Improving Therapeutic Odyssey: Preemptive Pharmacogenomics Utility in Patient Care.

Clin Pharmacol Ther. 2016 Nov 2;:

Authors: Lazaridis KN

PMID: 27804107 [PubMed - as supplied by publisher]

Genome-Wide and Gene-Based Meta-Analyses Identify Novel Loci Influencing Blood Pressure Response to Hydrochlorothiazide.

Hypertension. 2016 Oct 31;:

Authors: Salvi E, Wang Z, Rizzi F, Gong Y, McDonough CW, Padmanabhan S, Hiltunen TP, Lanzani C, Zaninello R, Chittani M, Bailey KR, Sarin AP, Barcella M, Melander O, Chapman AB, Manunta P, Kontula KK, Glorioso N, Cusi D, Dominiczak AF, Johnson JA, Barlassina C, Boerwinkle E, Cooper-DeHoff RM, Turner ST

Abstract
This study aimed to identify novel loci influencing the antihypertensive response to hydrochlorothiazide monotherapy. A genome-wide meta-analysis of blood pressure (BP) response to hydrochlorothiazide was performed in 1739 white hypertensives from 6 clinical trials within the International Consortium for Antihypertensive Pharmacogenomics Studies, making it the largest study to date of its kind. No signals reached genome-wide significance (P<5×10(-)(8)), and the suggestive regions (P<10(-5)) were cross-validated in 2 black cohorts treated with hydrochlorothiazide. In addition, a gene-based analysis was performed on candidate genes with previous evidence of involvement in diuretic response, in BP regulation, or in hypertension susceptibility. Using the genome-wide meta-analysis approach, with validation in blacks, we identified 2 suggestive regulatory regions linked to gap junction protein α1 gene (GJA1) and forkhead box A1 gene (FOXA1), relevant for cardiovascular and kidney function. With the gene-based approach, we identified hydroxy-delta-5-steroid dehydrogenase, 3 β- and steroid δ-isomerase 1 gene (HSD3B1) as significantly associated with BP response (P<2.28×10(-4)). HSD3B1 encodes the 3β-hydroxysteroid dehydrogenase enzyme and plays a crucial role in the biosynthesis of aldosterone and endogenous ouabain. By amassing all of the available pharmacogenomic studies of BP response to hydrochlorothiazide, and using 2 different analytic approaches, we identified 3 novel loci influencing BP response to hydrochlorothiazide. The gene-based analysis, never before applied to pharmacogenomics of antihypertensive drugs to our knowledge, provided a powerful strategy to identify a locus of interest, which was not identified in the genome-wide meta-analysis because of high allelic heterogeneity. These data pave the way for future investigations on new pathways and drug targets to enhance the current understanding of personalized antihypertensive treatment.

PMID: 27802415 [PubMed - as supplied by publisher]

The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response.

Transl Psychiatry. 2016 Nov 1;6(11):e937

Authors: Biernacka JM, Sangkuhl K, Jenkins G, Whaley RM, Barman P, Batzler A, Altman RB, Arolt V, Brockmöller J, Chen CH, Domschke K, Hall-Flavin DK, Hong CJ, Illi A, Ji Y, Kampman O, Kinoshita T, Leinonen E, Liou YJ, Mushiroda T, Nonen S, Skime MK, Wang L, Baune BT, Kato M, Liu YL, Praphanphoj V, Stingl JC, Tsai SJ, Kubo M, Klein TE, Weinshilboum R

PMID: 27801898 [PubMed - in process]

Positional proteomics in the era of the human proteome project on the doorstep of precision medicine.

