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

Lisa M. James1,2,3, Apostolos P. Georgopoulos1,2,3,4*

1Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN, 55417, USA

2Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA

3Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN 55455, USA

4Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA


Dementia and Parkinson’s disease are the two most common age-related neurodegenerative conditions. Recent studies have identified Human Leukocyte Antigen (HLA) Class II DRB1 alleles that are protective or neutral with respect to dementia. Here we extend those findings to evaluate the association of the population frequency of HLA DRB1 alleles with the prevalence of dementia and Parkinson’s disease in14 Continental Western European countries. Nine HLA DRB1 alleles were identified including four that are protective against dementia (DRB1*01:01, DRB1*04:01, DRB1*13:02, DRB1*15:01), three that are neutral (DRB1*03:01, DRB1*07:01, DRB1*08:01), and two susceptibility alleles (DRB1*11:01, DRB1*04:05). Results demonstrated that the population prevalence’s of dementia and Parkinson’s disease are highly correlated and that the association between the nine DRB1 alleles above and the population prevalence of dementia is highly overlapping with that of Parkinson’s disease. These findings suggest a common HLA Class II DRB1 profile. Given the diverse role of HLA Class II alleles in protection from foreign antigens, autoimmunity, and, possibly, neuroprotection, the shared HLA profile between dementia and Parkinson’s disease indicates that common immunogenetic mechanisms underlie the pathogenesis and manifestation of these diseases.


Dementia and Parkinson’s disease are the most common age-related neurodegenerative conditions, together affecting an estimated 50 million people worldwide according to recent epidemiological studies1,2. Dementia refers to conditions reflecting a decline in cognitive, behavioral, motor, and/or social functioning; Alzheimer’s disease is the most common type, accounting for up to 80% of dementia cases3. AD is characterized primarily by impairments in memory and executive functioning although effects on mood, personality, and motor symptoms are also common. Parkinson’s disease is characterized primarily by motor symptoms including bradykinesia, rigidity, and tremor, yet non-motor symptoms including cognitive and mood disruptions are common, particularly as the disease progresses4. A large percentage of patients with Parkinson’s Disease eventually develop dementia5. In light of the overlap in symptoms and the substantial and increasing global burden of these conditions1,2, research aimed at identifying putative risk and protective factors are of paramount importance to mitigate the significant impacts of these condition on global health.

Although the etiology of dementia and Parkinson’s disease is unknown, various genetic and environmental risk and protective factors have been identified. For dementia, risk factors include possession of apolipoprotein E4 allele, health conditions such as cardiovascular disease and Type II diabetes, modifiable lifestyle factors such as poor diet and sedentary lifestyle, and exposure to infectious agents6,7. For Parkinson’s disease, variations in genes associated with alpha-synuclein and other proteins have been implicated8, and environmental risk factors include exposure to pollutants, pesticides, and infectious agents, dairy consumption, and β2- adrenoreceptor agonists (2,9,10,11). With regard to protection, adherence to plant-based diet as well as physical, social, and intellectual activities have been shown to protect against dementia6; environmental factors that protect against Parkinson’s disease include smoking, caffeine and tea intake, physical activity, vitamin E intake, gout, non-steroidal anti-inflammatory drugs and β2- adrenoreceptor agonists10. In terms of genetic protection, studies have demonstrated that apolipoprotein E2 protects against dementia12,13 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) alleles16,17. The extent to which those HLA alleles protect against Parkinson’s disease is unknown.

HLA genes code for cell-surface glycoproteins that are instrumental in immune response to foreign antigens such as viruses and bacteria. Class I HLA proteins present intracellular foreign antigen peptides to cytotoxic T cells to signal cell destruction. Class II HLA proteins present peptides to CD4 receptors to promote antibody production and elimination of foreign antigens. However, HLA genes, which are the most highly polymorphic in the human genome, differ in their ability to bind with foreign antigens and mount an immune response. In the absence of sufficient binding affinity and/or immunogenicity, antigenic peptides may persist. We have speculated that persistent antigens lead to neuronal damage and inflammation, and may contribute to dementia and other neuroimmune conditions18-20.

Using a publicly available repository21 containing HLA data pooled from histocompatibility laboratories and published studies, coupled with dementia prevalence obtained from the Global Burden of Disease studies1 we have examined associations between HLA and dementia prevalence in 14 countries in Continental Western Europe where dementia prevalence is among the highest in the world. We demonstrated that three specific Class II HLA DRB1 alleles – DRB1*01:01, DRB1*13:02, and DRB1*15:01 - are highly protective against dementia, even after accounting for apolipoprotein E417. Moreover, the combined population frequency of the three alleles accounted for 67% of the variance in dementia prevalence and 48% of the change in dementia prevalence in those countries over the last 25 years. Given the role of Class II HLA in antibody production and host protection against re-exposure to foreign antigens, the finding that dementia prevalence is lower in countries with higher frequency of these alleles suggests that lower dementia rates may be partially attributable to protection against pathogens that bind with these alleles. In fact, a subsequent in silico study revealed that these three dementia alleles were found to bind with significantly higher affinity to herpes virus antigens than were three HLA alleles that are dementia-neutral - DRB1*03:01, DRB1*07:01, DRB1*08:0122. In the present study, we extend those findings to investigate the association of the population frequency21 of HLA -DRB1 dementia-protective, dementia-neutral alleles to Parkinson’s disease population prevalence2.

CWE countries. As in our previous studies16,17 we focused on the following 14 CWE countries: Austria, Belgium, Denmark, Finland, France, Germany, Greece, Italy, Netherlands, Portugal, Norway, Spain, Sweden, and Switzerland.

Prevalence of dementia and Parkinson’s disease. The Global Burden of Disease study is the most comprehensive epidemiological study of worldwide morbidity and mortality associated with several conditions including dementia1 and Parkinson’s disease2. The total number of people with dementia or Parkinson’s disease in each of the 14 CWE countries was retained for analyses in the present study. The Population Reference Bureau23 provides vital demographic data for over 200 countries based on several sources including official national data or analyses conducted by national, regional, or worldwide (e.g. United Nations Population Division) offices. The prevalences of dementia and Parkinson’s disease were computed by dividing the number of people with dementia1 or Parkinson’s disease2 in 2016 in each country by the total population of the country in 201623 and expressed as a percentage. These data are shown in Table 1. We have previously shown that life expectancy for these countries are virtually identical3 (Table 1); therefore, life expectancy was not included in the current analyses.

Table 1. Dementia prevalence for Countries in Continental Western Europe. Overall Dementia Prevalence = (N Disease x 100) / (N total population)

Country

N Dementiaa

N

Parkinson’s Diseaseb

N

total populationc

Dementia

Prevalence (%)

Parkinson’s Disease Prevalence (%)

Average life expectancyc

Austria

126914

15891

8800000

1.442

0.1806

81.5

Belgium

181350

20862

11300000

1.605

0.1846

81.5

Denmark

55336

9068

5700000

0.971

0.1591

80.5

Finland

83950

10258

5500000

1.526

0.1865

81.5

France

877760

120455

64600000

1.359

0.1865

82.0

Germany

1201668

162246

82600000

1.455

0.1964

80.5

Greece

192563

22837

10800000

1.783

0.2115

81.0

Italy

1370308

144606

60600000

2.261

0.2386

82.5

Netherlands

192425

33297

17000000

1.132

0.1959

81.5

Norway

67207

7517

5200000

1.292

0.1446

82.0

Portugal

166660

18496

10300000

1.618

0.1796

80.0

Spain

830915

92971

43300000

1.919

0.2147

82.5

Sweden

142735

19776

9900000

1.442

0.1998

82.0

Switzerland

115476

14979

8400000

1.375

0.1783

83.0

a Data obtained from ref1.

b Data obtained from ref2.

c Data obtained from refpop’n bureau.

