ABCMdb

ABCB1 p.Ala313Gly

Predicted by SNAP2:	C: N (72%), D: D (66%), E: D (71%), F: D (71%), G: N (87%), H: D (63%), I: N (53%), K: D (71%), L: D (59%), M: N (61%), N: N (53%), P: D (75%), Q: D (63%), R: D (66%), S: N (87%), T: N (72%), V: N (53%), W: D (75%), Y: D (71%),
Predicted by PROVEAN:	C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: N, T: D, V: D, W: D, Y: D,

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[hide] Pharmacokinetics and toxicity of docetaxel: role o... Clin Pharmacol Ther. 2006 Jun;79(6):570-80. Epub 2006 May 2. Tran A, Jullien V, Alexandre J, Rey E, Rabillon F, Girre V, Dieras V, Pons G, Goldwasser F, Treluyer JM
Pharmacokinetics and toxicity of docetaxel: role of CYP3A, MDR1, and GST polymorphisms.
Clin Pharmacol Ther. 2006 Jun;79(6):570-80. Epub 2006 May 2., [PMID:16765145]

Abstract [show]
OBJECTIVE: Patients initiating docetaxel chemotherapy were genotyped for CYP3A4, CYP3A5, MDR1, GSTM1, GSTT1, GSTM3, and GSTP1 to identify variability factors of docetaxel pharmacokinetics and toxicity. METHODS: Genotyping was performed by direct sequencing (CYP3A4), real-time polymerase chain reaction (CYP3A5), and polymerase chain reaction-restriction fragment length polymorphism (MDR1 and GST). The clearance and area under the curve of docetaxel were calculated by use of a Bayesian approach. Absolute neutrophil count was recorded twice weekly. RESULTS: With regard to the pharmacokinetic analysis, 58 patients were included. CYP3A4*1B carriers (*1A/*1B, n=4), who are also CYP3A5*1/*3 carriers, had a significantly higher clearance and lower dose-normalized area under the curve of docetaxel than those with the wild genotype (*1A/*1A, n=53): 55.2+/-13.5 L/h versus 37.3+/-11.7 L/h (P=.01) and 31.4+/-6.2 (microg . h/L)/(mg/m(2)) versus 52.7+/-18.2 (microg . h/L)/(mg/m(2)) (P=.005), respectively. No influence of MDR1 was evidenced. With regard to the pharmacodynamic analysis, febrile neutropenia occurred more frequently in GSTP1*A/*B carriers (31.6% versus 3.7% in *A/*A carriers and 0% in *A/*C, *B/*B, and *B/*C carriers) (P=.037). Grade 3 neutropenia occurred more frequently in 3435TT MDR1 genotype carriers: TT, 100%; CT, 77.3%; and CC, 54.5% (P=.046). No influence of GSTM1, GSTT1, or GSTM3 polymorphisms was evidenced on docetaxel toxicity. CONCLUSIONS: Patients carrying the CYP3A*1B allele may have enhanced docetaxel clearance and may be underexposed, whereas those carrying GSTP1*A/*B and 3435TT genotypes may have excessive hematologic toxicity. Further studies are warranted to determine the usefulness of genotyping before docetaxel treatment.

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144 Genetic characteristics of patients (N ϭ 58) and toxicity data SNP Genotype Patients evaluable for febrile neutropenia Patients with febrile neutropenia (%) Patients evaluable for grade 3 or grade 4 neutropenia Patients with grade 3 or grade 4 neutropenia: Absolute neutrophil count Ͻ1000/␮L (%) Patients with grade 4 neutropenia: Absolute neutrophil count Ͻ500/␮L (%) CYP3A5 (A6986G) *1/*3 11 1 (9.1) 11 9 (77.8) 7 (63.6) *3/*3 47 6 (12.8) 45 35 (81.8) 21 (46.7) CYP3A4 (-A392G) *1A/*1A 54 7 (13.0) 52 41 (78.8) 26 (50.0) *1A/*1B 4 0 4 3 (75.0) 2 (50.0) MDR1 C3435T C/C 11 0 11 6 (54.5) 5 (45.5) C/T 36 6 (16.7) 35 28 (80.0) 16 (45.7) T/T 11 1 (9.1) 10 10 (100)† 7 (70.0) MDR1 G2677T G/G 25 3 (12.0) 24 17 (70.8) 11 (45.8) G/T 23 2 (8.7) 22 17 (77.3) 11 (50.0) T/T 10 2 (20.0) 10 10 (100) 6 (60.0) GSTM1 Wild type 22 2 (9.1) 21 17 (81.0) 11 (52.4) Absent allele 36 5 (13.9) 35 27 (77.1) 17 (48.6) GSTT1 Wild type 41 4 (9.8) 40 33 (82.5) 22 (55.0) Absent allele 17 3 (17.6) 16 11 (68.8) 6 (37.5) GSTP1 *A/*A 27 1 (3.7) 25 21 (84.0) 14 (56.0) *A (wild type) *A/*B 19 6 (31.6)† 19 15 (78.9) 10 (52.6) *B (A313G) *A/*C 3 0 3 2 (66.7) 1 (33.3) *C (A313G ϩ C341T) *B/*B 7 0 7 5 (71.4) 3 (42.9) *D (C341T) *B/*C 2 0 2 1 (50.0) 0 GSTM3 *A (wild type) *A/*A 40 5 (12.5) 39 29 (74.4) 19 (48.7) *B (A310C) *A/*B 18 2 (11.1) 17 15 (88.2) 9 (52.9) †P Ͻ .05. initely conclude that it is clinically relevant. Login to comment

[hide] Multiple Genetic Polymorphisms of GSTP1 313AG, MDR... Ann Surg Oncol. 2008 Mar;15(3):872-80. Epub 2007 Dec 19. Huang MY, Wang YH, Chen FM, Lee SC, Fang WY, Cheng TL, Hou MF, Wang JY, Lin SR
Multiple Genetic Polymorphisms of GSTP1 313AG, MDR1 3435CC, and MTHFR 677CC highly correlated with early relapse of breast cancer patients in Taiwan.
Ann Surg Oncol. 2008 Mar;15(3):872-80. Epub 2007 Dec 19., [PMID:18095031]

