The protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants

NEUROBIOLOGY OF AGING

卷:35

Article

Heckman, Michael G.¹  Elbaz, Alexis^2,3  Soto-Ortolaza, Alexandra I.⁴  Serie, Daniel J.¹  Aasly, Jan O.⁵  Annesi, Grazia⁶  Auburger, Georg⁷  Bacon, Justin A.⁴  Boczarska-Jedynak, Magdalena⁸  Bozi, Maria⁹  Brighina, Laura¹⁰  Chartier-Harlin, Marie-Christine^11,12  Dardiotism, Efthimios¹⁴  Destee, Alain^11,12,15  Ferrarese, Carlo¹⁰  Ferraris, Alessandro¹⁶  Fiske, Brian¹⁷  Gispert, Suzana⁷  Hadjigeorgioum, Georgios M.^13,14  Hattori, Nobutaka¹⁸  Ioannidis, John P. A.^19,20  Jasinska-Myga, Barbara⁸  Jeon, Beom S.²¹  Kim, Yun Joong^22,23  Klein, Christine²⁴  Kruger, Rejko^25,26  Kyratzi, Elli^27,28  Lin, Chin-Hsien²⁹  Lohmann, Katja²⁴  Loriot, Marie-Anne^30,31,32  Lynch, Timothy^33,34  Mellick, George D.³⁵  Mutez, Eugenie^11,12,36  Opala, Grzegorz⁸  Park, Sung Sup³⁷  Petrucci, Simona¹⁶  Quattrone, Aldo^38,39  Sharma, Manu^25,26,40  Silburn, Peter A.⁴¹  Sohn, Young Ho⁴²  Stefanis, Leonidas^27,28  Tadic, Vera²⁴  Tomiyama, Hiroyuki¹⁸  Uitti, Ryan J.⁴³  Valente, Enza Maria^16,44  Vassilatis, Demetrios K.^27,28  Vilarino-Guell, Carles⁴⁵  White, Linda R.^46,47  Wirdefeldt, Karin^48,49  Wszolek, Zbigniew K.⁴³  Wu, Ruey-Meei⁵⁰  Xiromerisiou, Georgia^13,14  Maraganore, Demetrius M.⁵¹  Farrer, Matthew J.⁵¹  Ross, Owen A.⁴ 

[1] Mayo Clin Jacksonville, Sect Biostat, Jacksonville, FL 32224 USA

[2] INSERM, Ctr Res Epidemiol & Populat Hlth, U1018, Villejuif, France

[3] Univ Versailles St Quentin, UMRS 1018, Villejuif, France

[4] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA

[5] Norwegian Univ Sci & Technol, Dept Neurosci, N-7034 Trondheim, Norway

[6] CNR, Inst Neurol Sci, Cosenza, Italy

[7] Goethe Univ Frankfurt, Dept Neurol, D-60054 Frankfurt, Germany

[8] Med Univ Silesia, Dept Neurol, Katowice, Poland

[9] Gen Hosp Syros, Syros, Greece

[10] Univ Milano Bicocca, San Gerardo Hosp, Neurol Sect, Dept Neurosci, Monza, Italy

[11] Univ Lille Nord France, Ctr Rech Jean Pierre Aubert, Lille, France

[12] INSERM, U837, F-59045 Lille, France

[13] Univ Thessaly, Fac Med, Neurogenet Lab, Dept Neurol, Larisa, Greece

[14] CERETETH, Biomed Dept, Neurogenet Lab, Larisa, Greece

[15] CHRU, Univ Hosp, Lille, France

[16] CSS Mendel Lab, IRCCS Casa Sollievo Sofferenza, San Giovanni Rotondo, Italy

[17] Michael J Fox Fdn Parkinsons Res, New York, NY USA

[18] Juntendo Univ Sch Med, Dept Neurol, Tokyo, Japan

[19] Univ Ioannina Med Sch, Dept Hyg & Epidemiol, Clin & Mol Epidemiol Unit, Ioannina, Greece

