Pharmacogenomic Research and Practice in Japan

Transcription

1 1 Pharmacogenomic Research and Practice in Japan Naoyuki Kamatani, M.D., Ph.D. 1. Institute of Rheumatology, Tokyo Women s Medical University (Clinician and statistician) 2. Medical Informatics Group (Statistical geneticist), SNP Research Center (Yusuke Nakamura Director, Biobank Japan project), RIKEN 2 Examples of pharmacogenomic research and practice in Japan 1. Adverse events by Irinotecan and variation in UGT1A1 gene 2. Efficacy of drug treatment to eradicate Helicobacter Pyroli and variation in CYP2C19 3. Dose of warfarin and CYP2C9 and VKORC1 polymorphisms 4. Adverse events by sulfasalazine and NAT2 haplotype 5. Adverse events and effective dose of methotrexate and MTHFR gene polymorphisms

2 3 Institute of Rheumatology, Tokyo Women s Medical University Outpatient Department Our institution is located in three different facilities in Tokyo Main office, outpatient department, Research Unit Inpatient Department Institute of Rheumatology, Tokyo Women s Medical University is the world largest institution for rheumatology 4

3 5 For studies in genetic epidemiology 1. Quality of genotype data is important 2. Quality of clinical data is also important 6 IORRA 1. A cohort study for rheumatoid arthritis (RA) at Institute of Rheumatology, Tokyo Women s Medical University 2. The data have been collected for 7 years from an average of 5, RA patients.

4 7 Personal Average Quality control of doctors (QCD) based on IORRA database Each doctor can get the feedback of the results of one s own treatment in comparison to those of all doctors Proportion of patients NSAID 服用患者率 with NSAIDs Rather than making a superdoctor, we make 1 QCed doctors Phase time Proportion of DMARD patients 服用患者率 with DMARDs Proportion of MTX Phase Phase MTX 服用患者率 Combination of DMARDs DMARD 併用率 Average of all patients Average of my patients Phase Proportion of steroid use ステロイド服用患者率 Phase Dose of MTX 平均 MTX 服用量 Phase 8 Activity of Rheumatoid arthritis is improving year by year

5 9 Pharmacogenomics for a better treatment of rheumatoid arthritis 1 Road map for translation of genomic evidence into clinical practice (a) Result of the test of the association between a genomic variation and a phenotype (for example adverse events to a drug) proves to be significant by a valid statistical method. Validity (b) The conclusion of (a) is replicated using independent samples, and the result of the replicated study proves to be essentially the same as the previous result. (c) Algorithm for the application of the genomic evidence to the medical intervention can be constructed, and the application is expected to Utility give beneficial outcome to the patients. Taniguchi A et al. Pharmacogenet Genomics. 27; 17:383-9.

6 11 Drug delivery based on individual genomic information was started in Institute of Rheumatology, Tokyo Women s Medical University (~45 patients have been enrolled) 1. Prediction of the adverse events of methotrexate 2. Prediction of the efficacy of methotrexate 3. Prediction of the adverse events of sulfasalazine 4. Prediction of the complication of amyloidosis Taniguchi A et al. Pharmacogenet Genomics. 27; 17: Treatment of RA patients with methotrexate (MTX) and sulfasalazine is very important. 12 Bone destruction by RA can be repaired with MTX Ikari,K et al. N Engl J Med 353, 13, 25

7 13 Association between adverse events by MTX and MTHFR polymorphism 14 Association between C677T genotypes and adverse events by MTX(cohort study, 92 patients) C/C (n=35) 1 T/T+C/T 2(n=57) RR=3.68 ( ) P<.5 (.11) Urano et al. Pharmacogenetics, 22

8 15 Replication study in 156 patients C/C 1(n=66) T/T+C/T 2(n=9) RR=2.66 ( ) P<.5.1 Taniguchi A et al. Pharmacogenet Genomics. 27; 17: Gene dosage effect on adverse events % % % Cochrane-Armitage trend test P <.3 C/T (n=61) C/C (n=66) T/T (n=29) Taniguchi A et al. Pharmacogenet Genomics. 27; 17:383-9.

9 (1) Studies on the association between C677T genotype at MTHFR gene and adverse events by MTX 17 Authors Journal sample size conclusion Van Ede AE. Et al. Arthritis Rheum 44:2525-3, CC < CT+TT Urano W et al Pharmacogenetics 12:183-9, CC < CT+TT Kumagai K et al. Int J Mol Med 11: 593-6, (CC > CT+TT) Berkun Y et al. Ann Rheum Dis 63: , (CC < CT+TT) Schmeling H. et al. J Rheumatol 32:1832 6, CC < CT Weisman MH et al. Arthritis Rheum 54:67-12, CC+CT < TT (CNS abnormality) Kim S-K, et al. J Rheumatol 33, , CC < CT < TT Taniguchi et al. Pharmacogenetics Genomics, CC <CT <TT ( ) not significant 18 メトトレキサート ( リウマトレックス メトレート ) のオーダーメイド医療 MTHFR C677Tの検査 MTHFR C677T の検査では メトトレキサートの軽微な副作用の起きやすさ 起きにくさを予測します 深刻な間質性肺炎や骨髄抑制の副作用は予測できません 投与を受けた人 (1%) 18% 76% C/C の人 (42%) 12% 88% 軽微な副作用が出る人 C/T の人 (39%) 3% 7% 軽微な副作用が出ない人 T/T の人 (19%) 38% 62% この検査では 関節リウマチのなりやすさ なりにくさはわかりません It is very important to explain the results of genetic tests in conjunction with predicted phenotypes

