Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Children Medical Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Mol Neurobiol. 2021 Jun;58(6):2792-2802. doi: 10.1007/s12035-021-02295-z. Epub 2021 Jan 27.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting cognitive function. A number of allelic genes from HLA complex have shown variable associations with AD in different populations. In this study, we investigated the association of DQB106:00/x, DRB104:00/x, DRB115:00/x, and B07:00/x genotypes with AD and their relevance to the efficacy of rivastigmine treatment in the Iranian population. Our findings suggest that DQB106:00/x genotype offers strong protection against AD (P = 0.0074), while B07:00/x genotype imposes a significant susceptibility for sporadic Alzheimer's disease (SAD) (P = 0.009). Interestingly, B07:00/x genotype does not show any apparent associations with familial Alzheimer's disease (FAD). Our studies also suggest a pharmacogenetic relationship between drug treatment and presence of a particular genotype in the Iranian LOAD patient population. The Clinical Dementia Rating analysis showed that LOAD patients carrying DRB104:00/x genotype tend to display a downward trend in the disease severity and symptoms after 2-year follow-up with rivastigmine treatment. Moreover, in our total patient population, the carriers of DQB106:00/x and B07:00/x alleles have better and worse responses to rivastigmine respectively. We also measured the clinical relevance of the testing for these genotypes employing prevalence-corrected positive predictive value (PcPPV) formula. The PcPPV of testing for DQB106:00/x in the Iranian LOAD patients was 1.17% which means that people carrying this genotype have half of the probability of the absolute risk for developing LOAD, whereas the PcPPV of testing for B07:00/x was 4.45% for SAD, which can be interpreted as a doubling chance for developing LOAD among the Iranian population carrying this genotype. These results also suggest that DQβ1 peptide containing positively charged AAs histidine and arginine and HLA class I β chain containing negatively charges aspartic acid and glutamic acid in their binding groove plays important roles in protection against and susceptibility for LOAD respectively.
阿尔茨海默病（AD）是一种影响认知功能的进行性神经退行性疾病。HLA 复合体中的许多等位基因已显示出与不同人群 AD 的可变关联。在这项研究中，我们研究了 DQB106:00/x、DRB104:00/x、DRB115:00/x 和 B07:00/x 基因型与 AD 的关联及其与伊朗人群中利伐斯的明治疗效果的相关性。我们的研究结果表明，DQB106:00/x 基因型对 AD 提供了强有力的保护（P=0.0074），而 B07:00/x 基因型对散发性阿尔茨海默病（SAD）具有显著的易感性（P=0.009）。有趣的是，B07:00/x 基因型与家族性阿尔茨海默病（FAD）没有明显的关联。我们的研究还表明，在伊朗 LOAD 患者人群中，药物治疗与特定基因型之间存在一种药物遗传学关系。临床痴呆评分分析表明，携带 DRB104:00/x 基因型的 LOAD 患者在接受利伐斯的明治疗 2 年后，疾病严重程度和症状呈下降趋势。此外，在我们的总患者人群中，DQB106:00/x 和 B07:00/x 等位基因的携带者对利伐斯的明分别有更好和更差的反应。我们还使用校正后阳性预测值（PcPPV）公式测量了这些基因型检测的临床相关性。在伊朗 LOAD 患者中，DQB106:00/x 检测的 PcPPV 为 1.17%，这意味着携带这种基因型的人患 LOAD 的绝对风险的概率减半，而 B07:00/x 检测的 PcPPV 为 4.45%用于 SAD，可以解释为伊朗人群携带该基因型患 LOAD 的机会增加一倍。这些结果还表明，DQβ1 肽含有带正电荷的组氨酸和精氨酸，HLA Ⅰ类β 链在其结合槽中含有带负电荷的天冬氨酸和谷氨酸，它们分别在保护和易感性方面对 LOAD 起重要作用。
