Genetic risk and long-term outcomes associated with Drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in survivors

幸存者中药物引起的史蒂文斯-约翰逊综合征和中毒性表皮坏死松解症相关的遗传风险和长期结果

• 批准号: 10018069
• 负责人: Elizabeth Phillips
• 金额: $ 75.59万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-13 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10018069
• 关键词: Accounting; Acute; Adult; Affect; African; Age; Alleles; Allopurinol; Anticonvulsants; Antiepileptic Agents; Anxiety; Automobile Driving; Awareness; Bulla; Carbamazepine; Caring; Cessation of life; Clinical; Collection; Consent; DNA; DNA Databases; Data; Dermatologist; Disease; Drug Tolerance; Elderly; Emergency Situation; Ethnic Origin; Europe; European; Eye; Facebook; Family; Foundations; Future; Genes; Genetic; Genetic Risk; Genetic Screening; Genotype; HLA Antigens; Hispanics; Hospitalization; Immune; Impairment; International; Interview; Length; Life; Link; Long-Term Care; Major Histocompatibility Complex; Measures; Mediating; Medical; Medical Records; Mental Depression; Mental Health; Morbidity - disease rate; Mucous Membrane; Musculoskeletal System; Nature; Necrosis; Oral; Other Genetics; Outcome; Participant; Patient Recruitments; Patient Self-Report; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phenotype; Phenytoin; Population; Post-Traumatic Stress Disorders; Predictive Value; Prevention; Prevention strategy; Preventive; Preventive care; Productivity; Psychologist; Quality of life; Questionnaires; Race; Records; Registries; Research; Resolution; Risk; Risk Factors; Salivary; Severity of illness; Skin; Southeastern Asia; Stevens-Johnson Syndrome; Support Groups; Survivors; Time; Toxic Epidermal Necrolysis; Training; Translating; Trimethoprim-Sulfamethoxazole; United States; Variant; adjudicate; adjudication; biobank; cohort; comparative; cost effective; education resources; electronic data; eligible participant; follow-up; gastrointestinal; genetic association; genetic risk factor; health related quality of life; improved; instrument; interest; lamotrigine; mortality; novel; patient registry; patient subsets; physical conditioning; prognostic; psychological distress; recruit; research study; respiratory; screening; screening program; sex; urogenital tract; web site

PROJECT SUMMARY Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are associated with widespread epidermal necrosis with the clinical presentation consisting of widespread blisters and bullae and involvement of mucous membranes and the eyes. The mortality of SJS/TEN is up to 50% and long-term physical and mental health morbidity is considerable and understudied. In adults over 80% of SJS/TEN is drug associated, and promising discoveries have associated variation in class I specific major histocompatibility complex alleles such as HLA-B*15:02 and HLA-B*58:01 which are associated with carbamazepine and allopurinol SJS/TEN For most drugs, however, genetic factors driving risk for SJS/TEN are unknown. In the case of allopurinol although HLA- B*58:01 has close to 100% negative predictive value in Southeast Asia only 50-60% of Europeans and Africans who develop allopurinol SJS/TEN carry HLA-B*58:01. Common causes of SJS/TEN in the US include trimethoprim-sulfamethoxazole, allopurinol and aromatic anticonvulsants such as lamotrigine, phenytoin and carbamazepine where the prevalent genetic associations in US populations have yet to be defined which has stalled preventive efforts and implementation. The rarity of SJS/TEN and lack of access to large cohorts of survivors has impaired the ability to define genetic risk factors and long-term morbidity. We will utilize a registry developed by the SJS Foundation (http://sjsupport.org/) to develop a data and DNA biobank of phenotype adjudicated SJS/TEN survivors. Our testable hypothesis is that we will determine genetic risk factors for the most common drugs associated with SJS/TEN and the nature and risk of long-term complications associated with SJS/TEN both of which will have the potential to have significant impact on SJS/TEN prevention and patient outcomes. In Specific Aim 1 we will establish a large cohort of SJS/TEN survivors with an associated DNA biobank. Participants will be recruited through the SJS Foundation website, Facebook page and registry and consented for medical record review and oral DNA collection. Independent adjudication for drug-induced SJS/TEN will determine eligible participants. In Specific Aim 2 we will define long-term mental and physical health complications associated with SJS/TEN and associated risk factors. Validated questionnaires will assess mental and physical health complications cross- sectionally in patients at different time points following SJS/TEN through instruments validated for psychological distress, post-traumatic stress disorder and health-related quality of life. In Specific Aim 3 we will determine HLA and other genetic risk factors associated with drug-induced SJS/TEN. High resolution HLA, ERAP and KIR typing as well as expanded multi-ethnic genotyping array (MegaEx ) will be performed on 1000 patients who have been verified as having drug-induced SJS/TEN by an independent panel of three dermatologists. Controls will be the BioVu reference population of 100,000 with MegaEx typing, imputed HLA/KIR/ERAP typing as well as BioVu drug tolerant controls matched 2:1 on age, sex and race and underlying disease.