Biochimie. 2016 Mar;122:110-8

Authors: Eckhard U, Marino G, Butler GS, Overall CM

Abstract
Proteolytic processing is a pervasive and irreversible post-translational modification that expands the protein universe by generating new proteoforms (protein isoforms). Unlike signal peptide or prodomain removal, protease-generated proteoforms can rarely be predicted from gene sequences. Positional proteomic techniques that enrich for N- or C-terminal peptides from proteomes are indispensable for a comprehensive understanding of a protein's function in biological environments since protease cleavage frequently results in altered protein activity and localization. Proteases often process other proteases and protease inhibitors which perturbs proteolytic networks and potentiates the initial cleavage event to affect other molecular networks and cellular processes in physiological and pathological conditions. This review is aimed at researchers with a keen interest in state of the art systems level positional proteomic approaches that: (i) enable the study of complex protease-protease, protease-inhibitor and protease-substrate crosstalk and networks; (ii) allow the identification of proteolytic signatures as candidate disease biomarkers; and (iii) are expected to fill the Human Proteome Project missing proteins gap. We predict that these methodologies will be an integral part of emerging precision medicine initiatives that aim to customize healthcare, converting reactive medicine into a personalized and proactive approach, improving clinical care and maximizing patient health and wellbeing, while decreasing health costs by eliminating ineffective therapies, trial-and-error prescribing, and adverse drug effects. Such initiatives require quantitative and functional proteome profiling and dynamic disease biomarkers in addition to current pharmacogenomics approaches. With proteases at the pathogenic center of many diseases, high-throughput protein termini identification techniques such as TAILS (Terminal Amine Isotopic Labeling of Substrates) and COFRADIC (COmbined FRActional DIagonal Chromatography) will be fundamental for individual and comprehensive assessment of health and disease.

PMID: 26542287 [PubMed - indexed for MEDLINE]

Intravenous immunoglobulin, pharmacogenomics, and Kawasaki disease.

J Microbiol Immunol Infect. 2016 Feb;49(1):1-7

Authors: Kuo HC, Hsu YW, Wu MS, Chien SC, Liu SF, Chang WC

Abstract
Kawasaki disease (KD) is a systemic vasculitis of unknown etiology and it is therefore worth examining the multifactorial interaction of genes and environmental factors. Targeted genetic association and genome-wide association studies have helped to provide a better understanding of KD from infection to the immune-related response. Findings in the past decade have contributed to a major breakthrough in the genetics of KD, with the identification of several genomic regions linked to the pathogenesis of KD, including ITPKC, CD40, BLK, and FCGR2A. This review focuses on the factors associated with the genetic polymorphisms of KD and the pharmacogenomics of the response to treatment in patients with intravenous immunoglobulin resistance.

PMID: 25556045 [PubMed - indexed for MEDLINE]

Economic Evaluation of a Pharmacogenomics Test for Statin-Induced Myopathy in Cardiovascular High-Risk Patients Initiating a Statin.

Mol Diagn Ther. 2016 Oct 31;

Authors: Mitchell D, Guertin JR, Iliza AC, Fanton-Aita F, LeLorier J

Abstract
BACKGROUND: Statins are the mainstay hypercholesterolemia treatment and reduce the risk of cardiovascular events in patients. However, statin therapy is often interrupted in patients experiencing musculoskeletal pain or myopathy, which are common in this patient group. Currently, the standard tests for diagnosing statin myopathies are difficult to interpret. A pharmacogenomics (PGx) test to diagnose statin-induced myopathy would be highly desirable.
METHODS: We developed a Markov state model to assess the cost-effectiveness of a hypothetical PGx test, which aims to identify statin-induced myopathy in high-risk, secondary prevention cardiovascular patients. The alternative strategy hypothesized is that physicians or patients interrupt the statin therapy in the presence of musculoskeletal pain. Our model includes health states specific to the PGx test outcome which assesses the impact of test errors.
RESULTS: Assuming a perfect test, the results indicate that the PGx test strategy dominates when the test costs less than CAN$356, when the strategy is cost neutral. These results are robust to deterministic and probabilistic sensitivity analyses.
CONCLUSION: Our base-case results show that a PGx test for statin-induced myopathy in a high-risk, secondary prevention of a cardiovascular event population would be a dominant solution for a test cost of CAN$356 or less. Furthermore, the modelling of the complete range of diagnostic test outcomes provide a broader understanding of the economic value of the pharmacogenomics test.

