Sequence variants of interleukin 6 (IL-6) are significantly associated with a decreased risk of late-onset Alzheimer's disease

Journal of Neuroinflammation

Yen-Ching Chen³  Yi-Min Chu⁵  Ping-Keung Yip⁶  Li-Li Wen⁸  Yu Sun¹  Jen-Hau Chen⁴  Liang-Chuan Lai²  Ta-Fu Chen⁷  Shih-Yuan Chen⁹ 

[1] Department of Neurology, En Chu Kong Hospital, Taipei,Taiwan;Graduate Institute of Physiology, College of Medicine, NationalTaiwan University, Taipei, Taiwan;Research Center for Genes, Environment and Human Health,College of Public Health, National Taiwan University, Taipei,Taiwan;Department of Geriatrics and Gerontology, National TaiwanUniversity Hospital, Taipei, Taiwan;Department of Medicine, School of Medicine, Fu-Jen Catholic University, Taipei, Taiwan;Center of Neurological Medicine, Cardinal Tien Hospital,Taipei, Taiwan;Department of Neurology, National Taiwan University Hospital,Taipei, Taiwan;Center of Laboratory Medicine, En Chu Kong Hospital, Taipei, Taiwan;Institute of Epidemiology and Preventive Medicine, College ofPublic Health, National Taiwan University, Taipei, Taiwan

关键词: Inflammation;    Alzheimer's disease;    Haplotype;    SNP;    IL-6;   

Others  :  1212843
DOI  :  10.1186/1742-2094-9-21

 received in 2011-10-29, accepted in 2012-01-24,  发布年份 2012

【 摘 要 】

Background

Interleukin 6 (IL-6) has been related to beta-amyloid aggregation and the appearance of hyperphosphorylated tau in Alzheimer's disease (AD) brain. However, previous studies relating IL-6 genetic polymorphisms to AD included few and unrepresentative single nucleotide polymorphisms (SNPs) and the results were inconsistent.

Methods

This is a case-control study. A total of 266 patients with AD, aged≧65, were recruited from three hospitals in Taiwan (2007-2010). Controls (n = 444) were recruited from routine health checkups and volunteers of the hospital during the same period of time. Three common IL-6 haplotype-tagging SNPs were selected to assess the association between IL-6 polymorphisms and the risk of late-onset AD (LOAD).

Results

Variant carriers of IL-6 rs1800796 and rs1524107 were significantly associated with a reduced risk of LOAD [(GG + GC vs. CC): adjusted odds ratio (AOR) = 0.64 and (CC + CT vs. TT): AOR = 0.60, respectively]. Haplotype CAT was associated with a decreased risk of LOAD (0 and 1 copy vs. 2 copies: AOR = 0.65, 95% CI = 0.44-0.95). These associations remained significant in ApoE e4 non-carriers only. Hypertension significantly modified the association between rs2069837 polymorphisms and the risk of LOAD (p_interaction = 0.03).

Conclusions

IL-6 polymorphisms are associated with reduced risk of LOAD, especially in ApoE e4 non-carriers. This study identified genetic markers for predicting LOAD in ApoE e4 non-carriers.

