Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Human Leukocyte Antigen B (HLA-B) Genotype and Allopurinol Dosing: 2015 update

The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for HLA-B*58:01 Genotype and Allopurinol Dosing was originally published in February 2013. We reviewed the recent literature and concluded that none of the evidence would change the therapeutic recommendations in the original guideline; therefore, the original publication remains clinically current. However, we have updated the Supplemental Material and included additional resources for applying CPIC guidelines into the electronic health record. Up-to-date information can be found at PharmGKB (http://www.pharmgkb.org)

Higher-dose sitagliptin and the risk of congestive heart failure in older adults with CKD

Background and objectives Sitagliptin, a dipeptidylpeptidase-4 inhibitor, is commonlyprescribed to patientswith type 2 diabetes. As this drug is primarily eliminated by the kidney, a reduced dose is recommended for patients with CKD. Some evidence suggests that sitagliptin is associated with a higher risk of congestive heart failure, particularly at higher doses.Wecompare the 1-year risk of death or hospitalizationwith congestive heart failure in patients with CKD newly prescribed sitagliptin at \u3c50 versus ≤50 mg/d. Design, setting, participants, & measurements This population-based cohort study included older adults (\u3e66 years) with type 2 diabetes and an eGFR\u3c45 ml/min per 1.73 m2 (but not receiving dialysis) who were newly prescribed sitagliptin between 2010 and 2017 in Ontario, Canada. We used inverse probability of treatment weighting on the basis of propensity scores to balance baseline characteristics. The primary composite outcome was death or hospitalization with congestive heart failure. Secondary outcomes included hospitalization with pancreatitis or hypoglycemia, all-cause hospitalization, and glycemic control. Weighted hazard ratios were obtained using Cox proportional hazards regression, and 95%confidence intervalswere obtained using bootstrap variance estimators. Results Of 9215 patients, 6518 started sitagliptin at \u3e50 mg/d, and 2697 started sitagliptin at ≤50 mg/d. The 1-year risk of death or hospitalization with congestive heart failure did not differ significantly between groups (79 versus 126 events per 1000 person-years; weighted hazard ratio, 0.88; 95% confidence interval, 0.67 to 1.14); hospitalization with pancreatitis (weighted hazard ratio, 0.98; 95% confidence interval, 0.32 to 3.03) and hypoglycemia (weighted hazard ratio, 1.10; 95% confidence interval, 0.64 to 1.90) also did not differ significantly between groups. Patients starting sitagliptin at \u3e50 mg/d had lower mean glycated hemoglobin concentrations (weighted between-group difference, 20.12%; 95% confidence interval, 20.19 to 20.06) and a lower risk of allcause hospitalization (weighted hazard ratio, 0.81; 95% confidence interval, 0.66 to 0.98). Conclusions The risk of death or congestive heart failure was not higher in older adults with CKD starting sitagliptin at \u3e50 versus ≤50 mg/d

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

Response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably between patients. The International SSRI Pharmacogenomics Consortium (ISPC) was formed with the primary goal of identifying genetic variation that may contribute to response to SSRI treatment of major depressive disorder. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites. The primary outcomes were percent change in HRSD-17 score and response, defined as at least 50% reduction in HRSD-17. Data from two prior studies, the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, were used for replication, and a meta-analysis of the three studies was performed (N=2394). Although many top association signals in the ISPC analysis map to interesting candidate genes, none were significant at the genome-wide level and the associations were not replicated using PGRN-AMPS and STAR*D data. Top association results in the meta-analysis of response included single-nucleotide polymorphisms (SNPs) in the HPRTP4 (hypoxanthine phosphoribosyltransferase pseudogene 4)/VSTM5 (V-set and transmembrane domain containing 5) region, which approached genome-wide significance (P=5.03E-08) and SNPs 5' upstream of the neuregulin-1 gene, NRG1 (P=1.20E-06). NRG1 is involved in many aspects of brain development, including neuronal maturation and variations in this gene have been shown to be associated with increased risk for mental disorders, particularly schizophrenia. Replication and functional studies of these findings are warranted.JM Biernacka … BT Baune et. al

Interactions between the adducin 2 gene and antihypertensive drug therapies in determining blood pressure in people with hypertension

<p>Abstract</p> <p>Background</p> <p>As part of the NHLBI Family Blood Pressure Program, the Genetic Epidemiology Network of Arteriopathy (GENOA) recruited 575 sibships (n = 1583 individuals) from Rochester, MN who had at least two hypertensive siblings diagnosed before age 60. Linkage analysis identified a region on chromosome 2 that was investigated using 70 single nucleotide polymorphisms (SNPs) typed in 7 positional candidate genes, including adducin 2 (<it>ADD2</it>).</p> <p>Method</p> <p>To investigate whether blood pressure (BP) levels in these hypertensives (n = 1133) were influenced by gene-by-drug interactions, we used cross-validation statistical methods (i.e., estimating a model for predicting BP levels in one subgroup and testing it in a different subgroup). These methods greatly reduced the chance of false positive findings.</p> <p>Results</p> <p>Eight SNPs in <it>ADD2 </it>were significantly associated with systolic BP in untreated hypertensives (p-value < 0.05). Moreover, we also identified SNPs associated with gene-by-drug interactions on systolic BP in drug-treated hypertensives. The TT genotype at SNP rs1541582 was associated with an average systolic BP of 133 mmHg in the beta-blocker subgroup and 148 mmHg in the diuretic subgroup after adjusting for overall mean differences among drug classes.</p> <p>Conclusion</p> <p>Our findings suggest that hypertension candidate gene variation may influence BP responses to specific antihypertensive drug therapies and measurement of genetic variation may assist in identifying subgroups of hypertensive patients who will benefit most from particular antihypertensive drug therapies.</p