[20] Stanford Univ Sch Med, Stanford Prevent Res Ctr, Stanford, CA USA

[21] Seoul Natl Univ Hosp, Dept Neurol, Seoul 110744, South Korea

[22] Hallym Univ, ILSONG Inst Life Sci, Anyang, South Korea

[23] Hallym Univ, Dept Neurol, Anyang, South Korea

[24] Univ Lubeck, Inst Neurogenet, Lubeck, Germany

[25] Univ Tubingen, Dept Neurodegenerat Dis, Hertie Inst Clin Brain Res, Tubingen, Germany

[26] Univ Tubingen, German Ctr Neurodegenerat Dis DZNE, Tubingen, Germany

[27] Acad Athens, Biomed Res Fdn, Div Basic Neurosci, Athens, Greece

[28] Acad Athens, Biomed Res Fdn, Div Cell Biol, Athens, Greece

[29] Natl Taiwan Univ Hosp Yun Lin Branch, Dept Neurol, Yunlin, Taiwan

[30] INSERM, UMR S 775, Paris, France

[31] Univ Paris 05, Paris, France

[32] Georges Pompidou European Hosp HEGP, AP HP, Dept Biochem Pharmacogenet & Mol Oncol, Paris, France

[33] Univ Coll Dublin, Dublin Neurol Inst, Mater Misericordiae Univ Hosp, Dublin 2, Ireland

[34] Univ Coll Dublin, Conway Inst Biomol & Biomed Res, Dublin 2, Ireland

[35] Griffith Univ, Eskitis Inst Cell & Mol Therapies, Nathan, Qld 4111, Australia

[36] Ctr Hosp Reg Univ Lille, Lille, France

[37] Seoul Natl Univ Hosp, Dept Lab Med, Seoul 110744, South Korea

[38] Magna Graecia Univ Catanzaro, Inst Neurol, Dept Med Sci, Catanzaro, Italy

[39] CNR, Neuroimaging Res Unit, Catanzaro, Italy

[40] Univ Tubingen, Inst Clin Epidemiol & Appl Biometry, Tubingen, Germany

[41] Univ Queensland, Royal Brisbane Hosp, Clin Res Ctr, Brisbane, Qld 4072, Australia

[42] Yonsei Univ Coll Med, Dept Neurol, Seoul, South Korea

[43] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA

[44] Univ Salerno, Dept Med & Surg, I-84100 Salerno, Italy

[45] Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada

[46] Univ Trondheim Hosp, Trondheim, Norway

[47] Norwegian Univ Sci & Technol, N-7034 Trondheim, Norway

[48] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden

[49] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

[50] Natl Taiwan Univ, Dept Neurol, Natl Taiwan Univ Hosp, Coll Med, Taipei 10764, Taiwan

[51] North Shore Univ Hlth Syst, Dept Neurol, Evanston, IL USA

关键词: Parkinson's disease;    LRRK2;    SNCA;    MAPT;    Interaction;    Genetics;   

DOI  :  10.1016/j.neurobiolaging.2013.07.013

来源: Elsevier

【 摘 要 】

The best validated susceptibility variants for Parkinson's disease are located in the alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H-K1423K haplotype in the leucine-rich repeat kinase 2 (LRRK2) gene was identified, with p.R1398H appearing to be the most likely functional variant. To date, the consistency of the protective effect of LRRK2 p.R1398H across MAPT and SNCA variant genotypes has not been assessed. To address this, we examined 4 SNCA variants (rs181489, rs356219, rs11931074, and rs2583988), the MAPT H1-haplotype-defining variant rs1052553, and LRRK2 p.R1398H (rs7133914) in Caucasian (n = 10,322) and Asian (n = 2289) series. There was no evidence of an interaction of LRRK2 p.R1398H with MAPT or SNCA variants (all p >= 0.10); the protective effect of p.R1398H was observed at similar magnitude across MAPT and SNCA genotypes, and the risk effects of MAPT and SNCA variants were observed consistently for LRRK2 p.R1398H genotypes. Our results indicate that the association of LRRK2 p.R1398H with Parkinson's disease is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations. (c) 2014 Elsevier Inc. All rights reserved.

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