Pharmacogenomics study on cadherin 2 network with regard to HIV infection and methadone treatment outcome

<div><p>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 (<i>CDH2</i>) 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 <i>CDH2</i> 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 <i>R</i>-methadone. The results suggest a novel network involving HIV infection and methadone treatment outcome.</p></div

Multivariate regression analyses of the plasma CDH2 level (ng/ml).

<p>Multivariate regression analyses of the plasma CDH2 level (ng/ml).</p

Association analyses between SNPs in <i>CDH2</i> gene and blood pressure or plasma level of CDH2.

<p>Association analyses between SNPs in <i>CDH2</i> gene and blood pressure or plasma level of CDH2.</p

A schematic design from a pharmacogenomic study in methadone maintenance therapy.

<p>This design has led to systemic discovery of some hidden pathways among plasma IL-7, ADAM10 and CDH2, and their contributions to the methadone treatment responses.</p

General demography of methadone maintenance treatment patients.

<p>General demography of methadone maintenance treatment patients.</p

Missense mutation at <i>CLDN8</i> associated with a high plasma interferon gamma-inducible protein 10 level in methadone-maintained patients with urine test positive for morphine

<div><p>We previously reported a high plasma chemokine interferon gamma-inducible protein 10 (IP-10) level and prolonged electrocardiography QT-interval in methadone maintenance treatment (MMT) patients with HIV or HCV infection. The purpose of this study was to evaluate the genetic association of high plasma IP-10 level in the MMT patients. The gene-based and pathway-based association analyses were conducted using a genome-wide association study dataset in 344 MMT patients for identifying genes and pathways associated with plasma IP-10 level. We found that plasma IP-10 level was significantly associated with a pathway in the tight junction (<i>P</i> = 1.01x10^-5), where the claudin 8 (<i>CLDN8</i>) gene had the most significant association (<i>P</i> = 6.8x10^-5). A functional single nucleotide polymorphism (SNP) rs686364 at exon 1 of <i>CLDN8</i> showed strong association with plasma IP-10 levels, in the MMT subjects with positive urine test for morphine (dominant model, <i>P</i> = 0.00004). The minor allele type carriers had higher plasma IP-10 levels than the major allele type carriers. Our data support that the tight junction protein claudin 8 exon 1 is a predictor for the plasma levels of IP-10 in MMT patients with urine test positive for morphine.</p></div

Correlation matrix heatmap of the study variables.

<p>Spearman correlation coefficients are presented by a blue-white-red color scheme. Dark red indicates a more positive correlation; dark blue indicates a more negative correlation; white indicates no correlation.</p

Plasma level of CDH2 and IL-7 were associated with HIV infection status and the urine morphine test outcome.

<p>Plasma level of CDH2 and IL-7 were associated with HIV infection status and the urine morphine test outcome.</p

Demography of the methadone maintenance treatment patients.

<p>Demography of the methadone maintenance treatment patients.</p

The dominant model association analyses between the SNPs of <i>CLDN8</i> and IP-10 (pg/ml) in all MMT patients and urine morphine positive MMT patients.

<p>The dominant model association analyses between the SNPs of <i>CLDN8</i> and IP-10 (pg/ml) in all MMT patients and urine morphine positive MMT patients.</p