Genetically elevated high-density lipoprotein cholesterol through the cholesteryl ester transfer protein gene does not associate with risk of Alzheimer's disease

Gina M Peloso; Sven J van der Lee; International Genomics of Alzheimer's Project (IGAP); Anita L Destefano; Sudha Seshardi

doi:10.1016/j.dadm.2018.08.008

Genetically elevated high-density lipoprotein cholesterol through the cholesteryl ester transfer protein gene does not associate with risk of Alzheimer's disease

Alzheimers Dement (Amst). 2018 Sep 22:10:595-598. doi: 10.1016/j.dadm.2018.08.008. eCollection 2018.

Authors

Gina M Peloso¹, Sven J van der Lee²; International Genomics of Alzheimer's Project (IGAP); Anita L Destefano^{1

3

4}, Sudha Seshardi^{3

4

5}

Collaborators

International Genomics of Alzheimer's Project (IGAP):
R Sims, S J van der Lee, A C Naj, C Bellenguez, N Badarinarayan, J Jakobsdottir, B W Kunkle, A Boland, R Raybould, J C Bis, E R Martin, B Grenier-Boley, S Heilmann-Heimbach, V Chouraki, A B Kuzma, K Sleegers, M Vronskaya, A Ruiz, R R Graham, R Olaso, P Hoffmann, M L Grove, B N Vardarajan, M Hiltunen, M M Nöthen, C C White, K L Hamilton-Nelson, J Epelbaum, W Maier, S H Choi, G W Beecham, C Dulary, S Herms, A V Smith, C C Funk, C Derbois, A J Forstner, S Ahmad, H Li, D Bacq, D Harold, C L Satizabal, O Valladares, A Squassina, R Thomas, J A Brody, L Qu, P Sánchez-Juan, T Morgan, F J Wolters, Y Zhao, F S Garcia, N Denning, M Fornage, J Malamon, M C D Naranjo, E Majounie, T H Mosley, B Dombroski, D Wallon, M K Lupton, J Dupuis, P Whitehead, L Fratiglioni, C Medway, X Jian, S Mukherjee, L Keller, K Brown, H Lin, L B Cantwell, F Panza, B McGuinness, S Moreno-Grau, J D Burgess, V Solfrizzi, P Proitsi, H H Adams, M Allen, D Seripa, P Pastor, L A Cupples, N D Price, D Hannequin, A Frank-García, D Levy, P Chakrabarty, P Caffarra, I Giegling, A S Beiser, V Giedraitis, H Hampel, M E Garcia, X Wang, L Lannfelt, P Mecocci, G Eiriksdottir, P K Crane, F Pasquier, V Boccardi, I Henández, R C Barber, M Scherer, L Tarraga, P M Adams, M Leber, Y Chen, M S Albert, S Riedel-Heller, V Emilsson, D Beekly, A Braae, R Schmidt, D Blacker, C Masullo, H Schmidt, R S Doody, G Spalletta, W T Longstreth Jr, T J Fairchild, P Bossù, O L Lopez, M P Frosch, E Sacchinelli, B Ghetti, Q Yang, R M Huebinger, F Jessen, S Li, M I Kamboh, J Morris, O Sotolongo-Grau, M J Katz, C Corcoran, M Dunstan, A Braddel, C Thomas, A Meggy, R Marshall, A Gerrish, J Chapman, M Aguilar, S Taylor, M Hill, M D Fairén, A Hodges, B Vellas, H Soininen, I Kloszewska, M Daniilidou, J Uphill, Y Patel, J T Hughes, J Lord, J Turton, A M Hartmann, R Cecchetti, C Fenoglio, M Serpente, M Arcaro, C Caltagirone, M D Orfei, A Ciaramella, S Pichler, M Mayhaus, W Gu, A Lleó, J Fortea, R Blesa, I S Barber, K Brookes, C Cupidi, R G Maletta, D Carrell, S Sorbi, S Moebus, M Urbano, A Pilotto, J Kornhuber, P Bosco, S Todd, D Craig, J Johnston, M Gill, B Lawlor, A Lynch, N C Fox, J Hardy, R L Albin, L G Apostolova, S E Arnold, S Asthana, C S Atwood, C T Baldwin, L L Barnes, S Barral, T G Beach, J T Becker, E H Bigio, T D Bird, B F Boeve, J D Bowen, A Boxer, J R Burke, J M Burns, J D Buxbaum, N J Cairns, C Cao, C S Carlson, C M Carlsson, R M Carney, M M Carrasquillo, S L Carroll, C C Diaz, H C Chui, D G Clark, D H Cribbs, E A Crocco, C DeCarli, M Dick, R Duara, D A Evans, K M Faber, K B Fallon, D W Fardo, M R Farlow, S Ferris, T M Foroud, D R Galasko, M Gearing, D H Geschwind, J R Gilbert, N R Graff-Radford, R C Green, J H Growdon, R L Hamilton, L E Harrell, L S Honig, M J Huentelman, C M Hulette, B T Hyman, G P Jarvik, E Abner, L W Jin, G Jun, A Karydas, J A Kaye, R Kim, N W Kowall, J H Kramer, F M LaFerla, J J Lah, J B Leverenz, A I Levey, G Li, A P Lieberman, K L Lunetta, C G Lyketsos, D C Marson, F Martiniuk, D C Mash, E Masliah, W C McCormick, S M McCurry, A N McDavid, A C McKee, M Mesulam, B L Miller, C A Miller, J W Miller, J C Morris, J R Murrell, A J Myers, S O'Bryant, J M Olichney, V S Pankratz, J E Parisi, H L Paulson, W Perry, E Peskind, A Pierce, W W Poon, H Potter, J F Quinn, A Raj, M Raskind, B Reisberg, C Reitz, J M Ringman, E D Roberson, E Rogaeva, H J Rosen, R N Rosenberg, M A Sager, A J Saykin, J A Schneider, L S Schneider, W W Seeley, A G Smith, J A Sonnen, S Spina, R A Stern, R H Swerdlow, R E Tanzi, T A Thornton-Wells, J Q Trojanowski, J C Troncoso, V M Van Deerlin, L J Van Eldik, H V Vinters, J P Vonsattel, S Weintraub, K A Welsh-Bohmer, K C Wilhelmsen, J Williamson, T S Wingo, R L Woltjer, C B Wright, C E Yu, L Yu, F Garzia, F Golamaully, G Septier, S Engelborghs, R Vandenberghe, P P De Deyn, C M Fernadez, Y A Benito, H Thonberg, C Forsell, L Lilius, A Kinhult-Stählbom, L Kilander, R Brundin, L Concari, S Helisalmi, A M Koivisto, A Haapasalo, V Dermecourt, N Fievet, O Hanon, C Dufouil, A Brice, K Ritchie, B Dubois, J J Himali, C D Keene, J Tschanz, A L Fitzpatrick, W A Kukull, M Norton, T Aspelund, E B Larson, R Munger, J I Rotter, R B Lipton, M J Bullido, A Hofman, T J Montine, E Coto, E Boerwinkle, R C Petersen, V Alvarez, F Rivadeneira, E M Reiman, M Gallo, C J O'Donnell, J S Reisch, A C Bruni, D R Royall, M Dichgans, M Sano, D Galimberti, P St George-Hyslop, E Scarpini, D W Tsuang, M Mancuso, U Bonuccelli, A R Winslow, A Daniele, C K Wu, O Peters, B Nacmias, M Riemenschneider, R Heun, C Brayne, D C Rubinsztein, J Bras, R Guerreiro, A Al-Chalabi, C E Shaw, J Collinge, D Mann, M Tsolaki, J Clarimón, R Sussams, S Lovestone, M C O'Donovan, M J Owen, T W Behrens, S Mead, A M Goate, A G Uitterlinden, C Holmes, C Cruchaga, M Ingelsson, D A Bennett, J Powell, T E Golde, C Graff, P L De Jager, K Morgan, N Ertekin-Taner, O Combarros, B M Psaty, P Passmore, S G Younkin, C Berr, V Gudnason, D Rujescu, D W Dickson, J F Dartigues, A L DeStefano, S Ortega-Cubero, H Hakonarson, D Campion, M Boada, J K Kauwe, L A Farrer, C Van Broeckhoven, M A Ikram, L Jones, J L Haines, C Tzourio, L J Launer, V Escott-Price, R Mayeux, J F Deleuze, N Amin, P A Holmans, M A Pericak-Vance, P Amouyel, C M van Duijn, A Ramirez, L S Wang, J C Lambert, S Seshadri, J Williams, G D Schellenberg

