 |
|
Polymorphisms in Inflammatory Genes and the Risk of Alzheimer Disease
Patrick L. McGeer, MD, PhD;
Edith G. McGeer, PhD
Arch Neurol. 2001;58:1790-1792.
ABSTRACT
| |
The concept of inflammation as a
major factor in Alzheimer disease (AD) has heretofore been based on
postmortem findings of autodestructive changes associated with the
lesions coupled with epidemiological evidence of a protective effect of
anti-inflammatory agents.1 Now there is evidence that the
risk of AD is substantially influenced by a total of 10 polymorphisms
in the inflammatory agents interleukin 1 , interleukin 1ß,
interleukin 6, tumor necrosis factor ,
2-macroglobulin, and 1-antichymotrypsin.
The polymorphisms are all common ones in the general population, so
there is a strong likelihood that any given individual will inherit 1
or more of the high-risk alleles. The overall chances of an individual
developing AD might be profoundly affected by a "susceptibility
profile" reflecting the combined influence of inheriting multiple
high-risk alleles. Since some of the polymorphisms in question have
already been linked to peripheral inflammatory disorders, such as
juvenile rheumatoid arthritis, myasthenia gravis, and periodontitis,
associations between AD and several chronic degenerative diseases may
eventually be demonstrated. Such information could lead to strategies
for therapeutic intervention in the early stages of such disorders.
|
Interleukin (IL)–1, IL-1ß, IL-6, tumor necrosis factor
(TNF-), 2-macroglobulin (A2M), and
1-antichymotrypsin (ACT) are all up-regulated in tissue
from subjects with Alzheimer disease (AD) and are prominently
associated with AD lesions.2, 3 The inflammatory cytokines
IL-1, IL-6, and TNF- are products of both activated microglia and
activated astrocytes that powerfully stimulate their activity.
Localization of these cytokines to such activated cells has been
demonstrated in AD by immunohistochemical analysis.
1-Antichymotrypsin is a product of activated astrocytes
that is localized to beta-amyloid (Aß) deposits in brains affected
with AD. It has been suggested that ACT plays a role in plaque
formation by enhancing conversion of nonfibrillar forms of Aß to
insoluble Aß fibers. 2-Macroglobulin is a potent,
broad-spectrum protease inhibitor thought to have evolved as a
primitive host defense mechanism. 2-Macroglobulin and
its principle receptor, low-density lipoprotein receptor, function as a
clearance system for inflammatory proteins. They are detected
immunohistochemically in association with neurofibrillary tangles and
senile plaques in brains affected with AD.2, 3
The strongest evidence of polymorphisms in inflammatory agents
increasing the risk of AD involves the IL1 complex. Chromosome
2q14-21 contains a cluster of IL1-related genes, including
IL1A, IL1B, and IL1 receptor antagonist
protein, all of which have significant polymorphisms. The
IL1A-889 regulatory region exists in C (allele 1)
and T (allele 2) forms. Four groups4, 5, 6, 7 have now
reported that carriers of the T form have an increased risk of
AD. Grimaldi et al4 found a strong association between the
T/T genotype and early-onset AD (odds ratio [OR], 4.86),
with disease occurring 9 years earlier in T/T compared with
C/C carriers. In their case-control study of 318 Italians,
17% of patients with AD and 9% of control subjects were of the
T/T genotype.
Nicoll et al5 studied a British and
US case-control series of 399 individuals. They found that the
IL1AT/T genotype occurred in 12.9% of AD patients compared
with 6.6% of controls, confirming the general results of Grimaldi et
al.4 Du et al,6 studying a US and German
case-control series of 451 individuals, found that the T/T
genotype occurred in 8.1% of AD cases and only 1.6% of controls.
Statistical analysis following adjustments for sex and age group
indicated an AD vs control OR of 7.2 for homozygous T/T
carriers and 1.68 for heterozygous T/C carriers.
Rebeck7 analyzed yet another case-control series of 434
individuals from Massachusetts. He found an OR of 3.1 for early-onset
AD compared with the control group; 9% of his controls carried the
T/T genotype compared with 23% of early-onset AD cases,
although only 10% of AD cases overall were T/T. Although
these case-control studies essentially confirm each other, they
indicate a considerable variation in the frequency of T/T
carriers in control populations. In fact, statistical tests suggest
nonhomogeneity in the control populations. Obviously, studies of this
kind are prone to type I and type II statistical errors. It will be
important in the future to determine the influence of ethnicity on
allele frequency, as well as to rule out, to whatever extent possible,
the existence of latent disease in control populations. In these
studies, allowance was made for ApoE4 (the gene for
apolipoprotein E4) as a confounding factor, but numerous other
polymorphisms may have influenced the outcome.