【 授权许可】

   
2012 Chen et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Alzheimer's Association: 2010 Alzheimer's Disease Facts and Figures. Alzheimer's & Dementia. [http://www.alz.org/alzheimers_disease_facts_figures.asp?type=homepage] webcite
• [2]Fuh JL, Wang SJ: Dementia in Taiwan: past, present, and future. Acta Neurol Taiwan 2008, 17:153-161.
• [3]Gadient RA, Otten UH: Interleukin-6 (IL-6)--a molecule with both beneficial and destructive potentials. Prog Neurobiol 1997, 52:379-390.
• [4]Heyser CJ, Masliah E, Samimi A, Campbell IL, Gold LH: Progressive decline in avoidance learning paralleled by inflammatory neurodegeneration in transgenic mice expressing interleukin 6 in the brain. Proc Natl Acad Sci USA 1997, 94:1500-1505.
• [5]Castell JV, Andus T, Kunz D, Heinrich PC: Interleukin-6: the major regulator of acute-phase protein synthesis in man and rat. Ann NY Acad Sci 1989, 557:87-99.
• [6]Quintanilla RA, Orellana DI, Gonzalez-Billáult C, Maccioni RB: Interleukin-6 induces Alzheimer-type phosphorylation of tau protein by deregulating the cdk5/p35 pathway. Exp Cell Res 2004, 295:245-257.
• [7]Querfurth HW, LaFerla FM: Alzheimer's disease. N Engl J Med 2010, 362:329-344.
• [8]Licastro F, Grimaldi LM, Bonafè M, Martina C, Olivieri F, Cavallone L, Giovanietti S, Masliah E, Franceschi C: Interleukin-6 gene alleles affect the risk of Alzheimer's disease and levels of the cytokine in blood and brain. Neurobiol Aging 2003, 24:921-926.
• [9]Arosio B, Trabattoni D, Galimberti L, Bucciarelli P, Fasano F, Calabresi C, Cazzullo CL, Vergani C, Annoni G, Clerici M: Interleukin-10 and interleukin-6 gene polymorphisms as risk factors for Alzheimer's disease. Neurobiol Aging 2004, 25:1009-1015.
• [10]Depboylu C, Lohmüller F, Gocke P, Du Y, Zimmer R, Gasser T, Klockgether T, Dodel RC: An interleukin-6 promoter variant is not associated with an increased risk for Alzheimer's disease. Dement Geriatr Cogn Disord 2004, 17:170-173.
• [11]van Oijen M, Arp PP, de Jong FJ, Hofman A, Koudstaal PJ, Uitterlinden AG, Breteler MM: Polymorphisms in the interleukin 6 and transforming growth factor beta1 gene and risk of dementia. The Rotterdam study. Neurosci Lett 2006, 402:113-117.
• [12]He MX, Yang WL, Zhang MM, Lian YJ, Hua HY, Zeng JS, Zhang LR: Association between interleukin-6 gene promoter--572 C/G polymorphism and the risk of sporadic Alzheimer's disease. Neurol Sci 2010, 31:165-168.
• [13]Wang M, Jia J: The interleukin-6 gene--572 C/G promoter polymorphism modifies Alzheimer's risk in ApoE epsilon 4 carriers. Neurosci Lett 2010, 482:260-263.
• [14]Nishimura M, Sakamoto T, Kaji R, Kawakami H: Influence of polymorphisms in the genes for cytokines and glutathione S-transferase omega on sporadic Alzheimer's disease. Neurosci Lett 2004, 368:140-143.
• [15]Lim CS, Zheng S, Kim YS, Ahn C, Han JS, Kim S, Lee JS, Chae DW: The -174 G to C polymorphism of interleukin-6 gene is very rare in Koreans. Cytokine 2002, 19:52-54.
• [16]Fillit H, Nash DT, Rundek T, Zuckerman A: Cardiovascular risk factors and dementia. Am J Geriatr Pharmacother 2008, 6:100-118.
• [17]Román GC: Vascular dementia prevention: a risk factor analysis. Cerebrovasc Dis 2005, 20(Suppl 2):91-100.
• [18]Stozická Z, Zilka N, Novák M: Risk and protective factors for sporadic Alzheimer's disease. Acta Virol 2007, 51:205-222.
• [19]American Psychiatric Association: Diagnostic and statistical manual of mental disorders. Washington, DC. 4th edition. 1994.
• [20]McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM: 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 1984, 34:939-944.
• [21]Pfeiffer E: A short portable mental status questionnaire for the assessment of organic brain deficit in elderly patients. J Am Geriatr Soc 1975, 23:433-441.
