Sarah Cargnin

DPYD IVS14+1G>A and 2846A>T genotyping for the prediction of severe fluoropyrimidine-related toxicity: a meta-analysis

AIM In the present study we conducted a systematic review and meta-analysis of published data to quantify the impact of the DPYD IVS14+1G>A and 2846A>T variants on the risk of fluoropyrimidine-related toxicities and to determine sensitivity and specificity testing for DPYD variants. METHODS Relevant studies were identified through PubMed and Web of Knowledge databases, studies included were those published up until to May 2012. Study quality was assessed according to the HuGENET guidelines and Strengthening the Reporting of Genetic Association (STREGA) recommendations. RESULTS Random-effects meta-analysis provided evidence that carriers of DPYD IVS14+1G>A are at higher risk of ≥3 degrees of overall grade toxicity, hematological toxicity, mucositis and diarrhea. In addition, a strong association was also found between carriers of the DPYD 2846T allele and overall grade ≥3 toxicity or grade ≥3 diarrhea. An inverse linear relationship was found in prospective studies between the odds ratio of DPYD IVS14+1G>A and the incidence of overall grade ≥3 toxicity, indicating an higher impact in cohorts in which the incidence of severe toxicity was lower. CONCLUSION The results of this meta-analysis confirm clinical validity of DPYD IVS14+1G>A and 2846A>T as risk factors for the development of severe toxicities following fluoropyrimidine treatment. Furthermore, the sensitivity and specificity estimates obtained could be useful in establishing the cost-effectiveness of testing for DPYD variants.

An opposite-direction modulation of the COMT Val158Met polymorphism on the clinical response to intrathecal morphine and triptans.

UNLABELLED Genetic variation in the COMT gene is thought to have clinical implications for pain perception and pain treatment. In the present study, we first evaluated the association between COMT rs4680 and the analgesic response to intrathecal morphine in patients with chronic low back pain to provide confirmation of previously reported positive findings. Next, we assessed the relationship between rs4680 and headache response to triptans in 2 independent cohorts of migraine patients. In patients with chronic low back pain (n = 74), logistic stepwise regression analysis showed that age (odds ratio [OR]: .90, 95% confidence interval [CI]: .85-.96, P = .002) and the presence of the COMT Met allele (vs Val/Val, OR: .21, 95% CI: .04-.98, P = .048) were predictive factors for lower risk of poor analgesic response to intrathecal morphine. Intriguingly, in migraine patients, the COMT rs4680 polymorphism influenced headache response to triptans in the opposite direction. Indeed, in an exploratory cohort of migraine patients without aura (n = 75), homozygous carriers of the COMT 158Met allele were found at increased risk to be poor responders to frovatriptan when compared to homozygous patients for the Val allele (OR: 5.20, 95% CI: 1.25-21.57, P = .023). In the validation cohort of migraine patients treated with triptans other than frovatriptan (n = 123), logistic stepwise regression analysis showed that use of prophylactic medications (OR: .43, 95% CI: .19-.99, P = .048) and COMT Met/Met genotype (vs Val/Val, OR: 4.29, 95% CI: 1.10-16.71, P = .036) were independent risk factors for poor response to triptans. PERSPECTIVE This study highlights the importance of COMT rs4680 in influencing the clinical response to drugs used for chronic pain, including opioid analgesics and triptans. These findings also underline a complex relationship between COMT genotypes and pain responder status.

Diagnostic accuracy of HLA-B*57:01 screening for the prediction of abacavir hypersensitivity and clinical utility of the test: a meta-analytic review

AIM To determine diagnostic accuracy of HLA-B*57:01 testing for prediction of abacavir-induced hypersensitivity and to quantify the clinical benefit of pretreatment screening through a meta-analytic review of published studies. METHODS A comprehensive search was performed up to June 2013. The methodological quality of relevant studies was assessed by the QUADAS-2 tool. The pooled diagnostic estimates were calculated using a random effect model. RESULTS Despite the presence of heterogeneity in sensitivity or specificity estimates, the pooled diagnostic odds ratio to detect abacavir-induced hypersensitivity on the basis of clinical criteria was 33.07 (95% CI: 22.33-48.97, I(2): 13.9%), while diagnostic odds ratio for detection of immunologically confirmed abacavir hypersensitivity was 1141 (95% CI: 409-3181, I(2): 0%). Pooled analysis of risk ratio showed that prospective HLA-B*57:01 testing significantly reduced the incidence of abacavir-induced hypersensitivity. CONCLUSION This meta-analysis demonstrates an excellent diagnostic accuracy of HLA-B*57:01 testing to detect immunologically confirmed abacavir hypersensitivity and corroborates existing recommendations.