PMID: 27798813 [PubMed - as supplied by publisher]

Genomic sequencing of uric acid metabolizing and clearing genes in relationship to xanthine oxidase inhibitor dose.

Rheumatol Int. 2016 Oct 31;

Authors: Carroll MB, Smith DM, Shaak TL

Abstract
It remains unclear why the dose of xanthine oxidase inhibitors (XOI) allopurinol or febuxostat varies among patients though they reach similar serum uric acid (SUA) goal. We pursued genomic sequencing of XOI metabolism and clearance genes to identify single-nucleotide polymorphisms (SNPs) relate to differences in XOI dose. Subjects with a diagnosis of Gout based on the 1977 American College of Rheumatology Classification Criteria for the disorder, who were on stable doses of a XOI, and who were at their goal SUA level, were enrolled. The primary outcome was relationship between SNPs in any of these genes to XOI dose. The secondary outcome was relationship between SNPs and change in pre- and post-treatment SUA. We enrolled 100 subjects. The average patient age was 68.6 ± 10.6 years old. Over 80% were men and 77% were Caucasian. One SNP was associated with a higher XOI dose: rs75995567 (p = 0.031). Two SNPs were associated with 300 mg daily of allopurinol: rs11678615 (p = 0.022) and rs3731722 on Aldehyde Oxidase (AO) (His1297Arg) (p = 0.001). Two SNPs were associated with a lower dose of allopurinol: rs1884725 (p = 0.033) and rs34650714 (p = 0.006). For the secondary outcome, rs13415401 was the only SNP related to a smaller mean SUA change. Ten SNPs were identified with a larger change in SUA. Though multiple SNPs were identified in the primary and secondary outcomes of this study, rs3731722 is known to alter catalytic function for some aldehyde oxidase substrates.

PMID: 27798726 [PubMed - as supplied by publisher]

Pharmacogenomic study using bio- and nanobioelectrochemistry: Drug-DNA interaction.

Mater Sci Eng C Mater Biol Appl. 2016 Apr 1;61:1002-17

Authors: Hasanzadeh M, Shadjou N

Abstract
Small molecules that bind genomic DNA have proven that they can be effective anticancer, antibiotic and antiviral therapeutic agents that affect the well-being of millions of people worldwide. Drug-DNA interaction affects DNA replication and division; causes strand breaks, and mutations. Therefore, the investigation of drug-DNA interaction is needed to understand the mechanism of drug action as well as in designing DNA-targeted drugs. On the other hand, the interaction between DNA and drugs can cause chemical and conformational modifications and, thus, variation of the electrochemical properties of nucleobases. For this purpose, electrochemical methods/biosensors can be used toward detection of drug-DNA interactions. The present paper reviews the drug-DNA interactions, their types and applications of electrochemical techniques used to study interactions between DNA and drugs or small ligand molecules that are potentially of pharmaceutical interest. The results are used to determine drug binding sites and sequence preference, as well as conformational changes due to drug-DNA interactions. Also, the intention of this review is to give an overview of the present state of the drug-DNA interaction cognition. The applications of electrochemical techniques for investigation of drug-DNA interaction were reviewed and we have discussed the type of qualitative or quantitative information that can be obtained from the use of each technique.

PMID: 26838928 [PubMed - indexed for MEDLINE]

Individualization of antiretroviral therapy--pharmacogenomic aspect.