Abstract [show]
BACKGROUND: Genetic polymorphisms in drug-metabolizing enzymes, transporters, receptors, and other drug targets have been linked to inter-individual differences in the efficacy and toxicity of many medications. In the present study, multiple chemotherapeutic agent-related genetic polymorphisms, including GSTP1, MDR1, MTHFR, and TS tandem repeats, were analyzed in breast cancer patients and studied in correlation with the clinical outcome of patients receiving FEC adjuvant chemotherapy. METHODS: The genotypes from 192 stage II and III breast cancer patients who underwent operations and received six cycles of postoperative adjuvant chemotherapy (FEC) were determined by means of PCR-RFLP. The association of each genetic polymorphism with clinicopathological data of patients and early relapse status were analyzed. RESULTS: The results showed that the genotype distribution of GSTP1 A313G, MTHFR C677T, and TS 3R3R in Taiwanese subjects differed significantly from the distribution in Caucasians. After analysis of the relationship between the genotypes and clinicopathological data of the patients, a significant correlation was observed between postoperative early relapse in patients with genetic polymorphisms of both MDR1 3435CC and MTHFR 677CC (crude OR: 2.609, P = .013) and patients with additional GSTP1 313AG genetic polymorphism (crude OR: 2.833, P = .017). CONCLUSIONS: The results of the present study highly suggest that GSTP1, MDR1, and MTHFR genotypes could be prognostic factors for Taiwanese patients with breast cancer.

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4 Results: The results showed that the genotype distribution of GSTP1 A313G, MTHFR C677T, and TS 3R3R in Taiwanese subjects differed significantly from the distribution in Caucasians. Login to comment
36 GSTP1 exon5 A313G, MDR1 C3435T, and MDR1 C3435T were restricted by BsmAI, DpnII, and HinfI, respectively. Login to comment
54 PCR-RFLP Analysis Results of Chemotherapeutic Agent-Related Genetic Polymorphisms In our study, chemotherapeutic agent-related genetic polymorphisms are GSTP1 A313G, MDR1 C3435T, MTHFR C667T, and TS double or triple tandem repeat. Login to comment
60 Comparison of Genotypes Distribution between Taiwanese Breast Cancer Patients and Other Races We compared the distribution of genetic polymorphisms, such as GSTP1 A313G (AA, AG, GG), MDR1 C3435T (CC, CT, TT), MTHFR C677T (CC, CT, TT), and TS tandem repeat (3R3R, 2R3R, 2R2R), in various races, including Caucasian, Korean, African American, Chinese, Japanese American, and Taiwanese subjects from our work and literature reviews. Login to comment
62 The distribution of GSTP1 A313G genotypes in our data show significant differences from that of Caucasian (P = .001) and African American populations (P = .001)13 but no significant differences from Chinese (P = .410)14 and Korean populations (P = .242).15 The distribution of MDR1 C3435T genotypes also revealed significant differences from the Caucasian population (P = .003).16 Significantly different distributions of MTHFR C677T (CC, CT, TT) genotypes are evident when comparing our data with Caucasian (P = .001),17 Chinese (P < .0001),18 Korean (P < .0001),19 African American (P < .0001),20 and Japanese American populations (P < .0001),21 but our study is consistent with the other Taiwanese report (P = .150).22 Our study and the another Taiwanese study22 both showed that MTHFR C677T CC appeared more frequently than CT and TT, while another racial study showed that MTHFR C677T CT was the most frequent genetic polymorphism. Login to comment
64 Characteristics of the studied polymorphisms with primer sequences and restriction enzymes Gene polymorphism Primers PCR size PCR condition Restriction enzyme GSTP1Ile105Val (A313G) [F]:5'-GTAGTTTGCCCAAGGTCAAG-3' 433 Annealing: 62°C, 20 sec BsmAI [R]:5'-AGCCACCTGAGGGGTAAG-3' MDR1Ile1145Ile (C3435T) [F]:5'-gatctgtgaactcttgttttc-3' 244 Annealing: 58°C, 20 sec DpnII [R]:5'-GAAGAGAGACTTACATTAGGC-3' MTHFRAla222Val (C677T) [F]:5'-TGGCAGGTTACCCCAAAGGC-3' 400 Annealing: 70°C, 20 sec HinfI [R]:5'-ACTGTTGCTGGGTTTTGGGG-3' TS 28 bp tandem repeat [F]:5'-GTGGCTCCTGCGTTTCCCCC-3' 240 Annealing: 72°C, 15 sec - [R]:5'-TCCGAGCCGGCCACAGGCAT-3' patients presented TS 2R3R as the most frequent genetic polymorphism. Login to comment
68 Correlation between Early Relapse and Genotypes of Chemotherapeutic Agent-Related Genes The correlation between genetic polymorphisms (MTHFR C677T, MDR1 C3435T, GSTP1 A313G, and TS double or triple tandem repeat) and patients with or without early relapse was analyzed. Login to comment
78 GSTP1 exon5 A313G was restricted by BsmAI and resulted in: 329bp and 104bp GSTP1 313AA fragments; 329bp, 222bp, 107bp, and 104bp GSTP1 313AG fragments; and 222bp, 104bp, and 107bp GSTP1 313GG fragments. Login to comment
107 (%) GSTP1 A313G Sweeney13 Kim15 Sweeney13 Egan14 AA 93 (48.4) 122 (71.3) 17 (35) 723 (63.5) - - 122 (64.2) AG 80 (41.7) 44 (25.7) 27 (56) 363 (31.9) - - 65 (33.9) GG 19 (9.9) 5 (2.9) 4 (8) 53 (4.6) - - 5 (1.9) MDR1 C3435T Kafka16 CC 21 (21) - - - - - 79 (41.1) CT 57 (57) - - - - - 79 (41.1) TT 22 (22) - - - - - 34 (17.8) MTHFR C677T Campbell17 Lee19 Martin20 Shrubsole18 Chou22 Le Marchand21 CC 140 (41.8) 58 (31.2) 114 (81) 355 (34.2) 73 (51.4) 135 (42.5) 112 (58.3) CT 162 (48.4) 96 (51.6) 27 (19) 507 (48.8) 51 (35.9) 140 (44.0) 67 (34.9) TT 33 (9.8) 32 (17.2) 0 (0) 176 (17.0) 18 (12.7) 43 (13.5) 13 (6.8) TS tandem repeat Largillier24 Zhai23 3R3R 27 (32.7) - - 279 (64.6) - - 129 (67.2) 2R3R 43 (50) - - 130 (30.1) - - 61 (31.8) 2R2R 13 (17.3) - - 23 (5.3) - - 2 (1) a authorn in this table are presented with reference number (n ) and the abbreviated name of the first author in the previously reported paper. Login to comment
120 After comparing the Taiwanese with other races with regard to genetic polymorphism, we found that the Taiwanese, Korean, and Chinese demonstrate a higher frequency of GSTP1 A313G AA than Caucasians and African Americans do. Taiwanese demonstrate a higher frequency of MTHFR C677T CC than other races do. Caucasians demonstrate a higher frequency of MDR1 C3435T CT and TS tandem repeat 2R than the Taiwanese do. The differences in genetic polymorphisms may explain the variety of chemotherapeutic agent-related responses that occur worldwide. Login to comment

