Apolipoprotein E polymorphism in cerebrovascular & coronary heart diseases.

Abstract

The role of apolipoprotein E (apo E) in lipid metabolism and cholesterol transport is well established. About 14 per cent of the variation in plasma cholesterol levels is attributed to polymorphisms in APO E gene (APO E). APO E consists of three common alleles, designated as ε2, ε3 and ε4 which code for E2, E3 and E4 proteins respectively resulting in three homozygous (E2/E2, E3/E3, E4/E4) and three heterozygous (E3/E2, E4/E2 and E4/E3) phenotypes. Different populations studied worldwide inherit variable frequencies of the APO E alleles and genotypes, with the most frequent allele being ε3.The ε4 allele has been consistently shown to be associated with Alzheimer's disease, coronary heart disease and cerebrovascular disorders. In this review, we have discussed the role of APO E polymorphisms in cerebrovascular and coronary heart diseases. The status of APO E polymorphisms and their disease associations in Asian Indians besides, other populations has also been discussed. Further, studies elucidating the pathophysiology of apo E deficiency conducted in knock-out mice have been reviewed.

Full text

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Introduction

glycoprotein consisting of 299 amino acids found in
circulating chylomicrons, chylomicron remnants, very
low density lipoproteins (VLDL), intermediate density
lipoproteins (IDL) and high-density lipoproteins
(HDL)1. The apolipoprotein E gene (APO E) is
located at chromosome 19q 13.2 and consists of four
exons and three introns spanning 3,597 nucleotides1,2.
ApoE is a 35 kilodalton (kD) glycosylated protein
with multiple biological properties3. It is produced
primarily in the liver, but other organs and tissues also
The human apolipoprotein E (apo E) is a serum
Apolipoprotein E polymorphism in cerebrovascular & coronary
heart diseases
Shajith Anoop, Anoop Misra*, Kiran Meena** & Kalpana Luthra**
Department of Environmental Sciences, Bharathiar University, Coimbatore, *Department of Diabetes &
Metabolic Diseases, Fortis Group of Hospitals & **Department of Biochemistry, All India Institute of
Medical Sciences, New Delhi, India
Received June 23, 2009
The role of apolipoprotein E (apo E) in lipid metabolism and cholesterol transport is well established.
About 14 per cent of the variation in plasma cholesterol levels is attributed to polymorphisms in apo
E gene (apo E). apo E consists of three common alleles, designated as ε2, ε3 and ε4 which code for
E2, E3 and E4 proteins respectively resulting in three homozygous (E2/E2, E3/E3, E4/E4) and three
heterozygous (E3/E2, E4/E2 and E4/E3) phenotypes. Different populations studied worldwide inherit
variable frequencies of the apo E alleles and genotypes, with the most frequent allele being ε3.The ε4
allele has been consistently shown to be associated with Alzheimer’s disease, coronary heart disease
and cerebrovascular disorders. In this review, we have discussed the role of apo E polymorphisms in
cerebrovascular and coronary heart diseases. The status of apo E polymorphisms and their disease
associations in Asian Indians besides, other populations has also been discussed. Further, studies
elucidating the pathophysiology of apo E deficiency conducted in knock-out mice have been reviewed.
Key words Alzheimer’s disease - apolipoprotein E - cholesterol - coronary heart diseases - cholesterol - polymorphism
synthesize apo E, including brain, spleen, kidneys,
gonads, adrenals and macrophages. The structural
gene locus for plasma apo E is polymorphic having
three common alleles, designated as ε2, ε3 and ε4
which code for E2, E3 and E4 proteins, respectively.
Consequently three homozygous (E2/E2, E3/E3, E4/
E4) and three heterozygous (E3/E2, E4/E2 and E4/E3)
phenotypes are found in the general population4. The
product of the three alleles differ in such properties
as its affinity for binding to apo E and low-density
lipoprotein receptors (LDL-R), and its affinity for
lipoprotein particles5.
Indian J Med Res 132, October 2010, pp 363-378
363
Review Article

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Role of apo E in cholesterol transport

metabolism is as a ligand for receptor mediated
clearance of chylomicron and VLDL remnants. It
also participates in reverse cholesterol transport.
Lipoproteins play a major role in the development
of atherosclerotic cardiovascular disease (CVD) in
humans and the levels of lipoproteins in plasma are
determined by apolipoproteins present on their surface6.
It has been estimated that 60 per cent of the variation
in plasma cholesterol levels is genetically determined
and approximately 14 per cent variation in plasma
cholesterol levels is due to APO E polymorphisms5.
The best recognized role of apo E in lipid

E4), differ from each other at amino acid residues
112 and 158. E2 has cysteine residues at both sites
112 and 158 (cys 112, cys 158) whereas E4 has
arginine residues at both sites (arg 112, arg 158),
E3 has a cysteine at position 112 and an arginine at
position 1586. The amino terminal region of apo E is
responsible for binding of apo E to the LDL receptor
and the carboxy terminal mediates the binding of
apo E to surface lipoproteins. The apo E2 and apo
E4 are metabolically different from apoE3. The apo
E4 has arginine at position 112 and binds selectively
to triglyceride-rich lipoproteins such as VLDL but
apo E2 and E3 bind only to HDL. The VLDL-apo
E4 particles are removed faster from plasma than
VLDL-apo E3 particles resulting in a downregulation
of the LDL receptor5. It is vital to note that the E2
homozygotes have an inefficient catabolism of
VLDL clearance which is further aggravated by
environmental, hormonal or genetic factors resulting
in type III hyperlipoproteinaemia5.
The three common isoforms of apo E (E2, E3 and

clearance of chylomicron and VLDL remnants is of
vital significance; Apo E participates in the hepatic
clearance of chylomicron remnants and other apo E
containing lipoproteins7. Another role of apo E is in
reverse cholesterol transport. The dual role of apo
E is crucial for clearing the plasma of chylomicron
remnants and excess cholesterol8. The apo E can also
bind to LDL receptor related protein (LRP), VLDL
receptor, heparin and proteoglycans. By binding to
heparin and heparin like glycosoaminoglycans present
in the matrix of arterial walls, apo E has a possible
role in smooth muscle biology in which muscle cell
proliferation and migration in the intima is characteristic
of atherosclerotic vascular disease9.
The role of apo E as a ligand for receptor mediated
Influence of apo E polymorphism on blood lipids

