APOE indicates apolipoprotein E.
APOE (apolipoprotein E) summary score assigned
+1, 0 or −1 risk units for each ε2, ε3, or ε4 allele
of an individual with genotype scores of the following: ε2/ε2,
+2; ε2/ε3, +1; ε2/ε4, 0; ε3/ε3, 0; ε3/ε4,
−1; and ε4/ε4, −2. Data adjusted for baseline age,
sex, race, diabetes, body mass index, coronary heart disease, antihypertensive
use, systolic and diastolic blood pressure, glomerular filtration rate (GFR),
high-density lipoprotein, low-density lipoprotein, and trigylcerides. There
were no significant interactions of APOE and chronic
kidney disease risk categories on disease progression (all P interaction >.05). To convert cholesterol to mmol/L, mutiply values
Hsu CC, Kao WHL, Coresh J, Pankow JS, Marsh-Manzi J, Boerwinkle E, Bray MS. Apolipoprotein E and Progression of Chronic Kidney Disease. JAMA. 2005;293(23):2892-2899. doi:10.1001/jama.293.23.2892
Author Affiliations: Department of Epidemiology,
The Welch Center for Prevention, Epidemiology, and Clinical Research, The
Johns Hopkins Medical Institutions, Baltimore, Md (Drs Hsu, Kao, Coresh, and
Marsh-Manzi); Division of Epidemiology and Community Health, University of
Minnesota School of Public Health, Minneapolis (Dr Pankow); and The Human
Genetics Center, University of Texas–Houston Health Science Center (Drs
Boerwinkle and Bray).
Context Apolipoprotein E (APOE) genetic variation has
been implicated in diabetic nephropathy with the ε2 allele increasing
and the ε4 allele decreasing risk. APOE allelic
associations with chronic kidney disease beyond diabetic nephropathy are unknown,
with no studies reported in high-risk African American populations.
Objective To quantify the risk of chronic kidney disease progression associated
with APOE in a population-based study including white,
African American, diabetic, and nondiabetic individuals.
Design, Setting, and Participants Prospective follow-up (through January 1, 2003) of Atherosclerosis Risk
in Communities (ARIC) study participants, including 3859 African American
and 10 661 white adults aged 45 to 64 years without severe renal dysfunction
at baseline in 1987-1989, sampled from 4 US communities.
Main Outcome Measures Incident chronic kidney disease progression, defined as hospitalization
or death with kidney disease or increase in serum creatinine level of 0.4
mg/dL (35 μmol/L) or more above baseline, examined by APOE genotypes and alleles.
Results During median follow-up of 14 years, chronic kidney disease progression
developed in 1060 individuals (incidence per 1000 person-years: 5.5 overall;
8.8 in African Americans and 4.4 in whites). Adjusting for major chronic kidney
disease risk factors, ε2 moderately increased and ε4 decreased
risk of disease progression (likelihood ratio test, P = .03).
Further adjustment for low- and high-density lipoprotein cholesterol and triglycerides
did not attenuate relative risks (RRs) (ε2: 1.08 [95% CI, 0.93-1.25]
and ε4: 0.85 [95% CI, 0.75-0.95] compared with ε3; likelihood
ratio test, P = .008). ε4 decreased
risk of end-stage renal disease (RR, 0.60 [95% CI, 0.43-0.84]). ε2 was
associated with a decline in renal function (RR, 1.25 [95% CI, 1.02-1.53]),
though not with events, such as hospitalizations or end-stage renal disease.
Risks were similar stratified by race, sex, diabetes, and hypertension (all P values for interaction >.05). Excess risk of chronic
kidney disease in African Americans was not explained by APOE alleles.
Conclusions APOE variation predicts chronic kidney disease
progression, independent of diabetes, race, lipid, and nonlipid risk factors.
Our study suggests that nonlipid-mediated pathways, such as cellular mechanisms
of kidney remodeling, may be involved in the association of APOE alleles and progression of chronic kidney disease.