[hide] ERCC2 2251A>C genetic polymorphism was highly corr... BMC Cancer. 2008 Feb 12;8:50. Huang MY, Fang WY, Lee SC, Cheng TL, Wang JY, Lin SR
ERCC2 2251A>C genetic polymorphism was highly correlated with early relapse in high-risk stage II and stage III colorectal cancer patients: a preliminary study.
BMC Cancer. 2008 Feb 12;8:50., [PMID:18267032]

Abstract [show]
BACKGROUND: Early relapse in colorectal cancer (CRC) patients is attributed mainly to the higher malignant entity (such as an unfavorable genotype, deeper tumor invasion, lymph node metastasis and advance cancer stage) and poor response to chemotherapy. Several investigations have demonstrated that genetic polymorphisms in drug-targeted genes, metabolizing enzymes, and DNA-repairing enzymes are all strongly correlated with inter-individual differences in the efficacy and toxicity of many treatment regimens. This preliminary study attempts to identify the correlation between genetic polymorphisms and clinicopathological features of CRC, and evaluates the relationship between genetic polymorphisms and chemotherapeutic susceptibility of Taiwanese CRC patients. To our knowledge, this study discusses, for the first time, early cancer relapse and its indication by multiple genes. METHODS: Six gene polymorphisms functional in drug-metabolism - GSTP1 Ile105Val, ABCB1 Ile1145Ile, MTHFR Ala222Val, TYMS double (2R) or triple (3R) tandem repeat - and DNA-repair genes - ERCC2 Lys751Gln and XRCC1 Arg399Gln - were assessed in 201 CRC patients using a polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) technique and DNA sequencing. Patients were diagnosed as either high-risk stage II (T2 and 3 N0 M0) or III (any T N1 and 2 M0) and were administered adjuvant chemotherapy regimens that included 5-fluorouracil (5FU) and leucovorin (LV). The correlations between genetic polymorphisms and patient clinicopathological features and relapses were investigated. RESULTS: In this study, the distributions of GSTP1 (P = 0.003), ABCB1 (P = 0.001), TYMS (P < 0.0001), ERCC2 (P < 0.0001) and XRCC1 (P = 0.006) genotypes in the Asian population, with the exception of MTHFR (P = 0.081), differed significantly from their distributions in a Caucasian population. However, the unfavorable genotype ERCC2 2251A>C (P = 0.006), tumor invasion depth (P = 0.025), lymph node metastasis (P = 0.011) and cancer stage (P = 0.008) were significantly correlated with early relapse. Patients carrying the ERCC2 2251AC or2251CC genotypes had a significantly increased risk of early relapse (OR = 3.294, 95% CI, 1.272-8.532). CONCLUSION: We suggest that ERCC2 2251A>C alleles may be genetic predictors of early CRC relapse.

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86 PCR-RFLP analysis and automated sequencing of GSTP1 A313GFigure 1 PCR-RFLP analysis and automated sequencing of GSTP1 A313G. Login to comment
88 The GSTP1 exon5 A313G was restricted by BsmAI. Login to comment

[hide] Association of drug metabolism gene polymorphisms ... Leukemia. 2009 Mar;23(3):545-56. Epub 2008 Nov 13. Rocha V, Porcher R, Fernandes JF, Filion A, Bittencourt H, Silva W Jr, Vilela G, Zanette DL, Ferry C, Larghero J, Devergie A, Ribaud P, Skvortsova Y, Tamouza R, Gluckman E, Socie G, Zago MA
Association of drug metabolism gene polymorphisms with toxicities, graft-versus-host disease and survival after HLA-identical sibling hematopoietic stem cell transplantation for patients with leukemia.
Leukemia. 2009 Mar;23(3):545-56. Epub 2008 Nov 13., [PMID:19005482]

Abstract [show]
Individual differences in drug efficacy or toxicity can be influenced by genetic factors. We investigated whether polymorphisms of pharmacogenes that interfere with metabolism of drugs used in conditioning regimen and graft-versus-host disease (GvHD) prophylaxis could be associated with outcomes after HLA-identical hematopoietic stem cell transplantation (HSCT). Pharmacogenes and their polymorphisms were studied in 107 donors and patients with leukemia receiving HSCT. Candidate genes were: P450 cytochrome family (CYP2B6), glutathione-S-transferase family (GST), multidrug-resistance gene, methylenetetrahydrofolate reductase (MTHFR) and vitamin D receptor (VDR). The end points studied were oral mucositis (OM), hemorrhagic cystitis (HC), toxicity and venoocclusive disease of the liver (VOD), GvHD, transplantation-related mortality (TRM) and survival. Multivariate analyses, using death as a competing event, were performed adjusting for clinical factors. Among other clinical and genetic factors, polymorphisms of CYP2B6 genes that interfere with cyclophosphamide metabolism were associated with OM (recipient CYP2B6(*)4; P=0.0067), HC (recipient CYP2B6(*)2; P=0.03) and VOD (donor CYP2B6(*)6; P=0.03). Recipient MTHFR polymorphisms (C677T) were associated with acute GvHD (P=0.03), and recipient VDR TaqI with TRM and overall survival (P=0.006 and P=0.04, respectively).Genetic factors that interfere with drug metabolisms are associated with treatment-related toxicities, GvHD and survival after HLA-identical HSCT in patients with leukemia and should be investigated prospectively.