influenced by the composition of dietary fats with
saturated fats being the major determinant of serum
cholesterol as well as by endogenous synthesis10. The
absorption of dietary fat is regulated by numerous
genes at the erythrocyte level namely the ATP binding
cassette (ABC) transporters ABCA1, ABCG5,
ABCG811. Among these proteins, apo E has been
implicated to affect the efficiency of cholesterol
absorption. Kesaniemi et al12 first reported that the
subjects with the E4 phenotype have markedly high
intestinal absorption efficiency. They observed that
subjects who were either heterozygous or homozygous
for the E2 allele absorbed less cholesterol than those
with the genotype ε3/ε4 and ε4/ε412. Cholesterol
absorption and synthesis are inversely correlated13.
The lower the absorption efficiency of cholesterol,
the higher the rate of cholesterol synthesis. Hence ε2
carriers show higher hepatic cholesterol synthesis than
ε4 subjects12. The importance of apo E in accepting
cholesterol from cholesterol loaded macrophages and
facilitating the expansion of cholesterol ester core
of HDL in conjunction with the action of the plasma
enzyme - lecithin: cholesterol acyl transferase (LCAT)
was demonstrated in a series of studies with canine high
density lipoproteins (HDL). Canine - HDL with apo E
decreased cholesteryl ester formation and accumulation
in cholesterol loaded macrophages, reflecting enhanced
cholesterol efflux from the cells and the efficiency
of this effect was correlated with protection from
atherosclerosis in animal models lacking cholesteryl ester
transfer protein (CETP)14. Gordon et al15 demonstrated
the obligatory role for cholesterol and apo E in the
expansion of HDL. Incubation of apo E depleted canine
HDL in the presence of LCAT and cholesterol - loaded
J774 macrophages, which do not synthesize apo E, did
not result in significant expansion in size of the HDL.
However, adding exogenous apo E to the incubation
resulted in HDL size expansion, CE accumulation and
enrichment in apo E. In addition, the LDL receptor -
binding activity was proportional to the apo E content15.
Serum cholesterol concentration is profoundly

cholesterol homeostasis in the human body. The liver
membranes possess two high affinity receptors for
lipoproteins namely LDL (B/E) receptors and apo E
receptors (remnant receptors) of which the number of
LDL (B/E) receptors on the cell surface is regulated
whereas the apo E receptors are not regulated16. The
cholesterol delivered to cells by receptor mediated
Physiologically, the liver plays a vital role in
364 INDIAN J MED RES, OCTOBER 2010

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endocytosis is believed to regulate two important
steps involved in intracellular cholesterol homeostasis.
Importantly apo E receptors that deliver cholesterol of
exogenous origin to the liver do not undergo cholesterol
influx regulation.

the LDL and apo E receptors leads to accumulation
of remnant lipoproteins resulting in hyperlipidaemia.
However, most E2 homozygotes have subnormal
rather than elevated cholesterol and low LDL. This
is because the delayed catabolism of lipoproteins that
contain apo E, causes cholesterol of exogenous origin
and periphery to enter the liver through apo E mediated
uptake. For compensation, LDL (B/E) receptors may be
upregulated, resulting in enhanced uptake of LDL and
hence a lowering of LDL in plasma. In addition, a delay
in the interconversion of intermediate density lipids
(IDL) to LDL may contribute to the low LDL in plasma
of E2 homozygotes17. A similar but opposite mechanism
may account for the association of the ε4 allele with
hypercholesterolaemia. In vivo studies by Gregg et
al18 have demonstrated that apo E is catabolized more
rapidly than apo E3. Apo B concentrations increase in
the order E2/E2, E3/2, E3/3, E4/3, and E4/4 whereas
apo E concentrations decrease in the same order18.
Because of the enhanced catabolism of lipoproteins
that contain apo E4, more cholesterol is delivered to
liver cells by apo E mediated uptake in subjects with
a ε4 allele. The complex associations of APO E genes
with lipid levels and hyperlipidaemia suggest that APO
E alleles contribute to the genetic risk of developing
atherosclerotic vascular disease19. An association
between APO E alleles and various disorders such as
Alzheimer’s disease20, cognitive impairment21, gall stone
formation22, central nervous system tumours23, multiple
sclerosis24 and possibly the inflammatory response to
injury8 has been well documented.
In apo E2 homozygotes, failure of apo E2 to bind

in the distribution of apo E isoforms and so far, the most
frequent allele in all populations examined is ε3 which
codes for the isoform apo E3. Several studies have
shown that ε2 allele is associated with low levels of TC,
LDL-C and apolipoprotein B (apo B), whereas for ε4
allele the opposite is observed7. In this review, we focus
exclusively on the influence of APO E polymorphism on
cerebrovascular and coronary heart diseases.
Different populations exhibit variable frequencies
Apo E and its vital role in the neurological system

metabolism, apo E appears to play an important role
Originally identified for its role in cholesterol
in human neurological diseases. The role of apo E
in modifying susceptibility to the development of
Alzheimer’s disease has led to a resurgence of interest
in the neurobiology of this protein25. Studies26,27
indicate that apo E may play a role in regulating
calcium homeostasis, and therefore impacting neuronal
regulation of various ion-independent receptors,
including K+ antiporters. Apo E plays a vital role in
modulation of neurotransmitter release/sequestration,
including the enhancement of glutamate uptake and
prevents excitotoxicity28,29. Apo E may also salvage
neurons from oxidative stress thus allowing greater
neurite availability following injury. It is interesting
to note that apo E3 provided more protection
against oxidative stress than apo E2 or apo E4 and
that mice expressing tumour apo E3 alone had less
neurodegeneration following oxidative insult. These
results may be due to the ability of apo E to bind
trace metals such as iron or due to the regulation of
astrocyte activation by apo E30. Certain studies have
also demonstrated that apo E enhances the effects
of some growth factors such as ciliary neurotrophic
factor (CNTF) and sprouting31. Apo E expression is
upregulated following injury and promotes neurite
outgrowth in vitro and in vivo with apo E3 displaying
greater sprouting enhancement capabilities than
apo E2 or apo E432. These differences may pertain
to the variations in the ability of the isoforms to
transport lipids, bind receptors, or influence other
cellular functions such as cholesterol homeostasis and
microtubule stabilization31. The most striking function
of apo E in the brain is its role in regulating innate
and adaptive immune responses. Initial studies in apo
E demonstrated a role for the molecule in inhibiting
neutrophil and lymphocyte proliferation as well as
T-cell activation32.

