The Human Leukocyte Antigen (HLA) DRB1*13:02 Allele Protects against Dementia in Continental Western Europe

Abstract

Human Leukocyte Antigen (HLA) Class II DRB1*13 alleles have recently been found to protect against age-related brain deterioration, even in the presence of apolipoprotein E4 (apoE4), 1,2 suggesting a possible protection against dementia.Here we evaluated the association between the population frequency of common DRB1*13 alleles and the prevalence of dementia in Continental Western Europe. Prevalence of dementia in Continental Western Europe was derived from published reports on dementia frequency from the Global Burden of Disease Study 2016 and population totals obtained from the Population Reference Bureau. DRB1*13:01 and DRB1*13:02 allele frequencies were obtained from a publicly available database (allelefrequency.net) and apolipoprotein E was obtained from published reports on the world distribution of apoE4. The prevalence of dementia in 14 Continental Western European (CWE) countries, where life expectancy is practically identical, significantly decreases exponentially with increasing frequency of DRB1*13:02 (R 2 = 0.452, P = 0.008), even when adjusted for the prevalence of apolipoprotein E4 allele, a known risk factor for Alzheimer's disease. This finding documents the protective effect of DRB1*13:02 on dementia prevalence in CWE. Since the function of HLA class II genes is to aid in the elimination of pathogens by enabling the production of antibodies against their antigens in specific immunity, the protective effect of DRB1*13:02 points to the presence of persistent harmful antigens as causal factors in development of dementia, antigens specific to DRB1*13:02 that could not be eliminated in its absence.

Shared Human Leukocyte Antigen (HLA) Coverage in dementia and Parkinson’s disease

“…As in our previous studies 16,17 we focused on the following 14 CWE countries: Austria, Belgium, Denmark, Finland, France, Germany, Greece, Italy, Netherlands, Portugal, Norway, Spain, Sweden, and Switzerland.…”

“…analyses were used to evaluate the association between the population frequency of each the seven HLA alleles above (Table 2), alone and combined, and the prevalence of dementia and Parkinson's disease in Continental Western Europe. Previous analyses 16,17 had documented an exponential relation between dementia prevalence and allele frequency; hence, the prevalences of dementia and Parkinson's disease were natural-log transformed to analyze their relation to allele frequency using linear regression. Pairwise Pearson correlation coefficients were compared by calculating the normal deviate z-statistic 24 .…”

“…In terms of genetic protection, studies have demonstrated that apolipoprotein E2 protects against dementia 12,13 and may protect against Parkinson's disease-related dementia 14,15 . Moving beyond apolipoprotein E, recent studies have also demonstrated robust genetic protection against dementia conferred by specific Class II human leukocyte antigen (HLA) alleles 16,17 . The extent to which those HLA alleles protect against Parkinson's disease is unknown.…”

Tri-Allelic Human Leukocyte Antigen (HLA) Protection Against Dementia

“…Indeed, in a recent genetic epidemiological study we evaluated the relationship between the population frequency of DRB1*13:02 and dementia prevalence in 14 CWE countries and found that dementia prevalence decreased exponentially with increasing frequency of DRB1*13:02, even after adjusting for the prevalence of apoE4. 3 Remarkably, the population frequency of DRB1*13:02 accounted for 45% of the variance in dementia prevalence. In the 14 countries included in that study 3 , the frequency of DRB1*13:02 ranged from 0.025-0.062, which equates to 5-13% carriers in the respective country population, suggesting that other factors, such as additional protective HLA alleles, may account for the remaining variance in dementia prevalence.…”

“…3 Remarkably, the population frequency of DRB1*13:02 accounted for 45% of the variance in dementia prevalence. In the 14 countries included in that study 3 , the frequency of DRB1*13:02 ranged from 0.025-0.062, which equates to 5-13% carriers in the respective country population, suggesting that other factors, such as additional protective HLA alleles, may account for the remaining variance in dementia prevalence. Thus, in the present study, we evaluated the association between other common DRB1alleles and dementia prevalence in the same 14 CWE countries.…”