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14 Samples of 107 leukemia patients given HLA-identical HSCT and their respective donors were analyzed for the following candidate genes polymorphisms: P450 cytochrome family [CYP2B6*2(C64T), *3(C777A), *4(A785G), *5(C1459T), *6(G516T)] glutathione-S-transferases [GSTM1 (null), GSTT1 (null), GSTP1 (A313G)], Multidrug-resistance gene [MDR1 (C3435T)], Methylenetetrahydrofolate reductase [MTHFR (C677T, A1298C)], Vitamin D receptor [VDR (ApaI, TaqI and BsmI)]. Login to comment
53 However, both Table 2 Characteristics of genes and polymorphisms Allele polymorphisms Primers PCR 35 cycles Fragment enzyme References CYP2B6*2 50 -GCAGGGCAGTCAGACCAGGA-30 30 s 94 1C 215 bp 13 C64T 50 -GACCCCATTCGTCTGTGTCT-30 40 s 58 1C (Modified) Arg22 Cys 1 min 72 1C Hae II CYP2B6*3 50 -CACCACCCCTTCTTTCTTGC-30 30 s 94 1C 223 bp 14 C777A 50 -CCTTTTTCCTCTCCCAGACC-30 40 s 58 1C Ser259 Arg 1 min 72 1C Hae II CYP2B6*4 50 -GACAGAAGGATGAGGGAGGAA-30 30 s 94 1C 640 bp 13 A785G 50 -CTCCCTCTGTCTTTCATTGTGT-30 45 s 60 1C Lys262 Arg 1 min 72 1C StyI CYP2B6*5 50 -TGAGAATCAGTGGAAGCCATAGA-30 30 s 94 1C 1401 bp 13 C1459T 50 -TAATTTTCGATAATCTCACTCCTGC-30 40 s 58 1C Arg487 Cys 1 min 72 1C Bgl II CYP2B6*6 50 -CTTGACCTGCTGCTTCTTCC-30 30 s 94 1C 204 bp 14 G516T 50 -TCCCTCTCCGTCTCCCTG-30 40 s 58 1C Gln172 His 1 min 72 1C Bsr I GSTM1 50 -GAACTCCCTGAAAAGCTAAAGC-30 1 min 94 1C 215 bp 15 Present or null 50 -GTTGGGCTCAAATATACGGTGG-30 1 min 62 1C 1 min 72 1C GSTT1 50 -TTCCTTACTGGTCCTCACATCTC-30 1 min 94 1C 480 bp 15 Present or null 50 -TCACCGGATCATGGCCAGCA-30 1 min 62 1C 1 min 72 1C GSTP1 50 -ATCCCCAGTGACTGTGTGTT-30 30 s 94 1C 217 bp 16 A313G 50 -CTTTCTTTGTTCAGCCCCCA-30 40 s 53 1C (Modified) Ile105 Val 1 min 72 1C BsmAI MDR 50 - GATCTGTGAACTCTTGTTTTCA-30 30 s 94 1C 244 bp 17 C3435T 50 -GAAGAGAGACTTACATTAGGC-30 45 s 62 1C synonymous 1 min 72 1C Dpn II MTHFR 50 -AGGCGGTGCGGTGAGAGTG-30 50 s 94 1C 198 bp 18 C677T 50 -TGAAGGAGAAGGTGTCTGCGG GA-30 50 s 56 1C Ala222 Val 1 min 72 1C Hinf I MTHFR 50 -CTTTGGGGAGCTGAAGGACTACTAC-30 1 min 92 1C 163 bp 19 A1298C 50 -CAGTTTGTGACCATTCCGGTTTG-30 1 min 51 1C Glu429 Ala 30 s 72 1C Mbo II For each allele, the nucleotide and amino acid changes are indicated (when appropriate), together with the primer sequences, PCR conditions (35 cycles for all the amplification protocols), size of the fragment amplified and the restriction enzyme. Login to comment
61 of donors (%) CYP2B6*2A Cyclophosphamide CC (wt) Not described 92 (86) 91 (85) C64T CT 14 (13) 15 (14) TT 1 (1) 1 (1) CYP2B6*4 AA (wt) AG or GG trend to lower expression of the enzyme13 59 (55) 60 (56) A785G AG 38 (36) 37 (35) GG 10 (9) 10 (9) CYP2B6*5 CC (wt) CT or TT Significantly lower S-mephentytoin N-demethylase activity13 81 (76) 89 (83) C1459T CT 25 (23) 16 (15) TT 1 (1) 2 (2) CYP2B6*6 GG (wt) GT or TT decreased protein level and impact on CY 4-hydroxylation.8 Enhance 7-ethoxycoumarin O-deethylase activity14 61 (57) 63 (59) G516T1 GT 36 (34) 35 (33) A785G TT 10 (9) 9 (9) GSTM1* Null Reduced or no enzyme activity and therefore may be unable to eliminate electrophilic carcinogens24 61 (57) 60 (56) Busulfan Non-null 46 (43) 47 (44) GSTT1* Melphalan Null 20 (19) 27 (25) Cyclophosphamide Non-null 87 (81) 80 (75) GSTP1 AA (wt) Reduced ability to detoxify chemotherapeutic agents thereby increasing the effective dose of the drug within the cell.25 46 (43) 52 (49) A313G GA 53 (49) 42 (39) GG 8 (8) 13 (12) MTHFR Methotrexate CC (wt) It leads to a thermolabile variant of the enzyme and it is associated with reduced enzyme activity (70% for TT and 40% for CT), increased homocysteine levels18 45 (42) 41 (38) C677T CT 53 (50) 51 (48) TT 9 (8) 15 (14) MTHFR AA (wt) Reduced enzyme activity without increasing homocysteine levels.26 50 (47) ND A1298C AC 56 (52) ND CC 1 (1) ND MDR-1 Cyclosporine A C3435T Tracolimus CC (wt) CsA oral clearance is significantly higher in subjects who carried at least one T allele27 30 (28) 29 (27) CT 56 (52) 56 (52) TT 21 (20) 22 (21) VDR apaI aa Increased femoral and vertebral bone density.28 25 (23) 20 (19) Aa 57 (53) 56 (52) AA 25 (23) 31 (29) VDR taqI Cyclosporine A** tt Intervertebral disc degeneration in males29 Periodontal disease30 and infections31 13 (12) 15 (14) Tt 46 (43) 52 (49) Immunoregulatory activities of 1a,25-(OH)2D3 TT 48 (45) 40 (37) VDR bsmI bb Increased femoral and vertebral bone density.28 50 (47) 40 (37) Bb 34 (32) 41 (38) BB 23 (21) 26 (24) Abbreviations: ND, not done; wt, wild type. Login to comment
105 In univariate analysis we found that donor GSTP1 (A313G) genotype (GG or GA) was associated with higher incidence of chronic GvHD. Login to comment

