Division of Pediatric Gastroenterology, Hepatology, & Nutrition, MassGeneral Hospital for Children, Boston, Massachusetts, United States of America.
Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, United States of America.
PLoS One. 2018 Mar 26;13(3):e0192806. doi: 10.1371/journal.pone.0192806. eCollection 2018.
Mesalamine is commonly used to treat ulcerative colitis (UC). Although mesalamine acts topically, in vitro data suggest that intracellular transport is required for its beneficial effect. Genetic variants in mucosal transport proteins may affect this uptake, but the clinical relevance of these variants has not been studied. The aim of this study was to determine whether variants in genes involved in cellular transport affect the response to mesalamine in UC.
Subjects with UC from a 6-week clinical trial using multiple doses of mesalamine were genotyped using a genome-wide array that included common exome variants. Analysis focused on cellular transport gene variants with a minor allele frequency >5%. Mesalamine response was defined as improvement in Week 6 Physician's Global Assessment (PGA) and non-response as a lack of improvement in Week 6 PGA. Quality control thresholds included an individual genotyping rate of >90%, SNP genotyping rate of >98%, and exclusion for subjects with cryptic relatedness. All included variants met Hardy-Weinberg equilibrium (p>0.001).
457 adults with UC were included with 280 responders and 177 non-responders. There were no common variants in transporter genes that were associated with response to mesalamine. The genetic risk score of responders was similar to that of non-responders (p = 0.18). Genome-wide variants demonstrating a trend towards mesalamine response included ST8SIA5 (p = 1x10-5).
Common transporter gene variants did not affect response to mesalamine in adult UC. The response to mesalamine may be due to rare genetic events or environmental factors such as the intestinal microbiome.
美沙拉嗪常用于治疗溃疡性结肠炎（UC）。尽管美沙拉嗪具有局部作用，但体外数据表明其有益作用需要细胞内转运。黏膜转运蛋白的遗传变异可能会影响这种摄取，但这些变异的临床相关性尚未研究。本研究旨在确定参与细胞转运的基因变异是否会影响 UC 患者对美沙拉嗪的反应。
本研究对参加美沙拉嗪多剂量 6 周临床试验的 UC 患者进行了全基因组微阵列基因分型，该微阵列包括常见的外显子变异。分析重点是细胞转运基因变异，其次要等位基因频率 >5%。美沙拉嗪反应定义为第 6 周医师总体评估（PGA）改善，无反应定义为第 6 周 PGA 无改善。质量控制阈值包括个体基因分型率>90%、SNP 基因分型率>98%以及排除有血缘关系的受试者。所有纳入的变异均符合 Hardy-Weinberg 平衡（p>0.001）。
本研究共纳入 457 例 UC 成人患者，其中 280 例为应答者，177 例为无应答者。在转运基因中没有与美沙拉嗪反应相关的常见变异。应答者的遗传风险评分与无应答者相似（p = 0.18）。对美沙拉嗪有反应趋势的全基因组变异包括 ST8SIA5（p = 1x10-5）。
常见转运基因变异不会影响成人 UC 对美沙拉嗪的反应。美沙拉嗪的反应可能是由于罕见的遗传事件或环境因素，如肠道微生物组。