Indian J Med Res. 2015 Dec;142(6):663-74

Authors: Dalal B, Shankarkumar A, Ghosh K

Abstract
Combination therapy with three drug regimens for human immunodeficiency virus (HIV) infection significantly suppresses the viral replication. However, this therapeutic impact is restricted by adverse drug events and response in terms of short and long term efficacy. There are multiple factors involved in different responses to antiretrovirals (ARVs) such as age, body weight, disease status, diet and heredity. Pharmacogenomics deals with individual genetic make-up and its role in drug efficacy and toxicity. In depth genetic research has provided evidence to predict the risk of developing certain toxicities for which personalized screening and surveillance protocols may be developed to prevent side effects. Here we describe the use of pharmacogenomics for optimal use of HAART (highly active antiretroviral therapy).

PMID: 26831415 [PubMed - indexed for MEDLINE]

Advances in the Pharmacogenomics of Adverse Drug Reactions.

Drug Saf. 2016 Jan;39(1):15-27

Authors: Collins SL, Carr DF, Pirmohamed M

Abstract
Rapid developments in pharmacogenomics have been noticeable in recent years, and much of this knowledge has improved understanding of adverse drug reactions. This improved knowledge has largely been the result of improved sequencing technologies and falling costs in this area, as well as improved statistical techniques to analyse the data derived from studies. While the genetic reasons behind adverse drug reactions are becoming better understood, translation of this knowledge, particularly in terms of biomarkers that might be clinically applicable at the bedside, has been more difficult. Understanding of the technologies and their application is limited among practising clinicians. The cost of some of the technologies available may also be prohibitive in stretched healthcare economies. As education about the potential for applying pharmacogenomics improves and costs fall, understanding of adverse drug reactions and application of this knowledge in a clinical setting should improve.

PMID: 26650062 [PubMed - indexed for MEDLINE]

Influence of CYP3A5 genetic variation on everolimus maintenance dosing after cardiac transplantation.

Clin Transplant. 2015 Dec;29(12):1213-20

Authors: Lesche D, Sigurdardottir V, Setoud R, Englberger L, Fiedler GM, Largiadèr CR, Mohacsi P, Sistonen J

Abstract
BACKGROUND: Everolimus (ERL) has become an alternative to calcineurin inhibitors (CNIs) due to its renal-sparing properties, especially in heart transplant (HTx) recipients with kidney dysfunction. However, ERL dosing is challenging due to its narrow therapeutic window combined with high interindividual pharmacokinetic variability. Our aim was to evaluate the effect of clinical and genetic factors on ERL dosing in a pilot cohort of 37 HTx recipients.
METHODS: Variants in CYP3A5, CYP3A4, CYP2C8, POR, NR1I2, and ABCB1 were genotyped, and clinical data were retrieved from patient charts.
RESULTS: While ERL trough concentration (C0 ) was within the targeted range for most patients, over 30-fold variability in the dose-adjusted ERL C0 was observed. Regression analysis revealed a significant effect of the non-functional CYP3A5*3 variant on the dose-adjusted ERL C0 (p = 0.031). ERL dose requirement was 0.02 mg/kg/d higher in patients with CYP3A5*1/*3 genotype compared to patients with CYP3A5*3/*3 to reach the targeted C0 (p = 0.041). ERL therapy substantially improved estimated glomerular filtration rate (28.6 ± 6.6 mL/min/1.73 m(2)) in patients with baseline kidney dysfunction.
CONCLUSION: Everolimus pharmacokinetics in HTx recipients is highly variable. Our preliminary data on patients on a CNI-free therapy regimen suggest that CYP3A5 genetic variation may contribute to this variability.

PMID: 26458301 [PubMed - indexed for MEDLINE]

The R900S mutation in CACNA1S associated with hypokalemic periodic paralysis.

