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: 10441271
• 负责人: Elizabeth Phillips
• 金额: $ 79.97万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10441271
• 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; Hispanic; 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; disease prognostic; education resources; electronic consent; electronic data; eligible participant; follow-up; gastrointestinal; genetic association; genetic risk factor; health related quality of life; improved; instrument; interest; lamotrigine; mortality; multi-ethnic; novel; patient registry; patient subsets; physical conditioning; 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.

项目总结 史蒂文斯-约翰逊综合征(SJS)和中毒性表皮坏死松解症(TEN)与广泛的 表皮坏死，临床表现为广泛的水泡和水泡，并累及 粘膜和眼睛。SJS/TEN的死亡率高达50%，并长期存在身心障碍 健康发病率相当高，但研究不足。在成年人中，超过80%的SJS/TEN与毒品有关，并且 有希望的发现在I类特定的主要组织相容性复合体等位基因上有相关的变异 与卡马西平和别嘌醇SJS/TEN相关的主要为人类白细胞抗原B*15：02和人类白细胞抗原B*58：01 然而，药物导致SJS/TEN风险的遗传因素尚不清楚。在别嘌醇的情况下，尽管人类白细胞抗原- B*58：01在东南亚有接近100%的负面预测价值只有50%-60%的欧洲人和非洲人 患别嘌醇SJS/TEN者携带人类白细胞抗原B*58：01。在美国引发SJS/TEN的常见原因包括 甲氧嘧啶-磺胺甲恶唑、别嘌醇和芳香族抗惊厥药物，如拉莫三嗪、苯妥英钠和 卡马西平在美国人群中的普遍遗传关联尚未确定，它已经 预防工作和执行工作停滞不前。SJS/TEN的稀有性以及无法接触到大量的 幸存者削弱了确定遗传风险因素和长期发病率的能力。我们将使用注册表 由SJS基金会(http://sjsupport.org/))开发，以开发表型数据和DNA生物库 审判SJS/10名幸存者。我们的可检验假设是，我们将确定遗传风险因素 与SJS/TEN相关的最常见药物及其长期并发症的性质和风险 与SJS/TEN有关，这两者都有可能对SJS/TEN产生重大影响 预防和患者结局。在具体目标1中，我们将建立一大批SJS/10名幸存者 有一个相关的DNA生物库。参与者将通过SJS基金会的网站招募， Facebook页面和注册，并同意进行病历审查和口头DNA收集。 对毒品引起的SJS/TEN的独立裁决将确定合格的参与者。以特定的目标 2我们将定义与SJS/TEN相关的长期精神和身体健康并发症和 相关的风险因素。经过验证的问卷将评估心理和身体健康并发症 通过对SJS/TEN患者不同时间点的心理测试工具进行分段验证 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 人类白细胞抗原和其他与药物诱导的SJS/TEN相关的遗传危险因素。高分辨率人类白细胞抗原，ERAP 将对1000名患者进行KIR分型和扩展的多种族基因分型阵列(MegaEx) 由三名皮肤科医生组成的独立小组证实他们患有药物引起的SJS/TEN。 对照将是100,000名BioVu参考人群，具有MegaEx配型，归因于人类白细胞抗原/KIR/ERAP配型 以及BioVu耐药对照组在年龄、性别、种族和潜在疾病方面匹配2：1。

项目成果

Visual Genomics Analysis Studio as a Tool to Analyze Multiomic Data.

• DOI: 10.3389/fgene.2021.642012
• 发表时间: 2021
• 期刊: Frontiers in genetics
• 影响因子: 3.7
• 作者: Hertzman RJ;Deshpande P;Leary S;Li Y;Ram R;Chopra A;Cooper D;Watson M;Palubinsky AM;Mallal S;Gibson A;Phillips EJ
• 通讯作者: Phillips EJ

Genomic Risk Factors Driving Immune-Mediated Delayed Drug Hypersensitivity Reactions.

• DOI: 10.3389/fgene.2021.641905
• 发表时间: 2021
• 期刊: Frontiers in genetics
• 影响因子: 3.7
• 作者: Li Y;Deshpande P;Hertzman RJ;Palubinsky AM;Gibson A;Phillips EJ
• 通讯作者: Phillips EJ