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Pharmacogenetic analysis of inter-ethnic variability in the uptake transporter SLCO1B1 gene in colombian, mozambican, and portuguese populations
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Abstract(s)
As atividades de enzimas metabólicos e transportadores de fármacos determinam, em larga
medida, a resposta ao fármaco e a sua eliminação. A etnia é uma variável demográfica importante
que contribui para a variabilidade interindividual no metabolismo e transporte de fármacos. Como
resultado de diferenças étnicas na prevalência de polimorfismos de nucleótido único (SNP), pode
ocorrer maior risco de eventos adversos, falha do tratamento ou prevalência de patologias em
algumas populações. Os transportadores de influxo são um dos principais factores que contribuem
para o processo de eliminação de fármacos. Foi demonstrado que os genes que codificam esses
transportadores de influxo são polimórficos. O OATP1B1 é um transportador de influxo conhecido
por mediar a captação de vários compostos endógenos e xenobióticos. Várias variantes foram
descritas no gene SLCO1B1 que codifica o OATP1B1. Entre estas, a variante mais estudada,
c.521T> C, foi descrita como estando significativamente associada ao risco de miopatias induzidas
pela terapêutica com estatinas. Apesar da clara relevância clínica desta variante polimórfica, um
número reduzido de populações foram caracterizadas. Até o momento, não existem dados
epidemiológicos para a variante SLCO1B1 c.521T> C nas populações colombiana, moçambicana
e portuguesa.
Este estudo teve, assim, como objetivo, avaliar as frequências genotípicas e alélicas da variante
SLCO1B1 c.521T> C em voluntários saudáveis colombianos, moçambicanos e portugueses. O
DNA genómico isolado de amostras de sangue obtidas, sob consentimento informado, de 67
indivíduos colombianos, 53 moçambicanos e 61 portugueses foi analisado para este polimorfismo
através de um novo método de genotipagem por PCR-RFLP.
Um total de 47 (70,15%), 12 (17,91%) e 8 (11,94%) dos 67 indivíduos colombianos, 47 (88,68%),
5 (9,43%), 1 (1,89%) dos 53 indivíduos moçambicanos e 40 (65,57%), 16 (26,23%), 5 (8,20%),
dos 61 indivíduos portugueses eram portadores do genótipo T / T-homo, C / T-hetero e C / Chomozigota,
respectivamente . Em termos de frequências alélicas, observou-se um total de 106
alelos T (79,1%) e 28 alelos C (20,9%) em indivíduos colombianos; 99 alelos T (93,4%) e 7 alelos
C (6,6%) C em moçambicanos e 96 alelos T (78,7%) e 26 alelos C (21,3%) em indivíduos
portugueses. As frequências observadas em moçambicanos mostram uma diferença
estatisticamente significativa em relação às observadas em colombianos (p=0,0017) e portugueses
(p=0,0022). Por outro lado, as frequências observadas na amostra da população colombiana não
são significativamente diferentes (p=1.000) em relação às observadas em Portugal.
Em conclusão, os nossos dados demonstraram que o genótipo homozigota T / T é altamente
prevalente, o genótipo homozigota variante, C / C, apresenta a menor frequência em
moçambicanos, sendo por outro lado relativamente frequente em populações colombianas e
portuguesas. Como resultado, indivíduos (principalmente caucasianos) com o genótipo
homozigótico variante c.521C/C podem ser altamente suscetíveis a efeitos adversos relacionados à estatina do que aqueles com o genótipo c.521TT (referência) para o SNP c.521T> C.
