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

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 (P = 1.01x10-5), where the claudin 8 (CLDN8) gene had the most significant association (P = 6.8x10-5). A functional single nucleotide polymorphism (SNP) rs686364 at exon 1 of CLDN8 showed strong association with plasma IP-10 levels, in the MMT subjects with positive urine test for morphine (dominant model, P = 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.