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An intronic FTO variant rs16952570 confers protection against thiopurine-induced myelotoxicities in multiethnic Asian IBD patients

The Pharmacogenomics Journal volume 20, pages 505–515 (2020)Cite this article

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Abstract

Thiopurines are used in the treatment of inflammatory bowel disease (IBD) but remain clinically challenging to manage due to wide interpatient variability in clinical outcomes and adverse events. Apart from genetic variants in thiopurine S-methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) genes, polymorphisms in FTO alpha-ketoglutarate dependent dioxygenase (FTO) were found predictive of thiopurine-induced leukopenia, albeit with conflicting results. To clarify the role of FTO variants in a multiethnic Asian IBD cohort, we recruited 149 patients on thiopurine-based therapy and genotyped two FTO variants p.Ala134Thr (rs79206939) and rs16952570 T > C using Sanger sequencing. FTO p.Ala134Thr (rs79206939) was non-polymorphic and absent whereas intronic rs16952570 T > C was equally prevalent in Chinese (22%) and Indians (18%) and higher in Malays (28%). Higher nadir white blood cell (WBC) and absolute neutrophil count (ANC) levels were observed in patients harboring FTO rs16952570 CC genotypes compared with TT carriers at 4, 8, and 12 weeks after start of thiopurine therapy (P < 0.05). A similar trend was observed in patients carrying the previously well-characterized NUDT15 rs116855232 wild-type CC genotypes. Further in silico analysis suggests that FTO variants linked to rs16952570, particularly rs74018601, may play a regulatory role in altering the FTO expression. The findings from this study indicate a novel protective association with the FTO variant rs16952570 CC genotype and hematological parameters.

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Fig. 1: Nadir WBC counts
Fig. 2: Nadir WBC counts
Fig. 3: Canonical FTO transcript and other spliced variants visualised on UCSC Genome Browser with version GRCh37/hg19.

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Acknowledgements

The authors would like to thank all study participants and the research coordinators from the Singapore General Hospital and Tan Tock Seng Hospital for their contributions.

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Author notes

  1. Balram Chowbay

    Present address: Division of Cellular & Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, 11 Hospital Drive, Singapore, 169610, Singapore

Authors and Affiliations

  1. Clinical Pharmacology Laboratory, National Cancer Centre, Singapore, Singapore

    Sylvia Chen, Wei Zhi Tan, Sze Sing Lee & Balram Chowbay

  2. Clinical Pharmacology, SingHealth, Singapore, Singapore

    Natalia Sutiman, Wai Fook Leong, Madeline Tjai, Chunyan Wang & Balram Chowbay

  3. Biostatistics Unit, Clinical Trials & Epidemiology Sciences, National Cancer Centre, Singapore, Singapore

    Cindy Lim

  4. Department of Gastroenterology & Hepatology, Singapore General Hospital, Singapore, Singapore

    Chris San Choon Kong, Sai Wei Chuah, Brian John Schwender, Webber Chan, Hang Hock Shim & Khoon Lin Ling

  5. Department of General Medicine, Gastroenterology and Hepatology Service, Sengkang General Hospital, Singapore, Singapore

    Chris San Choon Kong

  6. Tucker Medical, Singapore, Singapore

    Brian John Schwender

  7. Department of Gastroenterology, Tan Tock Seng Hospital, Singapore, Singapore

    Wee Chian Lim

  8. Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore

    Chiea Chuen Khor

  9. Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Chiea Chuen Khor

  10. Division of Human Genetics, Genome Institute of Singapore, Singapore, Singapore

    Chiea Chuen Khor

  11. Centre for Clinician-Scientist Development, Duke-NUS Medical School, Singapore, Singapore

    Balram Chowbay

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Correspondence to Balram Chowbay.

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Chen, S., Tan, W.Z., Sutiman, N. et al. An intronic FTO variant rs16952570 confers protection against thiopurine-induced myelotoxicities in multiethnic Asian IBD patients. Pharmacogenomics J 20, 505–515 (2020). https://doi.org/10.1038/s41397-019-0126-9

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