Two common polymorphisms in the IL1B gene have been reported
to increase the risk of AD. These are located at the -511 position of
the regulatory region, where T and C alleles exist,
and in the +3953 position in exon 5, also where T and
C alleles exist. Grimaldi et al,4 using the same
population as for their IL1A genotyping, found that the
T/T genotype for the -511 polymorphism was associated with a
slightly increased risk for late-onset AD (OR, 1.95). Nicoll
et al5 reported on the IL1B +3953 polymorphism.
Homozygosity for the +3953 T allele is reported to increase
IL-1ß production 4-fold compared with homozygosity for the C
allele.5 They found the +3953 T/T genotype to
occur in 7.3% of AD patients and 4.8% of controls. When they analyzed
for simultaneous inheritance of the T/T alleles for
IL1A -889 and IL1B +3953, the OR for developing AD
rose to 10.8.
Interleukin 6 is a potent inflammatory cytokine that is hardly
detectable in the central nervous system of healthy adults. However, it
is rapidly induced in a variety of pathologic situations.
Papassotiropoulos et al8 and Licastro et al9
conducted case-control investigations of polymorphisms involving this
inflammatory cytokine. The IL6 gene is located on chromosome
7p21 and polymorphisms exist in the -174 promoter region and in the
region of a variable number of tandem repeats (VNTR). The
latter is located in the nontranslated 3' flanking region of IL-6. In a
white German case-control series of 293 AD cases and controls,
Papassotiropoulos et al8 found the C allele of the
VNTR region to be protective against AD (OR, 0.60), delaying the
initial disease onset. Licastro et al,9 in their
case-control series of 448 AD cases and controls from an Italian
population,9 found the D allele to have an
opposite effect, ie, it increased the risk of late-onset AD (OR,
1.42). They confirmed the findings of Papassotiropoulos et
al8 of a reduced risk of the C allele as well as
absence of the D allele (OR, 0.53). They also found
that the C allele of the C/G -174 promoter region
was associated with a risk for late-onset AD (OR, 1.56) and that there
was linkage disequilibrium between the -174 promoter and the VNTR
region. Plasma levels of IL-6 were higher in the AD patients than in
controls, with the highest levels occurring in patients carrying the
VNTR D allele. These results demonstrate that some alleles of
a given polymorphism can reduce the risk of AD, while others enhance
it. It is significant that the high-risk D allele of the VNTR
polymorphism is associated with the highest IL-6 plasma levels,
indicating that there is a systemic manifestation of the polymorphism.
Investigation of TNFA polymorphisms was initiated because
genome screening had suggested a putative association of AD with a
region on chromosome 6p21.3, which was within 20 centimorgans of the
TNFA gene. Furthermore, the TNFA -308 promoter
A allele had previously been shown to be associated with
autoimmune and inflammatory diseases, and it was also known to have
stronger transcriptional activity than the G allele.
Similarly, the TNFA microsatellite 2 allele, located
approximately 7 kilobases upstream of TNF, had previously been
associated with higher TNF secretion and a susceptibility to rheumatoid
arthritis. No associations had previously been found for polymorphisms
of the -238 TNF promoter region. Collins et al10
genotyped 145 high-risk families, consisting of 562 affected and
unaffected siblings for association of these 3 polymorphisms with AD.
They found that the TNFA microsatellite 2 allele alone was
significantly associated with AD (P = .04) but
that the 2-1-2 haplotype for -308, -238, and the microsatellite
polymorphism was even more strongly associated with AD
(P<.001). These data provide a correlation between
unbiased genome-linkage studies, polymorphisms known to promote
inflammatory disease, and enhanced production of an inflammatory
cytokine.
1-Antichymotrypsin is an acute-phase reactant that is
produced by activated astrocytes and is elevated in brains affected
with AD. Licastro et al11 investigated the combined effects
of ACT and IL1B polymorphisms on the risk of AD as
well as on levels of expression of the protein in plasma. The
genotyping was performed in 281 patients with probable AD and 201
controls without AD. For this Italian population, the ACT T/T
and IL1B T/T genotypes were slightly and independently
increased in AD patients. The concomitant presence of the ACT
T/T and IL1B T/T genotypes increased the OR for AD to 5.6.
