{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T00:41:02Z","timestamp":1786754462026,"version":"build-2736575974"},"reference-count":40,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,5,20]],"date-time":"2022-05-20T00:00:00Z","timestamp":1653004800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Taiwan Ministry of Science and Technology","award":["MOST 110-2314-B-039-050"],"award-info":[{"award-number":["MOST 110-2314-B-039-050"]}]},{"name":"Taiwan Ministry of Science and Technology","award":["MOST 109-2314-B-039-045"],"award-info":[{"award-number":["MOST 109-2314-B-039-045"]}]},{"name":"Taiwan Ministry of Science and Technology","award":["DMR-111-020"],"award-info":[{"award-number":["DMR-111-020"]}]},{"name":"Taiwan Ministry of Science and Technology","award":["DMR-110-012"],"award-info":[{"award-number":["DMR-110-012"]}]},{"name":"China Medical University Hospital","award":["MOST 110-2314-B-039-050"],"award-info":[{"award-number":["MOST 110-2314-B-039-050"]}]},{"name":"China Medical University Hospital","award":["MOST 109-2314-B-039-045"],"award-info":[{"award-number":["MOST 109-2314-B-039-045"]}]},{"name":"China Medical University Hospital","award":["DMR-111-020"],"award-info":[{"award-number":["DMR-111-020"]}]},{"name":"China Medical University Hospital","award":["DMR-110-012"],"award-info":[{"award-number":["DMR-110-012"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Background: The effects of methadone-induced severe prolongation of the corrected QT interval (QTc) and sudden cardiac death appear unpredictable and sex-dependent. Genetic polymorphisms in the nitric oxide synthase 1 adaptor protein (NOS1AP) have been implicated in QTc prolongation in general populations. We investigated whether common NOS1AP variants interact with methadone in relation to QTc prolongation in patients with heroin dependence. Methods: We genotyped 17 NOS1AP variants spanning the entire gene in heroin-dependent patients who received a 12-lead electrocardiography (ECG) examination both at baseline and during maintenance methadone treatment in Cohort 1 and only during maintenance methadone treatment in Cohort 2. The QT interval was measured automatically by the Marquette 12SL program, and was corrected for heart rate using Bazett\u2019s formula. Results: Cohort 1 consisted of 122 patients (age: 37.65 \u00b1 8.05 years, 84% male, methadone dosage: 42.54 \u00b1 22.17 mg\/day), and Cohort 2 comprised of 319 patients (age: 36.9 \u00b1 7.86 years, 82% male, methadone dosage: 26.08 \u00b1 15.84 mg\/day), with complete genotyping data for analyses. Before methadone, the QTc intervals increased with increasing age (r = 0.3541, p &lt; 0.001); the age-adjusted QTc showed dose-dependent prolongation in men (r = 0.6320, p &lt; 0.001), but abbreviation in women (r = \u22120.5348, p = 0.018) in Cohort 1. The pooled genotype-specific analysis of the two cohorts revealed that the QTc interval was significantly shorter in male carriers of the rs164148 AA variant than in male carriers of the reference GG genotype (GG: n = 262, QTc = 423 \u00b1 1.4 ms; AA: n = 10, QTc = 404.1 \u00b1 7 ms, p = 0.009), according to univariate analysis. The QTc remained shorter in male carriers of the rs164148 AA variant compared to GG genotype (423 \u00b1 1.4 ms vs. 405.9 \u00b1 6.9 ms, p = 0.016) in multivariate analysis after adjusting for age and methadone dosage. A cut-off QTc interval of &lt;410 ms identifies 100% of AA carriers compared to none of GG carriers when receiving a daily methadone dosage of 30.6 \u00b1 19.3 mg. There was no significant gene-drug interaction in contributing to the adjusted QTc (p = 0.2164) in male carriers of the rs164148 variants. Conclusions: Carriers of a common NOS1AP rs164148 AA genotype variant were associated with a shorter QTc interval in men receiving maintenance methadone treatment. This genetic polymorphism attenuates the QTc-prolonging effect by methadone, and thus may explain at least in part the unpredictable and heterogeneous risks for severe QTc prolongation and sudden cardiac death in patients on methadone.<\/jats:p>","DOI":"10.3390\/jpm12050835","type":"journal-article","created":{"date-parts":[[2022,5,20]],"date-time":"2022-05-20T13:56:12Z","timestamp":1653054972000},"page":"835","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Association of a Common NOS1AP Variant with Attenuation of QTc Prolongation in Men with Heroin Dependence Undergoing Methadone Treatment"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6476-9896","authenticated-orcid":false,"given":"Kuan-Cheng","family":"Chang","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital, Taichung 404332, Taiwan"},{"name":"Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7350-9604","authenticated-orcid":false,"given":"Ke-Wei","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital, Taichung 404332, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chieh-Liang","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Addiction Treatment, Tsaotun Psychiatric Center, Ministry of Health and Welfare, Nan-Tou County 54249, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Ling","family":"Liao","sequence":"additional","affiliation":[{"name":"Center for Personalized Medicine, China Medical University Hospital, Taichung 404332, Taiwan"},{"name":"Graduate Institute of Integrated Medicine, China Medical University, Taichung 404333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei-Yao","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Post-Baccalaureate Chinese Medicine, China Medical University, Taichung 40402, Taiwan"},{"name":"Department of Chinese Medicine, China Medical University Hospital, Taichung 404332, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Kai","family":"Lin","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital, Taichung 404332, Taiwan"},{"name":"Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Tzone","family":"Shiao","sequence":"additional","affiliation":[{"name":"Center of Institutional Research and Development, Asia University, Taichung 413305, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Hsin","family":"Chung","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital, Taichung 404332, Taiwan"},{"name":"Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yen-Nien","family":"Lin","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital, Taichung 404332, Taiwan"},{"name":"Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2162-8174","authenticated-orcid":false,"given":"Hsien-Yuan","family":"Lane","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404333, Taiwan"},{"name":"Department of Psychiatry, China Medical University Hospital, Taichung 404332, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"501","DOI":"10.7326\/0003-4819-137-6-200209170-00010","article-title":"Torsade de pointes associated with very-high-dose methadone","volume":"137","author":"Krantz","year":"2002","journal-title":"Ann. 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