Chronic kidney disease (CKD) is a significant public health concern
in the United States, particularly among African Americans whose disease risk
is 2 to 3 times that of whites.1 Chronic kidney
disease is a multifaceted disorder, with inherited components playing a role2 in addition to diabetes, hypertension, and dyslipidemia,
particularly high levels of triglycerides and low levels of high-density lipoprotein
(HDL) cholesterol.3,4 Heredity
may partially explain the excess risk in African Americans.2
Common variants (alleles ε2, ε3, and ε4) in the apolipoprotein
E gene (APOE) differentially modulate lipoprotein
metabolism, are expressed in the kidney,5 and
differ in frequency by race.6 Although the ε4
allele is a well-established risk factor for Alzheimer disease5,7 and
a weaker risk factor for coronary heart disease (CHD),8 increasing
evidence suggests a protective association with diabetic kidney disease.9 The ε2 allele is associated with type III hyperlipoproteinemia
and increased levels of triglycerides due to delayed clearance,5 both
associated with kidney disease.4,9 In
contrast, ε4 is associated with higher levels of HDL and lower levels
of triglycerides,5 a lipid profile that decreases
risk of CKD.4 Additionally, APOE may have isoform-specific effects on vascular smooth muscle10 and mesangial cell proliferation,11 which
may affect progression of CKD.
Several studies suggest that ε2 increases and ε4 decreases
risk of diabetic kidney disease. Previous studies have examined early (decline
in renal function/albuminuria) and late (hospitalizations, end-stage renal
disease [ESRD]) manifestations of kidney disease, with a focus on diabetic
individuals. Studies have been inconclusive due to small sample size, with
few prospective studies conducted. Additionally, magnitude of risk associated
with APOE alleles is uncertain and cannot be averaged
across studies due to the wide range of outcome definitions. Among statistically
significant findings, the directions of the associations were consistent in
all but 1 study.12 Carriers of ε2 were
more likely to have diabetic nephropathy (both types 1 and 2)13- 19 and
worse renal function20 in several small case-control
studies. On the other hand, among individuals with type 114 and
type 217,21 diabetes, ε4
carriers had better renal function and lower risk of diabetic nephropathy.
When late stages of kidney disease were examined, associations with ESRD demonstrated
a decreased risk among carriers of ε4,21- 23 and
1 study suggested increased risk with ε2.22 Thus,
allelic effects are in the same direction as APOE risk
associations with age-related maculopathy24 but
opposite in direction to those with CHD and Alzheimer disease.5,7
To date, there has been no investigation of APOE alleles
and CKD in a large population-based study of African Americans and whites;
furthermore, few studies have included persons without diabetes or examined
the mediating effects of lipids. With these considerations, we conducted a
prospective study of a community-based middle-aged cohort of 14 520 whites
and African Americans with the following objectives: to determine risk of
CKD progression associated with APOE alleles, to
investigate if risk is independent of lipid levels, and to determine if APOE alleles partially explain excess risk of CKD among
African Americans. Because the postulated role of APOE in
kidney remodeling and in modulating lipid clearance is in common pathways
of CKD progression, we hypothesized that the ε2 and ε4 alleles
would respectively increase and decrease risk of CKD progression, compared
with the ε3 allele, irrespective of kidney disease etiology. Because
African Americans have a higher frequency of the ε2 and ε4 alleles,
it was unclear if APOE variation would partially
explain the increased risk of CKD in African Americans.
The Atherosclerosis Risk in Communities (ARIC) study recruited 15 792
adults aged 45 to 64 years at baseline in 1987 through 1989 from 4 US communities:
Forsyth County, North Carolina; Jackson, Miss; suburbs of Minneapolis, Minn;
and Washington County, Maryland. Participants underwent 4 standardized examinations
approximately every 3 years, with the last visit ending in 1999.25 In
addition to yearly telephone interviews, hospitalizations and deaths were
ascertained and records abstracted as described previously, with most recent
follow-up to January 1, 2003.25 Institutional
review boards of participating institutions approved study protocols. Written
informed consent was obtained from participants at each examination. Of 4266
African Americans and 11 478 whites at baseline (N = 15 744),
1224 were excluded from this analysis: 587 without measurements of serum creatinine
or lipids at baseline, 40 with severe hypercreatinemia (creatinine ≥2.0
mg/dL [177 μmol/L] for men, ≥ 1.8 mg/dL [159 μmol/L] for women),26 42 with missing covariates, and 555 who refused use
of DNA for research or whose APOE genotype was missing
or unknown. There were no significant differences in frequency of APOE genotypes between our study cohort (N = 14 520)
and those excluded.