[hide] Meta-analysis on pharmacogenetics of platinum-base... PLoS One. 2012;7(6):e38150. Epub 2012 Jun 26. Yin JY, Huang Q, Zhao YC, Zhou HH, Liu ZQ
Meta-analysis on pharmacogenetics of platinum-based chemotherapy in non small cell lung cancer (NSCLC) patients.
PLoS One. 2012;7(6):e38150. Epub 2012 Jun 26., [PMID:22761669]

Abstract [show]
AIM: To determine the pharmacogenetics of platinum-based chemotherapy in Non Small Cell Lung Cancer (NSCLC) patients. METHODS: Publications were selected from PubMed, Cochrane Library and ISI Web of Knowledge. A meta-analysis was conducted to determine the association between genetic polymorphisms and platinum-based chemotherapy by checking odds ratio (OR) and 95% confidence interval (CI). RESULTS: Data were extracted from 24 publications, which included 11 polymorphisms in 8 genes for meta-analysis. MDR1 C3435T (OR = 1.97, 95% CI: 1.11-3.50, P = 0.02), G2677A/T (OR = 2.61, 95% CI: 1.44-4.74, P = 0.002) and GSTP1 A313G (OR = 0.32, 95% CI: 0.17-0.58, P = 0.0002) were significantly correlated with platinum-based chemotherapy in Asian NSCLC patients. CONCLUSION: Attention should be paid to MDR1 C3435T, G2677A/T and GSTP1 A313G for personalized chemotherapy treatment for NSCLC patients in Asian population in the future.

