PMID- 28350795 OWN - NLM STAT- MEDLINE DCOM- 20170612 LR - 20190320 IS - 1549-1676 (Electronic) IS - 1549-1277 (Print) IS - 1549-1277 (Linking) VI - 14 IP - 3 DP - 2017 Mar TI - Fine-mapping of the human leukocyte antigen locus as a risk factor for Alzheimer disease: A case-control study. PG - e1002272 LID - 10.1371/journal.pmed.1002272 [doi] LID - e1002272 AB - BACKGROUND: Alzheimer disease (AD) is a progressive disorder that affects cognitive function. There is increasing support for the role of neuroinflammation and aberrant immune regulation in the pathophysiology of AD. The immunoregulatory human leukocyte antigen (HLA) complex has been linked to susceptibility for a number of neurodegenerative diseases, including AD; however, studies to date have failed to consistently identify a risk HLA haplotype for AD. Contributing to this difficulty are the complex genetic organization of the HLA region, differences in sequencing and allelic imputation methods, and diversity across ethnic populations. METHODS AND FINDINGS: Building on prior work linking the HLA to AD, we used a robust imputation method on two separate case-control cohorts to examine the relationship between HLA haplotypes and AD risk in 309 individuals (191 AD, 118 cognitively normal [CN] controls) from the San Francisco-based University of California, San Francisco (UCSF) Memory and Aging Center (collected between 1999-2015) and 11,381 individuals (5,728 AD, 5,653 CN controls) from the Alzheimer's Disease Genetics Consortium (ADGC), a National Institute on Aging (NIA)-funded national data repository (reflecting samples collected between 1984-2012). We also examined cerebrospinal fluid (CSF) biomarker measures for patients seen between 2005-2007 and longitudinal cognitive data from the Alzheimer's Disease Neuroimaging Initiative (n = 346, mean follow-up 3.15 +/- 2.04 y in AD individuals) to assess the clinical relevance of identified risk haplotypes. The strongest association with AD risk occurred with major histocompatibility complex (MHC) haplotype A*03:01~B*07:02~DRB1*15:01~DQA1*01:02~DQB1*06:02 (p = 9.6 x 10-4, odds ratio [OR] [95% confidence interval] = 1.21 [1.08-1.37]) in the combined UCSF + ADGC cohort. Secondary analysis suggested that this effect may be driven primarily by individuals who are negative for the established AD genetic risk factor, apolipoprotein E (APOE) varepsilon4. Separate analyses of class I and II haplotypes further supported the role of class I haplotype A*03:01~B*07:02 (p = 0.03, OR = 1.11 [1.01-1.23]) and class II haplotype DRB1*15:01- DQA1*01:02- DQB1*06:02 (DR15) (p = 0.03, OR = 1.08 [1.01-1.15]) as risk factors for AD. We followed up these findings in the clinical dataset representing the spectrum of cognitively normal controls, individuals with mild cognitive impairment, and individuals with AD to assess their relevance to disease. Carrying A*03:01~B*07:02 was associated with higher CSF amyloid levels (p = 0.03, beta +/- standard error = 47.19 +/- 21.78). We also found a dose-dependent association between the DR15 haplotype and greater rates of cognitive decline (greater impairment on the 11-item Alzheimer's Disease Assessment Scale cognitive subscale [ADAS11] over time [p = 0.03, beta +/- standard error = 0.7 +/- 0.3]; worse forgetting score on the Rey Auditory Verbal Learning Test (RAVLT) over time [p = 0.02, beta +/- standard error = -0.2 +/- 0.06]). In a subset of the same cohort, dose of DR15 was also associated with higher baseline levels of chemokine CC-4, a biomarker of inflammation (p = 0.005, beta +/- standard error = 0.08 +/- 0.03). The main study limitations are that the results represent only individuals of European-ancestry and clinically diagnosed individuals, and that our study used imputed genotypes for a subset of HLA genes. CONCLUSIONS: We provide evidence that variation in the HLA locus-including risk haplotype DR15-contributes to AD risk. DR15 has also been associated with multiple sclerosis, and its component alleles have been implicated in Parkinson disease and narcolepsy. Our findings thus raise the possibility that DR15-associated