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

Date Published: March 28, 2017

Publisher: Public Library of Science

Author(s): Natasha Z. R. Steele, Jessie S. Carr, Luke W. Bonham, Ethan G. Geier, Vincent Damotte, Zachary A. Miller, Rahul S. Desikan, Kevin L. Boehme, Shubhabrata Mukherjee, Paul K. Crane, John S. K. Kauwe, Joel H. Kramer, Bruce L. Miller, Giovanni Coppola, Jill A. Hollenbach, Yadong Huang, Jennifer S. Yokoyama, Carol Brayne

Abstract: BackgroundAlzheimer 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 findingsBuilding 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.ConclusionsWe 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.

Partial Text: Alzheimer disease (AD) is a progressive neurodegenerative disorder and has a global burden of approximately 46 million people worldwide, with prevalence projected to double over the next 20 y [1]. The hallmark features of the disease include the accumulation of amyloid plaques, tau neurofibrillary tangles, and neuronal destruction, leading to brain atrophy and loss of cognitive function. The etiology of these processes stems from synergistic interactions of environmental and genetic factors, many of which remain obscure and therefore complicate research efforts aimed at identifying efficacious therapies.

Participants were consented (as described below) for research in accordance with the Institutional Review Board at the University of California, San Francisco, and institutional review boards at each site for multicenter study data approved all aspects of this study as they fall under the purview of the respective research groups (ADNI and ADGC).

In a total of over 11,000 individuals, we found evidence suggesting that the five-allele HLA haplotype A*03:01~B*07:02~DRB1*15:01~DQA1*01:02~DQB1*06:02 is a risk factor for AD and that this effect may be driven by men who do not carry the major AD risk factor, APOE ɛ4. Locus-level analysis further confirmed AD associations of the individual alleles B*07:02, DRB1*15:01, DQA1*01:02, and DQB1*06:02. In separate class I and class II haplotype analyses, the class I A*03:01~B*07:02 haplotype and the class II DRB1*15:01~DQA1*01:02~DQB1*06:02 (DR15) haplotype were both significantly associated with risk for AD. We assessed the clinical relevance of each of these haplotypes separately in a smaller cohort representing the spectrum of cognitively normal controls and individuals with MCI and AD. Carrying the MHC class I haplotype A*03:01~B*07:02 was associated with higher CSF amyloid levels, suggesting lower levels of amyloid in the brains of haplotype carriers across the AD spectrum. The class II haplotype DR15 was associated with greater rate of decline on two different measures of cognitive function relevant to AD in a dose-dependent manner. In a subset of the same cohort, carrying the DR15 risk haplotype was also associated with higher baseline levels of CC4, a biomarker of AD-related inflammation [46]. Taking these findings together, this study provides evidence for the contribution of the A*03:01~B*07:02~DRB1*15:01~DQA1*01:02~DQB1*06:02 haplotype and its components, A*03:01~B*07:02 and DR15, to risk of AD.



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