Pharmacogenetics of opioids: a narrative review

Advances in the field of pharmacogenomics have resulted in the discovery of some important single-nucleotide polymorphisms which are found to be associated with opioid dose variability. This, to a large extent, explains genetic variability in the analgesic dose of opioids. These polymorphisms are found in various areas relevant to pain perception, including the nociceptive and antinociceptive pathways, drug receptors, drug-metabolising enzymes and drug efflux molecules. An in-depth knowledge of single-nucleotide polymorphisms can help clinicians to address interindividual variability in opioid dosing and requirements. In the era of precision medicine, these genetic markers can also help us to design prognostic tools to accurately predict the analgesic dose of opioids.     

Germline prognostic markers for urinary bladder cancer: obstacles and opportunities

Urinary bladder cancer is a heterogeneous disease with diverse genetic and environmental risk factors that can influence disease risk or clinical course for recurrence, progression, and survival. Therefore, identification of these factors is paramount for disease prevention and optimal clinical management of bladder cancer patients. Of particular interest is the need to identify molecular biomarkers that can give accurate assessment of tumor biological potential and to predict treatment response. Recent advances in molecular biology, cytogenetic, and genomic research have spurred discovery efforts for novel genetic, epigenetic, and proteomic biomarkers that are prognostic for cancer. This review focuses on some of the important germ line polymorphisms found to be correlated with clinical outcomes in bladder cancer. So far, most of the identified candidate loci were based on prior knowledge of pathogenesis and had not been validated for clinical applications. The future challenges are to analyze the wealth of information from whole-genome studies, to understand the underlying biological mechanisms of these associations, the network of gene-gene and gene-environment interactions, and to apply these markers for the identification of high-risk population for targeted, personalized therapy.     

Genome-wide association studies in kidney transplantation: Advantages and constraints

Since the discovery of the human leukocyte antigen (HLA) system, the role of HLA molecules in the field of transplantation has been appreciated: better matching leads to better graft function. Since then, the association of other genetic polymorphisms with clinical outcome has been investigated in many studies. Genome-wide association studies (GWAS) represent a powerful tool to identify causal genetic variants, by simultaneously analyzing millions of single nucleotide polymorphisms scattered across the genome. GWAS in transplantation may indeed be useful to reveal novel markers that may potentially be involved in the mechanism of allograft rejection and graft failure. However, the relevance of GWAS for risk stratification or donor selection for an individual patient is limited as is already reflected by the fact that many parameters, significant in one study, cannot be confirmed in another one.     

Clinical Impact of Polymorphisms of Transport Proteins and Enzymes Involved in the Metabolism of Immunosuppressive Drugs

Individualization of immunosuppressive therapy after solid organ transplantation is a goal that has been pursued for a long time. Nevertheless, in clinical practice, we are still stratifying patients in subgroups in which risk is assessed using demographic information and population analysis. Then, a combination of immunosuppressive drugs is chosen and doses are individualized to compensate for intra- and interindividual variabilities in drug pharmacokinetics, to obtain similar plasma/blood concentrations that are believed to be therapeutic, again based on data derived from population analysis. One step further in this strategy is to recognize, before initiation of immunotherapy, those patients at higher risk to be either under- or overexposed to currently used immunosuppressive drugs. Several studies have been undertaken to correlate single nucleotide polymorphisms in genes encoding transport proteins and metabolizing enzymes involved in the disposition of immunosuppressive drugs. Overall, the results from these studies have been mixed. The causes of these sometimes conflicting results include methodologic, genetic, or nongenetic factors. The degree of linkage disequilibrium, the measure of nonrandom associations between polymorphisms at different loci, not necessarily on the same chromosome, is perhaps the main genetic factor. The influence of the environment, physiology (such as kidney and liver functions), disease state, use of multidrug regimens, and inherent drug-to-drug interactions are present nongenetic factors. Moreover, it is also important to increase our knowledge of the genetic factors involved in the variabilities observed in drug responses of pharmacodynamics. True individualized therapy, with the ability to improve health outcomes of each transplant recipient, will depend on our knowledge of the genetic factors involved in immunological response and drug pharmacokinetics and pharmacodynamics.     