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4 MDR1 C3435T (OR = 1.97, 95% CI: 1.11-3.50, P = 0.02), G2677A/T (OR = 2.61, 95% CI: 1.44-4.74, P = 0.002) and GSTP1 A313G (OR = 0.32, 95% CI: 0.17-0.58, P = 0.0002) were significantly correlated with platinum-based chemotherapy in Asian NSCLC patients. Login to comment
5 Conclusion: Attention should be paid to MDR1 C3435T, G2677A/T and GSTP1 A313G for personalized chemotherapy treatment for NSCLC patients in Asian population in the future. Login to comment
23 The same situation exists for GSTP1 A313G [9-11]. Login to comment
96 Genes Polymorphisms NCBI SNP ID Allele Responders Non-responders References ERCC1 C354T rs11615 C 210 285 [6-8,22,59-64] (Asn118Asn) T 199 308 C8092A rs3212986 C 85 87 [9,22,65] A 85 93 XPD G934A rs1799793 G 114 174 [7-9,59,63,66-68] (Asp312Asn) A 93 181 A2251C rs13181 A 259 528 [7-9,59,63,65-70] (Lys751Gln) C 172 372 XPG T138C rs1047768 C 13 20 [23,24] (His46His) T 41 131 XRCC1 G1196A rs25487 G 60 110 [9,23,68,69] (Arg399Gln) A 71 152 MDR1 C3435T rs1045642 C 49 46 [8,32,60,63,71] (Ile1145Ile) T 88 141 G2677T/A rs2032582 G 31 22 [32,60,71] (Ala893Ser/Thr) T/A 44 67 GSTP1 A313G rs1695 A 64 181 [9-11,72] (Ile105Val) G 67 113 GSTM1 Deletion NR presence 31 63 [9,62] deletion 38 40 RRM1 C-37A NR C 87 123 [8,36,63] A 65 92 NR: not reported. Login to comment
143 GSTP1 A313G was the most widely studied polymorphism. Login to comment
148 The result showed no association between GSTP1 A313G and platinum-based chemotherapy (OR = 0.61, 95% CI: 0.2921.28, P = 0.19) (Figure 6A). Login to comment
156 As showed in Figure 6 B and C, GSTP1 A313G was only significantly associated with drug response in Asian population. Login to comment
167 The results showed that MDR1 C3435T, G2677A/T and GSTP1 A313G were significantly correlated with platinum-based chemotherapy in the Asian NSCLC patients. Login to comment
187 Another polymorphism found to be significantly correlated with drug response was GSTP1 A313G, which is a non-synonymous SNP located in exon 5 [33]. Login to comment
190 Previous study showed that GSTP1 A313G resulted in reduced glutathione conjugating ability [33]. Login to comment
210 Meta-analysis of association between GSTP1 A313G and platinum-based chemotherapy in overall (A), Asian (B) and Caucasian (C) NSCLC patients. Login to comment
223 Although most of the separately analyzed results were consistent with overall population, two polymorphisms (MDR1 C3435T and GSTP1 A313G) showed ethnic difference. Login to comment
276 In conclusion, we identified that MDR1 C3435T, G2677A/T and GSTP1 A313G were significantly correlated with platinum-based chemotherapy in Asian NSCLC patients. Login to comment
137 Authors Year Ethnicity (Country) Number of patients Disease stageGenotyping method Chemotherapeutic drugs Genes and polymorphism Reference Camps et al. 2003 Caucasian (Spain) 38 IIIB-IV Direct sequencing Cisplatin/Gemcitabine XPD: G934A XPD: A2251C [67] Isla et al. 2004 Caucasian (Spain) 62 IIIB-IV TaqMan genotyping assay Cisplatin/Docetaxel ERCC1: C354T MDR1: C3435T RRM1: A-37C XPD: G934A XPD: A2251C [8] Ryu et al. 2004 Asian (Korea) 108 IIIB-IV SNaPShot assay Platinum-based chemotherapy ERCC1: C354T XPD: G934A XPD: A2251C [59] Booten et al. 2006 Caucasian (UK) 89 III-IV Direct sequencing Platinum-based chemotherapy GSTP1:A313G [11] Booton et al. 2006 Caucasian (UK) 89 III-IV PCR-RFLP Direct sequencing Platinum-based chemotherapy XPD: G934A XPD: A2251C [66] Su et al. 2007 Asian (China) 76 IIIA-IV TaqMan genotyping assay Platinum-based chemotherapy ERCC1: C354T [6] Giachino et al. 2007 Caucasian (Italy) 188 IIIA-IV PCR-RFLP Platinum-based chemotherapy XRCC1: G1196A XPD: A2251C [69] Tibaldi et al. 2008 Caucasian (Italy) 65 IIIB-IV TaqMan genotyping assay Cisplatin/Gemcitabine ERCC1: C354T XPD: G934A XPD: A2251C [7] Pan et al. 2008 Asian (China) 69 IIIB-IV PCR-RFLP Cisplatin/Vinorelbine MDR1: C3435T MDR1: G2677A/T [71] Yu et al. 2008 Asian (China) 117 NR Direct sequencing Carboplatin/Etoposide ERCC1: C354T ERCC1: C8092A [22] Kalikaki et al. 2009 Caucasian (Greece) 119 IIIA-IV PCR-RFLP Direct sequencing Platinum-based chemotherapy ERCC1: C354T ERCC1: C8092A GSTP1: A313G GSTM1: deletion XPD: G934A XPD: A2251C XRCC1: G1196A [9] Feng et al. 2009 Asian (China) 214 IIB-IV PCR-RFLP Platinum-based chemotherapy RRM1: A-37C [36] Yao et al. 2009 Asian (China) 102 IIIB-IV PCR-RFLP Platinum-based chemotherapy XRCC1: G1196A [68] Sun et al. 2009 Asian (China) 90 IV 3-D polyacrylamide gel-based DNA microarray Platinum-based chemotherapy XRCC1: G1196A [23] Pan et al. 2009 Asian (China) 54 IIIB-IV PCR-RFLP Cisplatin/Docetaxel MDR1: C3435T MDR1: G2677A/T [32] Zhou et al. 2010 Asian (China) 130 IIIB-IV TaqMan genotyping assay Platinum-based chemotherapy ERCC1: C354T [61] Chen et al. 2010 Asian (China) 95 IIIB-IV Ligase detection reactions (LDR) Platinum-based chemotherapy ERCC1: C354T MDR1: C3435T MDR1: G2677A/T [60] Sun et al. 2010 Asian (China) 113 IIIA-IV 3-D polyacrylamide gel-based DNA microarray Platinum-based chemotherapy GSTP1: A313G [10] Li et al. 2010 Asian (China) 115 IIIB-IV 3-D polyacrylamide gel-based DNA microarray Platinum-based chemotherapy ERCC1: C354T XPD: A2251C [65] Vinolas et al. 2011 Caucasian (Spain) 94 IIIB-IV 59 nuclease allelic discrimination assay Cisplatin/Vinorelbine ERCC1: C354T XPD: G934A XPD: A2251C MDR1: C3435T RRM1: A-37C [63] Zhou et al. 2011 Asian (China) 111 IV Direct sequencing Platinum-based chemotherapy GSTP1: A313G [72] Li et al. 2012 Asian (China) 58 NR PCR-RFLP Platinum-based chemotherapy GSTM1:deletion [62] Chen et al. 2012 Asian (China) 355 IIIB-IV TaqMan genotyping assay Platinum-based chemotherapy XPD: A2251C [70] Cheng et al. 2012 Asian (China) 142 IIIB-IV Direct sequencing Platinum-based chemotherapy ERCC1: C354T [64] NR: not reported. Login to comment
144 GSTP1 A313G was the most widely studied polymorphism. Login to comment
149 The result showed no association between GSTP1 A313G and platinum-based chemotherapy (OR = 0.61, 95% CI: 0.2921.28, P = 0.19) (Figure 6A). Login to comment
157 As showed in Figure 6 B and C, GSTP1 A313G was only significantly associated with drug response in Asian population. Login to comment
168 The results showed that MDR1 C3435T, G2677A/T and GSTP1 A313G were significantly correlated with platinum-based chemotherapy in the Asian NSCLC patients. Login to comment
188 Another polymorphism found to be significantly correlated with drug response was GSTP1 A313G, which is a non-synonymous SNP located in exon 5 [33]. Login to comment
191 Previous study showed that GSTP1 A313G resulted in reduced glutathione conjugating ability [33]. Login to comment
211 Meta-analysis of association between GSTP1 A313G and platinum-based chemotherapy in overall (A), Asian (B) and Caucasian (C) NSCLC patients. Login to comment
224 Although most of the separately analyzed results were consistent with overall population, two polymorphisms (MDR1 C3435T and GSTP1 A313G) showed ethnic difference. Login to comment
277 In conclusion, we identified that MDR1 C3435T, G2677A/T and GSTP1 A313G were significantly correlated with platinum-based chemotherapy in Asian NSCLC patients. Login to comment

[hide] [Pharmacogenetics and pharmacogenomics of cancers]... Pathol Biol (Paris). 2004 Jul;52(6):332-7. Robert J
[Pharmacogenetics and pharmacogenomics of cancers].
Pathol Biol (Paris). 2004 Jul;52(6):332-7., [PMID:15261376]

Abstract [show]
Sequencing the human genome brings new tools for the individualisation of cancer chemotherapy, firstly thanks to the identification of polymorphisms of genes involved in anticancer drug metabolism or activity (Pharmacogenetics), and secondly thanks to the determination of tumour gene expression profiles and their relationship to chemosensitivity and chemoresistance (Pharmacogenomics). A few functional polymorphisms have been known for a long time (thiopurine methyltransferase, glutathion S-transferases), but several new ones have been identified recently, at the level of the genes encoding drug targets (thymidylate synthase), at the level of DNA repair enzymes (XPD) or at the level of transport proteins (MDR1). On the other hand, the research of correlations between gene expression profiles and chemosensitivity has been performed on the in vitro models of the National Cancer Institute and may allow crucial improvements in the identification of patients who would best take advantage of a specific chemotherapy. Clinical trials, first on a retrospective basis, then on a prospective one, are implemented to validate this approach.

