Table 2.
Design characteristics of high-quality studies.
| Author | Year | Primary objective | Inclusion criteria | Age group | Disease group | Ethnicity | Number included | Ref. |
|---|---|---|---|---|---|---|---|---|
| Phenotype–genotype studies (n = 30) | ||||||||
| Ben Salah | 2013 | Investigate TPMT activity distribution and allele frequency of common alleles | Not specified | Not specified | Other | Tunisian | 88 | [13] |
| Fakhoury | 2007 | Study correlations between TPMT genotype and enzyme activity | Children diagnosed with ALL; enrolled in two consecutive European trials | Pediatric | ALL | European | 118 | [25] |
| Fangbin | 2012 | Role of phenotype and genotype in predicting leukopenia | Patients with steroid- dependent disease, frequent relapses, on remission maintenance and postoperative prophylaxis | Adult | IBD | Chinese Han nationality; lived in Henan Province, Peoples Republic of China | 499 | [26] |
| Ford | 2006 | Compare new method phenotype (whole blood) with old method (RBC lysate) and genotype | Routine samples collected over 4-week period | Not specified | Not specified | Not specified | 402 | [27] |
| Ford | 2009 | Examine phenotype–genotype concordance to investigate effectiveness as QA tool | All consecutive routinely collected samples | Not specified | Not specified | Not specified | Not specified | [28] |
| Ganiere- Monteil | 2004 | Investigate the impact of age on TPMT activity by comparing TPMT activity (pheno and geno) in healthy young Caucasians from birth (cord blood) to adolescence with adult Caucasians | Patients with IBD; taking AZA or 6-MP for at least 3 months or experienced adverse events with these drugs; dose between 0.3–2.5 mg/kg | Mix of adult and pediatric | Otherwise healthy | Caucasian | 468 | [58] |
| Gazouli | 2012 | Examine sensitivity and specificity of TPMT genotyping for TPMT enzymatic activity | Patients with diagnosis of IBD; patients using AZA or 6-MP >3 months or adverse event during treatment; dosage range specified | Pediatric | IBD | Not specified | 108 | [29] |
| Hindorf | 2012 | Investigate the correlation between TPMT genotype and phenotype; analyze the results from a clinical and practical perspective | Unselected and consecutive TPMT phenotype and genotype determinations sent to the study site | Not specified | IBD | Not specified | 7195 | [30] |
| Jorquera | 2012 | Study the TPMT activity and genotype in Chilean subjects | Healthy persons; older than 18 years; unrelated | Adult | Otherwise healthy | Spanish, Chilean | 200 | [38] |
| Langley | 2002 | Determine whether the phenotypes or genotypes correlate with clinical outcomes for AZA therapy | Patients attending the autoimmune liver disease outpatients’ clinic | Mix of adult and pediatric | Other | Not specified | 53 | [59] |
| Larussa | 2012 | Investigate TPMT genotype and phenotype status in southern Italian IBD patients | Patients with Crohn’s or UC | Adult | IBD | Caucasian, Italian | 51 | [31] |
| Lennard | 2013 | Investigate phenotype– gentoype TPMT concordance in children with ALL | Patients diagnosed with ALL in time frame specified, at treatment centers in the UK and Ireland | Pediatric | ALL | UK and Ireland (English, Irish) | 1117 | [32] |
| Liang | 2013 | Investigate the relationship between TPMT enzymatic activity and genetic variation in TPMT with AZA clinical efficacy, especially in prevention of rejection and safety in HTX recipients | Heart transplant recipients at Mayo Clinic; treated with AZA | Adult | Organ transplant | Not specified | 93 | [14] |
| Loennechen | 2001 | Identify TPMT mutant alleles in a Saami population to develop genotype tests for prediction of TPMT activity | Patients >18 years old | Adult | Patients admitted to a cardiology center | Caucasian, Saami | 260 | [23] |
| Ma | 2006 | Investigate the relationship between the TPMT gene polymorphisms and its enzymatic activity | Healthy blood donors; cord blood; patients with leukemia | Mix of adult and pediatric | ALL | Chinese | 630 | [39] |
| Marinaki | 2003 | Establish frequencies of genetic modifiers of TPMT activity in Asian residents of the United Kingdom | Patients originating from India and Pakistan attending an IBD clinic | Not specified | IBD | Originating from India and Pakistan; Caucasian | 85 | [60] |
| Milek | 2006 | Determine the frequency of clinically significant, low-activity TPMT alleles | Unrelated healthy volunteers | Not specified | Otherwise healthy | Slovenian | 95 | [33] |
| Oselin | 2006 | Develop and validate an HPLC method with UV detection to determine TPMT activity in human erythrocytes using 6-MP as a substrate | Volunteers; Estonian | Adult | Otherwise healthy | Estonian | 99 | [34] |
| Schaeffeler | 2004 | Sensitivity, specificity, PPV, and NPV for TPMT genotyping | No regular drug use with the exception of oral contraceptives and/or vitamins. | Adult | Otherwise healthy | Caucasian, German | 1214 | [62] |
| Schwab | 2002 | Whether AZA-related serious side-effects can be explained by TPMT polymorphism using both pheno and genotyping | Patients with IBD from Department of Gastroenterology at University Hospital Tubingen; on AZA therapy at present or previously | Adult | IBD | Caucasian | 93 | [64] |