Neuromuscul Disord. 2015 Dec;25(12):955-8

Authors: Ke Q, He F, Lu L, Yu P, Jiang Y, Weng C, Huang H, Yi X, Qi M

Abstract
Primary hypokalemic periodic paralysis is an autosomal dominant skeletal muscle channelopathy. In the present study, we investigated the genotype and phenotype of a Chinese hypokalemic periodic paralysis family. We used whole-exome next-generation sequencing to identify a mutation in the calcium channel, voltage-dependent, L type, alpha subunit gene (CACNA1S), R900S, which is a rare mutation associated with hypokalemic periodic paralysis. We first present a clinical description of hypokalemic periodic paralysis patients harboring CACNA1SR900S mutations: they were non-responsive to acetazolamide, but combined treatment with triamterene and potassium supplements decreased the frequency of muscle weakness attacks. All male carriers of the R900S mutation experienced such attacks, but all three female carriers were asymptomatic. This study provides further evidence for the phenotypic variation and pharmacogenomics of hypokalemic periodic paralysis.

PMID: 26433613 [PubMed - indexed for MEDLINE]

The pharmacokinetic and pharmacodynamic interaction of clopidogrel and cilostazol in relation to CYP2C19 and CYP3A5 genotypes.

Br J Clin Pharmacol. 2016 Feb;81(2):301-12

Authors: Kim HS, Lim Y, Oh M, Ghim JL, Kim EY, Kim DH, Shin JG

Abstract
AIM: The primary objective of the present study was to evaluate the pharmacokinetic and pharmacodynamic interactions between clopidogrel and cilostazol in relation to the CYP2C19 and CYP3A5 genotypes.
METHODS: In a randomized, three-way crossover study, 27 healthy subjects were administered clopidogrel (300 mg), cilostazol (100 mg) or clopidogrel + cilostazol orally. Plasma concentrations of clopidogrel, cilostazol and their active metabolites (clopidogrel thiol metabolite, 3,4-dehydrocilostazol and 4″-trans-hydroxycilostazol), and adenosine diphosphate-induced platelet aggregation were measured for pharmacokinetic and pharmacodynamic assessment.
RESULTS: The area under the plasma concentration-time curve (AUC) of the active thiol metabolite of clopidogrel was highest in the CYP2C19 extensive metabolizers (EM) and lowest in the poor metabolizers (PM). Cilostazol decreased the thiol metabolite AUC by 29% in the CYP3A5*1/*3 genotype [geometric mean ratio (GMR) 0.71; 90% confidence interval (CI) 0.58, 0.86; P = 0.020] but not in the CYP3A5*3/*3 genotype (GMR 0.93; 90% CI 0.80, 1.10; P = 0.446). Known effects of the CYP2C19 and CYP3A5 genotypes on the exposure of cilostazol and its metabolites were observed but there was no significant difference in the AUC of cilostazol and 3,4-dehydrocilostazol between cilostazol and clopidogrel + cilostazol. The inhibition of platelet aggregation from 4 h to 24 h (IPA4-24 ) following the administration of clopidogrel alone was highest in the CYP2C19 EM genotype and lowest in the CYP2C19 PM genotype (59.05 ± 18.95 vs. 36.74 ± 13.26, P = 0.023). However, the IPA of the CYP2C19 PM following co-administration of clopidogrel and cilostazol was comparable with that of the CYP2C19 EM and intermediate metabolizers (IM) only in CYP3A5*3/*3 subjects.
CONCLUSIONS: The additive antiplatelet effect of cilostazol plus clopidogrel is maximized in subjects with both the CYP2C19 PM and CYP3A5*3/*3 genotypes because of a lack of change of clopidogrel thiol metabolite exposure in CYP3A5*3/*3 as well as the highest cilostazol IPA in CYP2C19 PM and CYP3A5*3/*3 subjects.

PMID: 26426352 [PubMed - indexed for MEDLINE]

Recent Advances and Emerging Applications in Text and Data Mining for Biomedical Discovery.

Brief Bioinform. 2016 Jan;17(1):33-42

Authors: Gonzalez GH, Tahsin T, Goodale BC, Greene AC, Greene CS

Abstract
Precision medicine will revolutionize the way we treat and prevent disease. A major barrier to the implementation of precision medicine that clinicians and translational scientists face is understanding the underlying mechanisms of disease. We are starting to address this challenge through automatic approaches for information extraction, representation and analysis. Recent advances in text and data mining have been applied to a broad spectrum of key biomedical questions in genomics, pharmacogenomics and other fields. We present an overview of the fundamental methods for text and data mining, as well as recent advances and emerging applications toward precision medicine.