indicating that apo E may play a role in controlling
cytokine signaling by serving in a feed- forward or
negative feedback mechanism. However, the secretion
of apo E by the microglia and astrocytes is altered in the
brain following treatment with various inflammatory
stimuli, with apo E pretreatment reducing inflammatory
signaling in astrocytes and microglia33,34.
The production of apo E is regulated by cytokines
Apo E receptors and its functions in the CNS: Of the two
major apolipoproteins found in the cerebro spinal fluid
(CSF), apo E can associate with a number of extracellular
molecules and bind to four major CNS apo E receptors,
VLDLR, Apo ER2, LDLR and LRP. Apo E receptors
undergo rapid clathrin-mediated endocytosis following
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ligand binding to several signal transduction pathways35.
Apo E isoforms exhibit a differential effect on synaptic
function and VLDLR and Apo ER2 are shown to play a
role in synaptic plasticity and memory formation35.

mechanism for extracellular Aβ, and apo E is often
associated with Aβ deposits in post-mortem AD brains.
The apo E receptors, Apo ER2, LRP and LRP 1β can
directly interact with and stabilize amyloid precursor
causing increased alpha cleavage and reduced Aβ
producing cleavage. Thus, apo E and apo E receptors
can influence both levels and production of Aβ35.
Apo E receptors are believed to act as a clearance

binding to both Apo E2 and VLDLR and subsequent
Reelin dependent signaling in primary neuronal cells21.
The soluble apo E receptors may have a role in the
negative regulation of apo E and thus understanding
their generation is vital for elucidating the functions of
apo E in the central nervous system (CNS)35.
The soluble Apo ER2 can effectively block Reelin
Apo E in Alzheimer’s disease (AD)

cluster on chromosome 19 was shown to be a risk factor
for Alzheimer’s disease35. APO E gene was implicated,
based on the knowledge that apo E is found in plaques
and neurofibrillary tangles (NFT) where it binds the
Aβ peptide, and also due to the fact that it is also the
predominant brain apolipoprotein. Aβ can be detected in
the plasma, cerebrospinal fluid (CSF) and in cell culture
media36,37. It can be cleaved by three proteases, classified
as alpha, beta and gamma secretases38,39. The protease
alpha secretase cleaves APP within the Aβ domain
thereby precluding its formation. Risk factors for late
onset of AD include old age, family history of dementia
and possession of one or more APO E ε4 alleles37,40. The
discovery of AD neuropathology in a large proportion
of non-demented coronary heart disease (CHD) cases
at post mortem led researchers to investigate CAD as
a risk factor. High cholesterol levels, obesity, diabetes,
coronary artery disease (CAD), low density lipoprotein
receptor-related protein-1 (LRP-1) and apo E are all
found to be associated with the onset of Alzheimer’s
disease33,40.
In 1993, a locus within an apolipoprotein gene
Apo E polymorphisms and Alzheimer’s disease: Of the
several genetic factors for AD, only APO E has so far
been shown to be associated with both early and late
onset AD of sporadic and familial varieties16,35. The ε4
allele of the APO E gene has been consistently shown
to be associated with AD in many studies of white
populations, whereas the ε2 allele has in some studies
appeared to be protective against AD35. In certain
studies conducted in Africans, African-Americans,
and Hispanic populations, the evidence of an APO E
association in Alzheimer’s disease is mixed36, 41.

was conducted to compare the prevalence, incidence,
risk factors and outcome of AD and other dementias
between the rural communities of Ballabgarh in
northern India and the Monongahela Valley region in
South Western Pennsylvania. The prevalence of AD
and other dementias among the elderly subjects in
Ballabgarh was reported to be the lowest in the world,
indicating the probable existence of protective factors
in individuals of this community43.
The Indo-US cross-National Dementia study42

E E2, APO E E3 and APO E E4 genotypes in the three
different age groups studied showed no association with
age whereas the frequencies of APO E ε2 and APO E
ε4 alleles in the population aged 70 yr or older were
significantly lower than in the Monongahela Valley
Independent Elders Survey (MOVIES) cohort. The
frequencies of AD and the APO E ε4 allele were higher
among those who underwent genotyping within the US
samples than in the Indian samples included in their
study43. The APO E ε4 carrier status and the presence
of probable or possible AD was positively associated in
both the cohorts whereas no association was observed
between APO E ε2 and AD42. Previous studies of APO
E polymorphism in Indians or individuals of Indian
ancestry39,44 have reported marginally higher APO E
ε4 allele frequencies than the frequency in Ballabgarh
inhabitants aged 55 yr or older. On the basis of a multi-
centre meta-analysis, it was concluded that the APO E
ε4 allele represents a major risk factor for Alzheimer’s
disease in all the ethnic groups studied, across all ages
between 40 and 90 yr, in both men and women45,46.
In the Ballabgarh cohort, the frequencies of the APO

in 376 patients diagnosed with probable or possible
AD and 567 cognitively normal controls, all of
them being ethnic Norwegians, and revealed that
the frequency of the APO E ε4 allele in patients was
highest among subjects in the age group of 60-69 yr.
The oldest Alzheimer disease patients above 80 yr had
the lowest proportion of the APO E ε4 allele. Age at
onset in patients with low onset of AD (LOAD) was
significantly reduced by the APO E ε4 allele in a dose-
dependent manner, while it had no lowering effect in
patients with onset before 65 yr. This study confirmed
that individuals carrying the APO E ε4 allele are at
increased risk for developing Alzheimer disease47.
Sigrid et al47 examined APO E allele frequencies
366 INDIAN J MED RES, OCTOBER 2010

