The prevalence of TPH1 and TPH2 genetic polymorphisms susceptible to irritable bowel syndrome (IBS) among unrelated, healthy Malays in Malaysia

Abstract

Tryptophan hydroxylase (TPH) gene which encodes the first rate-limiting enzyme in the serotonin biosynthesis pathway is one of the leading candidate genes in the etiology of the most common gastrointestinal (GI) disease, the irritable bowel syndrome (IBS). The SNPs in the gene would distract the serotonergic function which led to the susceptibility to the syndrome. This study is aimed to determine the genotype distributions and allele frequencies of the three SNPs from two TPH genes; TPH1 and TPH2 genes among healthy, unrelated Malays in Malaysia. Nested-multiplex-allele specific PCR (NMAS-PCR) was subjected to 404 archived Malays’ DNA to genotype rs211105, rs4537731 and rs4570625 variants following the validation of genotyping results obtained through the direct Sanger sequencing. Results showed the genotype frequencies of AA in rs211105 and rs4537731 among Malays was 59.2 and 51.5%. The heterozygous of GT was found to be slightly higher than GG with 47.5 to 43.3% in rs4570625. Meanwhile, the mutant allele frequencies of rs211105 (G) and rs4537731 (T) were considerably comparable with 30.3 to 33.0% accordingly. Concurrently, no departure of HWE was detected except in rs4537731. This study described low frequencies of TPH1 and TPH2 SNPs mutant variants associated with the IBS among unrelated, healthy Malays. Data generated from this study is important to enhance our knowledge on the association of IBS pharmacogenetic profiles and the ethnic differences. Future studies on Malaysian IBS patients are recommended to determine the influence of rs211105, rs4537731 and rs4570625 to the syndrome locally.

Keywords

• Irritable bowel syndrome
• IBS
• rs211105
• rs4537731
• rs4570625
• Malay
• Malaysia

Supporting Institution

Universiti Sultan Zainal Abidin

Project Number

Lab Material (LABMAT) Research Grant, UniSZA/LABMAT/2018/03, R0044-R003

Thanks

Authors would like to thanks to all healthy volunteers from the Development of Ethno-pharmacogenetics Relatedness and Personalized Medicine project (Grant no: 1001/PSK/8620013) for the blood samples of this study.

References

1. Andreou, D., Saetre, P., Werge, T., Andreassen, O. A., Agartz, I., Sedvall, G. C., Hall, H., Terenius, L., and Jönsson, E. G. (2010). Tryptophan hydroxylase gene 1 (TPH1) variants associated with cerebrospinal fluid 5-hydroxyindole acetic acid and homovanillic acid concentrations in healthy volunteers. Psychiatry Research, 180, 63–67.
2. Andreou, D., Söderman, E., Axelsson, T., Sedvall, G .C., Terenius, L., Agartz, I., and Jönsson, E.G. 2014. Polymorphisms in genes implicated in dopamine, serotonin and noradrenalin metabolism suggest association with cerebrospinal fluid monoamine metabolite concentrations in psychosis. Behavioral Brain Function, 10, 1–10.
3. Baehne, C. G., Ehlis, A. C., Plichta, M. M., Conzelmann, A., Pauli, P., Jacob, C., Gutknecht, L., Lesch, K. P., and Fallgatter, A. J. (2009). Tph2 gene variants modulate response control processes in adult ADHD patients and healthy individuals. Molecular Psychiatry, 14, 1032–1039.
4. Camilleri, M. (2019). Implications of Pharmacogenomics to the Management of IBS. Clinical Gastroenterology Hepatology, 17, 584–594.
5. Davies, A., Rodriguez-Vicente, A. E., Austin, G., Loaiza, S., Foroni, L., Clark, R. E., & Pirmohamed, M. (2020). Serotonin re-uptake transporter gene polymorphisms are associated with imatinib-induced diarrhoea in chronic myeloid leukaemia patients. Scientific Reports, 10(8394), 1–9.
6. De Bortoli, N., Tolone, S., Frazzoni, M., Martinucci, I., Sgherri, G., Albano, E., Ceccarelli, L., Stasi, C., Bellini, M., Savarino, V., Savarino, E. V., & Marchi, S. (2018). Gastroesophageal reflux disease, functional dyspepsia and irritable bowel syndrome: Common overlapping gastrointestinal disorders. Annals of Gastroenterology, 31, 639–648.
7. Han, K-M., Won, E., Kang, J., Kim, A., Yoon, H-K., Chang, H. S., Son, K. R., Lee, M-S., Tae, W-S., and Ham, B-J. (2017). Local gyrification index in patients with major depressive disorder and its association with Tryptophan hydroxylase-2 (TPH2) polymorphism. Human Brain Mapp, 38, 1299–1310.
8. Jun, S., Kohen, R., Cain, K. C., Jarrett, M. E., & Heitkemper, M. M. (2011). Associations of tryptophan hydroxylase gene polymorphisms with irritable bowel syndrome. Neurogastroenterology and Motility, 23(3), 233–240.

