Replication of the association of HLA-B7 with Alzheimer's disease: a role for homozygosity?

BackgroundThere are reasons to expect an association with Alzheimer's disease (AD) within the HLA region. The HLA-B & C genes have, however, been relatively understudied. A geographically specific association with HLA-B7 & HLA-Cw*0702 had been suggested by our previous, small study.MethodsWe studied the HLA-B & C alleles in 196 cases of 'definite' or 'probable' AD and 199 elderly controls of the OPTIMA cohort, the largest full study of these alleles in AD to date.ResultsWe replicated the association of HLA-B7 with AD (overall, adjusted odds ratio = 2.3, 95% confidence interval = 1.4–3.7, p = 0.001), but not the previously suggested interaction with the ε4 allele of apolipoprotein E. Results for HLA-Cw*0702, which is in tight linkage disequilibrium with HLA-B7, were consistent with those for the latter. Homozygotes of both alleles appeared to be at particularly high risk of AD.ConclusionHLA-B7 and HLA-Cw*0702 are associated with AD in the Oxford population. Because of the contradictions between cohorts in our previous study, we suggest that these results may be geographically specific. This might be because of differences between populations in the structure of linkage disequilibrium or in interactions with environmental, genetic or epigenetic factors. A much larger study will be needed to clarify the role of homozygosity of HLA alleles in AD risk.

[1]  M. Folstein,et al.  Clinical diagnosis of Alzheimer's disease , 1984, Neurology.

[2]  H. Endo,et al.  HLA system in senile dementia of Alzheimer type and multi-infarct dementia in Japan. , 1986, Archives of gerontology and geriatrics.

[3]  R. Mohs,et al.  Consortium to establish a registry for Alzheimer's disease (CERAD) clinical and neuropsychological assessment of Alzheimer's disease. , 2002, Psychopharmacology bulletin.

[4]  M. Roth.  CAMDEX : the Cambridge examination for mental disorders of the elderly , 1999 .

[5]  H. Kagimoto,et al.  Reduced natural killer cell activity in patients with dementia of the Alzheimer type , 1991, Acta neurologica Scandinavica.

[6]  S. M. Sumi,et al.  The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) , 1991, Neurology.

[7]  PhilipR. Wenham,et al.  Apolipoprotein E genotyping by one-stage PCR , 1991, The Lancet.

[8]  E. Yunis,et al.  Polymorphic Hh genes in the HLA-B(C) region control natural killer cell frequency and activity , 1994, The Journal of experimental medicine.

[9]  M. Barnardo,et al.  Phototyping: comprehensive DNA typing for HLA-A, B, C, DRB1, DRB3, DRB4, DRB5 & DQB1 by PCR with 144 primer mixes utilizing sequence-specific primers (PCR-SSP). , 1995, Tissue antigens.

[10]  S. Govoni,et al.  Increased Natural Killer Cell Cytotoxicity in Alzheimer’s Disease May Involve Protein Kinase C Dysregulation , 1998, Neurobiology of Aging.

[11]  R Clarke,et al.  Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. , 1998, Archives of neurology.

[12]  J. Haines,et al.  No association between the HLA-A2 allele and Alzheimer disease , 1999, Neurogenetics.

[13]  J. Goedert,et al.  HLA and HIV-1: heterozygote advantage and B*35-Cw*04 disadvantage. , 1999, Science.

[14]  M. Owen,et al.  A full genome scan for late onset Alzheimer's disease , 1999 .

[15]  P. Ince,et al.  Frequency of HLA-A and B alleles in early and late-onset Alzheimer's disease , 1999, Neuroscience Letters.

[16]  M. Albert,et al.  Association of a haplotype for tumor necrosis factor in siblings with late-onset Alzheimer disease: the NIMH Alzheimer Disease Genetics Initiative. , 2000, American journal of medical genetics.

[17]  E. Ferrari,et al.  Variability of Interactions Between Neuroendocrine and Immunological Functions in Physiological Aging and Dementia of the Alzheimer's Type , 2000, Annals of the New York Academy of Sciences.

[18]  C. Plata-salamán,et al.  Inflammation and Alzheimer’s disease , 2000, Neurobiology of Aging.

[19]  A. Lloyd,et al.  The Influence of HLA Class I Alleles and Heterozygosity on the Outcome of Human T Cell Lymphotropic Virus Type I Infection1 , 2000, The Journal of Immunology.

[20]  Linkage of the genes controlling natural killer cell activity to HLA-B. , 2000, Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics.

[21]  D. Middleton,et al.  Association between polymorphism in regulatory region of gene encoding tumour necrosis factor alpha and risk of Alzheimer's disease and vascular dementia: a case-control study. , 2001, Lancet.

[22]  K. Morgan,et al.  HLA class I, II & III genes in confirmed late-onset Alzheimer’s disease , 2001, Neurobiology of Aging.

[23]  D. Middleton,et al.  Association between polymorphism in regulatory region of gene encoding tumour necrosis factor α and risk of Alzheimer's disease and vascular dementia: a case-control study , 2001, The Lancet.

[24]  David I. K. Martin,et al.  Retrotransposons as epigenetic mediators of phenotypic variation in mammals , 2001, Nature Genetics.

[25]  P. Zandi,et al.  Reduced incidence of AD with NSAID but not H2 receptor antagonists: The Cache County Study , 2002, Neurology.

[26]  F. Chiappelli,et al.  Mental deterioration correlates with response of natural killer (NK) cell activity to physiological modifiers in patients with short history of Alzheimer's disease , 2002, Psychoneuroendocrinology.

[27]  G. Schellenberg,et al.  HLA-A2 homozygosity but not heterozygosity is associated with Alzheimer disease , 2002, Neurology.

[28]  M. Etminan,et al.  Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer's disease: systematic review and meta-analysis of observational studies , 2003, BMJ : British Medical Journal.

[29]  Z. Husain,et al.  HLA-Cw7 Zygosity Affects the Size of a Subset of CD158b+ Natural Killer Cells , 2004, Journal of Clinical Immunology.

[30]  Andrew P Feinberg,et al.  An integrated epigenetic and genetic approach to common human disease. , 2004, Trends in genetics : TIG.

[31]  Antony V. Cox,et al.  Open access, freely available online PLoS BIOLOGY DNA Methylation Profiling of the Human Major Histocompatibility Complex: A Pilot Study , 2022 .

[32]  A. Lbert,et al.  Nonsteroidal Antiinflammatory Drugs and the Risk of Alzheimer's Disease , 2022 .