine . One of the methods in pharmacogenomic analysis is to build pathway network and observe gene-gene interaction status contributing to treatment responses. However, this kind of analysis often misses the opportunity to discover novel plasma proteins that may serve as potential biomarkers toward treatment response. In this study, we developed a new method by starting genetic variant association analyses, determining the plasma levels of proteins encoded by the candidate genes, then finally examining the protein-phenotype (treatment responses) correlations in a Taiwanese methadone maintenance treatment (MMT) population. Through this new approach, we were able to identified novel network among the gene encoding proteins involving cardiovascular function, inflammatory factors, and MMT treatment responses.
344 MMT patients from a cohort of 360 total recruitment had passed the genomewide genotyping quality check, and were included for analyses . The average age of the 344 patients was 38 years, and 82% were males (Table 1). Average blood pressures were 125.51 and 76.69 mmHg in systolic and diastolic blood pressure respectively. Approximately 50% of the patients were poor responders, who showed a positive urine morphine test following MMT. 22.55% patients were tested positive for HIV, and among them, 95% were also infected with HCV. Three patients receiving antiretroviral therapy were included in analyses in this study. All medications other than methadone were also recorded (S1 Table).
In this study, we performed genetic association analyses between SNPs in the CDH2 genetic region from a genomewide database and the methadone treatment responses. Two SNPs, rs8094439 and rs17446819, located at intron 2 of CDH2 showed significant associations with systolic and diastolic blood pressure. The two SNPs also showed significant associations with plasma level of CDH2. This result suggested equilibrium between the translation of CDH2 and MMP activity, which regulates the plasma level of CDH2. In further multiple regression analyses, plasma CDH2 level showed correlations with level of cytokine IL-7, HIV infection status, and the urine morphine test outcome. In this cohort, the HIV infection status was measured by plasma HIV antibody only. No information regarding viral load is available. Nevertheless, the results in this study remain the same when the data from the three patients who received antiretroviral therapy were removed from analysis. Details of HIV infection status vs. the plasma levels of CDH2 or IL-7 warrant further investigation. The results provided new information with regard to the environmental effects contributed by the status of HIV infection, and led to the discovery of a novel systemic regulatory mechanism involving CDH2 and the cytokine IL-7 in the methadone treatment outcome in heroin dependent patients.