Single and combined IL28B, ITPA and SLC28A3 host genetic markers modulating response to anti-hepatitis C therapy

Advances in hepatitis C pharmacogenomics identified modulations of a sustained virologic response (SVR) by frequent IL28B gene variants and of ribavirin-induced hemolysis by frequent ITPA gene variants. These associations have been widely reproduced in various ethnicities, clinical settings and hepatitis C viral genotypes. The IL28B minor alleles rs8099917G, rs12979860T and rs12980275G have been associated with non-SVR whereas the ITPA minor alleles rs1127354A and rs7270101C were associated with less hemolytic side effects, an effect also attributed to a nucleoside transporter gene SLC28A3 rs10868138G/rs56350726T haplotype. The significance levels of these associations, especially in genome-wide studies, were very high. We nevertheless tested how good clinical outcomes of peginterferon α/ribavirin therapy, such as SVR or hemolytic side effects, were predicted by these variants. An analysis in an example dataset of 115 patients revealed that the prediction of non-SVR or hemolysis by single variants was often only slightly better than guessing. Using combinations of IL28B variants provided a higher accuracy (64.5%) of predicting non-SVR than with single IL28B variants (accuracy 60-63%). Similarly, a decline in blood hemoglobin by ≥3 g/dl could be better predicted at an accuracy of 70% (10% better than guessing) with a combination of an ITPA variant with a nucleoside transporter gene (SLC28A3) haplotype. Thus, genotyping information about single IL28B or ITPA variants is reproducibly and statistically significantly associated with hepatitis C therapy outcomes; however, the clinical predictive utility of single variants can be increased by combinations of genotypes.     

Case‐control pharmacogenetic study of HCN1/HCN2 variants and genetic generalized epilepsies

Epilepsy is a common complex neurological disorder, and some forms are resistant to drug treatment. The HCN1/HCN2 genes encode hyperpolarization‐activated cyclic nucleotide‐gated channels, which play important roles in the electrophysiology of neurons. We investigated the association between HCN1/HCN2 variants and drug resistance or the risk of genetic generalized epilepsies (GGEs). We used matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry to assess nine variants of HCN1/HCN2 in 284 healthy participants and 483 GGEs (279 drug‐responsive, 204 drug‐resistant). Frequencies of HCN2 rs7255568 and rs3752158 G alleles differed in GGEs and in controls (P = .039, P = .027, respectively). The frequency of HCN2 haplotype (CAC) was higher in patients than controls (P = .046). The frequency of the HCN1 rs10462087 CC+CT genotype was lower in patients with childhood absence epilepsy (CAE) than controls (P = .047). Rs7255568 was associated with the risk of CAE (P = .028) and juvenile myoclonic epilepsy (JME) (P = .02). Rs3752158 was associated with the risk of generalized tonic‐clonic seizures, JME, and febrile seizures (all P < .05). The frequency of the HCN2 haplotype (CAC) was higher in patients with JME (P = .015) and in those with febrile seizures (P = .024) than in controls. No significant association was found between HCN1/HCN2 alleles, genotypes or haplotypes, and drug resistance in patients. After Bonferroni's multiple comparisons correction, only the HCN2 rs3752158 C allele and GC+CC genotype frequencies in patients with JME were higher than those in controls (19.2% vs 11.6%, odds ratio (OR) = 1.71, 95% CI = 1.18‐2.32), P = .004 < 0.05/9; 36% vs 22.2%, OR = 1.62(1.18‐2.23), P = .003 < 0.05/9). Our study suggests that HCN2 rs3752158 is involved in the susceptibility to JME.     

Lack of association between genetic polymorphisms of CYP3A4, CYP2C9 and CYP2C19 and antituberculosis drug‐induced liver injury in a community‐based Chinese population

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Liraglutide treatment improves endothelial function in the Ldlr−/− mouse model of atherosclerosis and affects genes involved in vascular remodelling and inflammation

