Croes Esther A, Alizadeh Behrooz Z, Bertoli-Avella Aida M, Rademaker Tessa, Vergeer-Drop Jeannette, Dermaut Bart, Houwing-Duistermaat Jeanine J, Wientjens Dorothee P W M, Hofman Albert, Van Broeckhoven Christine, van Duijn Cornelia M
Department of Epidemiology and Biostatistics, Erasmus MC, Rotterdam, The Netherlands.
Eur J Hum Genet. 2004 May;12(5):389-94. doi: 10.1038/sj.ejhg.5201161.
The prion protein gene (PRNP) plays a central role in the origin of Creutzfeldt-Jakob disease (CJD), but there is growing interest in other polymorphisms that may be involved in CJD. Polymorphisms upstream of PRNP that may modulate the prion protein production as well as polymorphisms in the prion-like doppel gene (PRND) have been studied, with inconsistent findings. We investigated the role of a single-nucleotide polymorphism (SNP 1368) located upstream of PRNP and three polymorphisms in PRND (T26M, P56L and T174M) in CJD. The study included a population-based sample of 52 patients with sporadic CJD and 250 controls. We analysed our data as single markers and haplotypes. Further, we conducted a meta-analysis on PRND T174M comparing the data of the four studies conducted to date. For SNP 1368 and PRNP M129V, we found significant evidence for linkage disequilibrium. No evidence was found for a relation of SNP 1368 to CJD independent of PRNP M129V. We further found a significant increased prevalence of M homozygotes at PRND T174M among sporadic CJD patients, when adjusting the analyses for the other genotypes. In the haplotype analyses, the association was strongest for persons homozygous for PRNP 129M and PRND 174M (odds ratio 4.35, 95% confidence interval 1.05-8.09; P=0.04). The meta-analysis on the PRND T174M polymorphism did not show a consistent effect across studies, raising the question as to whether PRND 174M is causally related to CJD, or whether the PRND allele is in linkage disequilibrium with another polymorphism related to CJD.
朊病毒蛋白基因（PRNP）在克雅氏病（CJD）的发病机制中起核心作用，但人们对其他可能与CJD相关的多态性越来越感兴趣。已对可能调节朊病毒蛋白产生的PRNP上游多态性以及类朊病毒多配体蛋白基因（PRND）中的多态性进行了研究，结果并不一致。我们研究了位于PRNP上游的单核苷酸多态性（SNP 1368）以及PRND中的三个多态性（T26M、P56L和T174M）在CJD中的作用。该研究纳入了一个基于人群的样本，包括52例散发性CJD患者和250名对照。我们将数据作为单个标记和单倍型进行分析。此外，我们对PRND T174M进行了荟萃分析，比较了迄今为止进行的四项研究的数据。对于SNP 1368和PRNP M129V，我们发现了显著的连锁不平衡证据。未发现SNP 1368与CJD独立于PRNP M129V的关系。在对其他基因型进行分析调整后，我们进一步发现散发性CJD患者中PRND T174M处M纯合子的患病率显著增加。在单倍型分析中，PRNP 129M和PRND 174M纯合子个体的关联最强（优势比4.35，95%置信区间1.05 - 8.09；P = 0.04）。对PRND T174M多态性的荟萃分析在各项研究中未显示出一致的效应，这引发了关于PRND 174M是否与CJD存在因果关系，或者PRND等位基因是否与另一个与CJD相关的多态性处于连锁不平衡的问题。