Impact of Human Leukocyte Antigen Molecules E,F, and G on the Outcome of Transplantation

BackgroundHLA class I molecules are divided into classic (Ia) and nonclassic (Ib). Nonclassic HLA molecules (E, F, and G) have acquired relevance owing to their immunomodulatory properties and possible repercussions for induction of tolerance in organ transplantation. The objective of this study was to identify the impact of these molecules on transplant success or failure.MethodsA systematic review of literature was performed with the use of MeSH terms in Pubmed. Clinical trials, randomized clinical trials, case-control studies, and reviews from the past 15 years were included.ResultsHLA-E*0103/E*0103 genotype is associated with lower risk of graft-versus-host disease, decreased mortality, and greater disease-free survival after bone marrow transplantation. There were no significant associations between HLA-F and clinical outcomes in any of the studies. Elevated serum levels of HLA-G were associated with a lower incidence of rejection in hepatic and renal transplantation during the 1st year and lower T-cell response after bone marrow, liver, and kidney transplantation. Detection of mRNA of HLA-G1 was also associated with less graft rejection.ConclusionsCurrent literature suggests that nonclassic HLA Ib molecules play an important role in immunotolerance in organ transplantation; however, more studies are required to predict outcomes related to specific genotypes.     

Genetic polymorphisms and bronchiolitis obliterans syndrome after lung transplantation: promising results and recommendations for the future

Survival rates after lung transplantation are the lowest among solid organ transplantations. Long-term survival is limited by the development of chronic rejection, known as bronchiolitis obliterans syndrome (BOS). Risk factors, such as acute rejection and cytomegalovirus infection, contribute to the development of BOS. However, these risk factors alone do not explain the interindividual variability seen in the development of BOS. There is growing evidence that genetic variations might contribute to an individual's susceptibility to rejection. In this systematic review, based on a literature search through Medline and Embase, an overview is given of the genetic polymorphisms that have been investigated in lung transplant recipients in relation to the devlopment of BOS. Functional genetic polymorphisms in the genes of IFNG (+874 A/T), TGFB1 (+915 G/C), and IL6 (-174 G/C) have been found to be associated with the development of BOS and allograft fibrosis after lung transplantation. However, confirmation was not consistent across all studied cohorts. Genetic polymorphisms in the genes of several Toll-like receptors, mannose-binding lectin, CD14, killer immunoglobulin-like receptors, and matrix metalloproteinase-7 were also found to be associated with the development of BOS, but these studies need to be replicated in independent cohorts. This review shows that there may be involvement of genetic polymorphisms in the development of BOS. Genetic risk profiling of lung transplant recipients could be a promising approach for the future, enabling individualized risk stratification and personalized immunosuppressive treatment after transplantation. Further studies are needed to define risk alleles.     

Polymorphisms in the myeloperoxidase gene locus are associated with acute kidney injury-related outcomes

Myeloperoxidase (MPO) is a lysosomal enzyme that may be involved in oxidative stress-mediated kidney injury. Using a two-step approach, we measured the association of four polymorphisms across the length of the MPO gene with systemic markers of oxidative stress: plasma MPO and urinary 15-F(2t)-isoprostane levels. Adverse outcomes were measured in a primary cohort of 262 adults hospitalized with acute kidney injury, and a secondary cohort of 277 adults undergoing cardiac surgery with cardiopulmonary bypass and at risk for postoperative acute kidney injury. Dominant and haplotype multivariable logistic regression analyses found a genotype-phenotype association in the primary cohort between rs2243828, rs7208693, rs2071409, and rs2759 MPO polymorphisms and both markers of oxidative stress. In adjusted analyses, all four polymorphic allele groups had 2-3-fold higher odds for composite outcomes of dialysis or in-hospital death or a composite of dialysis, assisted mechanical ventilation, or in-hospital death. The MPO T-G-A-T haplotype copy-number was associated with lower plasma MPO levels and lower adjusted odds for the composite outcomes. Significant but less consistent associations were found in the secondary cohort. In summary, our two-step genetic association study identified several polymorphisms spanning the entire MPO gene locus and a common haplotype marker for patients at risk for acute kidney injury.     