The activities of drug metabolizing enzymes and transporters greatly determine drug disposition and response. Ethnicity is an important demographic variable contributing to inter-individual variability in drug metabolism and transport. Influx transporters are one of the key contributors to the process of drug disposition. It has been demonstrated that the genes coding for these influx transporters are polymorphic. OATP1B1 is an influx transporter known to mediate the uptake of various endogenous compounds and xenobiotics. Several sequence variations have been discovered in the SLCO1B1 gene encoding OATP1B1. Statin-induced myopathy is reported to be significantly associated with the c.521T>C polymorphism. To date, there is no SLCO1B1 c.521T>C epidemiologic data for the Colombian, Mozambican and Portuguese populations. Therefore, this study aimed at assessing the genotype and allele frequencies of the SLCO1B1 c.521T>C variant in Colombian, Mozambican and Portuguese healthy volunteers. Genomic DNA isolated from blood samples obtained from 67 Colombian, 53 Mozambican and 61 Portuguese healthy individuals under informed consent was analyzed for the SLCO1B1 c.521T>C polymorphism using a novel PCR-RFLP genotyping method. A total of 47 (70.15%), 12 (17.91%) and 8 (11.94%) out of 67 Colombian individuals, 47(88.68%), 5(9.43%), 1(1.89%) out of 53 Mozambican individuals, and 40(65.57%), 16(26.23%), 5(8.20%), out of 61 Portuguese individuals were SLCO1B1 c.521T>C T/T-homo (reference), C/T-hetero, and C/C-homozygote genotypes, respectively. And the allelic frequency of the populations shows a total of 106 (79.1%) T and 28 (20.9%) C alleles of Colombian individuals, 99 (93.4%) T and 7 (6.6%) C alleles of Mozambican, and 96 (78.7%) T and 26 (21.3%) C alleles of Portuguese individuals. The frequency observed in Mozambicans shows statistically significant difference from the ones observed in Colombians (p=0.0017) and Portuguese (p=0.0022). Whereas the frequency observed in Colombians was not statistically significant (p=1.000) from the ones observed in Portugal. In conclusion, our data demonstrated that the homozygote T/T genotype is highly prevalent, and the homozygote C/C variant is very less frequent in Mozambicans, whereas the homozygote C/C variant was relatively frequent in Colombians and Portuguese populations. As a result, subjects (mainly Caucasians) with the homozygous variant c.521CC genotype may be highly susceptible to statin related adverse effects than those with the c.521TT genotype of the c.521T>C SNP. Key words; SNP, SLCO1B1, statins, influx transporters
The activities of drug metabolizing enzymes and transporters greatly determine drug disposition and response. Ethnicity is an important demographic variable contributing to inter-individual variability in drug metabolism and transport. Influx transporters are one of the key contributors to the process of drug disposition. It has been demonstrated that the genes coding for these influx transporters are polymorphic. OATP1B1 is an influx transporter known to mediate the uptake of various endogenous compounds and xenobiotics. Several sequence variations have been discovered in the SLCO1B1 gene encoding OATP1B1. Statin-induced myopathy is reported to be significantly associated with the c.521T>C polymorphism. To date, there is no SLCO1B1 c.521T>C epidemiologic data for the Colombian, Mozambican and Portuguese populations. Therefore, this study aimed at assessing the genotype and allele frequencies of the SLCO1B1 c.521T>C variant in Colombian, Mozambican and Portuguese healthy volunteers. Genomic DNA isolated from blood samples obtained from 67 Colombian, 53 Mozambican and 61 Portuguese healthy individuals under informed consent was analyzed for the SLCO1B1 c.521T>C polymorphism using a novel PCR-RFLP genotyping method. A total of 47 (70.15%), 12 (17.91%) and 8 (11.94%) out of 67 Colombian individuals, 47(88.68%), 5(9.43%), 1(1.89%) out of 53 Mozambican individuals, and 40(65.57%), 16(26.23%), 5(8.20%), out of 61 Portuguese individuals were SLCO1B1 c.521T>C T/T-homo (reference), C/T-hetero, and C/C-homozygote genotypes, respectively. And the allelic frequency of the populations shows a total of 106 (79.1%) T and 28 (20.9%) C alleles of Colombian individuals, 99 (93.4%) T and 7 (6.6%) C alleles of Mozambican, and 96 (78.7%) T and 26 (21.3%) C alleles of Portuguese individuals. The frequency observed in Mozambicans shows statistically significant difference from the ones observed in Colombians (p=0.0017) and Portuguese (p=0.0022). Whereas the frequency observed in Colombians was not statistically significant (p=1.000) from the ones observed in Portugal. In conclusion, our data demonstrated that the homozygote T/T genotype is highly prevalent, and the homozygote C/C variant is very less frequent in Mozambicans, whereas the homozygote C/C variant was relatively frequent in Colombians and Portuguese populations. As a result, subjects (mainly Caucasians) with the homozygous variant c.521CC genotype may be highly susceptible to statin related adverse effects than those with the c.521TT genotype of the c.521T>C SNP. Key words; SNP, SLCO1B1, statins, influx transporters
Description
Keywords
SNP SLCO1B1 Estatinas Transportadores de influxo