Rais Naushad, Hussain Arif, Chawla Yogesh Kumar, Kohli Krishan K
Department of Biotechnology, Manipal University, Dubai, United Arab Emirates ;
Exp Ther Med. 2013 Feb;5(2):527-532. doi: 10.3892/etm.2012.842. Epub 2012 Nov 29.
Genetic polymorphism of genes involved in renal salt handling and arterial vessel tone is considered to be one of the causes of hypertension. Numerous reports suggest that cytochrome P4503A5 (CYP3A5) catalyzes 6β-hydroxylation of endogenous cortisol (CS), which is associated with sodium and water retention in the kidney and involved in the regulation of blood pressure. The purpose of the present study was to study the associations of single nucleotide polymorphisms in the CYP3A5 gene with the urinary 6β-hydroxycortisol/cortisol (6β-OH-CS/CS) ratio considered as quantitative phenotypes. CS measurements of three hundred (n=300) healthy, normotensive North Indian individuals was performed on morning spot urine samples by high-performance liquid chromatography. Furthermore, genotyping for CYP3A53 and CYP3A56 was performed by PCR-RFLP. The results indicated a unimodal distribution of CYP3A phenotypes in the North Indian population. In further analysis, all the phenotypes were distributed into three groups, demonstrating low (n=75), intermediate (n=150) and high CYP3A activity (n=75) based on CS and 6β-OH-CS levels and log 6β-OH-CS/CS ratios. The subjects in the low and high activity groups were genotyped for the CYP3A53 and 6 alleles. The present study demonstrated that the allele frequencies of CYP3A51 and 3 were 0.29 (95% CI, 0.22-0.36) and 0.71 (95% CI, 0.64-0.78), respectively. Notably, the frequency of normal homozygotes (CYP3A51/1) was significantly higher in the high activity than the low activity group (11% vs. 5%). Similarly, the frequency of mutant homozygotes (CYP3A53/3) was significantly higher in the low activity group than the high activity group (57% vs. 44%). The allele frequency of CYP3A53 was significantly higher in the low activity group (0.76) than the high activity group (0.67). The mean 6β-OH-CS/CS ratios were 110, 76 and 69 in wild-type homozygotes (n=12), heterozygotes (n=62) and mutant homozygotes (n=76), respectively. The difference between the normal and mutant homozygotes was statistically significant (P<0.05). The CYP3A56 allele was absent from all the subjects genotyped. This is the first study to report the genetic polymorphism of CYP3A5 in a North Indian population and its association with urinary 6β-OH-CS/CS ratio reflecting the CYP3A phenotypes.
参与肾脏盐处理和动脉血管张力调节的基因的遗传多态性被认为是高血压的病因之一。众多报告表明，细胞色素P4503A5（CYP3A5）催化内源性皮质醇（CS）的6β-羟化反应，这与肾脏中的钠和水潴留有关，并参与血压调节。本研究的目的是研究CYP3A5基因单核苷酸多态性与被视为定量表型的尿6β-羟基皮质醇/皮质醇（6β-OH-CS/CS）比值之间的关联。通过高效液相色谱法对300名健康、血压正常的北印度个体的晨尿样本进行CS测量。此外，通过PCR-RFLP对CYP3A53和CYP3A56进行基因分型。结果表明，CYP3A表型在北印度人群中呈单峰分布。在进一步分析中，根据CS和6β-OH-CS水平以及log 6β-OH-CS/CS比值，将所有表型分为三组，分别显示低（n=75）、中（n=150）和高CYP3A活性（n=75）。对低活性和高活性组的受试者进行CYP3A53和6等位基因的基因分型。本研究表明，CYP3A51和3的等位基因频率分别为0.29（95%CI，0.22-0.36）和0.71（95%CI，0.64-0.78）。值得注意的是，高活性组中正常纯合子（CYP3A51/1）的频率显著高于低活性组（11%对5%）。同样，低活性组中突变纯合子（CYP3A53/3）的频率显著高于高活性组（57%对44%）。低活性组中CYP3A53的等位基因频率（0.76）显著高于高活性组（0.67）。野生型纯合子（n=12）、杂合子（n=62）和突变型纯合子（n=76）的平均6β-OH-CS/CS比值分别为110、76和69。正常纯合子与突变纯合子之间的差异具有统计学意义（P<0.05）。所有进行基因分型的受试者均未检测到CYP3A56等位基因。这是首次报道北印度人群中CYP3A5的遗传多态性及其与反映CYP3A表型的尿6β-OH-CS/CS比值之间的关联。