Analysis of IL-6, IL-10 and IL-17 genetic polymorphisms as risk factors for sepsis development in burned patients

Infection risk, sepsis and mortality after severe burn are primarily determined by patient age, burn size, and depth. Whether genetic differences contribute to otherwise unexpected variability in outcomes is unknown. We sought to determine whether there was an association between IL-6, IL-10 and IL-17 polymorphisms with cytokine production and development of sepsis. We evaluated 71 patients with burns ≥15% TBSA and 109 healthy subjects. The genotypes of IL-6 (-174C/G), IL-10 (-819C/T and -1082A/G) and IL-17 (7488T/C) polymorphisms were identified applying polymerase chain reaction protocols. The cytokine levels in serum were determined with enzyme-linked immunoabsorbent assays. Our results demonstrated no significant differences in the genotype frequencies studied between burn patients and healthy subjects. No significant associations were found among IL-6 and IL-17F genotypes and the related cytokine serum levels. Only IL-10 promoter -1082GG genotype was related to an increased IL-10 production in burned patients. In addition, septic subjects bearing -1082G/G genotype have shown the highest and non-septic bearing -1082A/* genotypes the lowest IL-10 serum levels. All together these data seem to indicate that genetically determined individual difference in IL-10 production might influence the susceptibility to septic complications in burned patients and suggest that these markers might be useful in burned patient management.     

The Elephant in the Room: Failings of Current Clinical Endpoints in Kidney Transplantation

In this opinion piece, we address the limitations of the two most common clinical endpoints in kidney transplantation trials (acute rejection and renal function) and attempt to offer a reasonable framework by which to find true and reliable early endpoints that reflect long‐term outcomes. Other potential endpoints tested in recent years, including the use of genomic and proteomic markers are still in development. Until other reliable endpoints are established, it is important to understand what can be inferred from ongoing studies that utilize these endpoints and what further information we need to derive ‘true’ surrogate endpoints. We consider evaluation of current markers using the ‘Prentice criteria’, which bases assessment of endpoints as true surrogates on four primary rules. Based on our assessment, progress in understanding the safety and efficacy of new therapies and interventions in kidney transplantation will remain limited with current makers. Prospectively, we advocate: (i) significant caution in extrapolating long‐term outcomes from currently utilized clinical markers, (ii) use of traditional hard endpoints whenever feasible and (iii) dedication of efforts for more data collection on specific disease entities and greater diligence in determining the onset of deleterious processes.     

Role of genetic variability in the renin-angiotensin system in diabetic and nondiabetic renal disease.

Studies on genetic variability in the renin-angiotensin system (RAS) provide intriguing data that support its possible relevance to renal pathophysiology. However, from the discrepancies between different studies it is clear that RAS polymorphisms do not provide simple markers for renal prognosis or therapy response. Rather than attempting to force a conclusion from the available discrepancies, we should attempt to develop strategies from the current state of knowledge to attack this complex issue from different angles. Unraveling their functional impact in renal pathophysiology can provide a framework for understanding that can guide further studies with the eventual purpose of improving the prognosis of renal patients. Clinical association studies should be large and prospective, to obtain the necessary robustness, with proper attention paid to the role of contextual factors. Moreover, studies elucidating the physiologic mechanisms of the genetic determinants of the disease phenotype are of prime importance. Such information is vital, not only to make sense of observed associations, but all the more so if one wants to apply the insights on the role of genetic factors into better strategies for disease intervention.     