Genetic determinants of chronic oxaliplatin-induced peripheral neurotoxicity: a genome-wide study replication and meta-analysis

We aimed at validating the role of genetic variants identified by a recent genome‐wide association study (GWAS) as determinants of chronic oxaliplatin‐induced peripheral neurotoxicity (OXAIPN). Eight polymorphisms (rs10486003, rs2338, rs843748, rs797519, rs4936453, rs12023000, rs17140129, and rs6924717) were genotyped in a total of 150 colorectal cancer patients of Caucasian origin receiving oxaliplatin‐based chemotherapy. The severity grade of chronic OXAIPN was assessed by NCI‐CTC criteria and the clinical version of the Total Neuropathy Score© (TNSc©). None of the polymorphisms investigated was found associated with grade ≥ 2 chronic OXAIPN (NCI‐CTC criteria), while a nominal association emerged for ACYP2 rs843748 when using the TNSc© scale (dominant model: odds ratio [OR]: 0.27, 95% confidence interval [CI]: 0.10–0.75, P = 0.008). In the combined analysis of this results with data of the two previously published studies which assessed chronic OXAIPN by NCI‐CTC criteria, evidence suggestive of association with chronic OXAIPN (NCI‐CTC criteria) was found for ACYP2 rs843748 (dominant model: OR: 2.40, 95%CI: 1.40–5.24, P = 0.027), which, however, did not remain significant after correction for multiple testing (threshold P‐value <0.00625). These findings suggest a minor role of the single nucleotide polymorphisms (SNPs) investigated as genetic determinants of chronic OXAIPN. These results also highlight the importance of replication studies with meta‐analysis for validation of GWAS findings.

Lack of association between GRIA1 polymorphisms and haplotypes with migraine without aura or response to triptans

The present study was designed to replicate previous findings reporting a significant association between the rs548294 polymorphism at the glutamate receptor subunit GluR1 gene (GRIA1) and migraine without aura, either as a single marker or in haplotype combination with rs2195450. In addition, the role of GRIA1 polymorphisms and haplotypes was evaluated in migraine patients without aura as predictive factors for consistency in headache response to triptans. Analysis of rs548294 and rs2195450 polymorphisms of GRIA1 was conducted by Real-time PCR allelic discrimination assay in 186 migraine patients without aura and 312 healthy controls, respectively. In the logistic regression analysis adjusted for gender and age, genotype and haplotype frequencies for the two polymorphisms did not significantly differ between migraine patients without aura and controls. In addition, no evidence of association was found between GRIA1 polymorphisms/haplotypes and consistent response to triptans. This study failed to replicate previously reported association between GRIA1 rs548294 and migraine without aura, either as single marker or when analyzed in haplotype combination with rs2195450. In addition, no evidence was found for a relevant role of GRIA1 polymorphisms and haplotypes as modulating factors of headache response to triptans.

Association of RAMP1 rs7590387 With the Risk of Migraine Transformation Into Medication Overuse Headache

We herein investigated the role of polymorphisms in calcitonin gene‐related peptide (CGRP)‐related genes looking at the association of rs3781719 (T > C) in the calcitonin gene‐related polypeptide‐alpha (CALCA) gene and of rs3754701 (T > A) and rs7590387 (C > G) at the receptor activity modifying 1 (RAMP1) locus with triptan response in patients with migraine without aura (MwoA). In addition, their role was evaluated as risk factors for transformation of episodic migraine into medication overuse headache (MOH). The CGRP has a central role in the pathogenesis of migraine; however, little information is currently available concerning the role of polymorphisms in CGRP‐related genes as determinants of clinical response to anti‐migraine drugs or as risk factors for migraine chronification.

Triptan use in Italy: Insights from administrative databases.

Introduction In this drug utilization study, we aimed at assessing the pattern of triptan use in Italy by means of the drug prescription databases of two local health authorities, accounting for approximately 1 million citizens. Methods The study population included all residents aged 18 to 84 years in the Vercelli province (about 175,000 inhabitants) and in the Umbria region (about 885,000 inhabitants), who had at least one dispensation for triptans in 2012. A frequent user, who might be at risk of medication-overuse headache (MOH), was defined as a patient being dispensed at least 10 defined daily doses (DDD) of triptans every month for at least three consecutive months. Results Triptans were used by 0.7%–1% of the population. While most patients were dispensed fewer than 60 DDDs per year, about 10% of all triptan users were classified as frequent users. In both areas, patients below the age of 29 were less likely to be frequent users while the 40- to 49-year-old population was the most affected, with no sex difference. About two-thirds of frequent users persisted in this behavior for an additional three-month period in the following six months. Conclusions Our data indicate that approximately 10% of all triptan users in the Italian population are potentially at risk for MOH. An approach based on drug prescription databases could be useful to identify patients at risk for MOH.

