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
基本信息
- 批准号:10441271
- 负责人:
- 金额:$ 79.97万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AccountingAcuteAdultAffectAfricanAgeAllelesAllopurinolAnticonvulsantsAntiepileptic AgentsAnxietyAutomobile DrivingAwarenessBullaCarbamazepineCaringCessation of lifeClinicalCollectionConsentDNADNA DatabasesDataDermatologistDiseaseDrug ToleranceElderlyEmergency SituationEthnic OriginEuropeEuropeanEyeFacebookFamilyFoundationsFutureGenesGeneticGenetic RiskGenetic ScreeningGenotypeHLA AntigensHispanicHospitalizationImmuneImpairmentInternationalInterviewLengthLifeLinkLong-Term CareMajor Histocompatibility ComplexMeasuresMediatingMedicalMedical RecordsMental DepressionMental HealthMorbidity - disease rateMucous MembraneMusculoskeletal SystemNatureNecrosisOralOther GeneticsOutcomeParticipantPatient RecruitmentsPatient Self-ReportPatient-Focused OutcomesPatientsPharmaceutical PreparationsPhenotypePhenytoinPopulationPost-Traumatic Stress DisordersPredictive ValuePreventionPrevention strategyPreventivePreventive careProductivityPsychologistQuality of lifeQuestionnairesRaceRecordsRegistriesResearchResolutionRiskRisk FactorsSalivarySeverity of illnessSkinSoutheastern AsiaStevens-Johnson SyndromeSupport GroupsSurvivorsTimeToxic Epidermal NecrolysisTrainingTranslatingTrimethoprim-SulfamethoxazoleUnited StatesVariantadjudicateadjudicationbiobankcohortcomparativecost effectivedisease prognosticeducation resourceselectronic consentelectronic dataeligible participantfollow-upgastrointestinalgenetic associationgenetic risk factorhealth related quality of lifeimprovedinstrumentinterestlamotriginemortalitymulti-ethnicnovelpatient registrypatient subsetsphysical conditioningpsychological distressrecruitresearch studyrespiratoryscreeningscreening programsexurogenital tractweb site
项目摘要
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
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Visual Genomics Analysis Studio as a Tool to Analyze Multiomic Data.
- DOI:10.3389/fgene.2021.642012
- 发表时间:2021
- 期刊:
- 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:
- 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
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Elizabeth Phillips其他文献
Elizabeth Phillips的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Elizabeth Phillips', 18)}}的其他基金
Stevens Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) 2023
史蒂文斯约翰逊综合症/中毒性表皮坏死松解症 (SJS/TEN) 2023
- 批准号:
10682795 - 财政年份:2023
- 资助金额:
$ 79.97万 - 项目类别:
NATIENS: A Phase III Randomized Double Blinded Study to Determine the Mechanisms and Optimal Management of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
NATIENS:一项 III 期随机双盲研究,以确定史蒂文斯-约翰逊综合征和中毒性表皮坏死松解症的机制和最佳治疗
- 批准号:
10217036 - 财政年份:2020
- 资助金额:
$ 79.97万 - 项目类别:
NATIENS: A Phase III Randomized Double Blinded Study to Determine the Mechanisms and Optimal Management of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
NATIENS:一项 III 期随机双盲研究,以确定史蒂文斯-约翰逊综合征和中毒性表皮坏死松解症的机制和最佳治疗
- 批准号:
10402818 - 财政年份:2020
- 资助金额:
$ 79.97万 - 项目类别:
NATIENS: A Phase III Randomized Double Blinded Study to Determine the Mechanisms and Optimal Management of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
NATIENS:一项 III 期随机双盲研究,以确定史蒂文斯-约翰逊综合征和中毒性表皮坏死松解症的机制和最佳治疗