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ε4 alleles were 8.1 times likely and those with one ε4
allele were 2.8 times likely to develop AD than the non
carriers of the ε4 allele. This study also demonstrated
that there was an inverse correlation between the dose
of ε4 allele and age at onset of AD in families with
Alzheimer’s disease25. Lucotte et al48 showed that the
risk of AD is increased and the cumulative probability
of remaining unaffected by AD is decreased for each
dose of APO E ε4 allele in sporadic Alzheimer’s
disease.
Corder et al25 showed that those with two APO E

and heterozygous carriers of the APO E ε4 allele
were at a higher risk for AD but they did not develop
the disease. Thus it was suggested that about half the
number of all AD cases is not caused by ε4 allele.
Conversely Raber et al50 considered the ε4 allele
to be responsible for as much as 95 per cent of the
AD cases in North America. Other studies51,52 have
produced inconsistent support for ε2 as a protective
factor against AD in subjects with Down’s syndrome.
Deb et al53 observed a higher frequency of the ε4
allele and a lower frequency of the protective ε2 allele
among subjects with dementia and Down’s syndrome
compared with those without dementia. Hyman et al54
reported that the African Americans and Hispanics
with an ε4 allele were at a risk to develop AD by
the age of 90 yr similar to that of the Whites but in
the absence of an ε4 allele, the African Americans
and Hispanics were 2 to 4 times more likely than
the Whites to develop AD by the age of 90 yr. This
difference was not related to the individual socio-
economic status or familial disease history54.
In the Framingham Heart Study49, homozygous

the ε4 allele develop AD and not all AD patients carry
at least one ε4 allele. The ε4 allele is the only known
risk factor for LOAD. Sigrid et al47 demonstrated that
the ε4 allele is a strong risk factor for dementia in the
Norwegian population, as seen in other Caucasian
populations. In contrast, Hendrie et al55 observed
no relation between AD and ε4 in elderly Nigerian
populations.
Hyman et al54 emphasized that not all carriers of

polymorphism with vascular dementia (VaD) and
Alzheimer’s disease in northern Asian Indians56. In this
study the frequency of ε4 allele among AD cases was
similar to that reported by Farrer et al46. The frequency
of the APO E ε4 allele was much higher compared to
that by Ganguli et al43. We observed that the presence
We have reported the association of APO E
of even one allele of E4 conferred a risk of developing
both AD and vascular dementia. The association of
the ε4 allele with cerebrovascular disease in ageing
populations has also been well documented57,58.

ε4 allele and the genotypes ε3 /ε4 and ε4 /ε4 were
significantly higher in stroke patients as compared to
normal subjects59. Moreover, subjects with the ε4 allele
had four-fold higher odds of developing stroke when
compared with carriers of ε3 and ε2 alleles. A five-
fold higher odds for developing stroke was observed
in subjects with the E3/E4 genotype and those with
E4/E4 had a three times higher odds of developing
stroke. Juan Pedro-Botel et al60 studied the lipoprotein
and apolipoprotein profile in survivors of ischaemic
non cardio embolic stroke and observed a significantly
higher prevalence of the E4/E3 phenotype in stroke
subjects than the controls. The higher prevalence of
epsilon 4 allele in ischaemic cerebrovascular disease
(ICVD) patients found in this study was similar to that
reported earlier5.
In a double blinded study, the frequency of the

important APO E polymorphisms namely SNPT- 427C
in the promoter region and epsilon polymorphism in
the coding region which were significantly associated
with ischaemic stroke in the carotid region with its
atherothrombotic subtype. This study reported a
negative association between ischaemic stroke and
APO E ε2 allele, but no significant associations with ε3
and ε4 alleles61.
Parfenov et al61 reported two functionally

of APO E ε2/ ε3/ ε4 and LDLR C 1773T polymorphisms
with the risk of having an episode of ischaemic stroke
in northern Han Chinese population. It further added
the evidence of an independent role of hypertension
and APO E ε2/ ε3/ ε4 in the development of this
disorder. The overall distribution of genotype and
allele frequencies of APO E ε2/ ε3/ ε4 polymorphism
differed significantly between ischaemic stroke cases
and controls. Compared to APO E ε3 homozygote,
the APO E ε2 allele conferred a protective effect to
ischaemic stroke but the APO E ε4 allele conferred a
significant risky effect62.
Another study62 demonstrated potential interactions

the potential interactions of APO E polymorphism and
conventional risk factors with ischaemic stroke. This
study supported the independent role of APO E ε4
allele on risk of ischaemic stroke and also suggested
that the synergistic role of APO E ε4 allele and cigarette
In contrast to this study, Pezzini et al63 explored
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Page 6

smoking might increase an individual’s propensity to
have a cerebral ischaemic event63.

subjects. This study included epileptic Asian Indian
patients with or without lateralized seizure features
and the results revealed that the ε3 allele and the ε3/ε3
genotype were prominent in both cases and controls64.
However, no association was found between APO E
alleles or genotypes with epilepsy and which was
in accordance to the studies reported in the Italian
population65. We observed significantly high circulating
levels of apo E protein in epilepsy patients as compared
We investigated APO E polymorphism in epileptic
to controls. Whether this elevation of the apo E protein
is the cause or the consequence of the disease remains to
be assessed. The association of APO E polymorphisms
with cerebrovascular disease in populations worldwide
is summarized in Table I.
Role of APO E polymorphisms in coronary heart
disease: A link between APO E polymorphism and
atherosclerosis was first established with the observation
that patients with type III hyperlipoproteinaemia and
patients with APO E E2/2 phenotype had premature
coronary heart disease (CHD)65. The APO E ε4 allele
has been found to be associated with an increased
Table I. Polymorphism in relation to cerebrovascular disease
Sample size
Elderly population of Ballabagarh
Cohort-India and Monongahela
Valley Pennsylvania
MOVIES Cohort
Reference
Ganguli
et al
(2000)43
Study population Observations/conclusion of the study
The frequencies of AD and the ε4 allele were higher with the
US sample than the Indian cohort. The ε4 carrier status and
the presence of probable or possible Alzheimer’s disease were
positively associated in both cohorts.
Ballabagarh
Cohort
(n = 4450)
(n=886)
White non
Hispanics n=601
White Hispanics
(n=359)
Harwood
et al(2004)66
White Hispanics and white non
Hispanics susceptible to AD
This clinic-based study found that the ε4 allele conferred a dose-
dependant impact on age of onset in the cohort of non Hispanic
White patients included in the study. A significant association
between the ε4 allele and age of onset of AD was observed in
White Hispanics.
This study confirmed that individuals carrying the ε4 allele are at
an increased risk for developing AD. The occurrence of the APO
E ε4 allele did not influence age at onset in patients with early
onset of Alzheimer’s disease
This study confirmed that the APO E ε4 allele is a significant risk
factor for Alzheimer’s disease and for vascular dementia in the
Canadian population.
Sando et al
(2008)47
Alzheimer’s disease patients(n = 376 )
Yuek et al
(2004)67
Subjects with incident cognitive
impairment No dementia (CIND)
Incident Alzheimer’s disease
Incident Vascular dementia
CIND
CIND AD
CIND VaD
White European Alzheimer’s
Disease
(n=337)
(n=140)
(n= 51)
(n =85)
(n =70)
(n =9)
Patients
(n =285)
Males
(n =117)
Females
(n =168)
Age 71+ 7 yr
(n= 630)
Mean age
56.4+ 13.1 yr
Mooser
et al (2000)68
This study concluded that lipoprotein (a) was associated with an
increased risk for late-onset Alzheimer’s disease in carriers of the
ε4 allele that the non carriers of the ε4 allele
Luthra
et al(2002)59
Stroke patients from IndiaThe frequency of the ε4 allele and that of the genotypes ε3/ ε4 and
ε4/ ε4 were significantly higher in stroke subjects as compared to
controls subjects with the ε4 allele had a four-fold higher odds of
developing a stroke than those with the є 3 and є 2 alleles.
No significant association of alleles or genotypes with epilepsy
was observed in epileptic patients. The ε3 allele and ε3/ε3
genotype was commonest in cases and controls.
A higher frequency of APO E ε4 allele was observed in this study.
The presence of even one ε4 conferred a risk of developing both
AD and VaD.
Kumar et al
(2006)64
Temporal lobe epileptic cases(n=58)
Luthra et al
(2004)56
Cases of Alzheimer’s disease (AD)
and vascular dementia (VaD)
AD cases
( n=29)
Va D cases
(n=25)
368 INDIAN J MED RES, OCTOBER 2010