At each visit, demographic, anthropometric, and cardiovascular risk
factor data were collected.25 Racial affiliation
as African American or white was by self-report. Collection of fasting blood
samples and processing for creatinine, total cholesterol, triglycerides, HDL,
and low-density lipoprotein (LDL) are described in detail elsewhere, following
standard ARIC protocols.25 Triglyceride levels
were log transformed because of a skewed distribution. Hypertension was defined
as systolic blood pressure of 140 mm Hg or higher, diastolic blood pressure
of 90 mm Hg or higher, or use of antihypertensive medications. Diabetes mellitus
was defined as fasting glucose of 126 mg/dL (7 mmol/L) or higher, nonfasting
glucose of 200 mg/dL (11.1 mmol/L) or higher, or history/treatment of diabetes.
Prevalent CHD was defined as history of CHD revascularization procedures or
electrocardiogram evidence of myocardial infarction. Glomerular filtration
rate (GFR) was estimated from calibrated serum creatinine with the simplified
equation developed using Modification of Diet in Renal Disease Study27 data as follows:
GFR mL/min/1.73 m2 =186.3 × (Serum Creatinine)−1.154 × (Age)−0.203 ×
(0.742 if Female) × (1.21 if African American)
Genotyping of APOE polymorphisms coding for ε2
and ε4 were detected separately using the TaqMan assay (Applied Biosystems,
Foster City, Calif) as previously described28 and
completed in 2004 for the entire cohort. The κ statistic for 3666 replicates
Progression of CKD was defined as either an increase in creatinine of
at least 0.4 mg/dL (35 μmol/L) above baseline or a hospitalization (discharge
or death) coded for chronic renal disease (International
Classification of Diseases, Ninth Revision [ICD-9] codes 581-583 or 585-588), hypertensive renal disease (ICD-9 code 403), hypertensive heart and renal disease (ICD-9 code 404), unspecified disorder of kidney and ureter (ICD-9 code 593.9), diabetes with renal manifestations (ICD-9 code 250.4), kidney transplantation, renal dialysis, or adjustment/fitting
of catheter (ICD-9 codes V42.0, V45.1, or V56), hemodialysis
(ICD-9 code 39.95) or peritoneal dialysis (ICD-9 code 54.98), without acute renal failure (ICD-9 codes 584, 586, 788.9, and 958.5) as the primary or secondary
hospitalization code. Serum creatinine was measured at baseline and at the
3-year (University of Minnesota) and 9-year (ARIC central laboratory, Houston)
follow-up visits using a modified kinetic Jaffe method.25,29 Serum
creatinine measurements were corrected for interlaboratory differences and
calibrated indirectly to the Cleveland Clinic measurement standards. Assessment
of short-term variability within ARIC participants revealed that 0.18 mg/dL
(16 μmol/L) was the minimal change in creatinine at which 95% confidence
existed that a true change had occurred (methodological variability, SD = 0.05
mg/dL [4.4 μmol/L]; and within-person variability, SD = 0.04
mg/dL [3.5 μmol/L]).29 An increase in serum
creatinine was defined as a change of at least twice this amount (0.4 mg/dL
[35 μmol/L]) as in previous analyses.1,4 Ancillary
analyses compared association with CKD hospitalization and creatinine increase
as separate outcomes as well as alternative definitions of CKD.
Differences in baseline characteristics by race and CKD progression
were assessed using t and χ2 tests.
Primary analysis evaluated associations of APOE variation
with time to CKD progression, defined as time to the visit date at which the
increase in serum creatinine occurred (creatinine-based CKD cases), date of
hospitalization discharge or death date (hospitalization-based CKD cases),
or the earlier of the date of last contact or January 1, 2003 (for noncases).
