Aldiban Weam, Aljamali Majd N, Youssef Lama A
Department of Pharmaceutics and Pharmaceutical Technology, Program of Clinical and Hospital Pharmacy, Faculty of Pharmacy, Damascus University, Damascus, Syrian Arab Republic.
Faculty of Pharmacy, International University for Science and Technology (IUST), Ghabagheb, Daraa, Syrian Arab Republic.
BMC Genomics. 2025 Feb 13;26(1):140. doi: 10.1186/s12864-025-11310-9.
The cytochrome P450 family 2 subfamily C member 9 (CYP2C9) exhibits extensive genetic variability that may influence the metabolism of approximately 16-20% of all drugs. Understanding the frequency and functional impact of the CYP2C9 variants is crucial for the implementation of pharmacogenetics. Our study aims to determine the frequencies of CYP2C9 variants in the Syrian population, contributing to the limited information available for Middle Eastern populations.
One hundred thirty-eight unrelated individuals from two major Syrian cities (Damascus and Homs) enrolled in this cross-sectional study. Genomic DNA was extracted from peripheral blood and specific PCR amplification products were purified and sequenced. The length of the amplicons allowed for the detection of 17 star alleles (i.e. *2, *8, *14, *20, *26, *33, *40, *41, *42, *43, *45, *46, *62, *63, *72, *73, and *78) in exon three, and seven star alleles (i.e., *3, *4, *5, *24, *55, 66, 68) in exon seven, in addition to two intronic variants. The frequencies of the functionally compromised CYP2C92 and CYP2C93 alleles were compared to same variants in other populations.
Of the 24 exonic alleles investigated, only the *2, *3, *41, and *46 alleles were detected at frequencies of 14.8%, 8.3%, 1.45%, and 0.72%, respectively, with 43.5% of the study subjects carrying at least one dysfunctional variant. The genotype frequencies observed were as follows: *1/*1 (56.5%), *1/*2 (23.9%), *2/*2 (0.7%), *3/*1 (12.3%), *2/*3 (4.3%), *3/*3 (0%), *1/*41 (0.7%), *2/*41 (0%), *3/*41 (0.7%), *1/*46 (0.7%), *46/*2 (0%), and *46/*3 (0%). Moreover, frequencies of the rs933120 and rs933119 intronic alleles were 12.3% and 6.1%, respectively. A high linkage disequilibrium (LD) was found (D'=0.78) between the intronic rs933119 and exonic rs1799853 (*2 allele).
This study provides evidence for high prevalence of the CYP2C9 *2 and *3 alleles, and consequently the intermediate and poor metabolizer phenotypes in Syrians. Two rare putative function-relevant variants (*41 and *46) were detected in three individuals. These findings pave the path to the efforts for implementing CYP2C9 pharmacogenetics-based personalized pharmacotherapy in this Middle Eastern population.
细胞色素P450 2C9家族成员9（CYP2C9）存在广泛的基因变异，这可能影响约16% - 20%的所有药物的代谢。了解CYP2C9变异的频率和功能影响对于实施药物遗传学至关重要。我们的研究旨在确定叙利亚人群中CYP2C9变异的频率，以补充中东人群有限的可用信息。
来自叙利亚两个主要城市（大马士革和霍姆斯）的138名无亲缘关系的个体参与了这项横断面研究。从外周血中提取基因组DNA，对特定的PCR扩增产物进行纯化和测序。扩增子的长度使得能够检测外显子3中的17个星号等位基因（即*2、*8、*14、*20、*26、*33、*40、*41、*42、*43、*45、*46、*62、*63、72、73和78），以及外显子7中的7个星号等位基因（即3、*4、*5、*24、*55、66、68），此外还有两个内含子变异。将功能受损的CYP2C92和CYP2C93等位基因的频率与其他人群中的相同变异进行比较。
在所研究的24个外显子等位基因中，仅检测到*2、*3、41和46等位基因，频率分别为14.8%、8.3%、1.45%和0.72%，43.5%的研究对象携带至少一个功能失调的变异。观察到的基因型频率如下：*1/*1（56.5%）、*1/*2（23.9%）、*2/*2（0.7%）、*3/*1（12.3%）、*2/*3（4.3%）、*3/*3（0%）、*1/*41（0.7%）、*2/*41（0%）、*3/*41（0.7%）、*1/*46（0.7%）、*46/2（0%）和46/*3（0%）。此外，内含子rs933120和rs933119等位基因的频率分别为12.3%和6.1%。在内含子rs933119和外显子rs1799853（*2等位基因）之间发现了高度连锁不平衡（D' = 0.78）。
本研究为CYP2C9 2和3等位基因在叙利亚人中的高流行率提供了证据，因此也证明了叙利亚人群中存在中间代谢型和慢代谢型表型。在三名个体中检测到两个罕见的可能与功能相关的变异（41和46）。这些发现为在这个中东人群中实施基于CYP2C9药物遗传学的个性化药物治疗的努力铺平了道路。
