Abstract
Pharmacogenomics (PGx) is a promising field of precision medicine where efficacy of drugs is maximized while side effects are minimized for individual patients. Knowledge of the frequency of PGx-relevant variants (pharmacovariants) in the local population is a pre-requisite to informed policy making. Unfortunately, such knowledge is largely lacking from the Middle East. Here, we describe the use of a large clinical exome database (n = 13,473) and HLA haplotypes (n = 64,737) from Saudi Arabia, one of the largest countries in the Middle East, along with previously published data from the local population to ascertain allele frequencies of known pharmacovariants. In addition, we queried another exome database (n = 816) of well-phenotyped research subjects from Saudi Arabia to discover novel candidate variants in known PGx genes (pharmacogenes). Although our results show that only 26% (63/242) of class 1A/1B PharmGKB variants were identified, we estimate that 99.57% of the local population have at least one such variant. This translates to a minimum estimated impact of 9% of medications dispensed by our medical center annually. We also highlight the contribution of rare variants where 71% of the pharmacogenes devoid of common pharmacovariants had at least one potentially deleterious rare variant. Thus, we show that approaches that go beyond the use of commercial PGx kits that have been optimized for other populations should be implemented to ensure universal and equitable access of all members of the local population to personalized prescription practices.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abou Tayoun AN, Fakhro KA, Alsheikh-Ali A, Alkuraya FS (2021) Genomic medicine in the Middle East. Genome Med 13:184. https://doi.org/10.1186/s13073-021-01003-9
Alali M, Ismail Al-Khalil W, Rijjal S, Al-Salhi L, Saifo M, Youssef LA (2022) Frequencies of CYP2D6 genetic polymorphisms in Arab populations. Hum Genom 16:6. https://doi.org/10.1186/s40246-022-00378-z
Aldahmesh MA, Khan AO, Meyer BF, Alkuraya FS (2009) Mutational spectrum of SLC4A11 in autosomal recessive CHED in Saudi Arabia. Invest Ophthalmol vis Sci 50:4142–4145. https://doi.org/10.1167/iovs.08-3006
Al-Dosari MS, Al-Jenoobi FI, Alkharfy KM, Alghamdi AM, Bagulb KM, Parvez MK, Al-Mohizea AM, Al-Muhsen S, Halwani R (2013) High prevalence of CYP2D6*41 (G2988A) allele in Saudi Arabians. Environ Toxicol Pharmacol 36:1063–1067. https://doi.org/10.1016/j.etap.2013.09.008
Alfraih F, Alawwami M, Aljurf M, Alhumaidan H, Alsaedi H, El Fakih R, Alotaibi B, Rasheed W, Bernas SN, Massalski C (2021) High-resolution HLA allele and haplotype frequencies of the Saudi Arabian population based on 45,457 individuals and corresponding stem cell donor matching probabilities. Hum Immunol 82:97–102
Al-Jenoobi FI, Alkharfy KM, Alghamdi AM, Bagulb KM, Al-Mohizea AM, Al-Muhsen S, Halwani R, Parvez MK, Al-Dosari MS (2013) CYP2C19 genetic polymorphism in Saudi Arabians. Basic Clin Pharmacol Toxicol 112:50–54. https://doi.org/10.1111/j.1742-7843.2012.00919.x
Al-Saikhan FI (2020) Genetic risk assessment towards warfarin application: Saudi Arabia study with a potential to predict and prevent side effects. Saudi J Biol Sci 27:456–459. https://doi.org/10.1016/j.sjbs.2019.11.007
Beutler E (1993a) Study of glucose-6-phosphate dehydrogenase: history and molecular biology. Am J Hematol 42:53–58. https://doi.org/10.1002/ajh.2830420111
Chanfreau-Coffinier C, Hull LE, Lynch JA, DuVall SL, Damrauer SM, Cunningham FE, Voight BF, Matheny ME, Oslin DW, Icardi MS (2019) Projected prevalence of actionable pharmacogenetic variants and level A drugs prescribed among US Veterans Health Administration pharmacy users. JAMA Netw Open 2:e195345–e195345
Chen P, Lin JJ, Lu CS, Ong CT, Hsieh PF, Yang CC, Tai CT, Wu SL, Lu CH, Hsu YC, Yu HY, Ro LS, Lu CT, Chu CC, Tsai JJ, Su YH, Lan SH, Sung SF, Lin SY, Chuang HP, Huang LC, Chen YJ, Tsai PJ, Liao HT, Lin YH, Chen CH, Chung WH, Hung SI, Wu JY, Chang CF, Chen L, Chen YT, Shen CY, Taiwan SJSC (2011) Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan. N Engl J Med 364:1126–1133. https://doi.org/10.1056/NEJMoa1009717