Proportional hazards models were constructed to examine APOE variation as an independent predictor of CKD progression. Race-stratified
analyses and assessments of interaction with race were performed. To determine
excess risk of CKD in African Americans explained by APOE, the relative risk (RR) of CKD associated with race was compared in
multivariate models with and without APOE. APOE variation was modeled as an additive model with number
of ε2 and ε4 alleles and as an APOE summary
score model. APOE alleles appear additive in effect
in lipid modulation and in Alzheimer disease.5,7 Effects
of APOE were also examined by genotype, with similar
results (not shown). Because previous literature suggested that ε4 conferred
protection while ε2 increased risk, a genotypic scoring system was devised
that respectively assigned +1, 0, or −1 per ε2, ε3, or ε4
allele of an individual with genotypes (and scores) of: ε2/ε2
(+2), ε2/ε3(+1), ε2/ε4(0), ε3/ε3 (0), ε3/ε4
(−1), ε4/ε4 (−2). Summary scores have been demonstrated
to increase power in modeling genetic exposures.30
Variables thought to influence CKD risk were chosen as baseline covariates:
sex, age, race, body mass index (BMI), diabetes mellitus, blood pressure,
antihypertensive medication use, CHD history, GFR, total cholesterol, LDL,
HDL, and log-transformed triglycerides. The likelihood ratio test was used
to evaluate combined significance of APOE ε2
and ε4 terms in predicting risk in multivariate models and to assess
significance of interaction terms. To verify consistency across high-risk
subgroups, we also stratified by diabetes, hypertension, hypercholesterolemia
(cholesterol ≥240 mg/dL [6.2 mmol/L]), and subnormal baseline kidney function
(GFR <90 mL/min/1.73m2). Cross-sectional analyses of APOE and macroalbuminuria (albumin-to-creatinine ratio ≥300 μg/mg)
at visit 4 used logistic regression methods, using STATA statistical software
version 8 (STATA Inc, College Station, Tex). A P value
of <.05 was considered statistically significant.
Table 1 summarizes baseline characteristics
by race and incident CKD progression status of participants without severe
baseline kidney dysfunction. Chronic kidney disease risk factors were predominantly
worse in African Americans, with more prevalent diabetes mellitus and hypertension.
However, African Americans had better baseline GFR and comparable lipid profiles
compared with whites. Persons who had incident CKD progression were older,
more likely to be men or African American; to have a history of diabetes,
hypertension, or CHD; to have lower GFR and HDL levels; and to have higher
BMI, total cholesterol, triglycerides, and LDL levels. Genotypic frequencies
for African Americans and whites were consistent with previously published
estimates,6 and APOE variation
was in Hardy-Weinberg equilibrium in each racial group. When combined, the
3 common genotypes—ε2/ε3, ε3/ε3, and ε4/ε3—constituted
93.4% of all participants; 89.3% of African Americans and 94.9% of whites.
During a median follow-up of 14 years, CKD progression developed in
1060 individuals (incidence rates per 1000 person-years: 5.5 overall; 8.8
in African Americans and 4.4 in whites). Of cases, 55.7% were hospitalized
or died with a CKD diagnosis code (n = 590), 27.9% were identified
by an increase in serum creatinine (n = 296), and 16.4% were established
by both criteria (n = 174). Consistent with the hypothesis of increased
CKD risk for ε2 and decreased risk for ε4, cases of CKD progression
tended to have greater frequency of ε2 and a lower frequency of ε4
compared with cases without progression (ε2: 9.7% vs 8.8%; ε4:
15.8% vs 16.8%; χ2P value = .24),
particularly among cases identified by an increase in serum creatinine (n = 470
cases; ε2: 11.7% vs 8.8%; ε4: 16.1% vs 16.8%; χ2P value = .007).
APOE genotype–specific incidence rates
of CKD progression (Figure 1) suggest
a dose-response relationship in African Americans (P for
trend = .11). With ε3/ε3 as the reference, the incidence
rate increased with the number of ε2 alleles and decreased with the
number of ε4 alleles. The relationship was less significant in whites
(P for trend = .26 for all genotypes and .08
for the common genotypes ε2/ε3, ε3/ε3, and ε4/ε3). APOE genotype–specific incidence rates of CKD progression
identified by an increase in serum creatinine were also similar, and the dose-response
relationship was more evident in African Americans (P for
trend = .02).
Risk of CKD progression for African Americans was 2.31 (95% CI, 2.04-2.61)
times that of whites, after adjustment for age and sex. Further inclusion
of APOE in the model showed that it did not explain
the excess risk of CKD in African Americans (APOE-adjusted
RR, 2.36; 95% CI, 2.09-2.68). There were no differential effects of APOE variation by race. Race-stratified analyses demonstrated
that effects of APOE alleles on CKD progression were
slightly stronger in African Americans but not significantly different by
racial group (Table 2; P for interaction = .27). Therefore, analyses were performed
in the full cohort, adjusting for race.
