Inference from the relationships between linkage disequilibrium and allele frequency distributions of 240 candidate SNPs in 109 drug-related genes in four Asian populations

Abstract

The extensive nucleotide diversity in drugrelated genes predisposes individuals to different drug responses and is a major problem in current clinical practice and drug development. Striking allelic frequency differences exist in these genes between populations. In this study, we genotyped 240 sites known to be polymorphic in the Japanese population in each of 270 unrelated healthy individuals comprising 90 each of Malaysian Malays, Indians, and Chinese. These sites are distributed in 109 genes that are drug related, such as genes encoding drug-metabolizing enzymes and drug transporters. Allele frequency and linkage disequilibrium distributions of these sites were determined and compared. They were also compared with similar data of 752 Japanese. Extensive similarities in allele frequency and linkage disequilibrium distributions were observed among Japanese, Malaysian Chinese, and Malays. However, significant differences were observed between Japanese and Malaysian Chinese with Malaysian Indians. These four populations were grouped into two genetic clusters of different ancestries. However, a higher correlation was found between Malaysian Malays and Indians, indicating the existence of extensive admixture between them. The results also imply the possible and rational use of existing single nucleotide polymorphism databases as references to assist future pharmacogenetic studies involving populations of similar ancestry.

Similarity of the allele frequency and linkage disequilibrium pattern of single nucleotide polymorphisms in drug-related gene loci between Thai and northern East Asian populations: implications for tagging SNP selection in Thais

“…At close physical distance with less than 100 base pair intervals, there is more variation in D¢ statistics resulting in lower mean D¢ statistics for these markers. These findings are similar to those observed in Malays (Cha et al 2004). …”

“…A transferability study in Caucasians and Asians was encouraging, with evidence supporting the transferability for the Hapmap population-derived tagSNPs to their populations (Cha et al 2004;Lim et al 2006;Mueller et al 2005;Ribas et al 2006). We demonstrated here the similarity of Thais with East Asian Hapmap populations using 280 individuals.…”

“…There was also a contribution from central Asia to the present-day northern East Asian population (Hammer 1995;Qian et al 2001), especially the Japanese. There was also evidence of a high similarity of the Malaysian population with the Japanese for polymorphisms within drug-related genes (Cha et al 2004).…”

Evaluation of resequencing on number of tag SNPs of 13 atherosclerosis-related genes in Thai population

“…Not surprisingly, the results showed that the allele frequency distribution of the Thai population was more correlated to other Asian populations, Chinese and Japanese, than to Caucasian and African populations. Correlation coefficients were similar to other recent studies (Cha et al 2004;Kim et al 2005;Mahasirimongkol et al 2006). When compared with a similar study performed on the Korean population (Kim et al 2005), the allele frequency of Korean populations was very similar to that of the Japanese population (correlation coefficient r = 0.907), whereas it had very different patterns of allele frequency compared with Caucasian (correlation coefficient r = 0.359) or African (correlation coefficient r = 0.156) populations.…”

Genetic diversity and new therapeutic concepts

“…From the foregoing evidence, it is clear that there are striking examples of allelic frequency differences in drugrelated genes that predispose individuals to different drug responses in different populations (Cha et al 2004). DNA-based tests may, therefore, identify optimal dosing, maximize drug efficacy, reduce the risk of toxicity and related hospitalization, and improve drug selection (Oscarson 2003;Evans and McLeod 2003).…”