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88 Un polymorphisme g&#e9;n&#e9;tique a &#e9;t&#e9; r&#e9;cemment identifi&#e9; [20] : il s`agit d`une mutation ponctuelle A313G conduisant &#e0; une substitution Ile105val et &#e0; une diminution de l`activit&#e9; de l`enzyme. Dans une &#e9;tude sur 107 patients trait&#e9;s pour cancer colorectal par 5-FU et oxaliplatine, les dix homozygotes porteurs de la variation ont pr&#e9;sent&#e9; une survie trois fois sup&#e9;rieure &#e0; la survie des homozygotes &#ab; sauvages &#bb;. Login to comment

[hide] Polymorphisms in genes involved in drug detoxifica... Cancer Biol Ther. 2012 Mar;13(5):264-71. doi: 10.4161/cbt.18920. Epub 2012 Mar 1. Ji M, Tang J, Zhao J, Xu B, Qin J, Lu J
Polymorphisms in genes involved in drug detoxification and clinical outcomes of anthracycline-based neoadjuvant chemotherapy in Chinese Han breast cancer patients.
Cancer Biol Ther. 2012 Mar;13(5):264-71. doi: 10.4161/cbt.18920. Epub 2012 Mar 1., [PMID:22310978]

Abstract [show]
BACKGROUND: The large individual variability for anticancer drugs in both outcome and toxicity risk makes the identification of pharmacogenetic markers that can be used to screen patients before therapy selection an attractive prospect. AIMS: This work aimed to evaluate the importance of genetic polymorphisms involved in drug detoxification to predict clinical outcomes of anthracycline-based neoadjuvant chemotherapy for breast cancer. RESULTS: GSTP1 313 AA genotype was associated with a poor clinical response relative to G allele carrier (58.4% vs 80.8%; p = 0.006), and MDR1 3435 TT genotype had a worse response compared with C allele carrier (33.3% vs 71.2% p = 0.001). Patients with both the adverse genotypes of GSTP1 314AA and MDR 3435TT showed the worst therapy efficacy in all (14.3%; p = 0.000). Kaplan-Meier survival analysis showed that the patients with no adverse genotype were associated with decreased hazard of relapse (p = 0.002), compared with those with 1 or 2 adverse genotypes. Multivariate analysis demonstrated that clinical response and no adverse genotype was independent predictors of disease-free survival (DFS). METHODS: Genotyping was performed by allele-specific oligonucleotide ligation reaction (MnSOD, CAT, GSTP1), multiplex PCR (GSTM1, GSTT1) or PCR-RFLP (MDR1). Based on 153 patients received anthracycline-based neoadjuvant chemotherapy, these genotypes or their combinations in relation to treatment-related response, hematologic toxicity and DFS were investigated. CONCLUSIONS: These results suggest that polymorphisms in GSTP1 and MDR1 may help to predict clinical response and DFS of anthracycline-based chemotherapy, and a polygenic pathway approach should provide more useful information. The findings required independent prospective confirmation.

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17 The polymorphism of GSTP1 A313G and null variants of GSTM1 and GSTT1 that lead to the diminished or abolished enzyme activity have been associated with increased drug treatment benefit in some cancer patients.5,7 In addition to these enzymes, drug transporters are increasing recognized to be important to drug disposition and response. Login to comment
48 The combined effects of GSTP1 A313G and MDR1 C3435T were greater than those for either polymorphism alone, and an increased response with decreasing number of adverse genotypes was observed (14.3 vs. 66.0 vs. 82.2%; p = 0.000). Login to comment
84 The combined adverse genotypes in GSTP1 A313G and MDR1 C3435T and clinical response to anthracycline-based chemotherapy Adverse genotype No. Clinical response x2 p RR (CI 95%)a CR + PR (%) SD + PD (%) GSTP1 313AA and MDR1 3435TT 0 45 37 (82.2) 5 (17.8) 26.223 0.000 1.0 (Ref.) 1 (AA or TT) 94 62 (66.0) 32 (34.0) 3.82 (1.37-10.66) 2 (AA + TT) 14 2 (14.3) 12 (85.7) 44.40 (7.61-259.20) a The relative risk (RR) of not responding to treatment with a 95% confidence interval. Login to comment
102 Volume 13 Issue 5 Single nucleotide polymorphisms (SNPs) of MnSOD (T47C), CAT (C-262T), GSTP1 (A313G) and the deletion polymorphisms of GSTM1 and GSTT1 were determined using allele-specific oligonucleotide ligation reaction (ASOLR) and a multiplex PCR developed in our laboratory, respectively.28 ASOLR was a technique for multiplex genetic typing. Login to comment
103 The assay was implemented via three steps: a triplex PCR that resulted in the amplified target sequences with MnSOD T47C, CAT C-262T and GSTP1 A313G loci, a triplex allele-specific oligonucleotide probe ligation reaction that generates the ligation between perfectly matched probes at their junctions while no ligation occurred between mismatched ones and an analysis of genotype-specific ligation products by both fluorescence and size after electrophoresis on ABI PRISM 377 DNA sequencer.28,29 MDR1 C3435T, G2677T/A and C1236T polymorphisms were analyzed by PCR-RFLP as described by Ni et al. PCR reaction was performed on a DNA thermal cycler (Bio-Rad iCycle). Login to comment

[hide] Genetic risk factors for glucocorticoid-induced os... Steroids. 2013 Apr;78(4):401-8. doi: 10.1016/j.steroids.2013.01.004. Epub 2013 Jan 25. Gong LL, Fang LH, Wang HY, Peng JH, Si K, Zhu J, Han FF, Wang YH, Du GH, Pei LX, Liu LH
Genetic risk factors for glucocorticoid-induced osteonecrosis: a meta-analysis.
Steroids. 2013 Apr;78(4):401-8. doi: 10.1016/j.steroids.2013.01.004. Epub 2013 Jan 25., [PMID:23357434]