Genetic polymorphisms in peroxisome proliferator-activated receptor delta associated with obesity

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors regulating the expression of genes involved in lipid and glucose metabolism. Three different PPARs, PPAR-alpha, -gamma, and -delta, have been characterized, and they are distinguished from each other by tissue distribution and cell activation. All PPARs are, to different extents, activated by fatty acids and derivatives. Recently, it has been shown that PPAR-delta serves as a widespread regulator of fat burning, suggesting that it might be a potential target in the treatment of obesity and type 2 diabetes. In an effort to identify polymorphic markers in potential candidate genes for type 2 diabetes, we have sequenced PPAR-delta, including -1,500 bp of the 5' flanking region. Nine polymorphisms were identified in PPAR-delta: four in the intron, one in the 5' untranslated region (UTR), and four in the 3' UTR. Among identified polymorphisms, five common sites, including c.-13454G>T, c.-87T>C, c.2022+12G>A, c.2629T>C, and c.2806C>G, were genotyped in subjects with type 2 diabetes and normal control subjects (n = 702). The genetic associations with the risk of type 2 diabetes and metabolic phenotype were analyzed. No significant associations with the risk of type 2 diabetes were detected. However, several positive associations of PPAR-delta polymorphisms with fasting plasma glucose and BMI were detected in nondiabetic control subjects. The genetic information about PPAR-delta from this study would be useful for further genetic study of obesity, diabetes, and other metabolic diseases.     

Interleukin-6 and interferon-gamma gene polymorphisms in the development of bronchiolitis obliterans syndrome after lung transplantation

BACKGROUND: A number of genetic polymorphisms have been shown to regulate the production and secretion of tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1, interferon (IFN)-gamma, interleukin (IL)-6, and IL-10. Several of these genetic polymorphisms have been shown to be associated with either acute or chronic rejection of kidney, liver, and heart allografts and with development of allograft fibrosis after lung transplantation. The aim of this study was to assess the effect of these genetic polymorphisms on the development of bronchiolitis obliterans syndrome (BOS) after lung transplantation. METHODS: Genetic polymorphisms were detected by means of polymerase chain reaction in 93 lung allograft recipients for functional polymorphisms in the TNF-alpha (-308), TGF-beta1 (+869 and +915), IL-6 (-174), IFN-gamma (+874), and IL-10 (-1082, -819, and -592) genes. Then, a correlation between BOS development and the presence of these cytokine genotypes was determined using Kaplan-Meier actuarial analysis. RESULTS: A significant correlation was detected between the presence of high-expression polymorphisms of the IL-6 and IFN-gamma genes and BOS development after lung transplantation (P =0.045 and 0.039, respectively). Also, patients with high-expression polymorphisms in both genes developed BOS significantly earlier than patients with low-expression polymorphisms in one or both genes, suggesting a synergistic effect of the alleles during BOS pathogenesis (P =0.016). No correlation was detected between polymorphisms of the TNF-alpha, TGF-beta1, and IL-10 genes and development of BOS after lung transplantation. CONCLUSIONS: The presence of high-expression polymorphisms at position -174 of the IL-6 gene and position +874 of the IFN-gamma gene significantly increases the risk for BOS development after lung transplantation.     

MicroRNAs as Biomarkers in Solid Organ Transplantation

Important progress has been made in improving short‐term outcomes in solid organ transplantation. However, long‐term outcomes have not improved during the last decades. There is a critical need for biomarkers of donor quality, early diagnosis of graft injury and treatment response. MicroRNAs (miRNAs) are a class of small single‐stranded noncoding RNAs that function through translational repression of specific target mRNAs. MiRNA expression has been associated with different diseases and physiological conditions. Moreover, miRNAs have been detected in different biological fluids and these circulating miRNAs can distinguish diseased individuals from healthy controls. The noninvasive nature of circulating miRNA detection, their disease specificity and the availability of accurate techniques for detecting and monitoring these molecules has encouraged a pursuit of miRNA biomarker research and the evaluation of specific applications in the transplant field. miRNA expression might develop as excellent biomarkers of allograft injury and function. In this minireview, we summarize the main accomplishments of recently published reports focused on the identification of miRNAs as biomarkers in organ quality, ischemia‐reperfusion injury, acute rejection, tolerance and chronic allograft dysfunction emphasizing their mechanistic and clinical potential applications and describing their methodological limitations.     