Page 7

risk of cardiovascular ailments such as myocardial
infarction, hypertension, coronary heart disease etc.
Lehtinen et al69 in their study on patients with clinically
proven coronary artery disease, observed increasing
plasma total and LDL cholesterol according to the
APO E phenotype in the order APO E3/2 < E3/3<E3/4
and E4/4. The study suggested that the ε4 allele affects
plasma cholesterol and LDL cholesterol levels and the
potential of developing severe coronary heart disease.

Risk Factor Intervention Trial (MRFIT) study70
observed a strong association of the ε4 allele and
coronary heart disease. Brscic et al70 observed APO E
polymorphism to be a strong independent predictor of
coronary heart disease in young Italian subjects. The
CARDIA study71 on African Americans and Whites
in the United States suggested that APO E phenotype
could be a risk factor for cardiovascular disease (CVD)
in both the populations, and association of CVD patients
with ε4 allele occurred more frequently as compared to
the controls. Certain studies have linked the ε4 allele
with a greater risk for coronary artery disease (CAD)
and myocardial infarction. In a case-control study72,
the frequency of homozygotes for the ε4 allele in men
aged less than 40 yr with clinical coronary angioplasty
was considerably higher than in healthy subjects. It was
observed that men with the ε4 allele have significantly
lower coronary event free survival rates than the carriers
of other apo E alleles72. In a five year longitudinal study
involving elderly Finnish men65, the ε4 allele frequency
was significantly higher in men with fatal myocardial
infarction that the survivors. A meta analysis of nine
case-control studies73 showed that the ε4 genotype
was more frequent among patients with ischaemic
cerebrovascular disease as compared to non-ischaemic
subjects. In a case-control study conducted by us
in north Indian patients with premature myocardial
infarction74, a significant association of APO E gene
polymorphism with coronary heart disease in Asian
Indians was observed. In a study on an unrelated
heterogeneous group of Indian subjects75, a higher
frequency of apo ε3 allele was observed similar to the
reports on the Mala community of southern India76.
Within the subjects with angiographically verified
CHD, the total cholesterol levels were significantly
elevated in apo ε4 carriers by 16 per cent as compared
to apo E3/3 carriers76. Lenzen et al77 reported that
60 per cent of patients having the E4/E3 genotype
suffered myocardial infarction before 60 yr of age
while this pattern was reversed in patients with the E3/
The Framingham Offspring Study and the Multiple
E2 genotype. Our study conducted on CHD patients
revealed apo ε3 as the most common allele in CHD
patients and in the normal subjects with the ε4 allele
frequency being comparable between the two groups78,
similar to the Caucasian population79 which reported a
significant decrease in the frequency of APO ε4 between
patients and controls, indicating a negative correlation
of apo E4 with the risk of myocardial infarction. Gerdes
et al80 examined the relation between apo E genotype
and a major coronary event or death in 966 Danish and
Finnish survivors of myocardial infarction enrolled
in the Scandinavian Simvastatin survival study. This
extensive follow up study concluded that myocardial
infarction survivors carrying the ε4 allele had an 80
per cent accelerated risk of death compared to other
patients. Further, it indicated that the APO E genotype
had no predictive value on a major nonfatal coronary
event.

Determinants in Cardiovascular disease) project, a
multi-national study sponsored by the World Health
Organization, monitors trends in cardiovascular mortality
and morbidity and assesses the relation of these trends to
changes in risk factor levels and/or medical care. The
project suggested that increase in the relative frequency
of ε4 allele increases the CHD death rate by 24.5 per
100,00081. Study conducted by Sing and Moll82 stated
that approximately six per cent of the variation in the
threat of CHD in North America can be attributed to apo
E. Studies from Finland, Scotland and Northern Ireland
have shown that populations with higher cholesterol
levels and higher CHD mortality rates also have a
higher frequency of ε4 allele83. The association between
apo ε2/2 genotype and type III hyperlipoproteinaemia
has been evidenced since a long time77. Overt type III
hyperlipoproteinaemia occurs at a frequency of 1-5 per
5000 whereas homozygosity for ε2/ε2 occurs with a
frequency of 0.5-1.0 per 100 in Caucasian populations83.
In general, the homozygous ε4/ε4 genotype is used to
determine the risk of coronary heart disease.
The MONICA (Monitoring of Trends and

is 2-3 times higher than the cholesterol raising
potential of ε4 allele. The ε2 allele lowers cholesterol
levels by approximately 14 mg/dl and ε4 raises it by
approximately 8 mg/dl. This effect is evident in most
populations, despite highly variable mean concentration
of cholesterol. The gene products of APO E seem to
function in a relatively uniform physiologic way in all
populations despite differences in genetic background,
diet and exercise patterns83.
The total cholesterol lowering effect of ε2 allele
ANOOP et al: APO E IN VASCULAR DISEASES 369