- 批准号:
10612063 - 财政年份:2020
- 资助金额:
$ 79.97万 - 项目类别:
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:
10214660 - 财政年份:2019
- 资助金额:
$ 79.97万 - 项目类别:
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 - 财政年份:2019
- 资助金额:
$ 79.97万 - 项目类别:
Single Cell definition of pathogenic T cells in Drug-induced Stevens-Johnson-Syndrome/Toxic epidermal necrolysis
药物诱导史蒂文斯-约翰逊综合征/中毒性表皮坏死松解症中致病性 T 细胞的单细胞定义
- 批准号:
9574331 - 财政年份:2018
- 资助金额:
$ 79.97万 - 项目类别:
Stevens-Johnson Syndrome/Toxic Epidural Necrolysis 2017: Building Multidisciplinary Networks to Drive Science and Translation
史蒂文斯-约翰逊综合症/中毒性硬膜外坏死松解术 2017:建立多学科网络以推动科学和翻译
- 批准号:
9261224 - 财政年份:2017
- 资助金额:
$ 79.97万 - 项目类别:
Understanding and preventing HLA-associated drug reactions
了解和预防 HLA 相关药物反应
- 批准号:
8934766 - 财政年份:
- 资助金额:
$ 79.97万 - 项目类别:
Understanding and preventing HLA-associated drug reactions
了解和预防 HLA 相关药物反应
- 批准号:
9100798 - 财政年份:
- 资助金额:
$ 79.97万 - 项目类别:
相似海外基金
Un/kindness, shame & resistance: the care of inpatients in NHS adult acute mental health units and how it might be improved
Un/善良,羞耻
- 批准号:
2885806 - 财政年份:2023
- 资助金额:
$ 79.97万 - 项目类别:
Studentship
Post-Acute Care Transitions for Older Adult Medicare Beneficiaries with Serious Mental Illness
患有严重精神疾病的老年医疗保险受益人的急性后护理过渡
- 批准号:
10772386 - 财政年份:2023
- 资助金额:
$ 79.97万 - 项目类别:
Paving The Way to a Canadian Standard of Care with CAR-T Cellular Therapy: Phase II Trial of CD19 CAR-T for Relapsed/Refractory Adult Acute Lymphoblastic Leukemia (CLIC-01A)
通过 CAR-T 细胞疗法为加拿大护理标准铺平道路:CD19 CAR-T 治疗复发/难治性成人急性淋巴细胞白血病的 II 期试验 (CLIC-01A)
- 批准号:
474619 - 财政年份:2022
- 资助金额:
$ 79.97万 - 项目类别:
Operating Grants
Investigating the impact acute inhalation of cannabis with a high content of delta-9-tetrahydrocannabinol has on myelination and microglia in adult and aged mice
研究急性吸入高含量 delta-9-四氢大麻酚的大麻对成年和老年小鼠髓鞘形成和小胶质细胞的影响
- 批准号:
485965 - 财政年份:2022
- 资助金额:
$ 79.97万 - 项目类别:
Studentship Programs
Paving The Way to a Canadian Standard of Care with CAR-T Cellular Therapy: Phase II Trial of CD19 CAR-T for Relapsed/Refractory Adult Acute Lymphoblastic Leukemia (CLIC-01A)
通过 CAR-T 细胞疗法为加拿大护理标准铺平道路:CD19 CAR-T 治疗复发/难治性成人急性淋巴细胞白血病的 II 期试验 (CLIC-01A)
- 批准号:
466358 - 财政年份:2022
- 资助金额:
$ 79.97万 - 项目类别:
Operating Grants
Metabolomics for prediction of cisplatin mediated acute kidney injury: a Canadian multi-centre adult and pediatric study
预测顺铂介导的急性肾损伤的代谢组学:加拿大多中心成人和儿童研究
- 批准号:
402040 - 财政年份:2019
- 资助金额:
$ 79.97万 - 项目类别:
Operating Grants
Study of pathogenic mechanism of age-dependent chromosome translocation in adult acute lymphoblastic leukemia
成人急性淋巴细胞白血病年龄依赖性染色体易位发病机制研究
- 批准号:
18K16103 - 财政年份:2018
- 资助金额:
$ 79.97万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Causal effect of time-varying driving pressures on mortality in mechanically ventilated, adult patients with acute respiratory distress syndrome
时变驱动压力对机械通气成年急性呼吸窘迫综合征患者死亡率的因果影响
- 批准号:
377313 - 财政年份:2017
- 资助金额:
$ 79.97万 - 项目类别:
Studentship Programs
Role of SETBP1 in adult Ph+ acute lymphoblastic leukemia
SETBP1 在成人 Ph 急性淋巴细胞白血病中的作用
- 批准号:
9315111 - 财政年份:2016
- 资助金额:
$ 79.97万 - 项目类别:
Acute Inhibition of Adult-born Granule Cells and its Effect on Antidepressant Act
成体颗粒细胞的急性抑制及其抗抑郁作用
- 批准号:
8734273 - 财政年份:2013
- 资助金额:
$ 79.97万 - 项目类别: