Research square · 2025
Multi-omic insights from a multi-ancestry genome-wide meta-analysis of ankylosing spondylitis reveal novel pathways of disease susceptibility.
СтатьяПрепринтНазвание 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.
Brown Matthew, Li Zhixiu, Wu Xin, Harvey Nicholas, Garrido-Mesa Jose, Wang Xiaobing, Xu Zhihao, Wang Geng, Marzo-Ortega Helena, McGonagle Dennis, Morgan Ann, Akkoc Nurullah, Artin Gokce Kenar, Macfarlane Gary, Jones Gareth, Bradbury Linda, Leo Paul, Zimmerman Kate, Duncan Emma, Brown Julia, Merriman Tony, Stebbings Simon, Mahmoudi Mahdi, Jamshidi Ahmadreza, Farhadi Elham, Haroon Nigil, Inman Robert, Breban Maxime, Lianne Gensler, Ward Michael, Wordsworth B, Weisman Michael, Evans David, Kenna Tony, Kim Tae-Hwan, Reveille John, Xu Huji
Аннотация
We report the largest genome-wide association study meta-analysis in ankylosing spondylitis (AS) to date (25,645 cases, 71,224 controls), identifying 27 novel loci and 86 independent genetic associations. Variations in FUT2 (non-secretor status) and ABO (blood group A) increase AS risk, with Mendelian randomisation (MR) linking non-secretor status to increased AS risk from reduced gut carriage of Ruminococcus torques. Associations with three telomerase maintenance genes (TERT, TERC, RTEL1), and MR analysis, suggest increased telomere length causally increases AS susceptibility. Fine-mapping prioritised likely causal variants at multiple loci. Transcriptome- and proteome-wide association studies implicated 644 genes, highlighting immune-related pathways. Lower genetically-determined IL-6 and IL-12, and similar IL-23, levels were found in AS cases, offering a genetic explanation for the failure of IL-6, IL-12, and IL-23 inhibition in AS treatment. Finally, multi-omic analyses showed chromosome 2p15 association acts via reduced B3GNT2 expression. These findings deepen understanding of AS pathogenesis, highlighting new pathways and therapeutic opportunities.