Page 8

plasma levels of apo E, cardiovascular risk factors and
mortality in a cohort of 561 inhabitants in a community
of Leiden, and reported that elderly individuals with
high plasma levels of apo E were at a higher risk of
cardiovascular mortality, irrespective of their APO E
genotype, lipid levels and other cardiovascular risk
factors. The apo E has proinflammatory properties
and thus contributes to cardiovascular disease. The
concomitant inflammatory response of apo E on
binding to lipid antigens adequately eliminates the lipid
antigen from the circulation. Thus high plasma levels
of apo E in combination with increased lipid-antigen
presentation lead to chronic inflammation and these
may contribute to arteriosclerosis77. They also found
that, as in other studies involving young populations,
APO E genotypes associate with plasma levels of apo
E. It is also reported that plasma apo E levels are highly
dependent on heritable factors84.
Mooijaart et al84 analyzed the relationship between

consistently been shown to be associated with variation
in plasma LDL cholesterol and apo B levels, with E4
having a greater influence that E3 and in turn, E3 having
a greater influence than E2 across a 10-15 per cent
range35. This effect is clinically important because high
levels of plasma LDL cholesterol is an indispensable
risk factor for cardiovascular disease especially CHD.
The genetically determined 5-7 per cent difference in
LDL cholesterol level from the reference (wild type)
E3/E3 genotype to carriers of either the ε4 (higher LDL-
cholesterol levels) or ε2 alleles (lower LDL cholesterol
levels) becomes even more important in light of the
fact that only approximately 50 per cent of individuals
in most populations have the ε3/ ε3 genotype, with the
remainder carrying at least one ε4 or ε2 allele31.
Over the past 25 years, apo E isoforms have

analysis of 48 studies on apolipoprotein E genotypes
and risk for coronary heart disease and found that
carriers of the apo ε4 allele had a higher risk for coronary
heart disease than the carriers of ε3/ε3 genotype. On
the contrary, no consistent association between the ε2
allele and CHD risk was observed85. However, these
data were observational and confounding biases might
have affected the pooled estimates. There are potential
chances of argument toward the fact that the true
genetic effects of APO E genotypes on CHD cannot be
quantified from any pooling or meta analysis of studies
with heterogeneous samples. This was answered by
using multiple sensitivity analysis which produced
consistent pooled estimates, although false-positive
Song et al85 conducted a comprehensive meta
findings were possible even in stratified analyses. To
sum up, this meta analysis supported the notion that the
ε4 allele is significantly related to an increased risk for
CHD while the ε2 allele has no effect84.

that APO E genotype modifies the effect of smoking
in CHD patients. Karvonen et al87 reported the
interaction between APO E genotype and smoking in
relation to cardiovascular disease. Their study included
hypertensive men and age-matched normotensive
controls who participated in the population based
OPERA. (Olulu Project Elucidating Risk of
Atherosclerosis project). In hypertensive men, there
was a significant interaction between presence of the ε4
allele and smoking in relation to mean carotid intima-
media thickness (IMT) whereas no effect of the ε4 allele
on carotid IMT was seen in hypertensive non-smokers.
The presence of ε4 was positively associated with mean
carotid IMT in hypertensive smokers, further IMT
increased with age in hypertensive smokers carrying
the ε4 allele but to a lesser extent in non-carrier, non-
smokers and normotensive subjects. The authors
suggested that the interaction between APO E genotype
and smoking can be due to the combined pro-oxidant
effects of smoking and the decreased protection against
oxidation has been attributed more to the ε4 allele that
the ε2 and ε3 allele.
Humphries et al86 published a report hypothesizing

identified that the ε3 allele and ε3/ ε3 genotypes were
most common in normal and angiographically diagnosed
CHD patients. Data from European populations
suggested that the low frequency of the apo ε4 allele
in Southern Europeans was partly responsible for the
low incidence and mortality of CHD in the southern
population compared to the northern populations90.
Lehtimaki et al91 conducted an extensive six year follow
up study on Finnish children and adults to analyse the
relationship of apo E phenotype and lipid metabolism.
Their results were similar to those of Ehnholm et al92
with a higher frequency of ε4 and a lower frequency of
ε2 alleles among the Finnish population. The relative
changes in serum total and LDL cholesterol during the
study period was highest in the subjects having the apo
E4/E2 phenotype. The mean concentrations of total
cholesterol, LDL cholesterol and apo B were highest
in the E4/4 homozygotes and the lowest concentrations
were observed in E2/2 homozygotic individuals92. Heide
et al93 investigated the role of APO E 3/4 and APO E 4/4
genotypes in premature coronary arteriosclerosis among
autopsy cases. In this study, no significant association
Studies conducted by Singh et al88,89 in Punjab, India,
370 INDIAN J MED RES, OCTOBER 2010

Page 9

of the apo E4 genotype and coronary heart disease was
observed both in healthy individuals and CHD patients
similar to the observations of Volcik et al94.