mechanisms may contribute to pan-neuronal disease vulnerability. FAU - Steele, Natasha Z R AU - Steele NZ AD - Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America. AD - University of Washington School of Medicine, Seattle, Washington, United States of America. FAU - Carr, Jessie S AU - Carr JS AUID- ORCID: 0000-0001-6247-7494 AD - Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America. AD - Gladstone Institute of Neurological Disease, San Francisco, California, United States of America. FAU - Bonham, Luke W AU - Bonham LW AD - Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America. AD - Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. FAU - Geier, Ethan G AU - Geier EG AD - Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America. FAU - Damotte, Vincent AU - Damotte V AD - Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America. FAU - Miller, Zachary A AU - Miller ZA AUID- ORCID: 0000-0002-5991-3053 AD - Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America. FAU - Desikan, Rahul S AU - Desikan RS AUID- ORCID: 0000-0002-4151-6017 AD - Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, United States of America. FAU - Boehme, Kevin L AU - Boehme KL AD - Brigham Young University, Provo, Utah, United States of America. FAU - Mukherjee, Shubhabrata AU - Mukherjee S AD - University of Washington School of Medicine, Seattle, Washington, United States of America. FAU - Crane, Paul K AU - Crane PK AD - University of Washington School of Medicine, Seattle, Washington, United States of America. FAU - Kauwe, John S K AU - Kauwe JS AD - Brigham Young University, Provo, Utah, United States of America. FAU - Kramer, Joel H AU - Kramer JH AD - Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America. FAU - Miller, Bruce L AU - Miller BL AD - Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America. FAU - Coppola, Giovanni AU - Coppola G AUID- ORCID: 0000-0003-2105-1061 AD - Departments of Neurology and Psychiatry, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California, United States of America. FAU - Hollenbach, Jill A AU - Hollenbach JA AD - Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America. FAU - Huang, Yadong AU - Huang Y AD - Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America. AD - Gladstone Institute of Neurological Disease, San Francisco, California, United States of America. AD - Department of Pathology, University of California, San Francisco, San Francisco, California, United States of America. FAU - Yokoyama, Jennifer S AU - Yokoyama JS AUID- ORCID: 0000-0001-7274-2634 AD - Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America. LA - eng GR - K01 AG049152/AG/NIA NIH HHS/United States GR - U24 AG021886/AG/NIA NIH HHS/United States GR - U01 AG032984/AG/NIA NIH HHS/United States GR - U01 AG016976/AG/NIA NIH HHS/United States GR - K23 AG048291/AG/NIA NIH HHS/United States GR - P01 AG019724/AG/NIA NIH HHS/United States GR - U01 AG006781/AG/NIA NIH HHS/United States GR - R01 AI128775/AI/NIAID NIH HHS/United States PT - Journal Article DEP - 20170328 PL - United States TA - PLoS Med JT - PLoS medicine JID - 101231360 RN - 0 (HLA Antigens) SB - IM MH - Aged MH - Aged, 80 and over MH - Alzheimer Disease/epidemiology/*genetics MH - Case-Control Studies MH - *Chromosome Mapping MH - Female MH - HLA Antigens/cerebrospinal fluid/*genetics MH - Haplotypes MH - Humans MH - Male MH - Middle Aged MH - Risk Factors MH - San Francisco/epidemiology MH - United States/epidemiology PMC - PMC5369701 COIS- YH is a co-founder and SAB member for E-Scape Bio, Inc. BLM served as a guest editor on PLOS Medicine's Dementia Special Issue. EDAT- 2017/03/30 06:00 MHDA- 2019/03/21 06:00 PMCR- 2017/03/28 CRDT- 2017/03/29 06:00 PHST- 2016/10/07 00:00 [received] PHST- 2017/02/17 00:00 [accepted] PHST- 2017/03/29 06:00 [entrez] PHST- 2017/03/30 06:00 [pubmed] PHST- 2019/03/21 06:00 [medline] PHST- 2017/03/28 00:00 [pmc-release] AID - PMEDICINE-D-16-03275 [pii] AID - 10.1371/journal.pmed.1002272 [doi] PST - epublish SO - PLoS Med. 2017 Mar 28;14(3):e1002272. doi: 10.1371/journal.pmed.1002272. eCollection 2017 Mar.