Distribution and linkage disequilibrium of the enhancer SNP rs5758550 among Latin American populations: influence of continental ancestry

Elias, Anna Beatriz Ribeiro; Araújo, Gilderlanio Santana de; Souza, Sandro José de; Suarez-Kurtz, Guilherme

Distribution and linkage disequilibrium of the enhancer SNP rs5758550 among Latin American populations: influence of continental ancestry

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dc.contributor.author	Elias, Anna Beatriz Ribeiro
dc.contributor.author	Araújo, Gilderlanio Santana de
dc.contributor.author	Souza, Sandro José de
dc.contributor.author	Suarez-Kurtz, Guilherme
dc.date.accessioned	2020-05-13T13:55:46Z
dc.date.available	2020-05-13T13:55:46Z
dc.date.issued	2020-06
dc.description.resumo	Objectives: A single nucleotide polymorphism (SNP), rs5758550, in a critical enhancer region downstream of the CYP2D6 promoter was proposed to modulate CYP2D6 activity, depending on its linkage disequilibrium (LD) with the common CYP2D6 SNP, rs16947. We examined the influence of individual biogeographical ancestry on the frequency distribution of rs5758550 and its LD with rs16947 in Latin American populations. We then inferred the impact of rs5758550 on the predictive accuracy of CYP2D6 metabolizer status based on CYP2D6 haplotypes. Methods: The study cohorts consisted of the Admixed American (AMR) superpopulation of the 1000 Genomes Project (n = 347) plus an admixed Brazilian (BR) cohort (N = 224). Individual proportions of Native, African and European ancestry estimated by ADMIXTURE analysis, were used to design four sub-cohorts, in which one of the three ancestral roots predominated largely (>6 fold) over the other two: AMR-NAT and AMR-EUR, comprised 80 AMR individuals each, with >70% Native or >70% European ancestry, BR-EUR and BR-AFR comprised Brazilians with >90% European (n = 80) or >70% African ancestry (n = 64), respectively. CYP2D6 haplotypes were inferred based on 10 commonly reported CYPD6 variants with or without addition of the enhancer rs5758550 SNP, pairwise LD was assessed by the R parameter, and activity scores were used to infer CYP2D6 metabolizer status. Results: Minor allele frequency (MAF) of all CYP2D6 SNPs, except the rare (<0.02) rs5030656 and rs35742688, differed significantly across sub-cohorts, whereas no difference was observed for rs5758550. The R values for LD between rs5758550 and rs16947 ranged from 0.15 (BR-AFR) to 0.85 (AMR-NAT), with intermediate values in the predominantly European sub-cohorts (0.34-0.67). As a consequence, distribution of CYP2D6 haplotypes containing the rs16947 SNP plus rs5758550 wild-type (A) or variant (G) allele differed markedly across sub-cohorts. Comparison of the CYP2D6 activity scores assigned to the wild-type (CYP2D6*1) and the rs16947-containing haplotypes with or without inclusion of rs5758550, showed that knowledge of the rs5758550 genotype has negligible impact on predicted CYP2D6 phenotypes in AMR-EUR and AMR-NAT, but affects prediction in 10.7 and 21.6% of BR-EUR and BR-AFR individuals, respectively. Conclusion: Collectively, the present results reveal potential pharmacogenomic (PGx) implications of the population diversity in Latin America, affecting a major drug-metabolizing pathway. Thus, the influence of enhancer rs5758550 on assignment of CYP2D6 metabolic phenotypes varies markedly, according to the individual proportions of Native, European and African ancestry. This conclusion reinforces the notion that extrapolation of PGx data across the heterogeneous Latin American is risky, if not inappropriate.	pt_BR
dc.identifier.citation	ELIAS, A. B. R.; ARAÚJO, G. S.; SOUZA, S. J.; SUAREZ-KURTZ, G. Distribution and linkage disequilibrium of the enhancer SNP rs5758550 among Latin American populations: influence of continental ancestry. Pharmacogenet Genomics, [S. l.], v. 30, n. 4, p. 67-72, jun. 2020.	pt_BR
dc.identifier.doi	10.1097/FPC.0000000000000398
dc.identifier.uri	https://repositorio.ufrn.br/jspui/handle/123456789/28973
dc.language	en	pt_BR
dc.subject	Biogeographical ancestry	pt_BR
dc.subject	CYP2D6	pt_BR
dc.subject	metabolic phenotypes	pt_BR
dc.subject	population diversity	pt_BR
dc.title	Distribution and linkage disequilibrium of the enhancer SNP rs5758550 among Latin American populations: influence of continental ancestry	pt_BR
dc.type	article	pt_BR