A study of plasma levels in a subset of patients showed that the plasma
levels of ACT and IL-1ß were increased in AD patients with
T/T genotypes. This study is a further illustration of a
robust increase in OR when high-risk alleles of multiple inflammatory
agents are carried simultaneously. It is also another example of how
high-risk alleles can manifest themselves by higher systemic expression
of the protein in question.
As with TNFA, investigations of the role of A2M were
initiated as a result of screening studies of the genome. In this case,
linkage was found in the region of chromosome 12p, where A2M
and its low-density lipoprotein
receptor are found. Blacker et al12
tested for associations of polymorphisms in A2M with AD in the
National Institutes of Health Genetic Initiative AD sample. This sample
is a large collection of affected sibling pairs and other small
families with AD. It is now being used as a reference standard by many
laboratories. Blacker et al12 found that a deletion in the
A2M gene at the 5' splice site of exon 18 conferred an
increased risk for AD (OR, 3.56). The OR was comparable to
that for the ApoE4 allele in the same population, although
this A2M-2 allele did not affect the age of onset. These data
did not confirm previously published linkage data to chromosome 12 and,
in fact, have been challenged. Although further work is required on a
larger population, the results strongly suggest involvement of the
A2M gene in AD.
In summary, at least 10 polymorphisms involving 4 inflammatory
cytokines and 2 acute-phase reactants have been shown to enhance the
risk of developing AD. When 2 or more polymorphisms in linkage
disequilibrium have been evaluated simultaneously, the risk has
substantially increased beyond that of each one assessed separately. In
most cases, the polymorphisms in question have also been linked to
peripheral inflammatory disorders. In general, they have also been
shown to correlate with increased production of the protein product.
The overall implication is that individuals carrying 1 or more of these
high-risk alleles are hypersensitive to abnormalities that provoke a
chronic inflammatory response with consequent vulnerability to
autodestructive processes.
If risk factors operate independently, the overall OR should be the
product of individual ORs. In the case of AD, where the prevalence
doubles every 5 years beyond age 65 years, each doubling of the overall
OR should reduce the average age of onset by 5 years. Given that each
of the 10 polymorphisms described above significantly affects the OR,
their overall impact could be severe. More detailed genetic analyses in
the future should make it possible to estimate a susceptibility profile
for the development of AD with much greater accuracy. Perhaps other
chronic inflammatory diseases will be included. Such information could
prove valuable in devising strategies for therapeutic intervention,
either before disease onset or in its early stages. This is
particularly important for AD, because the inflammation is silent and
the consequences are devastating.
AUTHOR INFORMATION
Accepted for publication March 13, 2001.
From the Department of Psychiatry, Kinsmen Laboratory of
Neurological Research, University of British Columbia, Vancouver.
Corresponding author: Patrick L. McGeer, MD, PhD, Kinsmen Laboratory of
Neurological Research, University of British Columbia, 2255 Wesbrook
Mall, Vancouver, British Columbia, Canada V6T 1Z3 (e-mail: mcgeerpl{at}interchange.ubc.ca).
REFERENCES
| |
1. McGeer PL, McGeer EG. Autotoxicity and Alzheimer disease. Arch
Neurol. 2000;57:789-790.
FREE FULL TEXT
2. McGeer PL, McGeer EG. The inflammatory response system of brain:
implications for therapy of Alzheimer and other neurodegenerative
diseases. Brain Res Rev. 1995;21:195-218.
FULL TEXT
| PUBMED
3. Akiyama H, Barger S, Barnum S, et al for the Neuroinflammatory Working Group. Inflammation and Alzheimer's disease. Neurobiol Aging. 2000;21:383-421.
FULL TEXT
|
ISI
| PUBMED
4. Grimaldi LME, Casadei CM, Ferri C, et al. Association of early-onset
Alzheimer's disease with an interleukin-1 gene polymorphism. Ann Neurol. 2000;47:361-365.
FULL TEXT
|
ISI
| PUBMED
5. Nicoll JAR, Mrak RE, Graham DI, et al. Association of interleukin-1
gene polymorphisms with Alzheimer's disease. Ann Neurol. 2000;47:365-368.
FULL TEXT
|
ISI
| PUBMED
6. Du Y, Dodel RC, Eastwood BJ, et al. Association of an interleukin-1 alpha polymorphism with Alzheimer's disease. Neurology. 2000;55:480-483.
FREE FULL TEXT
7. Rebeck GW. Confirmation of the genetic association of interleukin-1A with early onset sporadic Alzheimer's disease. Neurosci Lett. 2000;293:75-77.
