RESUMO
This Commentary focuses on genetic polymorphisms in membrane transporters. We present two polymorphisms for which there is a compelling body of literature supporting their clinical relevance: OATP1B1 (c.521T>C, p.V174A, rs4149056) and BCRP (c.421C>A, p.Q141K, rs2231142). The clinical evidence demonstrating their role in variation in pharmacokinetics and pharmacodynamics is described along with their allele frequencies in ethnic populations. Recommendations for incorporating studies of transporter polymorphisms in drug development are provided, along with the regulatory implications.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Proteínas de Membrana Transportadoras/genética , Proteínas de Neoplasias/genética , Transportadores de Ânions Orgânicos/genética , Polimorfismo Genético/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Ensaios Clínicos como Assunto , Descoberta de Drogas , Frequência do Gene/genética , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado , FarmacogenéticaRESUMO
HLA class II nucleotide sequence polymorphisms were examined in eight ethnic groups of Asia-Oceania using DNA typing methods. Allele frequencies and characteristic DR/DQ haplotypes were determined and compared with those of other populations of Asia-Oceania. Genetic distances were measured to show the genetic relationship within the studied populations as well as between the studied populations and previously published populations. Phylogenetic trees were constructed based on HLA allele frequencies using the neighbour-joining method. The populations, mainly Trobriand Islanders, Roro, Tolai, Western Samoans and Taiwanese Aborigines, are characterized by a reduced diversity at the HLA loci examined, especially for DPB1. The high frequency of the 'Asian'-specific DPB1*0501 allele in Trobrianders and Roro, but also in Western Samoans and Taiwanese Aborigines, was the most striking result. The prevalence of DPB1*0501 and the short genetic distance from Trobriander and Roro to Taiwanese Aborigines provide evidence that the origin of the Austronesian odyssey is south-east Asia, and Taiwan could be an important part of it. The relatedness of Trobrianders to the Polynesian population from Western Samoa indicates a probable recent common ancestor. The observed lack of diversity may reflect bottleneck(s) and/or limited diversity of the founding population. Analysis of HLA class I antigens, together with mt-DNA and Y-chromosomal studies, will give us further information about the settlement of the Trobriand and other islands during the colonization of the Pacific.
Assuntos
Etnicidade/genética , Genes MHC da Classe II , Antígenos HLA-DP/genética , Antígenos HLA-DR/genética , Polimorfismo Genético , Grupos Raciais/genética , Alelos , Sudeste Asiático/etnologia , Emigração e Imigração , Efeito Fundador , Frequência do Gene , Cadeias beta de HLA-DP , Cadeias HLA-DRB1 , Haplótipos/genética , Humanos , Desequilíbrio de Ligação , Melanesia , Havaiano Nativo ou Outro Ilhéu do Pacífico/genética , Ilhas do Pacífico/etnologia , Filogenia , Polinésia/etnologiaRESUMO
Present-day Pacific islanders are thought to be the descendants of Neolithic agriculturalists who expanded from island South-east Asia several thousand years ago. They speak languages belonging to the Austronesian language family, spoken today in an area spanning half of the circumference of the world, from Madagascar to Easter Island, and from Taiwan to New Zealand. To investigate the genetic affinities of the Austronesian-speaking peoples, we analysed mitochondrial DNA, HLA and Y-chromosome polymorphisms in individuals from eight geographical locations in Asia and the Pacific (China, Taiwan, Java, New Guinea highlands, New Guinea coast, Trobriand Islands, New Britain and Western Samoa). Our results show that the demographic expansion of the Austronesians has left a genetic footprint. However, there is no simple correlation between languages and genes in the Pacific.