Association of FcγRIIa R131H polymorphism with idiopathic pulmonary fibrosis severity and progression

<p>Abstract</p> <p>Background</p> <p>A significant genetic component has been described for idiopathic pulmonary fibrosis (IPF). The R131H (rs1801274) polymorphism of the IgG receptor FcγRIIa determines receptor affinity for IgG subclasses and is associated with several chronic inflammatory diseases. We investigated whether this polymorphism is associated with IPF susceptibility or progression.</p> <p>Methods</p> <p>In a case-control study, we compared the distribution of FcγRIIa R131H genotypes in 142 patients with IPF and in 218 controls using allele-specific PCR amplification.</p> <p>Results</p> <p>No differences in the frequency of FcγRIIa genotypes were evident between IPF patients and control subjects. However, significantly impaired pulmonary function at diagnosis was observed in HH compared to RR homozygotes, with evidence of more severe restriction (reduced forced vital capacity (FVC)) and lower diffusing capacity for carbon monoxide (D<smcaps>L</smcaps>_CO). Similarly, increased frequency of the H131 allele was observed in patients with severe disease (D<smcaps>L</smcaps>_CO< 40% predicted) (0.53 vs. 0.38; p = 0.03). Furthermore, the H131 allele was associated with progressive pulmonary fibrosis as determined by > 10% drop in FVC and/or > 15% fall in D<smcaps>L</smcaps>_COat 12 months after baseline (0.48 vs. 0.33; p = 0.023).</p> <p>Conclusions</p> <p>These findings support an association between the FcγRIIa R131H polymorphism and IPF severity and progression, supporting the involvement of immunological mechanisms in IPF pathogenesis.</p

Genome-Wide Meta-Analysis Identifies Variants in DSCAM and PDLIM3 that correlate with efficacy outcomes in metastatic renal cell carcinoma patients treated with sunitinib

Individual response to sunitinib in metastatic renal cell carcinoma (mRCC) patients is highly variable. Earlier, sunitinib outcome was related to single nucleotide polymorphisms (SNPs) in CYP3A5 and ABCB1. Our aim is to provide novel insights into biological mechanisms underlying sunitinib action. We included mRCC patients from the European EuroTARGET consortium (n = 550) and the RIKEN cohort in Japan (n = 204) which were analysed separately and in a meta-analysis of genome-wide association studies (GWAS). SNPs were tested for association with progression-free survival (PFS) and overall survival (OS) using Cox regression. Summary statistics were combined using a fixed effect meta-analysis. SNP rs28520013 in PDLIM3 and the correlated SNPs rs2205096 and rs111356738 both in DSCAM, showed genome-wide significance (p Personalised Therapeutic

Adverse Health Outcomes in Relationship to Hypogonadism After Chemotherapy: A Multicenter Study of Testicular Cancer Survivors.

Background This study examined the prevalence of hypogonadism, its clinical and genetic risk factors, and its relationship to adverse health outcomes (AHOs) in North American testicular cancer survivors (TCS) after modern platinum-based chemotherapy.Patients and methods Eligible TCS were <55 years of age at diagnosis and treated with first-line platinum-based chemotherapy. Participants underwent physical examinations and completed questionnaires regarding 15 AHOs and health behaviors. Hypogonadism was defined as serum testosterone levels ≤3.0 ng/mL or use of testosterone replacement therapy. We investigated the role of 2 single nucleotide polymorphisms (rs6258 and rs12150660) in the sex hormone-binding globulin (SHBG) locus implicated in increased hypogonadism risk in the general population.Results Of 491 TCS (median age at assessment, 38.2 years; range, 18.7-68.4 years), 38.5% had hypogonadism. Multivariable binary logistic regression analysis identified hypogonadism risk factors, including age at clinical evaluation (odds ratio [OR], 1.42 per 10-year increase; P= .006) and body mass index of 25 to <30 kg/m2 (OR, 2.08; P= .011) or ≥30 kg/m2 (OR, 2.36; P= .005) compared with <25 kg/m2. TCS with ≥2 risk alleles for the SHBG SNPs had a marginally significant increased hypogonadism risk (OR, 1.45; P= .09). Vigorous-intensity physical activity appeared protective (OR, 0.66; P= .07). Type of cisplatin-based chemotherapy regimen and socioeconomic factors did not correlate with hypogonadism. Compared with TCS without hypogonadism, those with hypogonadism were more likely to report ≥2 AHOs (65% vs 51%; P= .003), to take medications for hypercholesterolemia (20.1% vs 6.0%; P<.001) or hypertension (18.5% vs 10.6%; P= .013), and to report erectile dysfunction (19.6% vs 11.9%; P= .018) or peripheral neuropathy (30.7% vs 22.5%; P= .041). A marginally significant trend for increased use of prescription medications for either diabetes (5.8% vs 2.6%; P= .07) or anxiety/depression (14.8% vs 9.3%; P= .06) was observed.Conclusions At a relatively young median age, more than one-third of TCS have hypogonadism, which is significantly associated with increased cardiovascular disease risk factors, and erectile dysfunction. Providers should screen TCS for hypogonadism and treat symptomatic patients