No Association of LOXL1 Gene Polymorphisms with Alzheimer’s Disease
- 205 Downloads
Aggregation of amyloid-beta is one of the major characteristics in brains of patients with Alzheimer’s disease (AD). Although several mechanisms behind the formation of such aggregates have been suggested the regulatory factors are still unknown. The present study aimed at investigating the association of lysyl oxidase-like 1 (LOXL1) polymorphisms with AD diagnosis and cerebrospinal fluid biomarkers (CSF) for the disease. Proteins of the lysyl oxidase (LOX) family are involved in cross-linking extracellular matrix proteins to insoluble fibers and have been associated with neurodegenerative diseases including AD. Genetic polymorphisms in LOXL1 (rs1048661, rs3825942, and rs2165241) have been linked to exfoliation syndrome and exfoliation glaucoma, conditions that have shown association with AD. The polymorphisms were genotyped by Taqman allelic discrimination in a study sample including AD patients (n = 318) and controls (n = 575). In a subgroup of the population, the polymorphisms were analyzed in relation to APOE ε4 genotype and to CSF (T-tau, P-tau, and Aβ1–42). No evidence for associations of these polymorphisms with risk for AD or any of the studied CSF biomarkers measured was found. These results do not support LOXL1 as being a major risk gene for AD.
KeywordsLysyl oxidase-like 1 LOXL1 Alzheimer’s disease SNP Haplotype
This work was supported by grants from the Swedish Research Council, the Swedish Society for Medical Research, the Sahlgrenska University Hospital, the Göteborg Medical Society, the Torsten and Ragnar Söderberg Foundation, Swedish Brain Power, Hjalmar Svenssons forskningsfond, Stiftelsen för Gamla Tjänarinnor and Alzheimerfonden.
- Altman, D. G. (1991). Practical statistics for medical research (1st ed.). London: Chapman & Hall.Google Scholar
- Come, J. H., Fraser, P. E,. & Lansbury, P. T., Jr. (1993). A kinetic model for amyloid formation in the prion diseases: Importance of seeding. In Proceedings of the National Academy of Sciences of the United States of America (Vol. 90, pp. 5959–5963).Google Scholar
- Fan, B. J., Pasquale, L., Grosskreutz, C. L., Rhee, D., Chen, T., DeAngelis, M. M., et al. (2008). DNA sequence variants in the LOXL1 gene are associated with pseudoexfoliation glaucoma in a US clinic-based population with broad ethnic diversity. BMC medical genetics, 9, 5.PubMedCrossRefGoogle Scholar
- Hayashi, K., Fong, K. S., Mercier, F., Boyd, C. D., Csiszar, K., & Hayashi, M. (2004). Comparative immunocytochemical localization of lysyl oxidase (LOX) and the lysyl oxidase-like (LOXL) proteins: Changes in the expression of LOXL during development and growth of mouse tissues. Journal of Molecular Histology, 35, 845–855.PubMedCrossRefGoogle Scholar
- Kirby, E., Bandelow, S., & Hogervorst, E. (2010). Visual Impairment in Alzheimer’s Disease: A critical review. Journal of Alzheimers Disease, 21, 15–34.Google Scholar
- McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., & Stadlan, E. M. (1984). Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA work group under the auspices of department of health and human services task force on Alzheimer’s Disease. Neurology, 34, 939–944.PubMedGoogle Scholar
- Pasutto, F., Krumbiegel, M., Mardin, C. Y., Paoli, D., Lammer, R., Weber, B. H., et al. (2008). Association of LOXL1 common sequence variants in German and Italian patients with pseudoexfoliation syndrome and pseudoexfoliation glaucoma. Investigative ophthalmology and visual science, 49, 1459–1463.PubMedCrossRefGoogle Scholar
- Pinnell, S.R, & Martin, G.R. (1968). The cross-linking of collagen and elastin: Enzymatic conversion of lysine in peptide linkage to alpha-aminoadipic-delta-semialdehyde (allysine) by an extract from bone. In Proceedings of the National Academy of Sciences of the United States of America (Vol. 61 pp. 708–716).Google Scholar
- Sharma, S., Chataway, T., Burdon, K. P., Jonavicius, L., Klebe, S., Hewitt, A. W., et al. (2009). Identification of LOXL1 protein and Apolipoprotein E as components of surgically isolated pseudoexfoliation material by direct mass spectrometry. Experimental Eye Research, 89, 479–485.PubMedCrossRefGoogle Scholar
- Vanmechelen, E., Vanderstichele, H., Davidsson, P., Van Kerschaver, E., Van Der Perre, B., Sjogren, M., et al. (2000). Quantification of tau phosphorylated at threonine 181 in human cerebrospinal fluid: A sandwich ELISA with a synthetic phosphopeptide for standardization. Neuroscience Letters, 285, 49–52.PubMedCrossRefGoogle Scholar
- von Otter, M., Landgren, S., Nilsson, S., Zetterberg, M., Celojevic, D., Bergstrom, P., et al. (2010). Nrf2-encoding NFE2L2 haplotypes influence disease progression but not risk in Alzheimer’s disease and age-related cataract. Mechanisms of Ageing and Development, 131, 105–110.CrossRefGoogle Scholar