10 19 Prediction of severe adverse events by sulfasalazine Association between diplotype configurations of NAT2 gene and severe adverse events (Cohort study 34 subjects) 2 Proportion of the subjects with severe adverse events PPV=19% NPV=99.3% 19%.97% M/M 1 2 W/M+W/W RR=19.6 (4.7-82), P < 2.7 x 1-8 Taniguchi A et al. Pharmacogenet Genomics. 27; 17:383-9.

11 21 Association between diplotype configurations of NAT2 gene and severe adverse events (Cohort 33subjects) Proportion of the subjects with severe adverse events %.97% This is the algorithm of the medical intervention All patients 1(n=33) W/W+W/M 2 (n=39) If we exclude 21 subjects (6.4%) from the treatment with sulfasalazine, the proportion of the severe adverse events would be reduced by 57%. 22 Results from combined cohort studies All adverse events Subjects with and without severe adverse events with AE without AE Sum Severe adverse events Subjects with and without severe adverse events with AE without AE Sum Test positive Test negative Sum Test positive Test negative Sum Positive predictive value = 55% Negative predictive value = 88% Risk ratio = 4.5 Sensitivity = 24% Specificity = 96% NNT = 28 Positive predictive value = 18% Negative predictive value = 99% Risk ratio = 19 Sensitivity = 57% Effect size Specificity = 94% Maximum reduction NNT = 83 Taniguchi A et al. Pharmacogenet Genomics. 27; 17: Several statistical measures should be provided to evaluate utility

12 Studies on the association between M/M genotype at NAT2 gene and development of adverse events by sulfasalazine 23 Authors Journal sample size conclusion Tanaka et al J Rheumatol 29:2492-9, MM > MN+NN Ohtani T et al. Br J Dermatol 148:135-9, 23 2 vs 2 MM > MN+NN Teshima D et al. Clin Pharm Ther 28:239-42, 23 1 (MM) Kumagai S et al. Pharm Res 21:324-9, (MM > MN+NN) Taniguchi et al. Pharmaco Genomics 17:383-9, MM > MN+NN ( Severe ) not significant adverse events from sulfasalazine have been reported exclusively from Japanese Composition of haplotypes of NAT2 gene is quite different between Japanese and Caucasoids. 24 Haplotypes of NAT2 gene SNP G191A C282T T341C C481T G59A A83G G857A haplotype NAT2*4 G C T C G A G NAT2*5B G C C T G G G NAT2*5E G C C C A A G NAT2*6A G T T C A A G NAT2*7B G T T C G A A NAT2*13 G T T C G A G Very high in Europeans but very low in Asians

13 One year experience in personalized medicine project in TWMU 25 Four patients were hospitalized due to severe adverse events of sulfasalazine 1. Female 31 M/M (*5B/*7B) Fever, skin rash 2. Male 7 M/M (*6A/*6A) Pancytopenia 3. Female 35 M/M(*6A/*13 ) Pancytopenia 4. Female 28 M/M (*6A/*6A) Fever, SJS P.1 Algorithm Patients with M/M diplotype are excluded from the treatment with sulfasalazine The severe adverse events of 4 among 4 patients would have been avoided by the personalized medicine. Soejima M et al. Prospective study of the association between NAT2 gene haplotypes and severe adverse events with sulphasalazine therapy in patients with rheumatoid arthritis. J Rheumatol in press 26 Questions about PGx for different populations 1. Allele frequencies seem to differ between Asian, Black and Caucasoid populations, and even between Asian subpopulations but to what extent? 2. What care should be taken to analyze the genomic data from different populations, and in what conditions can we translate the evidence in one ethnic group to another?

14 27 Principle component analysis (PCA; Eigenstrat) Draw a line in the space with 7, dimension so that the variance of the projections of the points to the line becomes the largest. Use of 14, SNP genotypes from 7, subjects A point corresponds to a SNP 14, points in a 5, dimension space Use of factors of Eigenvectors to separate subjects PCA analysis for African, European and Asian subjects 28 Second component Asian African 13, SNP genotypes from 7,3 Japanese subjects and HapMap Databse were used European First component

15 PCA analysis for African, European and Asian subjects 29 Forth component Third component All Japanese samples + HapMap Han-Chinese and Japanese samples 3 1. HLA was the most highly differentiated region between Hondo and Okinawa clusters. 2. Even CYP2C9*6 allele frequencies were significantly different. 3. We have proposed methods to perform analyses of the data from different Hondo subgroups. cluster Okinawa cluster Han-Chinese cluster

16 Samples from Okinawa 31 Hondo cluster Okinawa cluster Han-Chinese cluster 32 Conclusions 1. QC of not only genotype data but also clinical data is important for PGx. 2. Validity and utility should be considered in translating genomic evidence into clinical practice. 3. Sophisticated analyses of the structure of populations are necessary for PGx in multiple populations.