A pharmacogenomic approach to Alzheimer's disease

Single nucleotide polymorphisms (susceptibility genetics) and genomic point mutations (mendelian genetics) can be used in Alzheimer's disease (AD) for diagnostic, predictive and therapeutic purposes. Using a matrix genetic model, including APOE, PS1 and PS2 allelic variants, we have studied the distribution of 36 different genotypes in the AD population ( N =479) and the genotype-related cognitive response to a multifactorial therapy in AD patients with mild-to-moderate dementia. The 10 most frequent AD genotypes are the following: 1) E33P112P2+ (17.75%), 2) E33P112P2− (15.55%), 3) E33P111P2+ (10.85%), 4) E34P112P2+ (9.60%), 5) E34P112P2− (7.56%), 6) E33P111P2− (7.10%), 7) E34P111P2+ (4.80%), 8) E33P122P2+ (4.38%), 9) E34P111P2− (4.18%), and 10) E34P122P2+ (3.55%). APOE-4/4-related genotypes represent less than 3% in the following order: E44P112P2+> E44P111P2+=E44P111P2−>E44P112P2+>E44P122P2+= E44P122P2−. Multifactorial therapy with CDP-choline (1000 mg/day)+piracetam (2400 mg/day)+anapsos (360 mg/day) did improve mental performance during the first 6–15 months in a genotype-specific fashion. The best responders in the APOE series were patients with APOE-3/4 genotype ( r =+0.013), while the worst responders were APOE-4/4 patients ( r =−0.93). PS1-related genotypes responded in a similar manner; and patients with a defective PS2 gene exon 5 (PS2+) always showed a poorer therapeutic response than PS2− patients. All these data suggest that the therapeutic outcome in AD exhibits a genotype-specific pattern, and that a pharmacogenomic approach to AD might be a valuable strategy for drug development and monitoring.     

深圳市509例2型糖尿病患者常见口服降糖药物基因多态性分析

目的：探索深圳市糖尿病患者口服降糖药物相关单核苷酸多态性（single nucleotide polymorphism，SNPs）的分布特征，为糖尿病患者个体化用药指导提供参考。方法：采用外周血DNA抽提/焦磷酸测序检测509例糖尿病患者四大类降糖药物4个药物相关基因位点SNPs。采用SPSS 25.0软件统计相关基因位点的等位基因和基因型的频率分布差异。参照国内外不同人群的基因型频率数据，回顾性分析深圳市2020—2021年社区糖尿病患者的降糖药物相关SNPs的分布特征。结果：PPARG、SLCO1B1的SNPs与国外人群存在较大差异，与国内报道基本相符。CYP2C9*3的SNPs与欧洲人群存在差异，但与中国人群和美洲人群相关报道基本相符。然而有机阳离子转运体OCT2的SNPs与中国南方人群存在一定的差异，但与中国北京、欧洲、美洲相关报道的情况基本相符。结论：深圳市糖尿病患者降糖药物相关SNPs分布有自身特点，临床药师及医生应根据药物相关SNPs提供个体化用药指导建议。药物基因组学的个体化用药在参考PharmGKB等数据库的同时应结合国人的特点，不能完全参考国外人群数据库。