PMID: 26420781 [PubMed - indexed for MEDLINE]

Pharmacogenetics and ethnicity: relevance for clinical implementation, clinical trials, pharmacovigilance and drug regulation in Latin America.

Pharmacogenomics. 2016 Oct 28;

Authors: Sosa-Macías M, Teran E, Waters W, Fors MM, Altamirano C, Jung-Cook H, Galaviz-Hernández C, López-López M, Remírez D, Moya GE, Hernández F, Fariñas H, Ramírez R, Céspedes-Garro C, Tarazona-Santos E, LLerena A

Abstract
Congress of Pharmacogenetics and Personalized Medicine. Ethnicity, clinical implementation and regulatory environment (MESTIFAR 2016 Quito). Quito, Ecuador, 19-21 May 2016. The Ibero-American Network of Pharmacogenetics and Pharmacogenomics (RIBEF) was created in 2006 with the main aim of promoting personalized medicine and collaborative pharmacogenetics research in Spanish- and Portuguese-speaking countries in America and the Iberian Peninsula. The final goal of this initiative was the inclusion of Latin American populations that may benefit from the implementation of personalized medicine in drug therapy. Several initiatives have been promoted including the MESTIFAR project, which aimed to analyze the ethnicity, genotype and/or metabolic phenotype in Ibero-American populations. To date, 6060 healthy volunteers have been analyzed; among them, 2571 were admixed, 1824 were Caucasians, 1395 were Native Americans, 174 were Jews and 96 were Afro-descendants. Due to the large genetic variability within Latin Americans, ethnicity may be a relevant factor for the clinical implementation of personalized medicine. Moreover, the present status of clinical implementation and the future perspectives of pharmacogenetics, pharmacovigilance and clinical trials for drug regulation in Latin America compared with the EMA-Pharmacogenomics Working Party and the US FDA initiatives were analyzed.

PMID: 27790935 [PubMed - as supplied by publisher]

The path to implementation of personalized medicine of aromatase inhibitors in patients with breast cancer.

Pharmacogenomics. 2016 Oct 28;

Authors: Liu X, Beith J, Low SK, Boddy AV

PMID: 27790931 [PubMed - as supplied by publisher]

Pharmacogenomics education and research at the Department of Pharmacy, University of Patras, Greece.

Pharmacogenomics. 2016 Oct 28;

Authors: Patrinos GP, Katsila T

Abstract
The Pharmacogenomics and Personalized Medicine group belongs to the Laboratory of Molecular Biology and Immunology, Department of Pharmacy and is active since 2009 mainly in the field of pharmacogenomics and personalized medicine. Herein, we describe the research interests, collaborations and accomplishments of the Pharmacogenomics and Personalized Medicine group together with the teaching activities of the group that greatly enhance the pharmacogenomics knowledge of graduate/postgraduate students and healthcare professionals.

PMID: 27790924 [PubMed - as supplied by publisher]

Pharmacogenomics of inhaled corticosteroids and leukotriene modifiers: A systematic review.

