TY - JOUR
T1 - Chitinase-3-like 1 protein (CHI3L1) locus influences cerebrospinal fluid levels of YKL-40
AU - Deming, Yuetiva
AU - Black, Kathleen
AU - Carrell, David
AU - Cai, Yefei
AU - Del-Aguila, Jorge L.
AU - Fernandez, Maria Victoria
AU - Budde, John
AU - Ma, Sheng Mei
AU - Saef, Benjamin
AU - Howells, Bill
AU - Bertelsen, Sarah
AU - Huang, Kuan lin
AU - Sutphen, Courtney L.
AU - Tarawneh, Rawan
AU - Fagan, Anne M.
AU - Holtzman, David M.
AU - Morris, John C.
AU - Goate, Alison M.
AU - Dougherty, Joseph D.
AU - Cruchaga, Carlos
N1 - Funding Information:
JCM reported having participated in or currently participating in clinical trials of antidementia drugs sponsored by Janssen Immunotherapy, Pfizer, Eli Lilly and Co/Avid Radiopharmaceuticals, SNIFF (Study of Nasal Insulin to Fight Forgetfulness), and A4 Study (Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease) and serving as a consultant for Lilly USA, ISIS Pharmaceuticals, and the Charles Dana Foundation. DMH reported being a cofounder of C2N Diagnostics LLC; serving on the scientific advisory boards of AstraZeneca, Genentech, Neurophage, and C2N Diagnostics; and serving as a consultant for Eli Lilly and Co. Washington University receives grants to the laboratory of DMH from the Tau Consortium, Cure Alzheimer’s Fund, the JPB Foundation, Eli Lilly and Co, Janssen, and C2N Diagnostics. AMF reported serving on the scientific advisory boards of IBL International and Roche and serving as a consultant for AbbVie and Novartis. The other co-authors reported no potential conflicts of interest.
Funding Information:
This work was supported by grants from the National Institutes of Health (R01-AG044546, P01-AG003991, RF1AG053303, R01-AG035083, and R01-NS085419), and the Alzheimer’s Association (NIRG-11-200110). This research was conducted while CC was a recipient of a New Investigator Award in Alzheimer’s disease from the American Federation for Aging Research. CC is a recipient of a BrightFocus Foundation Alzheimer’s Disease Research Grant (A2013359S). The recruitment and clinical characterization of research participants at Washington University were supported by NIH P50 AG05681, P01 AG03991, and P01 AG026276. Some of the samples used in this study were genotyped by the ADGC and GERAD. ADGC is supported by grants from the NIH (#U01AG032984) and GERAD from the Wellcome Trust (GR082604MA) and the Medical Research Council (G0300429). This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders and the Departments of Neurology and Psychiatry at Washington University School of Medicine.
Publisher Copyright:
© 2016 The Author(s).
PY - 2016/11/10
Y1 - 2016/11/10
N2 - Background: 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/Aβ42 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 (Aβ42) 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. Methods: 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/Aβ42 ratio, Aβ42, tau, and phosphorylated tau (ptau181). 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/Aβ42 ratio, Aβ42, tau, and ptau181. Results: 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 ptau181 (r=0.521) and the strength of the correlation significantly increased with the addition of genetic information (r=0.573, p=0.006). Conclusions: 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 ptau181 levels is significantly improved. Our results suggest that studies of potential biomarkers may benefit from including genetic information.
AB - Background: 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/Aβ42 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 (Aβ42) 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. Methods: 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/Aβ42 ratio, Aβ42, tau, and phosphorylated tau (ptau181). 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/Aβ42 ratio, Aβ42, tau, and ptau181. Results: 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 ptau181 (r=0.521) and the strength of the correlation significantly increased with the addition of genetic information (r=0.573, p=0.006). Conclusions: 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 ptau181 levels is significantly improved. Our results suggest that studies of potential biomarkers may benefit from including genetic information.
KW - Alzheimer disease
KW - CHI3L1
KW - Cerebrospinal fluid
KW - YKL-40
UR - http://www.scopus.com/inward/record.url?scp=84995532107&partnerID=8YFLogxK
U2 - 10.1186/s12883-016-0742-9
DO - 10.1186/s12883-016-0742-9
M3 - Article
C2 - 27832767
AN - SCOPUS:84995532107
SN - 1471-2377
VL - 16
JO - BMC Neurology
JF - BMC Neurology
IS - 1
M1 - 217
ER -