SLC22A2（rs201919874）和SLC47A2（rs138244461）基因变异对巴基斯坦2型糖尿病患者二甲双胍药代动力学的影响。

Effects of SLC22A2 (rs201919874) and SLC47A2 (rs138244461) genetic variants on Metformin Pharmacokinetics in Pakistani T2DM patients.

作者信息

Moeez Sadaf, Khalid Zoya, Jalil Fazal, Irfan Muhammad, Ismail Muhammad, Arif Mohammad Ali, Niazi Rauf, Khalid Sumbul

机构信息

International Islamic University, Islamabad.

Sabanci University, Istanbul.

出版信息

J Pak Med Assoc. 2019 Feb;69(2):155-163.

PMID:30804576

Abstract

OBJECTIVE

To determine the frequencies of single nucleotide polymorphisms rs201919874 and rs138244461 in genes SLC22A2 and SLC47A2 respectively in Pakistani diabetes patients in order to characterise the genetic variants and determine their association with the pharmacokinetics of metformin.

METHODS

The case-control study was conducted at the International Islamic University, Islamabad, Pakistan, from June 2016 to June 2017, and comprised genotypes of diabetic cases and matching controls which were determined following allele-specific polymerase chain reaction. Cases were further divided into Group A and Group B. The former consisted of diabetics who were on monotherapy of metformin, while the latter consisted of diabetics treated with a combination of metformin and sulfonylureas. In-silico analysis was performed to verify the effect of single nucleotide polymorphisms rs201919874 and rs138244461 on the structure of genes. Association was statistically determined using SPSS 18.

RESULTS

Of the 1200 subjects, 800(66.6%) were cases and 400(33.3%) were controls. Among the cases, 400(50%) each were in Group A and Group B. Significant difference was observed in the distribution of rs201919874 between Group A and controls (p<0.05) and between Group B and controls (p<0.05) for heterozygous genotypic frequency and for allelic frequency. Conversely, statistically significant difference was observed in rs138244461 (p<0.05) for all genotypic and allelic frequencies. Genotypes were significantly associated with glycated haemoglobin, random and fasting glucose levels in Group A compared to Group B (p<0.05). In-silico analysis showed that both single nucleotide polymorphisms were expected to create significantly damaging structural changes in domains and helix (p<0.05 each).

CONCLUSIONS

Both exonic single nucleotide polymorphisms were found to be associated with the pharmacokinetics of metformin.

摘要

目的

分别测定巴基斯坦糖尿病患者中基因SLC22A2和SLC47A2的单核苷酸多态性rs201919874和rs138244461的频率，以表征基因变异并确定它们与二甲双胍药代动力学的关联。

方法

病例对照研究于2016年6月至2017年6月在巴基斯坦伊斯兰堡国际伊斯兰大学进行，包括糖尿病病例和匹配对照的基因型，通过等位基因特异性聚合酶链反应进行测定。病例进一步分为A组和B组。前者由接受二甲双胍单药治疗的糖尿病患者组成，而后者由接受二甲双胍和磺脲类药物联合治疗的糖尿病患者组成。进行了电子分析以验证单核苷酸多态性rs201919874和rs138244461对基因结构的影响。使用SPSS 18进行统计学关联测定。

结果

在1200名受试者中，800名（66.6%）为病例，400名（33.3%）为对照。在病例中，A组和B组各有400名（50%）。在杂合基因型频率和等位基因频率方面，A组与对照之间（p<0.05）以及B组与对照之间（p<0.05）观察到rs201919874分布的显著差异。相反，在rs138244461的所有基因型和等位基因频率方面观察到统计学显著差异（p<0.05）。与B组相比，A组的基因型与糖化血红蛋白、随机血糖和空腹血糖水平显著相关（p<0.05）。电子分析表明，两种单核苷酸多态性预计都会在结构域和螺旋中产生显著的有害结构变化（各p<0.05）。