Collins FS, Varmus H (2015) A new initiative on precision medicine. N Engl J Med 372:793–795. https://doi.org/10.1056/NEJMp1500523
Cooper-DeHoff RM, Niemi M, Ramsey LB, Luzum JA, Tarkiainen EK, Straka RJ, Gong L, Tuteja S, Wilke RA, Wadelius M, Larson EA, Roden DM, Klein TE, Yee SW, Krauss RM, Turner RM, Palaniappan L, Gaedigk A, Giacomini KM, Caudle KE, Voora D (2022) The clinical pharmacogenetics implementation consortium guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and statin-associated musculoskeletal symptoms. Clin Pharmacol Ther 111(5):1007–1021. https://doi.org/10.1002/cpt.2557
Elalem EG, Jelani M, Khedr A, Ahmad A, Alaama TY, Alaama MN, Al-Kreathy HM, Damanhouri ZA (2022) Association of cytochromes P450 3A4*22 and 3A5*3 genotypes and polymorphism with response to simvastatin in hypercholesterolemia patients. PLoS ONE 17:e0260824. https://doi.org/10.1371/journal.pone.0260824
Fatumo S, Chikowore T, Choudhury A, Ayub M, Martin AR, Kuchenbaecker K (2022) A roadmap to increase diversity in genomic studies. Nat Med 28:243–250. https://doi.org/10.1038/s41591-021-01672-4
Flockhart DA, O’Kane D, Williams MS, Watson MS, Flockhart DA, Gage B, Gandolfi R, King R, Lyon E, Nussbaum R, O’Kane D, Schulman K, Veenstra D, Williams MS, Watson MS, Acmg Working Group on Pharmacogenetic Testing of Cyp2C VAfWU (2008) Pharmacogenetic testing of CYP2C9 and VKORC1 alleles for warfarin. Genet Med 10:139–150. https://doi.org/10.1097/GIM.0b013e318163c35f
Goettler M, Schneeweiss S, Hasford J (1997) Adverse drug reaction monitoring—cost and benefit considerations. Part II: cost and preventability of adverse drug reactions leading to hospital admission. Pharmacoepidemiol Drug Saf 6(Suppl 3):79–90. https://doi.org/10.1002/(sici)1099-1557(199710)6:3+%3cs79::aid-pds294%3e3.3.co;2-f
Haas DW, Ribaudo HJ, Kim RB, Tierney C, Wilkinson GR, Gulick RM, Clifford DB, Hulgan T, Marzolini C, Acosta EP (2004) Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS 18:2391–2400
Hoonhout LH, de Bruijne MC, Wagner C, Zegers M, Waaijman R, Spreeuwenberg P, Asscheman H, van der Wal G, van Tulder MW (2009) Direct medical costs of adverse events in Dutch hospitals. BMC Health Serv Res 9:27. https://doi.org/10.1186/1472-6963-9-27
Jarvis JP, Peter AP, Keogh M, Baldasare V, Beanland GM, Wilkerson ZT, Kradel S, Shaman JA (2022) Real-world impact of a pharmacogenomics-enriched comprehensive medication management program. J Pers Med 12:10. https://doi.org/10.3390/jpm12030421
Jiang S, Mathias PC, Hendrix N, Shirts BH, Tarczy-Hornoch P, Veenstra D, Malone D, Devine B (2022) Implementation of pharmacogenomic clinical decision support for health systems: a cost-utility analysis. Pharmacogenomics J 22:188–197. https://doi.org/10.1038/s41397-022-00275-7
Jithesh PV, Abuhaliqa M, Syed N, Ahmed I, El Anbari M, Bastaki K, Sherif S, Umlai UK, Jan Z, Gandhi G, Manickam C, Selvaraj S, George C, Bangarusamy D, Abdel-Latif R, Al-Shafai M, Tatari-Calderone Z, Estivill X, Qatar Genome Program Research C (2022) A population study of clinically actionable genetic variation affecting drug response from the Middle East. NPJ Genom Med 7:10. https://doi.org/10.1038/s41525-022-00281-5
Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM, Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE, Altman RB, Clinical Pharmacogenetics Implementation C (2011) Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 90:625–629. https://doi.org/10.1038/clpt.2011.185
Kozyra M, Ingelman-Sundberg M, Lauschke VM (2017) Rare genetic variants in cellular transporters, metabolic enzymes, and nuclear receptors can be important determinants of interindividual differences in drug response. Genet Med 19:20–29
