Deming Yuetiva, Black Kathleen, Carrell David, Cai Yefei, Del-Aguila Jorge L, Fernandez Maria Victoria, Budde John, Ma ShengMei, Saef Benjamin, Howells Bill, Bertelsen Sarah, Huang Kuan-Lin, Sutphen Courtney L, Tarawneh Rawan, Fagan Anne M, Holtzman David M, Morris John C, Goate Alison M, Dougherty Joseph D, Cruchaga Carlos
Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.
Ronald M. Loeb Center for Alzheimer's disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
BMC Neurol. 2016 Nov 10;16(1):217. doi: 10.1186/s12883-016-0742-9.
Alzheimer's disease (AD) pathology appears several years before clinical symptoms, so identifying ways to detect individuals in the preclinical stage is imperative. The cerebrospinal fluid (CSF) Tau/Aβ ratio is currently the best known predictor of AD status and cognitive decline, and the ratio of CSF levels of chitinase-3-like 1 protein (CHI3L1, YKL-40) and amyloid beta (Aβ) were reported as predictive, but individual variability and group overlap inhibits their utility for individual diagnosis making it necessary to find ways to improve sensitivity of these biomarkers.
We used linear regression to identify genetic loci associated with CSF YKL-40 levels in 379 individuals (80 cognitively impaired and 299 cognitively normal) from the Charles F and Joanne Knight Alzheimer's Disease Research Center. We tested correlations between YKL-40 and CSF Tau/Aβ ratio, Aβ, tau, and phosphorylated tau (ptau). We used studentized residuals from a linear regression model of the log-transformed, standardized protein levels and the additive reference allele counts from the most significant locus to adjust YKL-40 values and tested the differences in correlations with CSF Tau/Aβ ratio, Aβ, tau, and ptau.
We found that genetic variants on the CH13L1 locus were significantly associated with CSF YKL-40 levels, but not AD risk, age at onset, or disease progression. The most significant variant is a reported expression quantitative trait locus for CHI3L1, the gene which encodes YKL-40, and explained 12.74 % of the variance in CSF YKL-40 in our study. YKL-40 was positively correlated with ptau (r = 0.521) and the strength of the correlation significantly increased with the addition of genetic information (r = 0.573, p = 0.006).
CSF YKL-40 levels are likely a biomarker for AD, but we found no evidence that they are an AD endophenotype. YKL-40 levels are highly regulated by genetic variation, and by including genetic information the strength of the correlation between YKL-40 and ptau levels is significantly improved. Our results suggest that studies of potential biomarkers may benefit from including genetic information.
阿尔茨海默病（AD）病理变化在临床症状出现前数年就已出现，因此确定在临床前阶段检测个体的方法势在必行。脑脊液（CSF） Tau/Aβ 比值是目前已知的预测 AD 状态和认知衰退的最佳指标，并且据报道，几丁质酶 -3 样 1 蛋白（CHI3L1，YKL - 40）与淀粉样β蛋白（Aβ）的脑脊液水平比值具有预测性，但个体差异和组间重叠限制了它们在个体诊断中的应用，因此有必要找到提高这些生物标志物敏感性的方法。
我们使用线性回归来确定来自查尔斯·F 和乔安妮·奈特阿尔茨海默病研究中心的 379 名个体（80 名认知受损者和 299 名认知正常者）中与脑脊液 YKL - 40 水平相关的基因位点。我们测试了 YKL - 40 与脑脊液 Tau/Aβ 比值、Aβ、tau 和磷酸化 tau（ptau）之间的相关性。我们使用对数转换后的标准化蛋白水平的线性回归模型的学生化残差以及最显著位点的加性参考等位基因计数来调整 YKL - 40 值，并测试与脑脊液 Tau/Aβ 比值、Aβ、tau 和 ptau 相关性的差异。
我们发现 CH13L1 基因座上的遗传变异与脑脊液 YKL - 40 水平显著相关，但与 AD 风险、发病年龄或疾病进展无关。最显著的变异是一个已报道的 CHI3L1 的表达数量性状位点，CHI3L1 是编码 YKL - 40 的基因，在我们的研究中解释了脑脊液 YKL - 40 中 12.74%的变异。YKL - 40 与 ptau 呈正相关（r = 0.521），并且随着遗传信息的加入，相关性强度显著增加（r = 0.573，p = 0.006）。
脑脊液 YKL - 40 水平可能是 AD 的生物标志物，但我们没有发现证据表明它们是 AD 的内表型。YKL - 40 水平受遗传变异高度调控，并且通过纳入遗传信息，YKL - 40 与 ptau 水平之间的相关性强度得到显著改善。我们的结果表明，潜在生物标志物的研究可能受益于纳入遗传信息。
