Labbé Catherine, Heckman Michael G, Lorenzo-Betancor Oswaldo, Soto-Ortolaza Alexandra I, Walton Ronald L, Murray Melissa E, Allen Mariet, Uitti Ryan J, Wszolek Zbigniew K, Smith Glenn E, Kantarci Kejal, Knopman David S, Lowe Val J, Jack Clifford R, Ertekin-Taner Nilüfer, Hassan Anhar, Savica Rodolfo, Petersen Ronald C, Parisi Joseph E, Maraganore Demetrius M, Graff-Radford Neill R, Ferman Tanis J, Boeve Bradley F, Dickson Dennis W, Ross Owen A
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL, USA.
Alzheimers Dement. 2016 Dec;12(12):1297-1304. doi: 10.1016/j.jalz.2016.05.002. Epub 2016 Jun 7.
The MAPT H1 haplotype has been associated with several neurodegenerative diseases. We were interested in exploring the role of MAPT haplotypic variation in risk of dementia with Lewy bodies (DLB).
We genotyped six MAPT haplotype tagging SNPs and screened 431 clinical DLB cases, 347 pathologically defined high-likelihood DLB cases, and 1049 controls.
We performed haplotypic association tests and detected an association with the protective H2 haplotype in our combined series (odds ratio [OR] = 0.75). We fine-mapped the locus and identified a relatively rare haplotype, H1G, that is associated with an increased risk of DLB (OR = 3.30, P = .0017). This association was replicated in our pathologically defined series (OR = 2.26, P = .035).
These results support a role for H1 and specifically H1G in susceptibility to DLB. However, the exact functional variant at the locus is still unknown, and additional studies are warranted to fully explain genetic risk of DLB at the MAPT locus.
微管相关蛋白tau(MAPT)H1单倍型与多种神经退行性疾病有关。我们感兴趣的是探索MAPT单倍型变异在路易体痴呆(DLB)风险中的作用。
我们对6个MAPT单倍型标签单核苷酸多态性进行基因分型,并筛查了431例临床诊断的DLB病例、347例经病理定义的高可能性DLB病例和1049例对照。
我们进行了单倍型关联测试,在我们的合并系列中检测到与保护性H2单倍型有关联(优势比[OR]=0.75)。我们对该基因座进行了精细定位,并鉴定出一种相对罕见的单倍型H1G,它与DLB风险增加有关(OR=3.30,P=0.0017)。这种关联在我们经病理定义的系列中得到了重复验证(OR=2.26,P=0.035)。
这些结果支持H1尤其是H1G在DLB易感性中的作用。然而,该基因座的确切功能变异仍不清楚,需要进一步研究以充分解释MAPT基因座处DLB的遗传风险。