Krebs K, Milani L (2019) Translating pharmacogenomics into clinical decisions: do not let the perfect be the enemy of the good. Hum Genom 13:39. https://doi.org/10.1186/s40246-019-0229-z
Lee HH, Ho RH (2017) Interindividual and interethnic variability in drug disposition: polymorphisms in organic anion transporting polypeptide 1B1 (OATP1B1; SLCO1B1). Br J Clin Pharmacol 83:1176–1184
Lee S-b, Wheeler MM, Patterson K, McGee S, Dalton R, Woodahl EL, Gaedigk A, Thummel KE, Nickerson DA (2019) Stargazer: a software tool for calling star alleles from next-generation sequencing data using CYP2D6 as a model. Genet Med 21:361–372
Lehtisalo M, Taskinen S, Tarkiainen EK, Neuvonen M, Viinamäki J, Paile-Hyvärinen M, Lilius TO, Tapaninen T, Backman JT, Tornio A (2023) A comprehensive pharmacogenomic study indicates roles for SLCO1B1, ABCG2 and SLCO2B1 in rosuvastatin pharmacokinetics. Br J Clin Pharmacol 89:242–252
Magavern EF, Gurdasani D, Ng FL, Lee SS (2022) Health equality, race and pharmacogenomics. Br J Clin Pharmacol 88:27–33. https://doi.org/10.1111/bcp.14983
Martin A, Downing J, Maden M, Fleeman N, Alfirevic A, Haycox A, Pirmohamed M (2017) An assessment of the impact of pharmacogenomics on health disparities: a systematic literature review. Pharmacogenomics 18:1541–1550. https://doi.org/10.2217/pgs-2017-0076
McDonagh EM, Thorn CF, Bautista JM, Youngster I, Altman RB, Klein TE (2012) PharmGKB summary: very important pharmacogene information for G6PD. Pharmacogenet Genomics 22:219–228. https://doi.org/10.1097/FPC.0b013e32834eb313
McInnes G, Lavertu A, Sangkuhl K, Klein TE, Whirl-Carrillo M, Altman RB (2021) Pharmacogenetics at scale: an analysis of the UK Biobank. Clin Pharmacol Ther 109:1528–1537. https://doi.org/10.1002/cpt.2122
McLellan RA, Oscarson M, Seidegard J, Evans DA, Ingelman-Sundberg M (1997) Frequent occurrence of CYP2D6 gene duplication in Saudi Arabians. Pharmacogenetics 7:187–191. https://doi.org/10.1097/00008571-199706000-00003
Mizzi C, Peters B, Mitropoulou C, Mitropoulos K, Katsila T, Agarwal MR, Van Schaik RH, Drmanac R, Borg J, Patrinos GP (2014) Personalized pharmacogenomics profiling using whole-genome sequencing. Pharmacogenomics 15:1223–1234
Morris SA, Alsaidi AT, Verbyla A, Cruz A, Macfarlane C, Bauer J, Patel JN (2022) Cost effectiveness of pharmacogenetic testing for drugs with clinical pharmacogenetics implementation consortium (CPIC) guidelines: a systematic review. Clin Pharmacol Ther 112:1318–1328. https://doi.org/10.1002/cpt.2754
Nkhoma ET, Poole C, Vannappagari V, Hall SA, Beutler E (2009) The global prevalence of glucose-6-phosphate dehydrogenase deficiency: a systematic review and meta-analysis. Blood Cells Mol Dis 42:267–278. https://doi.org/10.1016/j.bcmd.2008.12.005
Pandi MT, Williams MS, van der Spek P, Koromina M, Patrinos GP (2020) Exome-wide analysis of the DiscovEHR cohort reveals novel candidate pharmacogenomic variants for clinical pharmacogenomics. Genes (basel). https://doi.org/10.3390/genes11050561
Pasanen MK, Neuvonen M, Neuvonen PJ, Niemi M (2006) SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid. Pharmacogenet Genom 16:873–879. https://doi.org/10.1097/01.fpc.0000230416.82349.90
Ramsey LB, Bruun GH, Yang W, Treviño LR, Vattathil S, Scheet P, Cheng C, Rosner GL, Giacomini KM, Fan Y (2012) Rare versus common variants in pharmacogenetics: SLCO1B1 variation and methotrexate disposition. Genome Res 22:1–8
Relling MV, Evans WE (2015) Pharmacogenomics in the clinic. Nature 526:343–350. https://doi.org/10.1038/nature15817
Relling MV, Klein TE, Gammal RS, Whirl-Carrillo M, Hoffman JM, Caudle KE (2020) The Clinical Pharmacogenetics Implementation Consortium: 10 Years Later. Clin Pharmacol Ther 107:171–175. https://doi.org/10.1002/cpt.1651
Runcharoen C, Fukunaga K, Sensorn I, Iemwimangsa N, Klumsathian S, Tong H, Vo NS, Le L, Hlaing TM, Thant M (2021) Prevalence of pharmacogenomic variants in 100 pharmacogenes among Southeast Asian populations under the collaboration of the Southeast Asian Pharmacogenomics Research Network (SEAPharm). Human Genome Variation 8:7
