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Cited by 101Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchGenetic Associations and Epidemiology

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Fine-mapping of the human leukocyte antigen locus as a risk factor for Alzheimer disease: A case–control study

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Steele, Natasha Z. R., Carr, Jessie S., Bonham, Luke W., Geier, Ethan G., Damotte, Vincent, Miller, Zachary A., Desikan, Rahul S., Boehme, Kevin L., Mukherjee, Shubhabrata, Crane, Paul K., Kauwe, John S. K., Kramer, Joel H., Miller, Bruce L., Coppola, Giovanni, Hollenbach, Jill A., Huang, Yadong, Yokoyama, Jennifer S.·2017·PLOS Medicine
DOI 10.1371/journal.pmed.1002272PMC PMC5369701
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Abstract

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) ɛ4. 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, β ± 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, β ± standard error = 0.7 ± 0.3]; worse forgetting score on the Rey Auditory Verbal Learning Test (RAVLT) over time [p = 0.02, β ± 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, β ± 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.

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Figures

Fig 1 Carrying the A*03:01~B*07:02 risk haplotype was associated with CSF (cerebrospinal fluid) amyloid β. CSF amyloid β levels were on average higher in carriers of the A*03:01~B*07:02 haplotype, suggesting that haplotype carriers may have lower average intracranial amyloid pathological burden compared to noncarriers. The plotted points are best linear unbiased predictions from a multiple regression model, which controlled for age, sex, education, CDR-SB score, and APOE ɛ4 status. Data shown are the mean ± standard deviation (SD).
Fig 1 Carrying the A*03:01~B*07:02 risk haplotype was associated with CSF (cerebrospinal fluid) amyloid β. CSF amyloid β levels were on average higher in carriers of the A*03:01~B*07:02 haplotype, suggesting that haplotype carriers may have lower average intracranial amyloid pathological burden compared to noncarriers. The plotted points are best linear unbiased predictions from a multiple regression model, which controlled for age, sex, education, CDR-SB score, and APOE ɛ4 status. Data shown are the mean ± standard deviation (SD).CC BY · PubMed Central
Fig 2 DR15 haplotype carriers showed greater change over time on the ADAS cognitive assessment when compared to noncarriers. Longitudinal ADAS 11-item cognitive subscale scores from the ADNI cohort are shown. The ADAS broadly measures cognitive functions impaired in AD [34], with higher scores representing more cognitive impairment. DR15 haplotype carriers (in red) showed worse cognitive function over time when compared to noncarriers (in black) (p = 0.03). The plotted data represent the best linear unbiased prediction results from the regression model specified (see Methods) with 95% CIs (shaded regions).
Fig 2 DR15 haplotype carriers showed greater change over time on the ADAS cognitive assessment when compared to noncarriers. Longitudinal ADAS 11-item cognitive subscale scores from the ADNI cohort are shown. The ADAS broadly measures cognitive functions impaired in AD [34], with higher scores representing more cognitive impairment. DR15 haplotype carriers (in red) showed worse cognitive function over time when compared to noncarriers (in black) (p = 0.03). The plotted data represent the best linear unbiased prediction results from the regression model specified (see Methods) with 95% CIs (shaded regions).CC BY · PubMed Central
Fig 3 DR15 haplotype carriers declined more on the RAVLT forgetting score when compared to noncarriers. Longitudinal RAVLT measurements from the ADNI cohort are shown. The RAVLT forgetting score is defined as the difference between the delayed recall and immediate recall scores on the RAVLT and represents a measure of memory consolidation. Over time, DR15 risk haplotype carriers showed more change on the forgetting score (i.e., more forgetting) than noncarriers. The plotted data represent the best linear unbiased prediction results from the regression model specified (see Methods) with 95% CIs (shaded regions).
Fig 3 DR15 haplotype carriers declined more on the RAVLT forgetting score when compared to noncarriers. Longitudinal RAVLT measurements from the ADNI cohort are shown. The RAVLT forgetting score is defined as the difference between the delayed recall and immediate recall scores on the RAVLT and represents a measure of memory consolidation. Over time, DR15 risk haplotype carriers showed more change on the forgetting score (i.e., more forgetting) than noncarriers. The plotted data represent the best linear unbiased prediction results from the regression model specified (see Methods) with 95% CIs (shaded regions).CC BY · PubMed Central
Fig 4 DR15 dosage was associated with higher baseline levels of chemokine CC4. As the number of DR15 risk haplotype alleles increases, there were higher average levels of chemokine CC4, suggesting higher levels of inflammation at baseline. Chemokine CC4 levels are quality controlled and transformed as described in S1 Methods. The plotted points are partial residuals with 95% confidence bands provided in shading.
Fig 4 DR15 dosage was associated with higher baseline levels of chemokine CC4. As the number of DR15 risk haplotype alleles increases, there were higher average levels of chemokine CC4, suggesting higher levels of inflammation at baseline. Chemokine CC4 levels are quality controlled and transformed as described in S1 Methods. The plotted points are partial residuals with 95% confidence bands provided in shading.CC BY · PubMed Central

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  1. JS Yokoyama, 2016, Association Between Genetic Traits for Immune-Mediated Diseases and Alzheimer Disease, JAMA Neurol, 94158, 1

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Metadata

Authors
Steele, N. Z. R., Carr, J. S., Bonham, L. W., Geier, E. G., Damotte, V., Miller, Z. A., Desikan, R. S., Boehme, K. L., Mukherjee, S., Crane, P. K., Kauwe, J. S. K., Kramer, J. H., Miller, B. L., Coppola, G., Hollenbach, J. A., Huang, Y., & Yokoyama, J. S.
Affiliations
  • University of California, San Francisco (US)
  • Gladstone Institutes (US)
  • Johns Hopkins University (US)
  • Brigham Young University (US)
  • University of Washington (US)
  • University of California, Los Angeles (US)
Corresponding author
Yokoyama, Jennifer S.
ORCID
Venue
PLOS Medicine
Publisher
Public Library of Science (PLoS)
Published
2017-03-28
Volume
14
Issue
3
Pages
e1002272
ISSN
  • 1549-1277 (ISSN-L)
  • 1549-1676
DOI
10.1371/journal.pmed.1002272
PMC
PMC5369701
OpenAlex
W2597790250
Cited by
91
References
82
Citations by year
2026: 8 · 2025: 8 · 2024: 10 · 2023: 10 · 2022: 14 · 2021: 15 · 2020: 5 · 2019: 8 · 2018: 10 · 2017: 3
FWCI
5.22
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • Larry L. Hillblom Foundation (2016-A-005-SUP, Hillblom Aging Network)
  • National Institute on Aging (AG049152, R01 AG048017, K23 AG048291, AG023501, AG1972403)
  • Tau Consortium
  • National Alzheimer's Coordinating Center (Junior Investigator Award)
  • Foundation of the American Society of Neuroradiology (Alzheimer's Imaging Grant)
  • National Institutes of Health (RC1 AG035610, R01 AG26938)
  • The John Douglas French Alzheimer's Foundation
  • Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
  • CHDI Foundation
  • Takeda Pharmaceutical Company
  • National Institute of Neurological Disorders and Stroke (P30 NS062691)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
Alzheimer's disease, human leukocyte antigen, HLA haplotypes, major histocompatibility complex, genetic risk, neuroinflammation, APOE ε4, APOE ε2, APOE ε3, cerebrospinal fluid biomarkers, CSF tau, cognitive decline
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Chromosome Mapping, Female, Haplotypes, HLA Antigens, Humans, Male, Middle Aged, Risk Factors, San Francisco, United States, Case-Control Studies

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