Review of nonimmunological causes for deteriorated graft function and graft loss after transplantation.

Various factors determine the graft- and patient survival after transplantation. HLA-matching and immunological factors are of importance for the short- and long-term survival. Apart from these obvious determinants, nonimmunological factors play an important role in defining the baseline organ quality as well as the recipients' status. The influence of these parameters on graft- and patient survival is still underestimated and is a topic of debate. On account of the increasing acceptance of marginal-donor organs these events are of increasing importance for graft survival and long-term function. We review nonimmunological causes for deteriorated graft function and graft loss after solid organ transplantation.     

Recipient gene polymorphisms in the Th-1 cytokines IL-2 and IFN-gamma in relation to acute rejection and graft vascular disease after clinical heart transplantation

IL-2 and IFN-gamma are associated with acute rejection (AR) and graft vascular disease (GVD) after clinical heart transplantation. Polymorphisms in the genes of IL-2 (T-330G in the promoter) and IFN-gamma (CA repeat in the first intron) influence the production levels of these cytokines. Therefore, these polymorphisms might have an effect on the outcome after transplantation. To investigate possible effects of genetic variations in IL-2 and IFN-gamma genes on AR and GVD, we analyzed the IL-2 T-330G and the IFN-gamma CA repeat polymorphism in DNA of 301 heart transplant recipients. No associations were found for allele or genotype distributions between patients with or without AR (IL-2 allele frequency: P=0.44, genotype distribution: P=0.46; IFN-gamma allele frequency P=0.10, genotype distribution 12 repeats allele: P=0.21). Also, no associations were found analyzing the number (0 vs. 1 vs. >or=1) of AR (IL-2 allele frequency: P=0.59; genotype distribution: P=0.37; IFN-gamma allele frequency: P=0.27, genotype distribution 12 repeats allele: P=0.41) or analyzing the polymorphisms in patients with AR within the first month or thereafter (IL-2 allele frequency: P=0.45, genotype distribution: P=0.38; IFN-gamma allele frequency: P=0.21, genotype distribution 12 repeats allele: P=0.41). Analyzing both polymorphisms in relation to GVD, resulted in comparable allele and genotype distributions (IL-2 allele frequency: P=0.75; genotype distribution: P=0.77; IFN-gamma allele frequency: P=0.70, genotype distribution 12 repeats allele: P=0.63). In conclusion, we did not detect an association between the IL-2 T-330G promoter polymorphism and CA repeat polymorphism in the first intron of the IFN-gamma gene and AR or GVD after heart transplantation.     

Pharmacogenetics in solid organ transplantation: current status and future directions

Tailoring of immunosuppressive drug therapy to the specific requirements of the individual patient to optimize efficacy and minimize toxicity remains one of the biggest challenges in solid organ transplantation. Pharmacogenetic and pharmacogenomic research, studying the effects of genetic polymorphisms on drug disposition and action, holds promise to produce useful clinical tools for individualizing immunosuppressive therapy. In the past years, many interesting studies have been reported, assessing the impact of single nucleotide polymorphisms of genes encoding drug metabolizing enzymes, drug transporters and—to lesser extent—pharmacological target molecules, on pharmacokinetics and pharmacodynamics of immunosuppressive drugs like tacrolimus, cyclosporine, sirolimus, mycophenolic acid, and corticosteroids. Currently, we still are in the early phases of this exciting research, and the question whether pharmacogenetic profiling will eventually become a useful clinical tool remains to be answered.     