Multivariate analysis of APOE alleles and CKD
progression among all participants were consistent with race-stratified findings
(Table 2). ε2 increased risk by
1.04 (95% CI, 0.90-1.20) and ε4 decreased risk by 0.85 (95% CI, 0.75-0.96),
independent of age, sex, and race (likelihood ratio test, P = .02). In model 2, ε2 conferred risk (RR, 1.07;
95% CI, 0.93-1.24) and ε4 was protective (RR, 0.87; 95% CI, 0.77-0.98),
independent of major CKD risk factors (likelihood ratio test, P = .03) including hypertension and diabetes. Similar results
were shown by the APOE summary score, with increasing
scores (ie, more ε2 and fewer ε4 alleles) associated with higher
risk of CKD progression (P<.01).
To examine lipid-independent effects of APOE,
we assessed models adjusting only for lipid level (total cholesterol, HDL,
LDL, or triglycerides) singly or in combination; the findings were comparable
(results not shown). Independent of both major CKD risk factors and lipids
(model 3), ε2 increased risk of CKD progression without reaching statistical
significance by 1.08 (95% CI, 0.93-1.25) and ε4 decreased risk in a
statistically significant manner by 0.85 (95% CI, 0.75-0.95) compared with ε3
(likelihood ratio test, P = .008). The
association between APOE alleles and CKD progression
was consistent across race and risk groups (Figure
2), and no interactions between APOE and
high-risk subgroups were significant (all P values
for interaction >.05). The association of APOE with
CKD risk was statistically significant in nondiabetic individuals (P = .002) while it was not in those with type 2 diabetes.
However, a test of interaction was not significant (P = .20).
Similarly, association between APOE and CKD progression
appeared stronger among individuals with an estimated baseline GFR of less
than 90 mL/min/1.73m2 (RR, 1.19; 95% CI, 1.06-1.33), but this could
be due to random variation as well (P for interaction = .29).
The association of APOE and CKD was robust
across several definitions of CKD progression (including those defined by
serum creatinine, GFR, and urine albumin), though the data suggested that
the association of ε4 was evident for both early (increase in serum
creatinine, change in GFR) and late (hospitalization, ESRD, and death) manifestations
of kidney disease, whereas the association with ε2 was stronger with
early manifestations of kidney disease. For an increase in serum creatinine
of at least 0.4 mg/dL (35 μmol/L), ε2 increased risk by 1.25 (95%
CI, 1.02-1.53) and ε4 decreased risk by 0.84 (95% CI, 0.70-1.01). For
a hospitalization or death with CKD or ESRD, in the fully adjusted model ε2
increased risk by only 1.03 (95% CI, 0.87-1.23) and ε4 decreased risk
by 0.83 (95% CI, 0.71-0.95). Per unit increase in the APOE summary score, RR was 1.21 (95% CI, 1.07-1.38) for an increase in
serum creatinine and 1.13 (95% CI, 1.02-1.26) for hospitalization or death
Results were also similar when we examined the incidence of moderately
decreased kidney function (GFR <60 mL/min/1.73 m2) instead of
an increase in serum creatinine. Individuals with moderately decreased kidney
function at baseline were less likely to carry the ε4 allele (odds ratio,
0.77; 95% CI, 0.63-0.94). For incidence of decreased kidney function during
follow-up, ε2 increased risk by 1.06 (95% CI, 0.91-1.23) and ε4
decreased risk by 0.86 (95% CI, 0.76-0.97) with APOE alleles
significantly associated (likelihood ratio test, P = .03).
Per unit increase in the APOE summary score, the
RR was 1.12 (95% CI, 1.03-1.23).
The RR of the APOE summary score for a hospitalization
with an ESRD code was similar as well, and it was statistically significant
after adjustment for demographics and nonlipid risk factors (RR, 1.29; 95%
CI, 1.05-1.59). In this analysis, the protective effect for ε4 on subsequent
ESRD was stronger (RR, 0.60; 95% CI, 0.43-0.84) than for CKD progression in
general, while the excess risk with ε2 was not observed (RR, 0.97; 95%
CI, 0.68-1.38), but the number of ESRD cases was relatively small (n = 175).