Clin Exp Allergy. 2016 Oct 27;:

Authors: Farzan N, Vijverberg SJ, Arets HG, Raaijmakers JA, Maitland-van der Zee AH

Abstract
BACKGROUND: Pharmacogenetics studies of anti-inflammatory medication of asthma have expanded rapidly in recent decades, but the clinical value of their findings remain limited.
OBJECTIVE: To perform a systematic review of pharmacogenomics and pharmacogenetics of inhaled corticosteroids (ICS) and leukotriene modifiers (LTMs) in asthmatic patients.
METHODS: Articles published between 1999 and June 2015 were searched using PubMed and Embase. Pharmacogenomics/genetics studies of asthmatic patients using ICS or LTMs were included if ≥1 of the following outcomes were studied: lung function, exacerbation rates or asthma symptoms. The studies of SNPs that had been replicated at least once were assessed in more detail.
RESULTS: In total, 59 publications were included in the systematic review: 26 addressed LTMs (including two Genome-Wide Association Studies [GWAS]) and 33 addressed ICS (including four GWAS). None of the GWAS reported similar results. Furthermore, none of the SNPs assessed in candidate gene studies were identified in a GWAS. No consistent reports were found for candidate gene studies of LTMs. In candidate gene studies of ICS, the most consistent results were found for rs28364072 in FCER2. This Single Nucleotide Polymorphism [SNP] was associated with all three outcomes of poor response and the largest effect was reported with the risk of exacerbations (hazard ratio, 3.95; 95% CI, 1.64-9.51).
CONCLUSION & CLINICAL RELEVANCE: There is a lack of replication of genetic variants associated with poor ICS or LTM response. The most consistent results were found for the FCER2 gene (encoding for a low affinity IgE receptor (CD23)) and poor ICS response. Larger studies with well phenotyped patients are needed to assess the clinical applicability of ICS and LTM pharmacogenomics/genetics. This article is protected by copyright. All rights reserved.

PMID: 27790783 [PubMed - as supplied by publisher]

Pharmacogenomics to achieve precision medicine.

Am J Health Syst Pharm. 2016 Oct 26;:

Authors: Empey PE

PMID: 27784662 [PubMed - as supplied by publisher]

The Impact of Methylenetetrahydrofolate Reductase C677T Polymorphism on Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation with Methotrexate Prophylaxis.

PLoS One. 2016;11(10):e0163998

Authors: Byun JM, Kim HL, Shin DY, Koh Y, Yoon SS, Seong MW, Park SS, Kim JH, Lee YG, Kim I

Abstract
Pharmacogenomics can explain the inter-individual differences in response to drugs, including methotrexate (MTX) used for acute graft-versus-host disease (aGVHD) prophylaxis during hematopoietic stem cell transplantation (HSCT). In real-world practice, preplanned MTX dose is arbitrarily modified according to observed toxicity which can lead to unexpected and severe aGVHD development. We aimed to validate the influence of MTHFR C677T polymorphism on the outcomes of allogenic HSCT in a relatively under-represented homogenous Asian population. A total of 177 patients were divided into 677TT group versus 677C-carriers (677CT+677CC), and clinical outcomes along with baseline characteristics were analyzed and compared. Although there was a tendency towards increased peak liver function test results and accordingly greater delta values between the highest and the baseline in 677TT group, we found no associations between genotypes and hepatotoxicity. However, the incidence of acute liver GVHD (≥ grade 2) was significantly higher in the 677TT group than in the 677CC + 677CT group (P = 0.016). A total of 25 patients (14.1%) expired due to transplantation related mortality (TRM) during the first 180 days after HSCT. Patients carrying 677TT genotype were more likely to experience early TRM than 677C-carriers. The same pattern was observed in the cumulative TRM rate, and 677TT genotype patients were more prone to cumulative TRM (P = 0.010). This translated into shorter OS for patients with 677TT compared to 677C-carriers (P = 0.010). The 3-year survival after HSCT was 29.9% for 677TT cases and 47.1% for 677C-carriers. The multivariate analysis identified 677TT genotype (HR = 1.775. 95% CI 1.122-2.808, P = 0.014) and non-CR state (HR = 2.841. 95% CI 1.627-4.960, P<0.001) as predictors for survival. In conclusion, the MTHFR 677TT genotype appears to be associated with acute liver GVHD, and represent a risk factor for TRM and survival in patients undergoing HSCT with MTX as GVHD prophylaxis.

PMID: 27783703 [PubMed - in process]