Abstract
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.
Highlights
There are reasons to expect an association with Alzheimer's disease (AD) within the human leukocyte antigen (HLA) region
Subgroup analysis, stratifying by gender and by APOE4 status, revealed various other associations before correction: HLA-B27 in APOE4 negatives; HLA-Cw1 in APOE4 negatives (3.4, 1.2– 9.6, 0.03) and in men (11.3, 1.4–89, 0.004); HLA-Cw15 in APOE4 positives (0.11, 0.01–0.99, 0.03) and in men (0.11, 0.01–0.9, 0.02)
We suggest that the only results meriting further scrutiny are those for HLA-B7 and HLA-Cw*0702 and possibly the potentially reduced risk associated with HLA-Cw15
Summary
There are reasons to expect an association with Alzheimer's disease (AD) within the HLA region. AD is characterised by chronic inflammation and altered immune function, including activation of immunocompetent glia expressing high levels of human leukocyte antigen (HLA) molecules, complement and pro-inflammatory cytokines [1]. Many of these proteins are encoded in the region. The region has proved a challenge for the study of disease associations, because it is highly variable, with a complex structure of linkage disequilibrium. It is true that, apart from the study of certain genes, e.g. TNF [7], and alleles, e.g. HLA-A2 [8], most studies of HLA genes in AD have been seriously underpowered. As that association was not replicated in two other cohorts involved in the study [9], it remains possible that these contrasts were due to geographical differences, for instance in the fine structure of linkage disequilibrium or in interactions with other risk factors (see Discussion)
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