项目概要 史蒂文斯-约翰逊综合征 (SJS) 和中毒性表皮坏死松解症 (TEN) 与广泛存在的 表皮坏死，临床表现包括广泛的水疱和大疱以及受累 粘膜和眼睛。 SJS/TEN死亡率高达50%，长期身心损害 健康发病率相当高，但尚未得到充分研究。在成人中，超过 80% 的 SJS/TEN 与药物相关，并且 有希望的发现与 I 类特定主要组织相容性复合体等位基因的变异相关，例如 如 HLA-B*15:02 和 HLA-B*58:01，与卡马西平和别嘌呤醇 SJS/TEN 相关 对于大多数 然而，导致 SJS/TEN 风险的遗传因素尚不清楚。就别嘌呤醇而言，尽管 HLA- B*58:01 在东南亚只有 50-60% 的欧洲人和非洲人具有接近 100% 的阴性预测值 产生别嘌呤醇 SJS/TEN 的人携带 HLA-B*58:01。在美国，SJS/TEN 的常见原因包括 甲氧苄啶-磺胺甲恶唑、别嘌呤醇和芳香族抗惊厥药，如拉莫三嗪、苯妥英和 卡马西平在美国人群中普遍存在的遗传关联尚未确定，这已经 预防工作和实施陷入停滞。 SJS/TEN 的稀有性和缺乏接触大量人群的机会 幸存者损害了定义遗传风险因素和长期发病率的能力。我们将利用注册表 由 SJS 基金会 (http://sjsupport.org/) 开发，用于开发表型数据和 DNA 生物库 裁定 SJS/10 名幸存者。我们可检验的假设是，我们将确定遗传风险因素 与 SJS/TEN 相关的最常见药物以及长期并发症的性质和风险 与 SJS/TEN 相关，两者都有可能对 SJS/TEN 产生重大影响 预防和患者结果。在具体目标 1 中，我们将建立一个由 SJS/10 名幸存者组成的大型队列 与相关的 DNA 生物库。参与者将通过 SJS 基金会网站招募， Facebook 页面和登记处并同意进行医疗记录审查和口腔 DNA 收集。 药物引起的 SJS/TEN 的独立裁决将确定合格的参与者。特定目标 2 我们将定义与 SJS/TEN 相关的长期精神和身体健康并发症，以及 相关的风险因素。经过验证的调查问卷将跨领域评估心理和身体健康并发症 通过经过心理验证的仪器对 SJS/TEN 后不同时间点的患者进行分段分析 痛苦、创伤后应激障碍和与健康相关的生活质量。在具体目标 3 中，我们将确定 HLA 和其他与药物诱导的 SJS/TEN 相关的遗传风险因素。高分辨率 HLA、ERAP 将对 1000 名患者进行 KIR 分型以及扩展的多种族基因分型芯片 (MegaEx) 由三名皮肤科医生组成的独立小组已证实患有药物诱发的 SJS/TEN。 对照将是 BioVu 100,000 参考群体，采用 MegaEx 分型、估算 HLA/KIR/ERAP 分型 BioVu 耐药对照在年龄、性别、种族和潜在疾病方面以 2:1 匹配。