Recent clinical intervention studies have shown that the GLP1 analogue liraglutide lowers cardiovascular risk, but the underlying mechanism has not yet been fully elucidated. This study investigated the effects of liraglutide on endothelial function in the Ldlr?/? mouse model. Mice (n = 12/group) were fed Western diet (WD) or chow for 12 weeks followed by 4 weeks of treatment with liraglutide (1 mg/kg/day) or vehicle subcutaneously. Weight loss, blood lipid content, plaque burden, vasomotor function of the aorta and gene expression pattern in aorta and brachiocephalic artery were monitored. Liraglutide treatment significantly induced weight loss (P < .0001), decreased blood triglycerides (P < .0001) and total cholesterol (P < .0001) in WD‐fed mice but did not decrease plaque burden. Liraglutide also improved endothelium‐mediated dilation of the distal thoracis aorta (P = .0067), but it did not affect phenylephrine or sodium nitroprusside responses. Fluidigm analyses of 96 genes showed significantly altered expression of seven genes related to inflammation, vascular smooth muscle cells and extracellular matrix composition in liraglutide‐treated animals. We conclude that treatment with liraglutide decreased endothelial dysfunction and that this could be linked to decreased inflammation or regulation of vascular remodelling.     

Association between genetic polymorphisms of SLCO1B1 and susceptibility to methimazole‐induced liver injury

Methimazole (MMI) has been used in the therapy of Grave's disease (GD) since 1954, and drug‐induced liver injury (DILI) is one of the most deleterious side effects. Genetic polymorphisms of drug‐metabolizing enzymes and drug transporters have been associated with drug‐induced hepatotoxicity in many cases. The aim of this study was to investigate genetic susceptibility of the drug‐metabolizing enzymes and drug transporters to the MMI‐DILI. A total of 44 GD patients with MMI‐DILI and 118 GD patients without MMI‐DILI development were included in the study. Thirty‐three single nucleotide polymorphisms (SNPs) in twenty candidate genes were genotyped. We found that rs12422149 of SLCO2B1, rs2032582_AT of ABCB1, rs2306283 of SLCO1B1 and rs4148323 of UGT1A1 exhibited a significant association with MMI‐DILI; however, no significant difference existed after Bonferroni correction. Haplotype analysis showed that the frequency of SLCO1B1*1a (388A521T) was significantly higher in MMI‐DILI cases than that in the control group (OR = 2.21, 95% CI = 1.11‐4.39, P = 0.023), while the frequency of SLCO1B1*1b (388G521T) was significantly higher in the control group (OR = 0.52, 95% CI = 0.29‐0.93, P = 0.028). These results suggested that genetic polymorphisms of SLCO1B1 were associated with susceptibility to MMI‐DILI. The genetic polymorphism of SLCO1B1 may be important predisposing factors for MMI‐induced hepatotoxicity.     

KCNJ11 E23K variant is associated with the therapeutic effect of sulphonylureas in Chinese type 2 diabetic patients

The aim of the present study was to investigate the effect of the E23K variant of the potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ11) gene on gliclazide modified release (MR) treatment in newly diagnosed patients with type 2 diabetes mellitus (T2DM). A total of 108 diabetic patients with no history of antidiabetic medication was treated with gliclazide MR for 16 weeks and underwent follow up at Weeks 2, 4, 8, 12 and 16. All patients were genotyped for KCNJ11 E23K (rs5219). At baseline, patients with the KK genotype had higher blood glucose and lower serum insulin levels after oral glucose administration than patients with the EE and EK genotypes (P < 0.05 for all). During treatment, individuals with the KK genotype had lower fasting glucose levels and were more likely to attain the target fasting glucose level (P_{log rank} = 0.028) than E allele carriers. Patients with the KK genotype had larger augmentations in changes (Δ) in acute insulin response (P = 0.049) and Δ body mass index (P = 0.003). Moreover, patients with the EK genotype had a lower variance in changes in fasting insulin levels (P = 0.049) and homeostasis model assessment of β‐cell function (P = 0.021) than those with the KK genotype. The findings of the present study suggest that the KCNJ11 E23K variant is associated with a greater effect of sulphonylurea treatment in newly diagnosed Chinese patients with T2DM.     