9. Katsumata, R., Shiotani, A., Murao, T., Ishii, M., Fujita, M., Matsumoto, H., & Haruma, K. (2018). The TPH1 rs211105 gene polymorphism affects abdominal symptoms and quality of life of diarrhea-predominant irritable bowel syndrome. Journal of Clinical Biochemistry and Nutrition, 62(3), 270–276.
10. Kim, Y. K., Lee, H. J., Yang, J. C., Hwang, J. A., and Yoon, H. K. (2009). A tryptophan hydroxylase 2 gene polymorphism is associated with panic disorder. Behavioral Genetics, 39, 170–175.
11. Narayanan, S. P., Anderson, B., and Bharucha, A. E. (2021). Sex- and Gender-Related Differences in Common Functional Gastroenterologic Disorders. Mayo Clinical Proceedings, 96, 1071–1089.
12. Relling, M. V., & Evans, W. E. (2015). Pharmacogenomics in the clinic. Nature, 526(7573), 343–350.
13. Reuter, M., Kuepper, Y., and Hennig, J. (2007). Association between a polymorphism in the promoter region of the TPH2 gene and the personality trait of harm avoidance. International Journal Neuropsychopharmacology, 10, 401–404.
14. Ruocco, A. C., Rodrigo, A. H., and Dean, C. (2016). Tryptophan Hydroxylase 1 gene polymorphisms alter prefrontal cortex activation during response inhibition. Neuropsychology, 30, 18–27.
15. Saetre, P., Lundmark, P., Wang, A., Hansen, T., Rasmussen, H. B., Djurovic, S., Melle, I., Andreassen, O. A., Werge, T., Agartz, I., Hall, H., Terenius, L., and Jönsson, E. G. (2010). The Tryptophan Hydroxylase 1 (TPH1) gene, schizophrenia susceptibility, and suicidal behavior: A multi-centre case-control study and meta-analysis. Am. Journal Medical Genetics, Part B 153, 387–396.
16. Serretti, A., Chiesa, A., Porcelli, S., Han, C., Patkar, A. A., Lee, S. J., Park, M. H., and Pae, C. U. (2011). Influence of TPH2 variants on diagnosis and response to treatment in patients with major depression, bipolar disorder and schizophrenia. Psychiatry Research, 189, 26–32.
17. Shiotani, A., Kusunoki, H., Ishii, M., Imamura, H., Manabe, N., Kamada, T., Hata, J., Merchant, J. L., & Haruma, K. (2015). Pilot study of Biomarkers for predicting effectiveness of ramosetron in diarrhea-predominant irritable bowel syndrome: Expression of S100A10 and polymorphisms of TPH1. Neurogastroenterology and Motility, 27, 81–91. doi.org/10.1111/nmo.12473
18. Snarska, J., Fiewdorowicz, E., Rozmus, D., Latacz, M., Kordulewska, N., Plominski, J., Grzybowski, R., Savelkoul, H. F. J., Kostyra, E., and Cieslinska, A. (2021). TPH1 gene polymorphism rs211105 influences serotonin and tryptophan hydroxylase 1 concentrations in acute pancreatitis patients. Research Sq, 1–21
19. Sperber, A. D., Bangdiwala, S. I., Drossman, D. A., Ghoshal, U. C., Simren, M., Tack, J., Whitehead, W. E., Dumitrascu, D. L., Fang, X., Fukudo, S., Kellow, J., Okeke, E., Quigley, E. M. M., Schmulson, M., Whorwell, P., Archampong, T., Adibi, P., Andresen, V., Benninga, M. A., … Palsson, O. S. (2021). Worldwide Prevalence and Burden of Functional Gastrointestinal Disorders, Results of Rome Foundation Global Study. Gastroenterology, 160, 99–117.
20. Sun, H. S., Tsai, H. W., Ko, H. C., Chang, F.M., and Yeh TL. (2004). Association of tryptophan hydroxylase gene polymorphism with depression, anxiety and comorbid depression and anxiety in a population-based sample of postpartum Taiwanese women. Genes, Brain Behavioral, 3, 328–336.
21. Talley, N. J. (2020). What Causes Functional Gastrointestinal Disorders? A Proposed Disease Model. The American Journal of Gastroenterology, 115(1), 41–48.
22. Wigington, W. C., Johnson, W. D., and Minocha, A. (2005). Epidemiology of Irritable Bowel Syndrome Among African Americans as Compared With Whites: A Population-Based Study. Clinical Gastroenterology Hepatology, 3, 647–653.
23. Wigner, P., Czarny, P., Synowiec, E., Bijak, M., Białek, K., Talarowska, M., Galecki, P., Szemraj, J., and Sliwinsk,i T. (2018). Association between single nucleotide polymorphisms of TPH1 and TPH2 genes, and depressive disorders. Journal Cellular Molecule Medicine, 22, 1778–1791.
24. Xiao, Q.-Y., Fang, X.-C., Li, X.-Q., & Fei, G.-J. (2020). Ethnic differences in genetic polymorphism associated with irritable bowel syndrome. In World Journal of Gastroenterology (Vol. 26, Issue 17, pp. 2049–2063). Baishideng Publishing Group Co.
25. Xu, X. M., Ding, M., Pang, H., and Wang, B. J. (2014). TPH2 gene polymorphisms in the regulatory region are associated with paranoid schizophrenia in Northern Han Chinese. Genetices Molecule Research, 13, 1497–1507.
26. Yeo, A., Boyd, P., Lumsden, S., Saunders, T., Handley, A., Stubbins, M., Knaggs, A., Asquith, S., Taylor, I., Bahari, B., Crocker, N., Rallan, R., Varsani, S., Montgomery, D., Alpers, D. H., Dukes, G. E., Purvis, I., & Hicks, G. A. (2004). Association between a functional polymorphism in the serotonin transporter gene and diarrhoea predominant irritable bowel syndrome in women. Gut, 53, 1452–1458.
27. Zhu, S., Wang, B., Jia, Q., & Duan, L. (2019). Candidate single nucleotide polymorphisms of irritable bowel syndrome: A systemic review and meta-analysis. BMC Gastroenterology, 19(165), 1–10.