Effect of Variation in CHI3L1 on Serum YKL-40 Level, Risk of Asthma, and Lung Function
Carole Ober, Ph.D., Zheng Tan, Ph.D., Ying Sun, M.S., Jennifer D. Possick, M.D., Lin Pan, M.S., Raluca Nicolae, D.D.S., Sadie Radford, Rodney R. Parry, M.D., Andrea Heinzmann, M.D., Klaus A. Deichmann, M.D., Lucille A. Lester, M.D., James E. Gern, M.D., Robert F. Lemanske, Jr., M.D., Dan L. Nicolae, Ph.D., Jack A. Elias, M.D., and Geoffrey L. Chupp, M.D.
Background The chitinase-like protein YKL-40 is involved ininflammation and tissue remodeling. We recently showed thatserum YKL-40 levels were elevated in patients with asthma andwere correlated with severity, thickening of the subepithelialbasement membrane, and pulmonary function. We hypothesized thatsingle-nucleotide polymorphisms (SNPs) that affect YKL-40 levelsalso influence asthma status and lung function.
Methods We carried out a genomewide association study of serumYKL-40 levels in a founder population of European descent, theHutterites, and then tested for an association between an implicatedSNP and asthma and lung function. One associated variant wasgenotyped in a birth cohort at high risk for asthma, in whichYKL-40 levels were measured from birth through 5 years of age,and in two populations of unrelated case patients of Europeandescent with asthma and controls.
Results A promoter SNP (–131CG) in CHI3L1, the chitinase3–like 1 gene encoding YKL-40, was associated with elevatedserum YKL-40 levels (P=1.1x10–13), asthma (P=0.047), bronchialhyperresponsiveness (P=0.002), and measures of pulmonary function(P=0.046 to 0.002) in the Hutterites. The same SNP could beused to predict the presence of asthma in the two case–controlpopulations (combined P=1.2x10–5) and serum YKL-40 levelsat birth (in cord-blood specimens) through 5 years of age inthe birth cohort (P=8.9x10–3 to 2.5x10–4).
ConclusionsCHI3L1 is a susceptibility gene for asthma, bronchialhyperresponsiveness, and reduced lung function, and elevatedcirculating YKL-40 levels are a biomarker for asthma and declinein lung function.
Source Information
From the University of Chicago, Chicago (C.O., Z.T., Y.S., L.P., R.N., S.R., L.A.L., D.L.N.); the University of Wisconsin, Madison (J.E.G., R.F.L.); Yale University School of Medicine, New Haven, CT (J.D.P., J.A.E., G.L.C.); the University of South Dakota Medical School, Sioux Falls (R.R.P.); and the University of Freiburg, Freiburg, Germany (A.H., K.A.D.). Drs. Elias and Chupp contributed equally to this article. This article (10.1056/NEJMoa0708801) was published at www.nejm.org on April 9, 2008.
Address reprint requests to Dr. Ober at the Department of Human Genetics, 920 E. 58th St., University of Chicago, Chicago, IL 60637, or at c-ober{at}genetics.uchicago.edu.
Agapov, E., Battaile, J. T., Tidwell, R., Hachem, R., Patterson, G. A., Pierce, R. A., Atkinson, J. J., Holtzman, M. J.
(2009). Macrophage Chitinase 1 Stratifies Chronic Obstructive Lung Disease. Am. J. Respir. Cell Mol. Bio.
41: 379-384
[Abstract][Full Text]
Murmann, A. E., Conrad, D. F., Mashek, H., Curtis, C. A., Nicolae, R. I., Ober, C., Schwartz, S.
(2009). Inverted duplications on acentric markers: mechanism of formation. Hum Mol Genet
18: 2241-2256
[Abstract][Full Text]
Rajagopalan, G., Tilahun, A. Y., Asmann, Y. W., David, C. S.
(2009). Early gene expression changes induced by the bacterial superantigen staphylococcal enterotoxin B and its modulation by a proteasome inhibitor. Physiol. Genomics
37: 279-293
[Abstract][Full Text]
Lee, C. G., Hartl, D., Lee, G. R., Koller, B., Matsuura, H., Da Silva, C. A., Sohn, M. H., Cohn, L., Homer, R. J., Kozhich, A. A., Humbles, A., Kearley, J., Coyle, A., Chupp, G., Reed, J., Flavell, R. A., Elias, J. A.
(2009). Role of breast regression protein 39 (BRP-39)/chitinase 3-like-1 in Th2 and IL-13-induced tissue responses and apoptosis. JEM
206: 1149-1166
[Abstract][Full Text]
Postma, D. S., Koppelman, G. H.
(2009). Genetics of Asthma: Where Are We and Where Do We Go?. Proc Am Thorac Soc
6: 283-287
[Abstract][Full Text]
Ober, C., Nord, A. S., Thompson, E. E., Pan, L., Tan, Z., Cusanovich, D., Sun, Y., Nicolae, R., Edelstein, C., Schneider, D. H., Billstrand, C., Pfaffinger, D., Phillips, N., Anderson, R. L., Philips, B., Rajagopalan, R., Hatsukami, T. S., Rieder, M. J., Heagerty, P. J., Nickerson, D. A., Abney, M., Marcovina, S., Jarvik, G. P., Scanu, A. M., Nicolae, D. L.
(2009). Genome-wide association study of plasma lipoprotein(a) levels identifies multiple genes on chromosome 6q. J. Lipid Res.
50: 798-806
[Abstract][Full Text]
Cai, Y., Kumar, R. K., Zhou, J., Foster, P. S., Webb, D. C.
(2009). Ym1/2 Promotes Th2 Cytokine Expression by Inhibiting 12/15(S)-Lipoxygenase: Identification of a Novel Pathway for Regulating Allergic Inflammation. J. Immunol.
182: 5393-5399
[Abstract][Full Text]
Lencz, T., Lipsky, R. H., DeRosse, P., Burdick, K. E., Kane, J. M., Malhotra, A. K.
(2009). Molecular differentiation of schizoaffective disorder from schizophrenia using BDNF haplotypes. Br. J. Psychiatry
194: 313-318
[Abstract][Full Text]
Sohn, M. H., Lee, J. H., Kim, K. W., Kim, S. W., Lee, S. H., Kim, K.-E., Kim, K. H., Lee, C. G., Elias, J. A., Lee, M. G.
(2009). Genetic Variation in the Promoter Region of Chitinase 3-Like 1 Is Associated with Atopy. Am. J. Respir. Crit. Care Med.
179: 449-456
[Abstract][Full Text]
Moffatt, M. F., Cookson, W. O.C.M.
(2008). Asthma and Chitinases. NEJM
358: 1725-1726
[Full Text]
G) in CHI3L1, the chitinase 3–like 1 gene encoding YKL-40, was associated with elevated serum YKL-40 levels (P=1.1x10–13), asthma (P=0.047), bronchial hyperresponsiveness (P=0.002), and measures of pulmonary function (P=0.046 to 0.002) in the Hutterites. The same SNP could be used to predict the presence of asthma in the two case–control populations (combined P=1.2x10–5) and serum YKL-40 levels at birth (in cord-blood specimens) through 5 years of age in the birth cohort (P=8.9x10–3 to 2.5x10–4). 
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