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Frequencies of poor metabolizer alleles of 12 pharmacogenomic actionable genes in Punjabi Sikhs of Indian Origin

Diversity in drug response is attributed to both genetic and non-genetic factors. However, there is paucity of pharmacogenetics information across ethnically and genetically diverse populations of India. Here, we have analyzed 21 SNPs from 12 pharmacogenomics genes in Punjabi Sikhs of Indian origin...

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Autores principales: Sanghera, Dharambir K., Bejar, Cynthia, Sapkota, Bishwa, Wander, Gurpreet S., Ralhan, Sarju
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200732/
https://www.ncbi.nlm.nih.gov/pubmed/30356105
http://dx.doi.org/10.1038/s41598-018-33981-z
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author Sanghera, Dharambir K.
Bejar, Cynthia
Sapkota, Bishwa
Wander, Gurpreet S.
Ralhan, Sarju
author_facet Sanghera, Dharambir K.
Bejar, Cynthia
Sapkota, Bishwa
Wander, Gurpreet S.
Ralhan, Sarju
author_sort Sanghera, Dharambir K.
collection PubMed
description Diversity in drug response is attributed to both genetic and non-genetic factors. However, there is paucity of pharmacogenetics information across ethnically and genetically diverse populations of India. Here, we have analyzed 21 SNPs from 12 pharmacogenomics genes in Punjabi Sikhs of Indian origin (N = 1,616), as part of the Sikh Diabetes Study (SDS). We compared the allele frequency of poor metabolism (PM) phenotype among Sikhs across other major global populations from the Exome Aggregation Consortium and 1000 Genomes. The PM phenotype of CYP1A2*1 F for slow metabolism of caffeine and carcinogens was significantly higher in Indians (SDS 42%, GIH [Gujarati] 51%, SAS [Pakistani] 45%) compared to Europeans 29% (p(genotype) = 5.3E-05). Similarly, South Asians had a significantly higher frequency of CYP2C9*3 (12% SDS, 13% GIH, 11% SAS) vs. 7% in Europeans (p(genotype) = <1.0E-05) and ‘T’ allele of CYP4F2 (36%) SDS, (43%) GIH, 40% (SAS) vs. (29%) in Europeans (p(genotype) = <1.0E-05); both associated with a higher risk of bleeding with warfarin. All South Asians –the Sikhs (0.36), GIH (0.34), and SAS (0.36) had a higher frequency of the NAT2*6 allele (linked with slow acetylation of isoniazid) compared to Europeans (0.29). Additionally, the prevalence of the low activity ‘C’ allele of MTHFR (rs1801131) was highest in Sikhs compared to all other ethnic groups [SDS (44%), GIH (39%), SAS (42%) and European (32%) (p(genotype) = <1.0E-05)]. SNPs in MTHFR affect metabolism of statins, 5-fluorouracil and methotrexate-based cancer drugs. These findings underscore the need for evaluation of other endogamous ethnic groups of India and beyond for establishing a global benchmark for pre-emptive genotyping in drug metabolizing genes before beginning therapeutic intervention.
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spelling pubmed-62007322018-10-25 Frequencies of poor metabolizer alleles of 12 pharmacogenomic actionable genes in Punjabi Sikhs of Indian Origin Sanghera, Dharambir K. Bejar, Cynthia Sapkota, Bishwa Wander, Gurpreet S. Ralhan, Sarju Sci Rep Article Diversity in drug response is attributed to both genetic and non-genetic factors. However, there is paucity of pharmacogenetics information across ethnically and genetically diverse populations of India. Here, we have analyzed 21 SNPs from 12 pharmacogenomics genes in Punjabi Sikhs of Indian origin (N = 1,616), as part of the Sikh Diabetes Study (SDS). We compared the allele frequency of poor metabolism (PM) phenotype among Sikhs across other major global populations from the Exome Aggregation Consortium and 1000 Genomes. The PM phenotype of CYP1A2*1 F for slow metabolism of caffeine and carcinogens was significantly higher in Indians (SDS 42%, GIH [Gujarati] 51%, SAS [Pakistani] 45%) compared to Europeans 29% (p(genotype) = 5.3E-05). Similarly, South Asians had a significantly higher frequency of CYP2C9*3 (12% SDS, 13% GIH, 11% SAS) vs. 7% in Europeans (p(genotype) = <1.0E-05) and ‘T’ allele of CYP4F2 (36%) SDS, (43%) GIH, 40% (SAS) vs. (29%) in Europeans (p(genotype) = <1.0E-05); both associated with a higher risk of bleeding with warfarin. All South Asians –the Sikhs (0.36), GIH (0.34), and SAS (0.36) had a higher frequency of the NAT2*6 allele (linked with slow acetylation of isoniazid) compared to Europeans (0.29). Additionally, the prevalence of the low activity ‘C’ allele of MTHFR (rs1801131) was highest in Sikhs compared to all other ethnic groups [SDS (44%), GIH (39%), SAS (42%) and European (32%) (p(genotype) = <1.0E-05)]. SNPs in MTHFR affect metabolism of statins, 5-fluorouracil and methotrexate-based cancer drugs. These findings underscore the need for evaluation of other endogamous ethnic groups of India and beyond for establishing a global benchmark for pre-emptive genotyping in drug metabolizing genes before beginning therapeutic intervention. Nature Publishing Group UK 2018-10-24 /pmc/articles/PMC6200732/ /pubmed/30356105 http://dx.doi.org/10.1038/s41598-018-33981-z Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Sanghera, Dharambir K.
Bejar, Cynthia
Sapkota, Bishwa
Wander, Gurpreet S.
Ralhan, Sarju
Frequencies of poor metabolizer alleles of 12 pharmacogenomic actionable genes in Punjabi Sikhs of Indian Origin
title Frequencies of poor metabolizer alleles of 12 pharmacogenomic actionable genes in Punjabi Sikhs of Indian Origin
title_full Frequencies of poor metabolizer alleles of 12 pharmacogenomic actionable genes in Punjabi Sikhs of Indian Origin
title_fullStr Frequencies of poor metabolizer alleles of 12 pharmacogenomic actionable genes in Punjabi Sikhs of Indian Origin
title_full_unstemmed Frequencies of poor metabolizer alleles of 12 pharmacogenomic actionable genes in Punjabi Sikhs of Indian Origin
title_short Frequencies of poor metabolizer alleles of 12 pharmacogenomic actionable genes in Punjabi Sikhs of Indian Origin
title_sort frequencies of poor metabolizer alleles of 12 pharmacogenomic actionable genes in punjabi sikhs of indian origin
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200732/
https://www.ncbi.nlm.nih.gov/pubmed/30356105
http://dx.doi.org/10.1038/s41598-018-33981-z
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