HLA alleles. In our previous studies we identified three HLA Class II alleles protective for dementia17 (DRB1*01:01, DRB1*13:02, DRB1*15:01) and three alleles that are neutral for dementia21 (DRB1*03:01, DRB1*07:01, DRB1*08:01); in addition, we now identified an allele protective for dementia (DRB1*04:01; Allele Frequency Net Database, http://www.allelefrequencies.net21). To obtain allele frequencies, the Allele Frequency Net Database was queried to provide the 4-digit HLA allele frequency for each country with no further restrictions by region, ethnicity, source of study, or other qualifiers. For countries in which were available for more than one population we obtained the average frequency. The frequencies of these seven alleles for each country are given in Table 2.

Table 2. Frequencies of 9 HLA Class II alleles for countries in Continental Western Europe used in this study.a N/A, not available.

Neuromed-20-1275-Fig29

a. Obtained from allelefrequencies.net October 19, 2019.

Statistical analyses. Regression and correlation 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 analyses16,17 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-statistic24. Regression coefficients were compared, as needed, using the following formula25:

Neuromed-20-1275-Fig1

where z is the normal deviate, b1 and b2 denote regression coefficients to be compared, and SE are their standard errors. Finally, correlation coefficients r were Fisher z-transformed24 r' to normalize their distribution:

Neuromed-20-1275-Fig2

All statistical analyses were conducted using the IBM-SPSS statistical package (version 23).

Association of dementia and Parkinson’s disease prevalences

The prevalences of dementia and Parkinson’s disease were highly significantly correlated (Fig. 1; r = 0.787, P = 0.000843, N = 14).

Neuromed-20-1275-Fig15

Figure 1: Dementia prevalence in 14 CWE countries is plotted against the prevalence of Parkinson’s disease. See text for details.

Association between dementia and Parkinson’s disease prevalences and the frequencies of four protective HLA alleles

The values of log-transformed dementia and Parkinson’s disease prevalences are plotted against the frequencies of the four protective (negatively associated) alleles in Figs. 2 and 3, respectively. The corresponding correlation coefficients are given in Table 3. There were no statistically different differences between any of the dementia- and Parkinson’s disease correlations (Table 3).

Table 3. Correlation statistics between disease prevalences and allele frequencies analyzed. P-values are in parentheses. Blue, protective alleles; black, neutral; red, predisposing.

 

Alleles

Correlation Coefficients

Comparison of Correlations

 

ln(Dementia prevalence)

ln(Parkinson’s disease prevalence)

 

 

HLA Profile for

Dementia

HLA Profile for Parkinson’s

Test statistic z

P value

N

1

DRB1*01:01

−0.727 (P=0.003)

−0.480 (0.082)

0.937

0.174

14

2

DRB1*04:01

−0.857 (0.00018)

−0.778 (0.002)

0.570

0.284

13

3

DRB1*13:02

−0.674 (0.008)

−0.428 (0.127)

0.846

0.199

14

4

DRB1*15:01

−0.686 (0.007)

−0.640 (0.014)

0.193

0.424

14

5

DRB1*03:01

0.102

(0.739)

−0.057 (0.854)

0.356

0.361

13

6

DRB1*07:01

0.212

(0.509)

−0.073 (0.821)

0.612

0.270

12

7

DRB1*08:01

−0.086 (0.780)

−0.046

(0.882)

0.090

0.464

13

8

DRB1*11:01

0.670

(0.009)

0.705

(0.005)

0.156

0.438

14

9

DRB1*04:05

0.854

(0.001)

0.676

(0.022)

0.898

0.185

11

Neuromed-20-1275-Fig16

Figure 2: Illustration of the different effects of each protective allele on the natural log of dementia prevalence as evidenced by the varying steepness of the slopes.

