Very important pharmacogenetic variants landscape and potential clinical relevance in the Zhuang population from Yunnan province

Abstract

The gradual evolution of pharmacogenomics has shed light on the genetic basis for inter-individual drug response variations across diverse populations. This study aimed to identify pharmacogenomic variants that differ in Zhuang population compared with other populations and investigate their potential clinical relevance in gene-drug and genotypic-phenotypic associations. A total of 48 variants from 24 genes were genotyped in 200 Zhuang subjects using the Agena MassARRAY platform. The allele frequencies and genotype distribution data of 26 populations were obtained from the 1000 Genomes Project, followed by a comparison and statistical analysis. After Bonferroni correction, significant differences in genotype frequencies were observed of CYP3A5 (rs776746), ACE (rs4291), KCNH2 (rs1805123), and CYP2D6 (rs1065852) between the Zhuang population and the other 26 populations. It was also found that the Chinese Dai in Xishuangbanna, China, Han Chinese in Beijing, China, and Southern Han Chinese, China showed least deviation from the Zhuang population. The Esan in Nigeria, Gambian in Western Division, The Gambia, and Yoruba in Ibadan, Nigeria exhibited the largest differences. This was also proved by structural analysis, Fst analysis and phylogenetic tree. Furthermore, these differential variants may be associated with the pharmacological efficacy and toxicity of Captopril, Amlodipine, Lisinopril, metoclopramide, and alpha-hydroxymetoprolol in the Zhuang population. Our study has filled the gap of pharmacogenomic information in the Zhuang population and has provided a theoretical framework for the secure administration of drugs in the Zhuang population.

Keywords: Personalized administration; Potential clinical relevance; Single nucleotide variants; Very important pharmacogene variant; Zhuang population.

Figure 1

The amount of difference variants between the Zhuang population and 26 populations. The size of the rectangle indicates the number of different variants between the Zhuang population and the other 26 populations from five regions.

Figure 2

Structure analysis of the genetic relationship between the Zhuang population and the other 26 populations. K denotes the possible numbers of parental population clusters. Each vertical bar represents a sample, dividing into color sections. K = 5 were utilized to evaluate the relationship between Zhuang and 26 populations.

Figure 3

Fst value heamap and phylogenetic tree among 27 populations. (A) Heatmap based on the pairwise Fst values between 27 populations. (B) The phylogenetic tree was constructed by the neighboring-joining method among 27 populations.

Figure 4

The distribution of genotype frequencies for significantly different SNVs in 27 populations at the rs776746, rs4291, rs1805123 and rs1065852.

Figure 5

The map of the allele frequency distribution for significantly different SNVs in 27 populations at the rs1065852, rs4291, rs776746 and rs1805123.

Figure 6

Structural prediction of point mutated proteins. (A) 3D structure of the CYP2D6 protein, with the yellow part being a SNV. (B) rs1065852 mutated local structure. (C) 3D structure of the KCNH2 protein, with the yellow part being a SNV mutation. (D) rs1805123 mutated local structure.