Short CommunicationA possible role for HLA-DRB1*04:06 in statin-related myopathy in Japanese patients
Introduction
Statin-related myopathy (SRM) is a clinically important adverse reaction that often occurs during treatment. Although no global consensus on SRM diagnostic criteria has yet been established, SRM is generally classified as consisting of myalgia, myositis, and rhabdomyolysis, according to the severity of the associated elevated CK levels [1], [2]. Although the prevalence of SRM is relatively low; 1%−5% for myalgia [2] and 0.15 per million prescriptions for fatal rhabdomyolysis in the USA [3], the substantial number of overall cases represents a major concern for drug safety.
Extensive pharmacogenomics studies on SRM have been conducted to identify the candidate genetic markers, focusing on drug-metabolizing enzymes and drug transporters for statins [4], [5], [6], [7], [8], [9]. Among these, a single nucleotide polymorphism (SNP) of solute carrier organic anion transporter family member 1B1 (SLCO1B1), rs4149056 T > C (521T > C (V174A)), has been most extensively studied [5], [6], [7], [8], [9], [10] and is regarded as the most promising marker for SRM, especially after simvastatin treatment in Caucasians [10].
As for other candidate genetic markers, the ryanosine receptor 2 (RYR2) SNP rs2819742 [9] and the glycine amidinotransferase (GATM) SNP rs9806699 [11] were also identified. Recently, although of very low prevalence, an immune-mediated necrotizing mechanism underlying SRM accompanied by the production of an autoantibody against HMGCR, a target molecule of statin, was demonstrated [12], and the association of HLA-DRB1*11:01 with antibody-positive myopathy was shown in Caucasians and African patients [13]. The aforementioned studies have been performed predominantly among non-Asian populations, and information regarding the potential role of these candidate SRM markers among Asians, including Japanese, remains scarce.
The aim of the present study was to explore the clinically important markers of SRM in Japanese patients. To this end, we investigated the associations of three SRM candidate markers and of four HLA genes with SRM in Japanese patients by comparing their frequencies with those in healthy subjects.
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Study population and ethics committee
Blood samples and medical charts from Japanese patients who were primarily diagnosed with rhabdomyolysis from 2003 to 2014 were collected from eight collaboration hospitals led by Kanazawa Medical University and through a nationwide blood sampling network in Japan operated by National Institute of Health Sciences (NIHS), in cooperation with the Ministry of Health, Labour and Welfare, the Pharmaceutical and Medical Devices Agency, and the Federation of Pharmaceutical Manufacturers' Association
Results and discussion
Patient profiles (N = 52) and the suspected statin drugs were summarized in Table 1. Among the reported candidate SNPs for SRM, we primarily focused on possible associations of SLCO1B1 rs4149056, RYR2 rs2819742, and GATM rs9806699 in Japanese patients (Table 2). For RYR2 rs2819742 (G > A), the MAF for SRM patients was lower than in the Japanese control group (Odds ratio (OR) [95% confidence interval (CI)]: 0.573 [0.104–2.341]), but the difference was not significant (P > 0.05). Regarding SLCO1B1
Acknowledgments
This study was supported in part by Health and Labour Sciences Research grants from the Ministry of Health, Labour and Welfare, Japan (H26-chikyukibo-ippan-001), and by the Commissioned Expenses for Research on Regulatory Harmonization and Evaluation of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics from the Japanese Agency for Medical Research and Development, AMED (16mk0101015j). K.K. was supported by a Grant for
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