| Serpe | 2009 | Elucidate the impact of genotype, age, gender on TPMT phenotype by comparing the activity of the enzyme among infants, children, adolescents and adults | Healthy, unrelated, Italian– Caucasian adults; newborn, Italian–Caucasian babies, children or adolescents | Mix of adult and pediatric | Otherwise healthy | Italian–Caucasian | 943 | [35] |
| Spire- Vayron de la Moureyre | 1998 | Describe and demonstrate the usefulness of a new SSCP procedure to assay simultaneously for known mutations within TPMT, and to detect new ones | Selected from previously phenotyped individuals; healthy volunteers or patients | Not specified | Otherwise healthy | European | 35 | [67] |
| Spire- Vayron de la Moureyre | 1998 | Overall mutational spectrum of TPMT gene | Unrelated, European, volunteers or patients starting AZA therapy | Not specified | Not specified | European | 191 | [24] |
| von Ahsen | 2005 | Analyze AZA tolerance in relation to ITPA and TPMT mutation status and TPMT activity | >18 years; active Crohn’s disease; prednisone treatment >300 mg during the last 4 weeks or a relapse within 6 months after steroid pulse therapy | Adult | IBD | Caucasian | 71 | [65] |
| Wennerstrand | 2013 | Investigate the fluctuation in TPMT enzyme activity from the time of diagnosis until after the end of maintenance treatment | Children starting their treatment per NOPHO ALL- 2000 study protocol | Pediatric | ALL | Scandinavian (Norway, Sweden, Finland) | 53 | [16] |
| Winter | 2007 | To determine if screening for TPMT status predicts side- effects to AZA in patients with IBD | Patients with IBD; no history of treatment with thiopurine drugs | Not specified | IBD | Not specified | 130 | [10] |
| Wusk | 2004 | Phenotype–genotype comparison of TPMT; develop a new screening strategy for patients prior to taking thiopurine drugs | Unrelated healthy volunteers; patients with IBD | Not specified | IBD | German | 240 | [11] |
| Xin | 2009 | Whether AZA-treated serious side effects can be explained by the TPMT polymorphism using both phenotype and genotype tests in adult patients with renal transplantation on AZA therapy | Renal transplant recipients treated with AZA presently or previously | Not specified | Organ transplant | Not specified | 150 | [36] |
| Yates | 1997 | Establish frequencies of the genetic modifiers of TPMT activity in an Asian population resident in the United Kingdom | Volunteer blood donors; children with ALL being treated or referred for evaluation | Mix of adult and pediatric | ALL | Caucasian | 48 | [66] |
| Zhang | 2007 | Phenotype–genotype comparison of the TPMT enzyme and develop a new screening strategy for patients prior to taking thiopurine drugs | Patients with chronic renal failure; no blood transfusion within 1 month prior to study | Adult | Other | Not specified | 278 | [37] |
| Genotype–genotype studies (n = 6) | ||||||||
| Chowdhury | 2007 | Study compared three methods of genotyping – conventional vs microchip RFLP, and used TaqMan as the ‘gold standard’. Also tested new steps in AS-PCR-CE and portable microchip CE, but these were not tested against the others | Patients with IBD; undergoing thiopurine immunosuppression | Not specified | IBD | Not specified | 80 | [71] |
| Kim | 2013 | Develop and validate a new AS-PCR for TPMT genotyping | Not specified | Not specified | Requiring AZA or mercaptopurine | Not specified | 244 | [75] |
| Lu | 2005 | Test feasibility of genotyping using APEX | Patients with β-thalassemia and random selection of patients for TPMT screening (healthy blood donors and children with ALL) | Children and adult | β-thalassemia + patient selected for TPMT screening, also healthy volunteers | 200 | [76] | |
| Ma | 2003 | To confirm and study the Chinese TPMT gene polymorphism; to compare and discuss the methodology for SNP tests; to find the best way and most suitable way to test the TPMT polymorphisms | ALL patients who were admitted inpatients by the Hematology Department of Beijing Children Hospital | Mix of adult and pediatric | ALL + healthy blood donors, cord blood | Chinese | 630 | [70] |
| Roman | 2012 | To validate a TPMT genotyping method by comparing it with a conventional PCR approach | Adult white patients from the Hospital Universitario de la Princesa (Spain) for whom genotyping was requested | Adult | For whom TPMT genotyping was requested – GE, derm, rheu, neph, inter med, hemato | White | 111 | [15] |
| Schaeffeler | 2008 | Establishment and application of a novel assay, called iPLEX, for detection of all functional relevant 22 TPMT allelic variants | Healthy unrelated volunteers; Korean, Ghanians | Not specified | Not specified | German (white) | 586 | [74] |
6-MP: 6-mercaptopurine; ALL: Acute lymphoblastic leukemia; APEX: Arrayed primer extension technology; AS-PCR: Allele-specific PCR; AZA: Azathioprine; CE: Capillary electrophoresis; IBD: Inflammatory bowel disease; ITPA: Inosine triphosphatase; NPV: Negative predictive value; PPV: Positive predictive value; QA: Quality assurance; RBC: Red blood cell; RFLP: Restriction fragment length polymorphism; SSCP: Single strand conformational polymorphism; TPMT: Thiopurine S-methyltransferase; UC: Ulcerative colitis; UV: Ultraviolet.