FULL TEXT
|
ISI
| PUBMED
8. Papassotiropoulos A, Bagli M, Jessen F, et al. A genetic variation of
the inflammatory cytokine interleukin-6 delays the initial onset and
reduces the risk for sporadic Alzheimer's disease. Ann Neurol. 1999;45:666-668.
FULL TEXT
|
ISI
| PUBMED
9. Licastro F, Pedrini S, Bonafe M, et al. Polymorphisms of the IL-6 gene
increase the risk for late onset Alzheimer's disease and affect IL-6
plasma levels [abstract]. Neurobiol Aging. 2000;21(1, suppl):S38.
10. Collins JS, Perry RT, Watson B Jr, et al. Association of a haplotype
for tumor necrosis factor in siblings with late-onset Alzheimer
disease: the NIMH Alzheimer Disease Genetics Initiative. Am J Med
Genet. 2000;96:823-830.
FULL TEXT
|
ISI
| PUBMED
11. Licastro F, Pedrini S, Ferri C, et al. Gene polymorphism
affecting 1-antichymotrypsin and interleukin-1 plasma levels
increases Alzheimer's disease risk. Ann Neurol. 2000;48:388-391.
FULL TEXT
|
ISI
| PUBMED
12. Blacker D, Wilcox MA, Laird NM, et al. Alpha-2 macroglobulin is
genetically associated with Alzheimer disease. Nat Genet. 1998;19:357-360.
FULL TEXT
|
ISI
| PUBMED
SECTION EDITOR: DAVID E. PLEASURE, MD
RELATED ARTICLE
Archives of Neurology Reader's Choice: Continuing Medical Education
Arch Neurol. 2001;58(11):1942-1944.
FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Effects of TNF{alpha}-Converting Enzyme Inhibition on Amyloid {beta} Production and APP Processing In Vitro and In Vivo
Kim et al.
J. Neurosci. 2008;28:12052-12061.
ABSTRACT
| FULL TEXT
Comparison of the Human and Canine Cytokines IL-1({alpha}/{beta}) and TNF-{alpha} to Orthologous Other Mammalians
Soller et al.
J Hered 2007;0:esm025v3.
ABSTRACT
| FULL TEXT
Inflammatory markers and the risk of Alzheimer disease: The Framingham Study
Tan et al.
Neurology 2007;68:1902-1908.
ABSTRACT
| FULL TEXT
Tumor Necrosis Factor {alpha} and Interleukin 10 Promoter Region Polymorphisms and Risk of Late-Onset Alzheimer Disease.
Ramos et al.
Arch Neurol 2006;63:1165-1169.
ABSTRACT
| FULL TEXT
Novel therapeutic opportunities for Alzheimer's disease: focus on nonsteroidal anti-inflammatory drugs
Townsend and Pratico
FASEB J. 2005;19:1592-1601.
ABSTRACT
| FULL TEXT
William M. Feinberg Lecture: Cognitive Vitality and the Role of Stroke and Cardiovascular Disease Risk Factors
Gorelick
Stroke 2005;36:875-879.
ABSTRACT
| FULL TEXT
Accelerated Prion Disease in the Absence of Interleukin-10
Thackray et al.
J. Virol. 2004;78:13697-13707.
ABSTRACT
| FULL TEXT
Risk Factors for Vascular Dementia and Alzheimer Disease
Gorelick
Stroke 2004;35:2620-2622.
ABSTRACT
| FULL TEXT
Interaction of atherosclerosis and inflammation in elderly subjects with poor cognitive function
van Exel et al.
Neurology 2003;61:1695-1701.
ABSTRACT
| FULL TEXT
GENES AND GENE POLYMORPHISMS ASSOCIATED WITH PERIODONTAL DISEASE
Kinane and Hart
Crit. Rev. Oral Biol. Med. 2003;14:430-449.
ABSTRACT
| FULL TEXT
Regular use of nonsteroidal anti-inflammatory drugs and cognitive function in aging women
Hee Kang and Grodstein
Neurology 2003;60:1591-1597.
ABSTRACT
| FULL TEXT
Metabolic Effects of Infection on Protein and Energy Status
Powanda and Beisel
J. Nutr. 2003;133:322S-327.
ABSTRACT
| FULL TEXT
Innate Immunity, Local Inflammation, and Degenerative Disease
McGeer and McGeer
Sci Aging Knowl Environ 2002;2002:re3-3.
ABSTRACT
| FULL TEXT
|