Identification of Damaging nsSNVs in HumanERCC2 Gene

The hERCC2 gene is an important DNA repair molecule for initiating Cutaneous melanoma (CM). Therefore, it is advisable to study the possible functional SNVs in hERCC2. To achieve this goal, we collected total 2, 253 SNVs in hERCC2from the EMBL website, of which 303 are non‐synonymous single nucleotide variants (nsSNVs). Then, SIFT and PolyPhen were used to predict the damaging nsSNVs, and four nsSNVs (rs368866996, rs377739017, rs370819591, and rs121913022) were suggested to be damaging mutations. Since I‐Mutant2.0 showed a decrease in stability for the mutants containing each of the four nsSNVs, a 3D protein structure was modeled. Based on the comparison of the energy after minimization, RMSD and stabilizing residues between the native and mutant proteins' structure, rs121913022 was proposed to be the most damaging variant among the nsSNVs in hERCC2 gene by decreasing the stability of protein. The mutant G713R of hERCC2 protein caused by rs121913022 was found to have less expression level than native hERCC2 protein in melanoma cells. These results suggest that rs121913022 may have potentially important clinical and drug target implications.     

GSTA1*‐69C/T and GSTO2*N142D as asthma‐ and allergy‐related risk factors in Italian adult patients

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Resveratrol and vitamin E rescue valproic acid‐induced teratogenicity: The mechanism of action

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Docetaxel–Chitosan nanoparticles for breast cancer treatment: cell viability and gene expression study

Docetaxel acts through the inhibition of tubulin polymerization and reduction in the expression of BCL‐2 gene. In this study, nanoparticles containing Docetaxel were prepared and their effects on the gene expression levels of BCL‐2 and BAX genes were investigated. The drug was first conjugated to chitosan, and the nanoparticles were assembled in the presence of hyaluronic acid. Conjugations were confirmed by ¹H‐NMR, and the obtained nanoparticles were characterized by dynamic light scattering and SEM. Cytotoxicity of the nanoparticles, cellular uptake, and cell death were evaluated. Finally, the effect of nanoparticles on the expression of BAX and BCL‐2 genes in MCF‐7 cells were investigated through real‐time PCR. The results revealed that the prepared NPs had spherical shape with narrow size distribution of <200 nm with positive zeta potentials. In vitro cytotoxicity of Cs nanoparticles and free Docetaxel investigations revealed that increasing the treatment time with nanoparticles led to decrease in the rate of cell viability. BAX and BCL‐2 gene expressions were decreased in nanoparticle‐treated cells in comparison with intact cells, while the BAX/BCL‐2 ratio was significantly elevated compared with free drug‐treated cells after 72 h. Docetaxel‐conjugated NPs may offer a promising treatment with low off‐target toxicity for breast cancer.     

Enhanced adherence to HCV therapy with higher dose ribavirin formulation: final analyses from the ADHERE registry

Aliment Pharmacol Ther 2010; 32: 535–542

Summary

Background Poor adherence to Hepatitis C virus (HCV) treatment is an important cause of treatment failure. Traditional ribavirin 200 mg (RBV) treatment is associated with a significant daily pill burden. RibaPak (RBP), available as 400 mg and 600 mg ribavirin tablets, offers simplified dosing at two pills daily. Aim To examine whether improved adherence was associated with RBP vs. RBV. Methods Accurate Dosing in Hepatitis C: Examining the RibaPak Experience (ADHERE) was a U.S., multi‐centre, prospective registry capturing data on adherence with RBP vs. RBV in adults with HCV. Adherence was measured by the proportion of subjects remaining on treatment at weeks 4, 12 and 24; by pill counts; and by the proportion of subjects who took ≥80% of their prescribed dose. Results A total of 503 patients (RBP = 346, RBV = 157) from 33 sites were included. A greater proportion of RBV vs. RBP subjects prematurely discontinued treatment. At 12 and 24 weeks, a greater proportion of RBP vs. RBV subjects took ≥80% of their prescribed doses (P < 0.05). For patients who remained on treatment, the mean milligrams missed per day was significantly greater for RBV vs. RBP at 24 weeks. Conclusions First line treatment with RBP may offer the best prospect for less discontinuation and improved treatment adherence.     