Affiliations

¹ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
² Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, Netherlands.
³ NHLBI's Framingham Heart Study, Framingham, MA, USA.
⁴ Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
⁵ Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX, USA.

Abstract

Introduction: There is conflicting evidence whether high-density lipoprotein cholesterol (HDL-C) is a risk factor for Alzheimer's disease (AD) and dementia. Genetic variation in the cholesteryl ester transfer protein (CETP) locus is associated with altered HDL-C. We aimed to assess AD risk by genetically predicted HDL-C.

Methods: Ten single nucleotide polymorphisms within the CETP locus predicting HDL-C were applied to the International Genomics of Alzheimer's Project (IGAP) exome chip stage 1 results in up 16,097 late onset AD cases and 18,077 cognitively normal elderly controls. We performed instrumental variables analysis using inverse variance weighting, weighted median, and MR-Egger.

Results: Based on 10 single nucleotide polymorphisms distinctly predicting HDL-C in the CETP locus, we found that HDL-C was not associated with risk of AD (P > .7).

Discussion: Our study does not support the role of HDL-C on risk of AD through HDL-C altered by CETP. This study does not rule out other mechanisms by which HDL-C affects risk of AD.

Keywords: Cholesteryl ester transfer protein; Genetics; HDL-C; Instrumental variables; Single nucleotide polymorphisms.

Abstract

Grants and funding