Response to anti-IL17 therapy in inflammatory disease is not strongly impacted by genetic background

Zhang, Cong; Shestopaloff, Konstantin; Hollis, Benjamin; Kwok, Chun Hei; Hon, Claudia; Hartmann, Nicole; Tian, Chengeng; Wozniak, Magdalena; Santos, Luis; West, Dominique; Gardiner, Stephen; Mallon, Ann-Marie; Readie, Aimee; Martin, Ruvie; Nichols, Thomas; Beste, Michael T.; Zierer, Jonas; Ferrero, Enrico; Vandemeulebroecke, Marc; Jostins-Dean, Luke

doi:10.1016/j.ajhg.2023.08.010

Cited by 4 publications

(2 citation statements)

References 44 publications

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“…Overall, we found only a few genetic variants to influence cardiometabolic drug response in line with other studies that often identified only a few or even no genome-wide significant signals [6,8,28]. A review on drug efficacy GWAS reported that only 15% of drugs exhibit robust gene-treatment interactions [2], the extent of which largely depends on the drug's mode of action.…”

Section: Discussionsupporting

confidence: 89%

Leveraging large-scale biobank EHRs to enhance pharmacogenetics of cardiometabolic disease medications

Sadler,

Apostolov,

Cevallos

et al. 2024

Preprint

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Electronic health records (EHRs) coupled with large-scale biobanks offer great promises to unravel the genetic underpinnings of treatment efficacy. However, medication-induced biomarker trajectories stemming from such records remain poorly studied. Here, we extract clinical and medication prescription data from EHRs and conduct GWAS and rare variant burden tests in the UK Biobank (discovery) and the All of Us program (replication) on ten cardiometabolic drug response outcomes including lipid response to statins, HbA1c response to metformin and blood pressure response to antihypertensives (N = 740-26,669). Our findings at genome-wide significance level recover previously reported pharmacogenetic signals and also include novel associations for lipid response to statins (N = 26,669) nearLDLRandZNF800. Importantly, these associations are treatment-specific and not associated with biomarker progression in medication-naive individuals. Furthermore, we demonstrate that individuals with higher genetically determined low-density and total cholesterol baseline levels experience increased absolute, albeit lower relative biomarker reduction following statin treatment. In summary, we systematically investigated the common and rare pharmacogenetic contribution to cardiometabolic drug response phenotypes in over 50,000 UK Biobank and All of Us participants with EHR and identified clinically relevant genetic predictors for improved personalized treatment strategies.

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Section: Discussionsupporting

confidence: 89%

Leveraging large-scale biobank EHRs to enhance pharmacogenetics of cardiometabolic disease medications

Sadler,

Apostolov,

Cevallos

et al. 2024

Preprint

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show abstract

“…A recent study published by Zhang et al focused on secukinumab, which targets genes thought to confer psoriasis risk both upstream (IL-23R, TYK2, JAK2, STAT3) and downstream (TRAF3IP2/ACT1, TNFAIP3/A20) of IL-17 production. They found that although genetic variation in the IL-17 pathway impacts psoriasis susceptibility, this same variation does not significantly impact treatment response to secukinumab [141]. However, due to possible conflict of interest, further studies in this subject would be useful.…”

Section: Biologic Withdrawal In Psoriasismentioning

confidence: 99%

Functional Genomics and Insights into the Pathogenesis and Treatment of Psoriasis

Shellard,

Rane,

Eyre

et al. 2024

Biomolecules

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Psoriasis is a lifelong, systemic, immune mediated inflammatory skin condition, affecting 1–3% of the world’s population, with an impact on quality of life similar to diseases like cancer or diabetes. Genetics are the single largest risk factor in psoriasis, with Genome-Wide Association (GWAS) studies showing that many psoriasis risk genes lie along the IL-23/Th17 axis. Potential psoriasis risk genes determined through GWAS can be annotated and characterised using functional genomics, allowing the identification of novel drug targets and the repurposing of existing drugs. This review is focused on the IL-23/Th17 axis, providing an insight into key cell types, cytokines, and intracellular signaling pathways involved. This includes examination of currently available biological treatments, time to relapse post drug withdrawal, and rates of primary/secondary drug failure, showing the need for greater understanding of the underlying genetic mechanisms of psoriasis and how they can impact treatment. This could allow for patient stratification towards the treatment most likely to reduce the burden of disease for the longest period possible.

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Functional genomics and insights into the pathogenesis and treatment of psoriasis.

Shellard,

Rane,

Eyre

et al. 2024

Preprint

View full text Add to dashboard Cite

Psoriasis is a lifelong, systemic, immune mediated inflammatory skin condition, affecting 1-3% of the world’s population, with an impact on quality of life similar to diseases like cancer or diabetes. Genetics are the single largest risk factor in psoriasis, with GWAS studies showing that many psoriasis risk genes lie along the IL23/Th17 axis. Potential psoriasis risk genes determined through GWAS can be annotated and characterised using functional genomics, allowing the identification of novel drug targets and the repurposing of existing drugs. The pathogenesis of psoriasis is complex and focusing on the IL23/Th17 axis can provide insight into key cell types, cytokines and intracellular signaling pathways involved. Examination of currently available biological treatments, time to relapse post drug withdrawal and rates of drug primary/secondary drug failure show the need for greater understanding of the underlying genetic mechanisms of psoriasis and how they can impact treatment. This could allow for patient stratification towards the treatment most likely reduce dis-ease burden for the longest period possible.

show abstract

Response to anti-IL17 therapy in inflammatory disease is not strongly impacted by genetic background

Cited by 4 publications

References 44 publications

Leveraging large-scale biobank EHRs to enhance pharmacogenetics of cardiometabolic disease medications

Leveraging large-scale biobank EHRs to enhance pharmacogenetics of cardiometabolic disease medications

Functional Genomics and Insights into the Pathogenesis and Treatment of Psoriasis

Functional genomics and insights into the pathogenesis and treatment of psoriasis.

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