Association of HMGB1 and HMGB2 genetic polymorphisms with lung cancer chemotherapy response

The aim of the present study was to investigate the association of genetic polymorphisms in high mobility group box 1 and 2 (HMGB1 and HMGB2, respectively) with platinum‐based chemotherapy responses in Chinese lung cancer patients. In total, 338 Chinese lung cancer patients (154 responders and 184 non‐responders) were recruited to the study. All patients received at least two cycles of first‐line platinum‐based chemotherapy. Three tagging single nucleotide polymorphisms (SNPs) of HMGB1 and two tagging SNPs of HMGB2 were detected in patients. We found that rs1412125 and rs2249825 of HMGB1 were significantly associated with the platinum‐based chemotherapy response in both recessive and genotypic models. In addition, rs1412125 showed significant association with platinum‐based chemotherapy response for the subgroup of patients aged >55 years in additive, recessive and genotypic models. No significant associations were detected between other SNPs and the platinum‐based chemotherapy response. The HMGB1 SNPs (rs1412125 and rs2249825) were associated with platinum‐based chemotherapy responses in Chinese lung cancer patients. In conclusion, HMGB1 SNPs may serve as potential biomarkers for predicting the efficacy of platinum‐based chemotherapy.     

Ledipasvir–Sofosbuvir: A Once‐Daily Oral Treatment Option for Chronic Hepatitis C Virus Genotype 1 Infection

Chronic hepatitis C virus (HCV) genotype 1 historically has been the most difficult to treat HCV genotype, and patients infected with this genotype had been previously treated with interferon‐based therapy. In recent years, however, treatment options for chronic HCV infection have rapidly changed to an all‐oral regimen. Ledipasvir–sofosbuvir is an oral fixed‐dose (ledipasvir 90 mg–sofosbuvir 400 mg) combination of two direct‐acting antiviral drugs. Four phase 3 clinical trials (ION‐1–4) evaluated ledipasvir–sofosbuvir with and without ribavirin in patients with HCV genotype 1. High rates of sustained virologic response (SVR) occurred with ledipasvir–sofosbuvir alone in treatment‐naïve and treatment‐experienced patients without cirrhosis as well as in treatment‐naïve patients with cirrhosis when administered for 12 weeks. In treatment‐experienced patients with cirrhosis, 24 weeks of ledipasvir–sofosbuvir was also highly effective. Furthermore, treatment‐naïve patients without cirrhosis (particularly those with HCV RNA serum concentrations < 6 million IU/ml) can achieve a similar SVR with only 8 weeks of therapy. Similarly, in patients coinfected with human immunodeficiency virus and HCV genotype 1 who were treated with ledipasvir–sofosbuvir for 12 weeks, a high SVR was observed in those with and without cirrhosis as well as treatment‐naïve and treatment‐experienced patients. Ledipasvir–sofosbuvir is well tolerated, with fatigue, headache, nausea, diarrhea, and insomnia being the most common adverse effects, which are typically mild to moderate in nature. This combination antiviral can be taken with or without food. Key factors to consider when prescribing ledipasvir–sofosbuvir are drug interactions including those mediated by the P‐glycoprotein transporter and increased pH, cost of the drug or insurance coverage, comorbid conditions, and patient and provider preferences. Postmarketing experience and ongoing clinical trials will further define the safety and role of ledipasvir–sofosbuvir in the treatment of HCV genotype 1.     

CCND1‐BCL2 Gene Network: A direct target of Amifostine in human acute megakaryocytic leukemia cells

Amifostine, 2‐(3‐aminopropyl) aminoethyl phosphorothioate, is a broad‐spectrum cytoprotective agent used to treat nuclear radiation and chemical weapon injuries. Recently, amifostine has been shown to have a profound biological influence on tumor cells. To examine the effects and mechanisms underlying the effects of amifostine on human acute megakaryocytic leukemia, we evaluated the efficacy of amifostine against Dami cells and observed a cell cycle arrest in G₂/M phase. Amifostine treatment also induced cell apoptosis of Dami cells which corresponds to formal studies. Through whole‐genome microarray and bioinformatics analyses, we found that amifostine affected the gene expression of CCND1, BCL2, and CASP3 which revealed the mechanism amifostine acted on Dami cells. Thus, CCND1‐BCL2 Gene Network is predicted to be a direct target of amifostine treating human acute megakaryocytic leukemia, which may provide a novel potential target for the therapy of several subtypes of human AML.     