allele in normal BMI men with CHD than in healthy
controls. In this study, the normoweight CHD patients
Kolovou et al7 observed a low frequency of the ε4
had a lower frequency of ε2ε2, ε3ε3 genotypes and the
ε2 allele compared with healthy controls. Specifically,
the obese CHD patients had a higher ε4 allele frequency
when compared with the lean patients with CHD95. The
association of APO E polymorphisms with CVD in
populations worldwide is summarized in Table II.
Table II. Polymorphism in relation to coronary heart disease
ReferenceStudy population Sample sizeObservations/conclusion of the study
Song
et al (2004) 85
Comprehensive review of
literature from 1996-2004
15,492 CHD patients
and 32,965 controls
pooled form 48
studies
This extensive meta-analysis identified and elevated risk or about 42
per cent for coronary heart disease among carriers of ε4 allele compared
with carriers of the ε 3/3 genotype. It was concluded that the ε 4 allele
has an influential role in CHD but the ε2 allele has no effect.
Elousa
et al(2004)96
Offsprings and spouses of the
participants of Framingham
Heart Study
Sample size
(n=2723 )
Men ( n=1315)
Women (n=1408)
This meta analysis supports that the ε4 allele is significantly related
to an increased risk for CHD while the episilon 3 allele has no effect.
In men a significant association between the ε2 allele and carotid
stenosis was observed but an inverse association between ε2 allele
and carotid arteriosclerosis was observed in women.
Peter
et al(1994)97
Participants of the
Framingham Offspring Study
Subjects (n=2800)
Men (n=1034)
Women (n=916)
Age group 40-77 yr
The Framingham data for women show less prevalence of
hypertriglyceridaemia and no associations with ε2 or ε4 allele was
evidenced. The relative odds for prevalent CHD increased with the
ε4 allele in both sexes
Srinivasan
et al (2001)68
Residents of the Biracial
community of Bogulasa
(n = 1930)
Age=20
32 yr
Prevalence of hypertriglyceridaemia without high LDL cholesterol
increased in the order apo ε2 group>apo ε3 > apo ε4 group with the
obese apo ε2 group showing significantly higher rates that the non
obese counterparts.
Belkovets
et al (2001)99
Samples of the WHO
multinational program –
MONICA
Women (n=875)
Age group
25-65 yr
Siberian subjects with ε2 allele showed lower mean average total
cholesterol and HDL values as compared to those carrying ε3 and ε
4 alleles. ε4 allele carriers supporting the notion that ε4 reflects a
genetic susceptibility to cardiovascular diseases.
Anuuraad
et al (2006)100
Caucasian and African
American patients undergoing
coronary arteriography
(n =648)The African-Americans had a higher frequency of the ε2 alleles and
a significantly lower frequency of the ε3 allele as compared to the
Caucasians. Among African Americans, there was a stepwise increase
in Lp (a) levels from ε2 to ε3 to ε4 carries but not in Caucasians.
Stakias et al
(2006)101
Random sample of healthy
aged individuals
391 subjects
Males (n =194)
Females (n = 197)
Age >80 yr
The frequency of the ε4 allele was significantly less in healthy aged
to population based samples. The frequency of the ε2 allele was
not different between the groups but in aged individuals a lower
frequency of APO ε4 allele was observed in individuals older than
80 yr.
Seet et al
(2004)102
Malay Chinese and Indian
subjects from Malaysia
(n= 295)ε3/ε3 was the most common genotype in Malays, Chinese and
Indians. In the Chinese the ε3/ε3 genotype was followed by ε3/ε4
and ε2/ε3. A rare genotype ε2 / ε4 was found only in the Chinese.
Leiva et al
(2004)103
Adult diabetic patients form
Chile
Subjects (n=200)
Males
(n=96)
Females (n=104)
The Chilean diabetic patients with ε3/ε4 genotype had
hypercholesterolaemia. Subjects with ε2/ε3 genotype had
hypertriglyceridaemia though a statistical relationship between
dyslipidaemia and genotype could not be established.
Kim et al
(1993)104
Normal subjects
Diabetic patients
Myocardial infarction
(n =79)
(n = 79)
(n =44)
In this study, the frequencies of 2/E3, E3/E4 were high in
hyperlipidaemic cardiovascular disease patients. It strongly supports
the view that there is a certain relation between apo ε4 and the
development of hypercholesterolemia. Apo ε4 allele frequency was
high in cardiovascular disease patients.
ANOOP et al: APO E IN VASCULAR DISEASES 371
Contd...

Page 10

Pathophysiology of Apo E deficiency in mice

gene to be deleted in mice106,107. The beta VLDL
particles are major lipoproteins in apo E knockout
mice and the lipoprotein profile is believed to play a
causal role in the accelerated atherogenesis in animal
model studies of APO E108. A significant decrease in
the activity of choline acetyl transferase was observed
in the hippocampus and frontal cortex of the apo E
knockout mice compared to the wild type mice109. APO
E knockout mice showed defective spatial learning
and memory, when compared to controls110. Krugers
et al110 observed alterations in synaptic plasticity
in the hippocampal CAI of both homozygous and
heterozygous apo E mutant mice. Clusters of granules
were detected in the cytoplasm of protoplasmic
astrocytes in 18 month old APO E knockout mice
but not in age-matched wild mice. Studies have also
revealed significant reduction in synaptic and neuritic
markers accompanied by widespread vacuolization of
apical dendrites in apo E knockout mice111. In addition
to its effects on atherogenic processes, apo E may
substantially contribute to the regulation of antioxidant
systems47 and inflammatory pathways112.
The APO E gene was the first lipoprotein transport

E, in APO E knockout mice, significantly influenced
cholesterol metabolism similar to apo E deficiency/
abnormalities. The APO E knockout mice had four-
fold increased total plasma cholesterol levels and a
two-fold increase in plasma triglyceride levels similar
Mohammed et al113 observed that the absence of apo
to apo E deficient humans. Moreover, APO E knockout
mice also developed severe atherosclerotic lesions and
cutaneous xanthomatosis most likely due to extremely
high plasma cholesterol levels, diminished HDL
cholesterol and the presence of less anti- atherogenic
HDL particles. The life span of APO E deficient mice
was less than the wild strains due to abnormalities
in lipid metabolism and early brain dysfunction.
APO E knockout mice developed progressive skin
lesions, mainly in the form of eruptive xanthomas on
the shoulder and back regions. These mice also had
decreased HMG-CoA reductase enzyme activity along
with a 15 per cent increase in cholesterol content113,114.

deposits in the brain of 6 month old apo E knockout
mice. Further investigations by cross-breeding APO E
knockout mice with transgenic mice overexpressing
a human mutant amyloid precursor protein gene
(V717F) provided strong evidence that apo E is critical
for amyloid deposition and neuritic plaque formation
in mice. The brains of APO E knockout mice did not
show plaque or tangle like changes when treated with
antibodies against beta amyloid.
Bales et al115 observed absence of amyloid

the clearance of apopotic bodies in APO E knockout
mice. The study demonstrated that complete deficiency
of apo E protein in macrophages selectively attenuates
the ingestion of apoptopic cells in vitro, without
influencing the general phagocytosis function. This
defect resulted in a marked accumulation of apoptotic
David et al116 demonstrated the role of APO E in
Takashi
Miida
et al (1990)105
Coronary artery disease
patients
Subjects
n=125
Males
(n=101)
Females
(n= 24)
Age 58.0+7.2 yr
A higher incidence of E4 was observed in the CAD group than in the
controls and the Apo ε4 was associated with high LDL-Tc levels in
both sexes. A variant i.e. ε5/ε3 was observed in the male CAD group
and it is associated with coronary atherosclerosis.
Luthra
et al (2002)78
Angiographically proven CHD
patients from northern India
Subjects (n=52 )
males
Mean = 50.9 yr
This study identified apo ε3 as the most common allele in both CHD
patients and in normal subjects. A marginally low ε2 allele frequency
was observed in patients. On the other hand, the ε4 allele frequency
was found to be comparable between the two groups.
Kumar
et al (2003)74
North India patients with a
history of MI at <40 yr of age
(or) first episode of MI
at < 40 yr of age
Subject
(n= 45)
Patients
(n= 35)
A higher frequency of the apo ε4 allele and a lower frequency of the
apo ε3 allele were observed in patients of MI than in the controls.
Higher frequencies of genotype ε3/ε4 and ε4/ε4 and a lower
frequency of ε3/ε3 genotype were observed in myocardial infarction
patients than the controls.
Table II (Contd.). Polymorphism in relation to coronary heart disease
Reference Study populationSample size Observations/conclusion of the study
372 INDIAN J MED RES, OCTOBER 2010