• [22]Chen YC, Giovannucci E, Lazarus R, Kraft P, Ketkar S, Hunter DJ: Sequence variants of Toll-like receptor 4 and susceptibility to prostate cancer. Cancer Res 2005, 65:11771-11778.
• [23]Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D: The structure of haplotype blocks in the human genome. Science 2002, 296:2225-2229.
• [24]Stram DO, Leigh Pearce C, Bretsky P, Freedman M, Hirschhorn JN, Altshuler D, Kolonel LN, Henderson BE, Thomas DC: Modeling and E-M estimation of haplotype-specific relative risks from genotype data for a case-control study of unrelated individuals. Hum Hered 2003, 55:179-190.
• [25]Chapman J, Estupiñan J, Asherov A, Goldfarb LG: A simple and efficient method for apolipoprotein E genotype determination. Neurology 1996, 46:1484-1485.
• [26]Ghebranious N, Ivacic L, Mallum J, Dokken C: Detection of ApoE E2, E3 and E4 alleles using MALDI-TOF mass spectrometry and the homogeneous mass-extend technology. Nucleic Acids Res 2005, 33(17):e149.
• [27]Benjamini Y, Hochberg Y: Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Statist Soc B 1995, 57:289-300.
• [28]Brull DJ, Montgomery HE, Sanders J, Dhamrait S, Luong L, Rumley A, Lowe GD, Humphries SE: Interleukin-6 gene -174 g > c and--572 g > c promoter polymorphisms are strong predictors of plasma interleukin-6 levels after coronary artery bypass surgery. Arterioscler Thromb Vasc Biol 2001, 21:1458-1463.
• [29]Wong LY, Leung RY, Ong KL, Cheung BM: Plasma levels of fibrinogen and C-reactive protein are related to interleukin-6 gene -572 C > G polymorphism in subjects with and without hypertension. J Hum Hypertens 2007, 21:875-882.
• [30]Nonogaki K, Iguchi A: Stress, acute hyperglycemia, and hyperlipidemia role of the autonomic nervous system and cytokines. Trends Endocrinol Metab 1997, 8:192-197.
• [31]Burgess BL, McIsaac SA, Naus KE, Chan JY, Tansley GH, Yang J, Miao F, Ross CJ, van Eck M, Hayden MR, van Nostrand W, St George-Hyslop P, Westaway D, Wellington CL: Elevated plasma triglyceride levels precede amyloid deposition in Alzheimer's disease mouse models with abundant A beta in plasma. Neurobiol Dis 2006, 24:114-127.
• [32]Hajjar IM, Keown M, Lewis P, Almor A: Angiotensin converting enzyme inhibitors and cognitive and functional decline in patients with Alzheimer's disease: an observational study. Am J Alzheimers Dis Other Demen 2008, 23:77-83.
• [33]Li NC, Lee A, Whitmer RA, Kivipelto M, Lawler E, Kazis LE, Wolozin B: Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis. BMJ 2010, 12:b5465.
• [34]Zheng SL, Liu W, Wiklund F, Dimitrov L, Bälter K, Sun J, Adami HO, Johansson JE, Sun J, Chang B, Loza M, Turner AR, Bleecker ER, Meyers DA, Carpten JD, Duggan D, Isaacs WB, Xu J, Grönberg H: A comprehensive association study for genes in inflammation pathway provides support for their roles in prostate cancer risk in the CAPS study. Prostate 2006, 66(14):1556-1564.
• [35]El Fakiri F, Bruijnzeels MA, Hoes AW: No evidence for marked ethnic differences in accuracy of self-reported diabetes, hypertension, and hypercholesterolemia. J Clin Epidemiol 2007, 60:1271-1279.
• [36]Okura Y, Urban LH, Mahoney DW, Jacobsen SJ, Rodehceffer RJ: Agreement between self-report questionnaires and medical record data was substantial for diabetes, hypertension, myocardial infarction and stroke but not for heart failure. J Clin Epidemiol 2004, 57:1096-1103.
• [37]St Sauver JL, Hagen PT, Cha SS, Bagniewski SM, Mandrekar JN, Curoe AM, Rodeheffer RJ, Roger VL, Jacobsen SJ: Agreement between patient reports of cardiovascular disease and patient medical records. Mayo Clin Proc 2005, 80:203-210.