Mechanisms underlying the renoprotective effect of GABA against ischaemia/reperfusion‐induced renal injury in rats

Excitation of the renal sympathetic nervous system is important for the development of ischaemic acute kidney injury (AKI) in rats. We reported that intravenous treatment with GABA has preventive effects against ischaemia/reperfusion (I/R)‐induced renal dysfunction with histological damage in rats; however, the mechanisms underlying these effects on renal injury remain unknown. Thus, the aim of the present study was to clarify how GABA mechanistically affects ischaemic AKI in rats. Ischaemic AKI was induced in rats by clamping the left renal artery and vein for 45 min and then reperfusing the kidney to produce I/R‐induced injury. Treatment with the GABA_B receptor antagonist CGP52432 (100 nmol/kg, i.v., or 1 nmol/kg, i.c.v.) abolished the suppressive effects of 50 μmol/kg, i.v., GABA on enhanced renal sympathetic nerve activity (RSNA) during ischaemia, leading to elimination of the renoprotective effects of GABA. Intracerebroventricular treatment with 0.5 μmol/kg GABA or i.v. treatment with 1 μmol/kg baclofen, a selective GABA_B receptor agonist, prevented the I/R‐induced renal injury equivalent to i.v. treatment with GABA. Conversely, i.v. treatment with 10 μmol/kg bicuculline, a GABA_A receptor antagonist, failed to affect the preventive effects of GABA against ischaemic AKI. We therefore concluded that GABA_B receptor stimulation in the central nervous system, rather than peripheral GABA_B receptor stimulation, mediates the preventive effect of GABA against ischaemic AKI by suppressing the enhanced RSNA induced by renal ischaemia.     

Pharmacogenetics of Risperidone‐Induced Insulin Resistance in Children and Adolescents with Autism Spectrum Disorder

The purpose of this study was to explore the association of genetic polymorphism of genes related to pharmacokinetics or pharmacodynamics with insulin resistance in children and adolescents with autism spectrum disorder (ASD) and treated with risperidone. All 89 subjects underwent measurement of fasting blood glucose and insulin levels, body‐weight and height. Genotyping was performed by TaqMan real‐time polymerase chain reaction (PCR) (pharmacokinetics genes: cytochrome P450 2D6 (CYP2D6) *4 (rs3892097), *5 (gene deletion), *10 (rs1065852) and *41 (rs28371725), ATP‐binding cassette transporter B1 (ABCB1) 2677 G>T/A (rs2032582) and 3435C>T (rs1045642) and pharmacodynamics genes: dopamine receptor D2 (DRD2) Tag‐SNP (C>T) (rs4436578), DRD2 Tag1A (C>T) (rs1800497), leptin gene (LEP) ‐2548G>A (rs7799039), ghrelin gene (GHRL) ‐604G>A (rs27647) and brain‐derived neurotrophic factor (BDNF) 196G>A (rs6265)). Drug levels were analysed by liquid chromatography–tandem mass spectrometry (LC‐MS/MS). The results revealed that 5 (5.62%) patients presented with hyperglycaemia. Insulin resistance was detected in 15 (16.85%) patients. Insulin resistance was associated with LEP 2548 G>A and BDNF 196 G>A polymorphism (p = 0.051 and p = 0.03). There was no association of pharmacokinetic gene polymorphisms (CYP2D6 and ABCB1) and risperidone levels with insulin resistance. Multiple regression analysis indicated that BDNF 196 G>A polymorphism was significantly associated with insulin resistance (p = 0.025). This finding suggested that BDNF 196 G>A polymorphism may be a genetic marker for predicting insulin resistance before initiating treatment in patients treated with risperidone. Because of the small sample size, further studies are needed to confirm these results.     

Renal risk‐benefit determinants of recombinant human erythropoietin therapy in the remnant kidney rat model – hypertension,anaemia, inflammation and drug dose

Clinical studies showed that high doses of recombinant human erythropoietin (rHuEPO) used to correct anaemia in chronic kidney disease (CKD) hyporesponsive patients may lead to deleterious effects. The aim of this study was to analyze the effects of rHuEPO in doses usually used to correct CKD‐anaemia (100, 200 IU/kg body weight (BW) per week) and in higher doses used in the treatment of hyporesponsive patients (400, 600 IU/kg BW per week), focusing on renal damage, hypoxia, inflammation and fibrosis. Male Wistar rats with chronic renal failure (CRF) induced by 5/6 nephrectomy were treated with rHuEPO or with vehicle, over a 3‐week period. Haematological, biochemical and renal function analyses were performed. Kidney and liver mRNA levels were evaluated by quantitative real‐time polymerase chain reaction (qPCR) and protein expression by Western blot and immunohistochemistry. Kidney histopathological evaluations were also performed. The CRF group developed anaemia, hypertension and a high score of renal histopathologic lesions. Correction of anaemia was achieved with all rHuEPO doses, with improvement in hypertension, renal function and renal lesions. In addition, the higher rHuEPO doses also improved inflammation. Blood pressure was reduced in all rHuEPO‐treated groups, compared to the CRF group, but increased in a dose‐dependent manner. The current study showed that rHuEPO treatment corrected anaemia and improved urinary albumin excretion, particularly at lower doses. In addition, it is suggested that a short‐term treatment with high doses, used to overcome an episode of hyporesponsiveness to rHuEPO therapy, can present benefits by reducing inflammation, without worsening of renal lesions; however, the pro‐hypertensive effect should be considered, and carefully managed to avoid a negative cardiorenal impact.     