Pharmacogenomics of episodic migraine: time has come for a step forward

Migraine is characterized by heterogeneous behavior in response to drugs. Many resources have been invested in attempting to unravel the genetic basis of migraine, while the role of genetics in responses to currently available drugs has received less attention. We performed a systematic literature search identifying original articles pertaining to pharmacogenomics of episodic migraine. Few primary studies on the pharmacogenomics of symptomatic and preventive medication in episodic migraine were found. The number of patients studied in the individual articles ranged from 40 up to 130. There was a strong heterogeneity among these studies. We believe that pharmacogenomics studies, if properly designed, could contribute towards optimizing the treatment and reducing the burden of migraine, in turn helping patients and optimizing resources. Our knowledge on the pharmacogenomics of migraine is growing too slowly, and concerted measures should be undertaken to speed up the process.

Quantitative Analysis of Circulating Cell-Free DNA for Correlation with Lung Cancer Survival: A Systematic Review and Meta-Analysis

Introduction: Despite the growing interest in circulating cell‐free DNA (cfDNA), no conclusive evidence exists on the value of quantitative analysis of cfDNA for the prediction of lung cancer survival. We performed a systematic review and meta‐analysis of primary studies to estimate the impact of higher baseline cfDNA levels on survival outcomes of patients with lung cancer. Methods: A comprehensive search was performed using the PubMed, Web of Knowledge, and Cochrane databases up to March 2016. The methodologic quality of identified studies was assessed by the Newcastle‐Ottawa scale. Potential sources of heterogeneity were investigated via subgroup and sensitivity analyses, while publication bias was evaluated by funnel plot and Eggers test. Results: Among the 17 studies identified, 16 studies (n = 1723 patients) and 5 studies (n = 640) were included in the meta‐analysis of overall survival (OS) and progression‐free survival (PFS), respectively. Despite the fact that the association with PFS did not reach statistical significance (hazard ratio 1.12% [95% confidence interval 0.91–1.37), the pooled analysis for OS showed evidence of an increased risk of death in patients with higher baseline cfDNA levels (hazard ratio 1.76 [95% confidence interval 1.38–2.25]; p < 0.001). Further subgroup and sensitivity analyses confirmed this relationship, although significant between‐study heterogeneity was still detected in most comparisons. The Eggers test revealed no statistical evidence of publication bias in the results. Conclusion: Our findings support the clinical validity of quantitative analysis of cfDNA for the prediction of lung cancer survival. Nevertheless, the establishment of a robust standardized method for determination of optimal cutoff thresholds is required to define the clinical relevance of cfDNA quantification for lung cancer management.

The Role of TCF7L2 rs7903146 in Diabetes After Kidney Transplant: Results From a Single-Center Cohort and Meta-Analysis of the Literature.

Background Several genetic polymorphisms modulate the risk of posttransplant diabetes mellitus (PTDM), a complication associated with an increased morbidity and mortality after kidney transplantation; however, their clinical utility is still undefined. Methods Genetic analysis was performed in 464 kidney transplantation recipients to evaluate whether transcription factor 7-like 2 (TCF7L2) rs7903146 gene polymorphism is associated with the risk of PTDM and a meta-analysis of similar studies including our results was performed (total kidney transplantation recipients, n = 3105). A predictive model of PTDM was built on the basis of this polymorphism and clinical parameters. Results In our cohort, 163 patients possessed the CC genotype of rs7903146 (35.1%), 237 were CT (51.1%), and 64 were TT (13.8%): their 2 years PTDM incidence was, respectively, 7.8%, 11.9%, and 22.7%. At multivariate analysis, age (per year; hazard ratio [HR], 1.029; 95% confidence interval [95% CI], 1.005-1.054; P = 0.017), body mass index (25.0-29.9 vs <25.0; HR, 2.43; 95% CI, 1.40-4.23; P = 0.0018; ≥30 vs <25.0; HR, 5.70; 95% CI, 2.77-11.74; P < 0.0001), TCF7L2 rs7903146 (per each T allele; HR, 1.81; 95% CI, 1.26-2.59; P = 0.001) and previous transplants (HR, 2.80; 95% CI, 1.39-5.64; P = 0.004) emerged as independent predictive factors for PTDM. Meta-analysis of present and 5 previous studies showed higher risk of PTDM in carriers of rs7903146 TT genotype (odds ratio, 1.95; 95% CI, 1.39-2.74; P < 0.0001) and absence of heterogeneity among studies (I2 = 0%). Inclusion of this polymorphism in a predictive model appeared to improve its ability to stratify patients according to the risk of PTDM. Conclusions In renal transplant patients, TCF7L2 rs7903146 is strongly and independently associated with PTDM and might hold the potential to identify patients at risk for this complication.