Shekhani R, Steinacher L, Swen JJ, Ingelman-Sundberg M (2020) Evaluation of current regulation and guidelines of pharmacogenomic drug labels: opportunities for improvements. Clin Pharmacol Ther 107:1240–1255. https://doi.org/10.1002/cpt.1720
Shendre A, Dillon C, Limdi NA (2018) Pharmacogenetics of warfarin dosing in patients of African and European ancestry. Pharmacogenomics 19:1357–1371. https://doi.org/10.2217/pgs-2018-0146
Tomlinson B, Hu M, Lee V, Lui S, Chu T, Poon E, Ko G, Baum L, Tam L, Li E (2010) ABCG2 polymorphism is associated with the low-density lipoprotein cholesterol response to rosuvastatin. Clin Pharmacol Ther 87:558–562
Turongkaravee S, Jittikoon J, Lukkunaprasit T, Sangroongruangsri S, Chaikledkaew U, Thakkinstian A (2021) A systematic review and meta-analysis of genotype-based and individualized data analysis of SLCO1B1 gene and statin-induced myopathy. Pharmacogenomics J 21:296–307. https://doi.org/10.1038/s41397-021-00208-w
Walker GJ, Harrison JW, Heap GA, Voskuil MD, Andersen V, Anderson CA, Ananthakrishnan AN, Barrett JC, Beaugerie L, Bewshea CM (2019) Association of genetic variants in NUDT15 with thiopurine-induced myelosuppression in patients with inflammatory bowel disease. JAMA 321:773–785
White C, Scott R, Paul CL, Ackland SP (2022) Pharmacogenomics in the era of personalised medicine. Med J Aust 217:510–513. https://doi.org/10.5694/mja2.51759
Wu C, Bell CM, Wodchis WP (2012) Incidence and economic burden of adverse drug reactions among elderly patients in Ontario emergency departments: a retrospective study. Drug Saf 35:769–781. https://doi.org/10.1007/BF03261973
Yang Y, Botton MR, Scott ER, Scott SA (2017) Sequencing the CYP2D6 gene: from variant allele discovery to clinical pharmacogenetic testing. Pharmacogenomics 18:673–685
Youssef E, Kirkdale CL, Wright DJ, Guchelaar HJ, Thornley T (2021) Estimating the potential impact of implementing pre-emptive pharmacogenetic testing in primary care across the UK. Br J Clin Pharmacol 87:2907–2925. https://doi.org/10.1111/bcp.14704
Yu MHC, Chan MCY, Chung CCY, Li AWT, Yip CYW, Mak CCY, Chau JFT, Lee M, Fung JLF, Tsang MHY (2021) Actionable pharmacogenetic variants in Hong Kong Chinese exome sequencing data and projected prescription impact in the Hong Kong population. PLoS Genet 17:e1009323
Zhou Y, Lauschke VM (2022) Population pharmacogenomics: an update on ethnogeographic differences and opportunities for precision public health. Hum Genet 141:1113–1136. https://doi.org/10.1007/s00439-021-02385-x
Zhu Y, Moriarty JP, Swanson KM, Takahashi PY, Bielinski SJ, Weinshilboum R, Wang L, Borah BJ (2021) A model-based cost-effectiveness analysis of pharmacogenomic panel testing in cardiovascular disease management: preemptive, reactive, or none? Genet Med 23:461–470. https://doi.org/10.1038/s41436-020-00995-w
Funding
The authors have not disclosed any funding.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
Authors declare no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
439_2023_2628_MOESM1_ESM.xlsx
Table S1: The list of the 242 actionable pharmacogenetic variants/alleles. The highlighted variants in yellow are not covered by our exome sequencing target regions (XLSX 34 KB)
439_2023_2628_MOESM2_ESM.xlsx
Table S2: Frequency of actionable phenotype(s) and projected impact for each drug over the period 2018-2021 (based on screened variants in WES) (Sheet 1). Frequency of actionable phenotype(s) and projected impact for each drug over the periond 2018-2021 (From screened variants in WES and from the literature for non-coding variants) (Sheet 2) (XLSX 40 KB)
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Abouelhoda, M., Almuqati, N., Abogosh, A. et al. Mining local exome and HLA data to characterize pharmacogenetic variants in Saudi Arabia. Hum. Genet. 143, 125–136 (2024). https://doi.org/10.1007/s00439-023-02628-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-023-02628-z