Successful Use of Ceftolozane‐Tazobactam to Treat a Pulmonary Exacerbation of Cystic Fibrosis Caused by Multidrug‐Resistant Pseudomonas aeruginosa

Ceftolozane‐tazobactam, a novel β‐lactam/β‐lactamase inhibitor, was recently approved for the treatment of complicated urinary tract and intraabdominal infections, as monotherapy and in combination with metronidazole, respectively. Ceftolozane‐tazobactam exhibits a wide spectrum of activity against both gram‐positive bacteria, gram‐negative bacteria including multidrug‐resistant (MDR) Pseudomonas aeruginosa, and some anaerobic bacteria. Although not currently approved for any pulmonary indication, studies have demonstrated excellent distribution to epithelial lining fluid, indicating that it may be an alternative agent to use in the treatment of respiratory tract infections caused by MDRP. aeruginosa. Unfortunately, data are lacking regarding the use of ceftolozane‐tazobactam in the treatment of respiratory tract infections including patients with cystic fibrosis (CF). We describe the first case report, to our knowledge, of a 25‐year‐old white man successfully treated with ceftolozane‐tazobactam for a pulmonary exacerbation of his CF caused by MDRP. aeruginosa. He was admitted for his fourth hospitalization in 7 months for a pulmonary exacerbation of his CF. After blood and sputum were cultured, prednisone, cefepime, inhaled tobramycin, and intravenous ciprofloxacin were started. On day 4, after no signs of clinical improvement, respiratory cultures revealed nonmucoid MDRP. aeruginosa, susceptible only to colistin. β‐Lactam therapy was subsequently changed to ceftolozane‐tazobactam 3 g intravenously every 8 hours while continuing ciprofloxacin and inhaled tobramycin. Ceftolozane‐tazobactam susceptibility was determined by the Etest method (minimum inhibitory concentration 1.5 μg/ml). By day 3 of therapy, the patient showed signs of clinical improvement and was discharged after completion of a 12‐day course of antibiotics. Until additional research is available, we hope this evidence will provide consideration of ceftolozane‐tazobactam for this novel off‐label indication.     

Effect of basic fibroblast growth factor (FGF2) gene polymorphisms on SSRIs treatment response and side effects

Antidepressant response usually appears in 2 to 4 weeks and 30–40% of patients do not show a significant response although biochemical changes of monoaminergic system occur within hours after administration. Genetic factors could play a role in this process and genes involved in synaptic plasticity and neurogenesis are possible candidates. In fact, antidepressants and electroconvulsive therapy increase basic fibroblast growth factor (FGF2) and the rs1449683C/T polymorphism within this gene has been found to be a predictor for both an elevated mRNA and protein level of FGF2. Therefore we examined the possible association of rs1449683C/T and a panel of tagging SNPs in SSRI efficacy and side effects in 144 Japanese major depressive subjects followed for 6 weeks. We observed a significant association of rs1449683T (p = 0.010) and rs308393C (p = 0.029) variant carriers toward a better response to SSRI and of rs1048201 with higher frequency of drop out due to side effects (p = 0.010), independently from clinical variables. Furthermore the rs308447T–rs308393C–rs1449683T haplotype was associated with higher response rate (p = 0.012) while the rs1048201T–rs3747676T haplotype was significantly associated with higher dropped out rate (p = 0.015). In conclusion, this is the first study investigating the association of antidepressant response and intolerance with FGF2 variants. This finding adds an important piece of information for the pathway of detecting the genetics of antidepressant response.