Lämsä R, Helisalmi S, Hiltunen M, Herukka S-K, Tapiola T, Pirttilä T, Vepsäläinen S, Soininen H
Unit of Neurology, Clinical Department, Brain Research Unit, Clinical Research Center, Mediteknia, University of Kuopio, 70211 Kuopio, Finland.
Am J Med Genet B Neuropsychiatr Genet. 2007 Oct 5;144B(7):906-10. doi: 10.1002/ajmg.b.30532.
DHCR24 gene in chromosome 1 encodes seladin 1, a cholesterol synthesizing enzyme. Seladin 1 protects neurons from Abeta(42) mediated toxicity and participates in regulation of Abeta(42) formation by organizing the placement of APP cleaving beta-secretase in cholesterol-rich detergent-resistant membrane domains (DRMs). In Alzheimer's disease (AD) the level of seladin 1 in affected neurons is reduced, DRMs are disorganized and Abeta(42) formation is increased. To examine genetic association of the DHCR24 with AD, we genotyped four single nucleotide polymorphism (SNP) sites (rs638944, rs600491, rs718265, and rs7374) in 414 Finnish AD cases and 459 controls and calculated the allelic and genotypic distribution of both cases and controls. The single locus association analysis indicated that men carrying the T allele of rs600491 had an increased risk of AD (OR 1.7 95% CI 1.2-2.4; P = 0.004, Bonferroni corrected P = 0.048 with 12 tests). We estimated haplotypes of SNPs rs638944 and rs600491 between cases and controls and found overall distribution of haplotypes highly significant (P < 0.001). There was a common protective haplotype TC with frequency of 0.22 in cases and 0.30 in controls (P < 0.001) and a risk haplotype GC with frequency of 0.10 in cases and 0.05 in controls (P < 0.001). We also measured CSF Abeta(42), tau and phosphorylated tau (ptau) levels in a subgroup of AD cases (n = 44) and controls (n = 10) and found that AD cases that carry rs718265 GG had lower levels of Abeta(42) than other genotype carriers. Our findings indicate that DHCR24 gene may be associated with AD risk.
位于1号染色体上的DHCR24基因编码硒代蛋白1，这是一种胆固醇合成酶。硒代蛋白1可保护神经元免受β淀粉样蛋白（Aβ42）介导的毒性作用，并通过将APP裂解β分泌酶定位在富含胆固醇的抗去污剂膜结构域（DRM）中来参与调节Aβ42的形成。在阿尔茨海默病（AD）中，受影响神经元中的硒代蛋白1水平降低，DRM紊乱，Aβ42的形成增加。为了研究DHCR24与AD的遗传关联，我们对414例芬兰AD患者和459例对照进行了4个单核苷酸多态性（SNP）位点（rs638944、rs600491、rs718265和rs7374）的基因分型，并计算了病例组和对照组的等位基因和基因型分布。单基因座关联分析表明，携带rs600491的T等位基因的男性患AD的风险增加（比值比1.7，95%置信区间1.2 - 2.4；P = 0.004，经Bonferroni校正，12次检验后P = 0.048）。我们估计了病例组和对照组之间SNP rs638944和rs600491的单倍型，发现单倍型的总体分布具有高度显著性（P < 0.001）。有一个常见的保护性单倍型TC，在病例组中的频率为0.22，在对照组中的频率为0.30（P < 0.001），还有一个风险单倍型GC，在病例组中的频率为0.10，在对照组中的频率为0.05（P < 0.001）。我们还测量了一部分AD病例组（n = 44）和对照组（n = 10）的脑脊液中Aβ42、tau蛋白和磷酸化tau蛋白（ptau）水平，发现携带rs718265 GG基因型的AD病例的Aβ42水平低于其他基因型携带者。我们的研究结果表明，DHCR24基因可能与AD风险相关。