Neuromed-20-1275-Fig17

Figure 3: Illustration of the different effects of each protective allele on the natural log of Parkinson’s disease prevalence as evidenced by the varying steepness of the slopes.

Association of dementia and Parkinson’s disease prevalences with the combined frequencies of the four protective alleles

The log-transformed prevalence of dementia is plotted against the sum of the frequencies of four protective alleles in Fig. 4:

Neuromed-20-1275-Fig18

Figure 4: The natural log of dementia prevalence is plotted against the sum of the frequencies of the four protective alleles (DRB1*01:01, DRB1*04:01, DRB1*13:02, DRB1*15:01). See text for details.

Neuromed-20-1275-Fig3

The regression equation was as follows.

Neuromed-20-1275-Fig4

r2 = 0.758, P = 0.001; value in parenthesis is the SE of the regression coefficient.

The log-transformed prevalence of Parkinson’s disease (PD) is plotted against the sum of the frequencies four protective alleles in Fig. 5. The regression equation was as follows.

Neuromed-20-1275-Fig19

Figure 5: The natural log of Parkinson’s disease prevalence is plotted against the sum of the frequencies of the four protective alleles (DRB1*01:01, DRB1*04:01, DRB1*13:02, DRB1*15:01). See text for details.

Neuromed-20-1275-Fig5

r2 = 0.546, P = 0.004; value in parenthesis is the SE of the regression coefficient.

The f[4 protective alleles] regression coefficient for dementia (– 1.766, equation 3) was 2x more negative (i.e. twice as protective) for dementia than that for Parkinson’s disease (– 0.876, equation 4), a highly significant difference (z = 5.36, P < 0.001, test of equation 1).

Association between dementia and Parkinson’s disease prevalences and the frequencies of three neutral HLA alleles

The values of log-transformed dementia and Parkinson’s disease prevalences are plotted against the frequencies of the three neutral (not significantly associated) alleles in Figs. 6 and 7, respectively. The corresponding correlation coefficients are given in Table 3. There were no statistically different differences between any of the dementia- and Parkinson’s disease correlations (Table 3).

Neuromed-20-1275-Fig20

Figure 6: The natural log of dementia prevalence is plotted against the frequency of the three neutral alleles; there is no significant association. See text for details.

Neuromed-20-1275-Fig21

Figure 7: The natural log of Parkinson’s disease prevalence is plotted against the frequency of the three neutral alleles; there is no significant association. See text for details.

Association of dementia and Parkinson’s disease prevalences with the combined frequencies of the three neutral alleles

The log-transformed prevalence of dementia is plotted against the sum of the frequencies of the three neutral alleles in Fig. 8:

Neuromed-20-1275-Fig22

Figure 8: The natural log of dementia prevalence is plotted against the sum of the frequencies of the three neutral (DRB1*03:01, DRB1*07:01, DRB1*08:01); there is no significant association. See text for details.

Neuromed-20-1275-Fig6

The regression equation was as follows.

Neuromed-20-1275-Fig7

r2 = 0.0001, P = 0.974; value in parenthesis is the SE of the regression coefficient. There was no statistically significant association.

The log-transformed prevalence of Parkinson’s disease is plotted against the sum of the frequencies four protective alleles in Fig. 9. The regression equation was as follows.

Neuromed-20-1275-Fig23

Figure 9: The natural log of Parkinson’s disease prevalence is plotted against the sum of the frequencies of the three neutral (DRB1*03:01, DRB1*07:01, DRB1*08:01); there is no significant association. See text for details.

Neuromed-20-1275-Fig8

r2 = 0.049, P = 0.491; value in parenthesis is the SE of the regression coefficient. There was no statistically significant association.

Association between dementia and Parkinson’s disease prevalences and the frequencies of two predisposing HLA alleles

The values of log-transformed dementia and Parkinson’s disease prevalences are plotted against the frequencies of the two predisposing alleles in Figs. 10 and 11, respectively. The corresponding correlation coefficients are given in Table 3. There were no statistically different differences between any of the dementia- and Parkinson’s disease correlations (Table 3).

