Protective association of HLA‐DRB1*04 subtypes in neurodegenerative diseases implicates acetylated tau PHF6 sequences
Authors: Guen Yann Le , Luo Guo , Ambati Aditya , Damotte Vincent , Jansen Iris E , Yu Eric , Nicolas Aude , de Rojas Itziar , Leal Thiago Peixoto , Miyashita Akinori , Bellenguez Céline , Lian Michelle Mulan , Parveen Kayenat , Morizono Takashi , Park Hyeonseul , Grenier‐Boley Benjamin , Naito Tatsuhiko , Küçükali Fahri , Talyansky Seth D. , Yogeshwar Selina Marie , Sempere Vicente , Satake Wataru , Álvarez‐Martínez Victoria , Arosio Beatrice , Belloy Michael E , Benussi Luisa , Boland Anne , Borroni Barbara , Bullido María J. , Caffarra Paolo , Clarimon Jordi , Daniele Antonio , Darling Daniel , Debette Stéphanie , Deleuze Jean‐François , Dichgans Martin , Dufouil Carole , During Emmanuel , Duzel Emrah , Galimberti Daniela , García‐Ribas Guillermo , García‐Alberca Jose María , García‐González Pablo , Giedraitis Vilmantas , Goldhardt Oliver , Graff Caroline , Grunblatt Edna , Hanon Olivier , Hausner Lucrezia , Heilmann‐Heimbach Stefanie , Holstege Henne , Hort Jakub , Jung Yoo Jin , Jurgen Deckert , Kern Silke , Kuulasmaa Teemu , Lee Kun Ho , Ling Ling , Masullo Carlo , Mecocci Patrizia , Mehrabian Shima , de Mendonça Alexandre , Boada Mercè , Mir Pablo , Moebus Susanne , Moreno Fermin , Nacmias Benedetta , Nicolas Gaël , Niida Shumpei , Nordestgaard Børge G. , Papenberg Goran , Papma Janne M. , Parnetti Lucilla , Pasquier Florence , Pastor Pau , Peters Oliver , Pijnenburg Yolande A.L. , Piñol‐Ripoll Gerard , Popp Julius , Molina Laura , Puerta Raquel , Pérez‐Tur Jordi , Rainero Innocenzo , Real Luis Miguel , Riedel‐Heller Steffi G. , Rodríguez Eloy Rodríguez , Royo José Luís , Rujescu Dan , Scarmeas Nikolaos , Scheltens Philip , Scherbaum Norbert , Schneider Anja , Seripa Davide , Skoog Ingmar , Solfrizzi Vincenzo , Spalletta Gianfranco , Squassina Alessio , van Swieten John C , Sanchez‐Valle Raquel , Tan Eng‐King , Tegos Thomas , Teunissen Charlotte E. , Thomassen Jesper Qvist , Tremolizzo Lucio , Vyhnalek Martin , Verhey Frans R.J. , Waern Margda , Wiltfang Jens , Zhang Jing , Zetterberg Henrik , Blennow Kaj , Williams Julie , Amouyel Philippe , Jessen Frank , Kehoe Patrick G , Andreassen Ole , van Duijn Cornelia M , Tsolaki Magda , Sanchez‐Juan Pascual , Frikke‐Schmidt Ruth , Sleegers Kristel , Toda Tatsushi , Zettergren Anna , Ingelsson Martin , Okada Yukinori , Rossi Giacomina , Hiltunen Mikko , Gim Jungsoo , Ozaki Kouichi , Sims Rebecca , Foo Jia Nee , van der Flier Wiesje M. , Ikeuchi Takeshi , Ramirez Alfredo , Mata Ignacio , Ruiz Agustin , Gan‐Or Ziv , Lambert Jean‐Charles , Greicius Michael D , Mignot Emmanuel 
Published: December 2022

Background

Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic Lateral Sclerosis (ALS) and other neurodegenerative diseases are responsible for considerable morbidity and mortality. With incidence rising with aging, these also represent a growing societal challenge. Pathophysiology involves accumulation of tau (neurofibrillary tangles) and Amyloid‐β‐rich (amyloid plaques) aggregates in AD, α‐synuclein‐rich aggregates (Lewy bodies) in PD and TDP‐43 aggregates in ALS, although co‐presence of these aggregates may occur. Consensus is also growing that tau may also play a key role in PD and ALS.

Method

Using genome‐wide association data, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with PD or Alzheimer’s AD disease versus controls across ancestry groups.

Result

A shared genetic association was observed across diseases at rs601945 (PD: odds ratio (OR)=0.84; 95% confidence interval, [0.80; 0.88]; p=2.2x10‐13; AD: OR=0.91[0.89; 0.93]; p=1.8x10‐22), and with a protective HLA association recently reported in ALS. Hierarchical protective effects of HLA‐DRB1*04 subtypes best accounted for the association, strongest with HLA‐DRB1*04:04 and HLA‐DRB1*04:07, intermediary with HLA‐DRB1*04:01 and HLA‐DRB1*04:03, and absent for HLA‐DRB1*04:05. The same signal was associated with decreased neurofibrillary tangles (but not neuritic plaque density) in postmortem brains and was more strongly associated with tau levels than Aβ42 levels in the cerebrospinal fluid. Finally, protective HLA‐DRB1*04 subtypes strongly bound the aggregation‐prone tau PHF6 sequence, but only when acetylated at K311, a modification central to aggregation.

Conclusion

An HLA‐DRB1*04‐mediated adaptive immune response, potentially against tau, decreases PD, AD and ALS risk, offering the possibility of new therapeutic avenues.