Pharmacogenomics fail to explain proton pump inhibitor refractory esophagitis in pediatric esophageal atresia.

BACKGROUND: Esophagitis is prevalent in patients with esophageal dysmotility despite acid suppression, likely related to poor esophageal clearance. Esophageal atresia (EA) is a classic model of dysmotility where this observation holds true. In adult non-dysmotility populations, failure of esophagitis to respond to proton pump inhibitors (PPI) has been linked to variants in CYP2C19 that influence the activity of the encoded enzyme. It is unknown if CYP2C19 metabolizer phenotype contributes to PPI-refractory, non-allergic esophagitis in EA. METHODS: We performed a cross-sectional study of 314 children with (N = 188) and without (N = 126) EA who were on PPI therapy at the time of endoscopy to evaluate for possible gastroesophageal reflux disease. Patients with eosinophilic esophagitis and/or fundoplication were excluded. Clinical and histology data were collected. Genomic DNA from biopsy samples was genotyped for polymorphisms in CYP2C19. RESULTS: CYP2C19 metabolizer phenotypes were not associated with presence or severity of esophagitis (P = 0.994). In a multivariate logistic regression adjusted for potential confounders, EA was the strongest and only significant predictor of esophagitis (odds ratio 2.72, P = 0.023). Using negative binomial regression, we found that CYP2C19 phenotype was not a significant predictor of eosinophil count in children with PPI-refractory esophagitis. CONCLUSIONS: Patients with EA are significantly more likely to experience PPI-refractory, non-allergic esophagitis than controls regardless of CYP2C19 metabolizer phenotype, suggesting that factors other than CYP2C19 genetics, including dysmotility, are the primary drivers of esophagitis in EA. CYP2C19 genotype failed to predict PPI-refractory, non-allergic esophagitis in both EA and non-EA children.

STAT6 Variants Associate With Relapse of Eosinophilic Esophagitis in Patients Receiving Long-term Proton Pump Inhibitor Therapy.

BACKGROUND & AIMS: Based on histologic features, variants in STAT6 are associated with a poor initial response to proton pump inhibitor (PPI) therapy in pediatric patients with eosinophilic esophagitis (EoE). We investigated whether these genetic variants are associated with a poor long-term response in children with EoE who initially responded to PPI therapy. METHODS: We performed a prospective longitudinal cohort study of children ages 2 to 16 years who met the diagnostic criteria for EoE (≥15 eosinophils/high-power field [eos/hpf]), responded to 8 weeks of treatment with 2 mg/kg/d PPI (<15 eos/hpf), and whose dose then was reduced to 1 mg/kg/d PPI (maintenance therapy) for 1 year, at which point biopsy specimens were collected by endoscopy. Genomic DNA was isolated from formalin-fixed paraffin-embedded biopsy tissue and was genotyped for variants of STAT6. Remission of inflammation was assessed at eos/hpf thresholds of <15 and ≤5. RESULTS: Among 73 patients who received 1 mg/kg/d PPI maintenance therapy for 1 year, 13 patients (18%) had 6 to 14 eos/hpf, 36 patients (49%) had 5 or fewer eos/hpf, and 24 patients (33%) relapsed to EoE (≥15 eos/hpf). Carriage of any of 3 STAT6 variants in linkage disequilibrium (r2 ≥0.8; rs324011, rs167769, or rs12368672) was associated with a 2.3- to 2.8-fold increase in the odds of EoE relapse, and with a 2.8- to 4.1-fold increase in the odds of having 6 to 14 eos/hpf. For rs324011, the odds ratio [95% CI] for relapse was 2.77 [1.11, 6.92]; P = .029, and the odds ratio [95% CI] for having 6 to 14 eos/hpf was 3.06 [1.27, 7.36]; P = .012. CONCLUSIONS: Pediatric EoE patients who initially respond to PPI therapy and carry STAT6 variants rs324011, rs167769, or rs12368672 are at increased risk of relapse after 1 year of PPI maintenance therapy.

Fish Oil Supplementation in Overweight/Obese Patients with Uncontrolled Asthma. A Randomized Trial.