Neuromed-20-1275-Fig24

Figure 10: Illustration of the different effects of each predisposing allele on the natural log of dementia prevalence as evidenced by the varying steepness of the slopes.

Neuromed-20-1275-Fig25

Figure 11: Illustration of the different effects of each predisposing allele on the natural log of Parkinson’s disease prevalence as evidenced by the varying steepness of the slopes.

Association of dementia and Parkinson’s disease prevalences with the combined frequencies of the three neutral alleles

The log-transformed prevalence of dementia is plotted against the sum of the frequencies of the three neutral alleles in Fig. 12:

Neuromed-20-1275-Fig26

Figure 12: The natural log of dementia prevalence is plotted against the sum of the frequencies of the two predisposing alleles (DRB1*04:05, DRB1*11:01). See text for details.

Neuromed-20-1275-Fig9

The regression equation was as follows.

Neuromed-20-1275-Fig10

r2 = 0.729, P = 0.001; value in parenthesis is the SE of the regression coefficient.

The log-transformed prevalence of Parkinson’s disease is plotted against the sum of the frequencies four protective alleles in Fig. 13. The regression equation was as follows.

Neuromed-20-1275-Fig27

Figure 13: The natural log of Parkinson’s disease prevalence is plotted against the sum of the frequencies of the two predisposing alleles (DRB1*04:05, DRB1*11:01). See text for details.

Neuromed-20-1275-Fig11

r2 = 0.688, P = 0.002; value in parenthesis is the SE of the regression coefficient.

A given disease may have varying associations with different HLA alleles. In the context of populations, this relation would be captured by the correlation between disease prevalence and allele frequency, since both of these measures typically vary across population samples (e.g. countries, ethnicities, etc.): this variation provides the requisite variety that makes disease-HLA associations possible. Let pi(k=1,M) be the prevalence of disease i in a sample population K (out of M available); let f(j=1,N)(k=1,M) be the frequency of a HLA allele j (out of N available) in that population. We call the vector of z-transformed correlations r' between the prevalence of the disease i in M populations and the frequency of N alleles in the same populations the “HLA profile of disease i”. In the present study, the HLA profiles of dementia and Parkinson’s disease, for the 9 HLA alleles studied, are shown in Table 4. Specifically, M = 14 CWE countries, N = 9 HLA alleles.

Table 4. HLA profiles for dementia and Parkinson’s disease. Numbers are Fisher z-transformed correlation coefficients r'. (See text for details.)

 

HLA Profile for

Dementia

HLA Profile for Parkinson’s

DRB1*01:01

−.0922

−0.523

DRB1*03:01

−1.286

−1.043

DRB1*04:01

−0.818

−0.457

DRB1*07:01

−0.840

−0.758

DRB1*08:01

0.102

−0.057

DRB1*13:02

0.215

−0.073

DRB1*15:01

−0.102

−0.129

DRB1*11:01

0.877

0.811

DRB1*04:05

0.822

1.271

The pairwise association between HLA disease profiles provides a quantitative estimate of the similarity of dependence of disease prevalence to an ensemble of HLA alleles. Since HLA alleles can be involved in pathogen elimination (positive aspect) and/or autoimmunity (negative aspect), determining the similarity between HLA disease profiles would provide an overall assessment of the similarity of involvement of such factors in the specific diseases in a pair. Since the HLA profile consists of z-transformed correlations, the Pearson correlation between two HLA disease profiles would give a quantitative assessment of the association, including its statistical significance and the percent of HLA profile variance explained. In this study, there was a highly positive association between the dementia and Parkinson’s HLA disease profiles (Fig. 14); the correlation coefficient was 0.965 (P = 0.000026; r2 = 0.931) and the percent of variance explained r2 x 100 = 93.1%.