Abstract [show]
Glucocorticoid-induced osteonecrosis is a common and severe adverse event. We conducted a meta-analysis to investigate whether polymorphisms in target genes were associated with the risk of corticosteroid-induced osteonecrosis. Published literature from PubMed and EMBASE were searched for eligible publications. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using a fixed- or random-effects model. There were 23 articles with 35 genes described the relationship between polymorphisms and glucocorticoid-induced osteonecrosis. Meta-analyses were carried out for those SNPs with three or more eligible studies, which included four SNPs located in three genes (PAI-1, MTHFR, ABCB1). The meta-analysis revealed that the PAI-1 4G allele was associated with an increased risk of osteonecrosis compared with the 5G allele (combined studies: OR=1.932, 95% CI=1.145-3.261). The OR for the 4G/4G vs. 5G/5G genotype of PAI-1 was 3.217 (95% CI 1.667-6.209 with combined studies), The relative risk of osteonecrosis was increased in the 4G allele vs. 5G/5G and 4G/4G genotype vs. 5G allele, with odds ratios of 2.304 (95% CI=1.235-4.299) and 2.307 (95% CI=1.527-3.485) in combined studies, respectively. The ABCB1 C3435T genotype distributions available confirmed that the C allele increased osteonecrosis risk compared with the T allele (OR 1.668, 95% CI=1.214-2.293) and TT genotype (OR 2.946, 95% CI=1.422-6.101). There was no evidence for significant association between MTHFR C677T and ABCB1 G2677T/A polymorphisms and risk of osteonecrosis. Results of this meta-analysis indicate that the PAI-1 4G/5G and ABCB1 C3435T polymorphisms may be risk factors for osteonecrosis.

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82 Gene rs No./genotype Number of cases/ controls Case Control Number of studies Refs. 11 12 22 11 12 22 1 PAI-1 -675 4G/5G 108/917 50 46 12 225 455 237 4 [8,10,24,36] rs6092 89/281 59 29 1 240 41 0 2 [31,35] 2 MTHFR C677T 103/537 61 31 11 324 168 45 5 [10,23-25,31] A1298C 25/39 8 15 2 16 21 2 1 [23] 3 Factor V Leiden N/A 26/39 24 2 0 35 4 0 2 [10,25] 4 Prothrombin G20210A 26/39 26 0 0 35 4 0 2 [10,25] 5 CBP rs3751845 113/246 68 23 22 105 36 105 2 [14,29] 6 ABCB1 C3435T 148/462 83 55 10 210 171 81 6 [14,21,23,30,31,34] G2677T/A 136/268 48 45 13 82 124 62 4 [21,23,30,34] 7 TYMS Enhancer repeat 25/39 5 13 7 16 19 4 2 [23,31] 8 VDR rs2228570 T/C 68/299 42 26 187 112 2 [23,31] Intron 8 G/A 25/39 12 8 5 14 18 7 1 [23] 9 ApoB C7623T 66/244 54 12 230 14 2 [12,14] G12619A 34/123 33 1 112 11 1 [12] 10 ApoA1 -75G/A 33/120 22 11 86 34 1 [12] C83T 33/120 29 4 106 14 1 [12] 11 LRP5 rs2306862 T/C 40/212 18 22 113 99 1 [31] 12 NR3C1 A1220G 25/39 25 0 0 38 1 0 1 [23] rs6196 T/C 34/123 31 3 0 115 8 0 1 [29] rs2282800 34/123 1 2 31 8 22 93 1 [29] 13 SREBP-2 T8408C 56/270 16 31 9 77 138 55 1 [32] G342T 54/422 32 20 2 241 149 32 1 [32] G414A 56/271 22 30 4 132 120 19 1 [32] G1667A 56/266 22 26 8 116 121 29 1 [32] 14 CYP3A4 /1B A/G 25/39 23 2 0 34 2 3 1 [23] rs3735451 34/123 24 9 1 77 46 0 1 [29] 15 CYP2D6 EM/IM/PM 26/54 21 5 0 45 9 0 1 [22] 16 CYP2C19 EM/PM 54/26 46 0 8 23 0 3 1 [22] 17 CYP3A5 /3 G/A 25/39 20 5 0 29 7 3 1 [23] 18 UGT1A1 /28 25/39 11 9 5 14 20 5 1 [23] 19 GSTM1 257 bp deletion (non-null/null) 25/39 14 11 26 13 1 [23] 20 GSTP1 A313G 25/39 5 16 4 13 19 7 1 [23] 21 GSTT1 Deletion (non-null/null) 24/39 18 6 32 7 1 [23] 22 TMPT /1//3 25/39 22 3 0 37 2 0 1 [23] 23 RFC G80A 25/39 10 11 4 12 18 9 1 [23] 24 NOS 27 bp repeat polymorphism in intron 4 29/103 0 3 26 0 5 98 1 [26] D298E 29/103 0 4 25 0 20 83 1 [26] 25 HIF C2755A 59/237 20 29 10 78 117 42 1 [27] T41224C 56/236 28 25 3 135 84 17 1 [27] C45319T 59/236 52 7 0 219 16 1 1 [27] C51610T 56/234 35 18 3 156 68 10 1 [27] 26 PPAR A796G 55/330 36 16 3 223 95 12 1 [28] C34G 54/328 51 3 0 296 32 0 1 [28] C82466T 55/333 39 15 1 242 85 6 1 [28] 27 NcoA2 rs2272670 C/T 34/123 22 11 1 62 50 11 1 [29] 28 BGLAP rs1800247 T/C 36/203 32 4 183 20 1 [31] 29 ESR1 rs2234693 C/T 32/190 13 19 95 95 1 [31] 30 PTH rs6254 A/G 44/229 19 25 115 114 1 [31] 31 PTHR rs1138518 C/T 35/213 16 19 117 96 1 [31] 32 ACP5 rs2229531 A/G 43/222 5 38 31 191 1 [31] rs2305799 T/C 43/235 8 35 54 181 1 [31] 33 TNFa T-1031C 15/35 6 8 1 28 7 0 1 [33] C-863A 16/37 9 7 0 33 4 0 1 [33] C-857T 16/37 12 4 0 26 11 0 1 [33] A-572C 16/37 16 0 0 36 1 0 1 [33] G-308A 16/37 14 2 0 32 4 1 1 [33] G-238A 16/37 13 3 0 33 4 0 1 [33] 34 VEGF A-2575C 74/160 5 24 45 9 68 83 1 [37] A-1154G 74/160 0 11 63 6 46 108 1 [37] C-634G 136/380 35 66 35 65 198 117 2 [37,39] C405G 74/160 19 33 22 25 84 51 1 [37] 35 Hapatic lipase rs59644784 A/G 143/96 20 69 54 16 43 37 1 [38] rs1800588 C/T 143/96 58 68 17 41 42 13 1 [38] 11 Indicate wild type genotype, 12 indicate heterozygous genotype, 22 indicate mutant genotype. Login to comment