非HLA基因多态性与异基因造血干细胞移植后并发症发生

越来越多的研究表明,非HLA的基因多态性可能在预测异基因造血干细胞移植后移植物抗宿主病、生存和感染等方面有着重要意义。本综述总结了IL-1基因家族、IL-2基因家族、IL-6基因、IL-10基因、TGF-β基因、TNF基因、维生素D受体基因、髓过氧化物酶基因、Fcγ受体基因、甘露糖结合凝集素基因、NOD2/CARD15基因、MTHFR基因、P2X7基因、HFE基因等基因多态性与造血干细胞移植相关性的最新研究结果 。     

Lack of association between thrombosis-associated and cytokine candidate gene polymorphisms and acute rejection or vascular complications after kidney transplantation.

BACKGROUND: Acute rejection episodes and vascular complications are common after renal transplantation and have negative impact on the long-term patient and graft survival. We investigated whether the risks of acute rejection, thrombosis, infarction and graft loss could be predicted based on the presence of functional polymorphisms in the genes of the coagulation and endothelial inflammation cascade. METHODS: The study consisted of 772 consecutive cadaver kidney transplantations from a single centre. The effects of gene polymorphisms FVL, F5R2, FII G20210A, MTHFR C677T, F13A1 V34L, TFPI P151L, PROC W380G, TNF G(-308)A, IL10 A(-592)C, IL10 A(-1082)G and IL6 C(-174)G of recipients and donors were investigated. RESULTS: We were unable to find statistically significant associations between any of the studied polymorphisms and clinical outcomes. CONCLUSIONS: Our results indicate that high-risk renal transplant candidates cannot be identified through the routine analysis of the polymorphisms.     

Use of DNA restriction fragment length polymorphisms to document marrow engraftment and mixed hematopoietic chimerism following bone marrow transplantation

We have studied the feasibility of using DNA restriction fragment-length polymorphisms (RFLP) to study marrow engraftment in 27 patients after allogeneic bone marrow transplantation, and have compared these results with those obtained using red blood cell antigens, cytogenetics, and immunoglobulin allotypes. Using highly polymorphic DNA probes, we have documented stable chronic mixed hematopoietic chimerism, have identified transient mixed chimeras, have excluded mixed chimerism with high probability in retrospective studies even when a pretransplant DNA sample was not available, have documented marrow engraftment in the early posttransplant period, and have studied the origin of leukemic cells in patients with recurrent disease. We have evaluated the advantages and disadvantages of several genetic markers and have developed tentative statements concerning the prognosis of patients with mixed chimerism. We conclude that DNA RFLP are powerful and practical genetic markers in bone marrow transplantation studies and that further studies of mixed hematopoietic chimerism are warranted.     

Polymorphisms in cytotoxic T lymphocyte associated antigen-4 influence the rate of acute rejection after renal transplantation in 167 Chinese recipients

Gene polymorphisms of cytotoxic T lymphocyte associated antigen 4 (CTLA4) play an influential role in the graft rejection and long-term clinical outcome of organ transplantation. We investigated the associations of five CTLA4 single nucleotide polymorphisms (SNPs) (rs733618T/C, rs4553808A/G, rs5742909C/T, rs231775G/A, rs3087243G/A) on the early acute rejection (AR) of Chinese deceased donor renal transplantation recipients. Genotyping of the CTLA4 SNPs was performed in 167 deceased donor renal transplantation recipients. Each patient underwent a 6-month follow-up observation for AR. The incidence of AR during the 6 months post-transplantation was 26.9% (45 out of 167 patients). Patients experiencing AR were found to have a higher frequency of the rs733618TT genotype and T allele (p=0.000 and p=0.002, respectively). While the haplotype CACAG was merely observed in non-AR group (corrected p=0.000), the frequency of haplotype TACGG was significantly higher in AR group than in non-AR group even after 50,000 permutation tests (corrected p=0.018). In conclusion, these polymorphisms statistically significantly associated with acute renal allograft rejection may be considered as a risk factor of AR in Chinese renal transplantation recipients except for haplotype CACAG as a protective one.