Neuromed-20-1275-Fig28

Figure 14: The HLA profile of Parkinson’s disease is plotted against the HLA profile of dementia; data from Table 4. Blue, protective alleles; black, neutral alleles; red, predisposing alleles.

Here we investigated the association of the population frequency of seven HLA Class II DRB1 alleles with respect to the prevalence of dementia and Parkinson’s disease in 14 countries in Continental Western Europe. Several findings emerged. First, the population prevalence of dementia and Parkinson’s disease were positively and highly significantly associated. Second, the average frequency of protective HLA alleles accounted for substantial variance in the population prevalence of dementia and, to a lesser extent, Parkinson’s disease. Finally, the associations of disease prevalence and the HLA alleles were highly similar for dementia and Parkinson’s disease. Taken together, these findings point to a common HLA profile, suggesting shared immunogenetic mechanisms (protective, neutral, and predisposing) underlying these diseases.

HLA Class II alleles, to which the DRB1 alleles investigated here belong, play a critical role in facilitating antibody production and immunological memory to foreign antigens. In light of that role, the highly protective effects of the four DRB1 alleles identified here can be interpreted as likely promoting pathogen elimination that may otherwise contribute to disease susceptibility. That is, those lacking immunogenetic protection conferred by possession of one or more of these DRB1 alleles (or other HLA alleles with similar sequences and, consequently, similar binding affinity) may be unable to sufficiently eliminate certain pathogens, leading to deleterious downstream effects that may include dementia and/or Parkinson’s disease. Indeed, several viral and bacterial pathogens have been implicated in both dementia7 and Parkinson’s disease9,11, many of which overlap across conditions consistent with the highly overlapping HLA profile observed here. In particular, human herpes viruses have been implicated in both conditions26-29, which is notable in light of a recent in silico study that demonstrated superior binding affinity of three of the HLA studies investigated here to human herpes viruses when compared to dementia-neutral HLA alleles22. Additional studies are currently underway to identify other antigens that bind with these protective HLA alleles and that, conversely, may be associated with dementia and/or Parkinson’s disease in the absence of HLA protection. Finally, with respect to predisposing HLA Class II alleles, such as those identified in this study, it is very likely that they are involved in autoimmunity mechanisms in both Alzheimer’s and Parkinson disease, as discussed recently30.

Although the current findings identified protective effects of four HLA DRB1 alleles, they neither preclude the possibility that other Class I or Class II HLA alleles may confer similar protection or predisposition nor that the HLA alleles shown to protect against dementia and Parkinson’s disease may promote risk for other conditions. For instance, DRB1*04:01, one of the alleles shown to protect against dementia and Parkinson’s disease in the current study, is associated with elevated risk of Type I diabetes31 and rheumatoid arthritis32. Similarly, DRB1*15:01 is a well-established risk factor for multiple sclerosis33, yet is protective against dementia and Parkinson’s disease at the population level. Research in our laboratory is underway to examine associations of other Class I and Class II HLA alleles with dementia, Parkinson’s disease, and other related conditions.

Partial funding for this study was provided by the University of Minnesota (the Anita Kunin Chair in Women's Healthy Brain Aging, the Brain and Genomics Fund, the McKnight Presidential Chair of Cognitive Neuroscience, and the American Legion Brain Sciences Chair). The sponsors had no role in the current study design, analysis or interpretation, or in the writing of this paper. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.

LMJ and APG contributed to data analysis and writing the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Article Info

  • Journal of Neurology & Neuromedicine
  • Article Type : Research Article
  • View/Download pdf

Article Notes

  • Published on: September 22, 2020

Keywords

  • Dementia

  • Parkinson’s Disease
  • Human Leukocyte Antigen
  • Immunity
  • Genetics

*Correspondence:

Dr. Apostolos P. Georgopoulos
Brain Sciences Center (11B), Minneapolis VAHCS, One Veterans Drive, Minneapolis, MN 55417, USA
Email: omega@umn.edu.

©2020 Georgopoulos AP. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License.