Frontiers in pharmacology · 2026
Genetic pharmacoepidemiology of JAK inhibitors in chronic immune-mediated skin diseases: implications for precision therapy and medication safety.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Zhang Yuping, Qu Yuan, Luo Qundi, Liang Bibo, Jiang Qiaomu, Zhu Xiaotong, Wu Jing, Bao Weijia
Аннотация
BACKGROUND: This study aims to investigate the associations between genetically proxied JAK inhibition and various disease outcomes and adverse effects, providing insights into therapeutic efficacy and potential side effects for immune-mediated skin diseases (IMIDs).
METHODS: Using Mendelian Randomization (MR), we analyzed genetic proxies for JAK1, JAK2, JAK3, and TYK2 inhibition. Data from the UK Biobank (N = 361,194) and FinnGen (N = 453,733) were utilized to explore associations with nine autoimmune skin diseases, and twelve adverse outcomes, including tuberculosis, non-melanoma skin cancer, lung cancer, and pulmonary embolism. A systematic review of randomized controlled trials (RCTs) on JAK inhibitors in IMIDs was performed to complement the genetic evidence, focusing on safety outcomes.
RESULTS: Summary-data-based MR (SMR) analysis revealed that genetically proxied loss of function mutation of TYK2 was linked to psoriasis (OR = 0.673, 95% CI = 0.512-0.884, p = 0.004), aligning with clinical evidence. Safety analyses yielded genetically supported, hypothesis-generating signals with effect sizes close to unity, including associations between JAK2 inhibition and pulmonary embolism (OR = 0.998, p = 0.035) and tuberculosis (OR = 1.004, p = 0.013), as well as TYK2 inhibition and malignant non-melanoma skin cancer (OR = 1.006, p = 0.047), and lung cancer (OR = 1.002, p = 0.029). These findings should be interpreted cautiously and do not constitute definitive evidence of drug-induced adverse effects. The systematic review partially confirmed the safety of JAK inhibitors in IMIDs.
CONCLUSION: This study supports TYK2 inhibition as a targeted therapy for psoriasis and provides hypothesis-generating genetic evidence for additional target-disease and target-safety associations that warrant further validation.
METHODS: Using Mendelian Randomization (MR), we analyzed genetic proxies for JAK1, JAK2, JAK3, and TYK2 inhibition. Data from the UK Biobank (N = 361,194) and FinnGen (N = 453,733) were utilized to explore associations with nine autoimmune skin diseases, and twelve adverse outcomes, including tuberculosis, non-melanoma skin cancer, lung cancer, and pulmonary embolism. A systematic review of randomized controlled trials (RCTs) on JAK inhibitors in IMIDs was performed to complement the genetic evidence, focusing on safety outcomes.
RESULTS: Summary-data-based MR (SMR) analysis revealed that genetically proxied loss of function mutation of TYK2 was linked to psoriasis (OR = 0.673, 95% CI = 0.512-0.884, p = 0.004), aligning with clinical evidence. Safety analyses yielded genetically supported, hypothesis-generating signals with effect sizes close to unity, including associations between JAK2 inhibition and pulmonary embolism (OR = 0.998, p = 0.035) and tuberculosis (OR = 1.004, p = 0.013), as well as TYK2 inhibition and malignant non-melanoma skin cancer (OR = 1.006, p = 0.047), and lung cancer (OR = 1.002, p = 0.029). These findings should be interpreted cautiously and do not constitute definitive evidence of drug-induced adverse effects. The systematic review partially confirmed the safety of JAK inhibitors in IMIDs.
CONCLUSION: This study supports TYK2 inhibition as a targeted therapy for psoriasis and provides hypothesis-generating genetic evidence for additional target-disease and target-safety associations that warrant further validation.