Rationale: Omega-3 fatty acid (n3PUFA) supplementation has been proposed as a promising antiasthma strategy. The rs59439148 ALOX5 polymorphism affects leukotriene production and possibly inflammatory responses to n3PUFA. Objectives: Assess the effects of n3PUFA supplementation and ALOX5 genotype on asthma control in patients with obesity and uncontrolled asthma. Methods: This multicenter trial among 12- to 25-year-olds with overweight/obesity and uncontrolled asthma randomized subjects in a 3:1 allotment to n3PUFA (4 g/d) or soy oil control for 24 weeks. Asthma Control Questionnaire was the primary outcome; secondary outcomes included blood leukocyte n3PUFA levels, urinary leukotriene-E4, spirometry, and asthma-related events. The number of SP1 tandem repeats in rs59439148 determined ALOX5 genotype status. Simple and multivariable generalized linear models assessed effects on outcomes. Results: Ninety-eight participants were randomized (77 to PUFA, 21 to control), and more than 86% completed all visits. Asthma and demographic characteristics were similar among treatment groups. n3PUFA treatment increased the n3-to-n6 PUFA ratio in circulating granulocytes (P = 0.029) and monocytes (P = 0.004) but did not affect mean Asthma Control Questionnaire change at 6 months (n3PUFA: mean, -0.09; 95% confidence interval [CI], 0.09 to 0.10; vs. control: mean, -0.18; 95% CI, -0.42 to 0.06; P = 0.58). Changes in urinary leukotriene-E4 (P = 0.24), forced expiratory volume in 1 second % predicted (P = 0.88), and exacerbations (relative risk [RR], 0.92; 95% CI, 0.30-2.89) at 6 months were similar in both groups. n3PUFA treatment was associated with reduced asthma-related phone contacts (RR, 0.34; 95% CI, 0.13-0.86; P = 0.02). ALOX5 genotype did not affect n3PUFA treatment responses. Conclusions: We did not find evidence that n3PUFA use improves most asthma-related outcomes and cannot recommend it as a prevention strategy for overweight/obese patients with asthma. Clinical trial registered with www.clinicaltrials.gov (NCT01027143).

Association between CYP2C19 extensive metabolizer phenotype and childhood anti-reflux surgery following failed proton pump inhibitor medication treatment.

When pediatric gastroesophageal reflux disease (GERD) that is refractory to proton pump inhibitor (PPI) medication treatment is identified in clinical practice and anti-reflux surgery (ARS) is being considered, genetic factors related to PPI metabolism by the CYP2C19 enzyme are currently not part of the clinical decision-making process. Our objective was to test the hypothesis that the distribution of the extensive metabolizer (EM) phenotypes among children undergoing ARS after failing PPI therapy would differ compared to controls (children with no history of ARS). We conducted a case-control study between children across the Nemours Health System from 2000 to 2014 who received ARS after failing PPI therapy and a control group comprised of healthy children. Our results demonstrated 2.9% of ARSs vs 20.8% of controls were poor metabolizers (PMs), 55.9% of ARSs vs 49.0% of controls were normal metabolizers (NMs), and 41.2% of ARSs vs 30.2% of controls were EMs; p = 0.035. Next, we performed a multiple-regression model to account for race as a potential confounding variable and the EM group was significantly associated with ARS compared to controls (OR 9.78, CI 1.25-76.55, p < 0.03). CONCLUSION: Among children with medically refractory GERD despite PPI therapy, carriage of CYP2C19*17 allele corresponding to the EM phenotype was associated with ARS. Prospective comparative personalized medicine effectiveness studies are needed to determine if CYP2C19 genotype-guided dosing improves response to PPI therapy without a corresponding increase in adverse effects in children. What is known: • Anti-reflux surgery (ARS) is one of the most common surgical procedures performed in children for the indication of refractory gastroesophageal reflux disease (GERD). What is new: • Individualizing PPI medication dosing based on CYP2C19 diplotype may avoid GERD treatment failures and reduce the need for anti-reflux surgery (ARS).

Association Between Serum 25-Hydroxy Vitamin D Levels and Blood Pressure Among Adolescents in Two Resource-Limited Settings in Peru.

INTRODUCTION: Serum 25-hydroxyvitamin D (25OHD) deficiency (<50 nmol/l or 20 ng/ml) has been associated with increased blood pressure (BP) in observational studies. A paucity of data on this relationship is available in Latin American or child populations. This study investigates the association between 25OHD levels and BP in adolescents at risk for vitamin D deficiency in 2 Peruvian settings. METHODS: In a population-based study of 1,441 Peruvian adolescents aged 13-15 years, 1,074 (75%) provided a serum blood sample for 25OHD analysis and BP measurements. Relationships between 25OHD and BP metrics were assessed using multiple linear regressions, adjusted for anthropometrics and sociodemographic factors. RESULTS: 25OHD deficiency was associated with an elevated diastolic BP (DBP) (1.09 mm Hg increase, 95% confidence interval: 0.04 to 2.14; P = 0.04) compared to nondeficient adolescents. Systolic BP (SBP) trended to increase with vitamin D deficiency (1.30 mm Hg increase, 95% confidence interval: -0.13 to 2.72; P = 0.08). Mean arterial pressure (MAP) was also greater in adolescents with 25OHD (1.16 mm Hg increase, 95% confidence interval: 0.10 to 2.22; P = 0.03). SBP was found to demonstrate a U-shaped relationship with 25OHD, while DBP and MAP demonstrated inverse J-shaped relationships with serum 25OHD status. The association between 25OHD deficiency and BP was not different across study sites (all P ≥ 0.19). DISCUSSION: Adolescents deficient in 25OHD demonstrated increased DBP and MAP and a trend toward increased SBP, when compared to nondeficient subjects. 25OHD deficiency early in life was associated with elevated BP metrics, which may predispose risk of hypertension later in adulthood.

Biologic mechanisms of environmental tobacco smoke in children with poorly controlled asthma: results from a multicenter clinical trial.

BACKGROUND: Environmental tobacco smoke (ETS) negatively affects children with asthma. The prevalence of ETS exposure among children with poor asthma control may be changing. Importantly, the mechanisms by which ETS worsens asthma control are poorly understood. OBJECTIVE: We describe how ETS affects gastroesophageal reflux (GER), respiratory infections, and leukotriene production among children with poor asthma control. METHODS: We analyzed data from 306 children between 6 and 17 years of age with poorly controlled asthma enrolled in a 6-month clinical trial. We evaluated prevalence and determinants of ETS exposure by interview, questionnaire, and urinary cotinine and the association of ETS exposure on leukotriene production, respiratory infections, GER, lung function, and asthma control. We used multivariable linear, logistic, and Poisson regressions to assess outcomes. RESULTS: ETS prevalence estimates ranged from 6% to 30%. Children with domestic indoor exposure had worse asthma control (c-Asthma Control Test, 17.8 vs 21.5; P = .04), worse FEV1 % predicted (84.1 vs 90.7; P = .02), and a trend for increased mean urinary leukotriene E4. ETS from any setting was associated with increased symptomatic respiratory infections (adjusted incidence rate ratio: 1.30; P = .02). However, children exposed to ETS did not have symptoms or pH probe results, suggestive of heightened GER. CONCLUSIONS: Domestic smoking exposure was associated with both higher rates of symptomatic respiratory infection and poorer asthma control despite generally intensive controller therapy. ETS exposure is common among asthmatic children with poor control and may worsen asthma control by promoting respiratory infections. Further investigation is required to elucidate ETS mechanisms in poor asthma control.

Absorption of montelukast is transporter mediated: a common variant of OATP2B1 is associated with reduced plasma concentrations and poor response.

OBJECTIVES: To (i) determine whether montelukast undergoes carrier-mediated uptake; (ii) classify the carrier protein(s) responsible for uptake; (iii) identify specific transporters that mediate transport of montelukast; and (iv) evaluate whether variation in the gene encoding the transport protein(s) influences the pharmacokinetics and pharmacodynamics of montelukast. METHODS: In-vitro permeability studies of montelukast are carried out using Caco-2 cell culture, a standard model of human intestinal drug transport. In-vivo plasma concentrations of montelukast in an asthmatic population are determined by high-performance liquid chromatography, and genotyping of transport proteins is by LightTyper analysis. RESULTS: Permeability of montelukast has an activation energy of 13.7+/-0.7 kcal/mol, consistent with carrier-mediated transport. Permeability is saturable at high concentrations of montelukast and follows Michaelis-Menten kinetics. Permeability is subject to competition by sulfobromophthalein, estrone-3-sulfate, pravastatin, taurocholic acid, and cholic acid (P<0.05, percentage of control: 72+/-7-86+/-7) and is inhibited by 5-10% citrus juice (P<0.05, maximal inhibition percentage of control: 31+/-2). An MDCKII cell line expressing OATP2B1 (coded for by the SLCO2B1 gene) displays significantly increased permeability of montelukast (P<0.05, percentage of control: 140+/-20). A nonsynonymous polymorphism in SLCO2B1, rs12422149; SLCO2B1 {NM_007256.2}:c.935G>A, associates with significantly reduced plasma concentration in patients measured on the morning after an evening dose (P<0.025, square root mean transformed plasma concentration+/-SE; c.[935G>A]+[935G]=3+/-1, c.[935G]+[935G]=7.0+/-0.9) and differential response as assessed by change in baseline Asthma Symptom Utility Index scores after 1 month of therapy (delta mean Asthma Symptom Utility Index; c.[935G>A]+[935G]=0.02+/-0.01, P=1.0; c.[935G]+[935G]=1.0+/-0.3, P<0.0001). CONCLUSION: Altogether, these observations suggest that the genetics of SLCO2B1 may be an important variable in determining the pharmacokinetics and the pharmacodynamics of montelukast.