Page 11

cells and fragments in a range of tissues in apo E
deficient mice in vivo and also in a larger population
of live macrophages in these tissues. This in turn, is
associated with a systemic increase in pro inflammatory
markers, including TNF alpha and fibrinogen. This
study further emphasized the systemic effect of apo E on
tissue macrophage recruitment which is independent of
lipoprotein recruitment and of lipoprotein metabolism,
resulting from impaired uptake of apotopic cell
remnants116.

deficient in apo E are more susceptible to endotoxaemia
and to Klebsiella pneumoniae infection than control
mice. In the apo E knockout mice, severe cytokinaemia,
in particular TNF alpha is most probably responsible for
death. These results are in accordance to those reported
by Roselaar and Daugherty118 who demonstrated that
apo E deficient mice are more susceptible to Listeria
monocytogenes. However, their results were in
marked contrast to those obtained by Mihai et al119
in hyperlipidaemic LDL receptor knockout mice that
had increased survival to challenge of Gram negative
bacteria and a hampered preinflammatory endotoxin.
The plasma of APO E knockout mice appeared to
have a low lipopolysaccharide (LPS) neutralizing
capacity, which was comparatively less than that
of normolipidaemic control mice. This study also
observed that in apo E deficient mice, TNF alpha plasma
concentrations were four to five fold higher than that
in controls after a challenge of bacterial LPS. It added
more evidence to the fact that the presence of apo E is
essential in the process of LPS detoxification, either
by catalyzing the binding of LPS to the lipoprotein
particle or by directing the LPS to the parenchymal
cells away from cytokine-producing kupffer cells or by
both mechanisms. Scavenger receptor class B Type I
Apo E double knockout mice that were fed on low-fat
chow rapidly develop coronary heart disease similar
to that of humans120. The simultaneous absence of
apo E and the LDL receptor SR-BI is responsible for
hypercholesterolaemic dyslipidaemia more severe than
that observed in a single gene knockout mouse.
de Bont et al117 showed that hyperlipidaemic mice

lymphocytes in the coronary heart disease of double
knockout mice (DKO) lacking B and T cells. Although
occlusive coronary atherosclerosis in DKO mice
appears to be the primary cause of coronary heart
disease and premature death, other mechanisms
could also contribute to its pathology. For instance,
immunoglobulin mediated inflammatory heart disease
Karackattu et al112 examined the role of
can cause murine myocardial infarction and death,
even in the absence of hypercholesterolaemia121. It was
observed that even when the immune infiltrate in the
damaged myocardium of DKO mice contained T cells,
there were apparently no differences in the occlusive
coronary atherosclerosis, myocardial infarction, cardiac
dysfunction and survival of DKO and T-cell knockout
mice. In DKO mice and APO E knock out mice fed
with a high fat, severe hypercholesterolaemia appeared
to eclipse the influence of B and T cell deficiency on
pathology. It was concluded that immunoglobulin-
mediated inflammatory heart disease is not a critical
mechanism influencing coronary heart disease in DKO
mice and B and T cells do not play a key role in the onset
or progression of disease in SR-BI/apo E knockout
mice122. Studies conducted on APO E deficient mice
and transgenic mice have aided in elucidating the role
of apo E and its isoforms in brain injury. It has also
been demonstrated that endogenous apo E helps to
protect the brain against acute brain injury. In APO E
deficient mice there is an increased susceptibility of
the brain to the effects of closed head injury123. APO E
knockout mice appear unable to respond to brain injury
with a surge in antioxidant compounds124. Increasing
evidence suggests that apo E influences the outcome
after brain injury by apo E isoform differences in
synaptic repair, remodeling and protection. The apo E4
isoform has a detrimental effect when compared with
the apo E3 isoform125. APO E genotype differences
have been studied in transgenic mice. Rodents have
only one APO E genotype, homologous to human APO
ε4. Insertion of human APO ε4 allele in mice has shown
that APO E mice have twice the hippocampal neuronal
damage after ischaemia than APO ε3 mice. APO ε4
mice have increased sensitivity to excitotoxic lesions
and age dependent neurodegeneration compared with
APO ε3 mice125.
Conclusions

as the undisputed leader of lipoprotein genetics114,126.
Several studies have demonstrated the impact of APO E
polymorphisms in cerebrovascular and cardiovascular
diseases in a reproducible fashion. The apo E isoforms
have consistently been shown to be associated with
variation in plasma LDL cholesterol and apo B level,
with the ε4 allele exerting a greater influence than
ε3. Apo E has consistently shown significant gene -
environment interactions modulating its association
with plasma lipid parameters as well as CVD risk125,127.
Genetic polymorphisms in apolipoprotein B and apo E
For decades, apolipoprotein E has been regarded
ANOOP et al: APO E IN VASCULAR DISEASES 373

Page 12

(APO B and APO E) have been studied for association
with plasma LDL cholesterol levels and of these,
only APO E polymorphisms have shown consistent
associations97,128,129. Several studies have established
the APO E ε4 allele as a risk allele for cardiovascular
diseases while others do not find any association. The
dual role of apo E remains enigmatic till date and needs
to be explored further in order to elucidate its precise
role in cardiovascular and cerebrovascular diseases.
Future prospects

consequences of APO E allele on children as compared
to that in adults. The APO E4 allele appears to have a
protective effect in brain development among children
perhaps through enhanced cholesterol absorption128.
Studies of APO E in children suggest differences in

to vital insights regarding individual variation and
response to neurological disease and injury as APO E is
a promising candidate gene. There are very few reports
from India on the implications of APO E in children.
The possible role of APO E in anxiety, abnormal
temperament, cognitive inhibitions and metabolic
disorders among children need to be investigated.
Future research of apo E in children may lead
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