Finally, quantitative data on albuminuria was available only at the
last study visit. Using logistic regression, associations with prevalence
of macroalbuminuria (odds ratios: APOE ε2,
1.20 [95% CI, 0.84-1.71]; ε4, 0.96 [95% CI, 0.71-1.31]; summary score:
1.10 [95% CI, 0.89-1.38]) were similar to those of the creatinine-based outcome
but nonsignificant in this limited cross-sectional examination of albuminuria.
An alternative explanation for the inverse association seen with APOE and CKD could be that it is an artifact due to a survival
effect. Specifically, individuals with ε4 may be lost to follow-up at
a higher rate due to vascular events and mortality, thus artificially increasing
CKD incidence in those with the ε2 allele. However, in this cohort,
loss to follow-up did not differ by APOE genotype
(P = .63 among African Americans, P = .83 among whites). Although ε4 may
lead to increased mortality, this association was very weak in this cohort
and could not account for the observed protective association with CKD. During
follow-up, there were 2083 deaths in our cohort. When we examined the effect
of APOE on CKD only among the 2083 mortality events,
the adjusted effect of ε4 on CKD (n = 414 cases) was similar
to that seen in the entire cohort (RRs, 0.85 and 0.85, respectively).
APOE allelic variation is a risk factor for
CKD progression in the general US adult population but does not explain the
excess risk of CKD in African Americans. Risk is lower for those with the ε4
allele and may increase with ε2, consistent with previous diabetic nephropathy
studies, and the risk is of comparable magnitude but in the opposite direction
to the association of APOE with CHD. The APOE association with CKD progression is not explained by established
CKD risk factors, including diabetes and hypertension. Furthermore, the CKD
risk association with APOE alleles is not directly
mediated through lipid levels. Additionally, the relationship between APOE and CKD risk is not an artifact due to the association
of APOE with serum lipid levels, vascular events,
To our knowledge, this is one of the first large population-based prospective
studies of the association between APOE and CKD progression.
Our results confirm a recent cross-sectional study of 158 type 2 diabetic
patients (51 overt nephropathy cases) that found increased risk with ε2
(odds ratio, 10.2 [95% CI, 1.18-87.93]) and protection with ε4
(odds ratio, 0.13 [95% CI, 0.03-0.49]).17 Notably,
our results are more conservative, consistent with findings that larger prospective
studies such as ours produce results of smaller magnitude with greater precision
compared with those of smaller studies.31 A
few studies demonstrated no significant association between APOE alleles and diabetic kidney disease,32- 35 but
positive studies consistently find ε2 to be a risk factor13- 20,22 and ε4
to be protective.14,17,21- 23 Although ε4
has “traditionally” been seen as a risk allele due to associations
with CHD8 and Alzheimer disease,6,7 our
findings of ε4 as protective for CKD progression are consistent with
the literature. Similar to previous studies, our results demonstrate ε2
to increase risk of early manifestations of kidney disease (increases in serum
creatinine and a trend for macroalbuminuria) with little risk of CKD hospitalization
and ESRD, whereas ε4 is associated with a lower risk of both early and
late manifestations of kidney disease. No study of diabetic kidney disease
has demonstrated that the ε4 allele increases risk.
This is the only study of APOE and CKD in African
Americans, a population at particularly high risk of kidney disease. The APOE and CKD association is not weaker in African Americans,
in further contrast to the Alzheimer disease association.36 This
study of APOE and kidney disease has the largest
sample to date, which afforded more precise estimates of the effect of APOE on CKD progression and a detailed analysis examining
alleles, genotypes, and subgroups not possible in smaller studies.
The prevailing explanation for the association between APOE and diabetic nephropathy focuses on its lipid transport role,
with subsequent effects on renal function.17 Glomerulosclerosis
and atherosclerosis may share similar pathophysiologic parameters in progression.37 Triglyceride-rich lipoproteins initiate glomerular
injury in experimental studies38 and in this
APOE variation may affect CKD progression through
2 different pathways: modulation of circulating lipid levels and separately
through nonlipid mechanisms, such as a direct effect on kidney remodeling.
The influence of APOE could extend beyond lipid effects,
as with ε4, β-amyloid, and Alzheimer disease.39APOE is expressed in the kidney,5 and
its isoforms differentially inhibit mesangial cell proliferation through induction
of matrix heparan sulfate proteoglycan (HSPG).11 ε2
possesses the least competent antiproliferative effect. Additionally, among
patients with IgA nephropathy, more severe histological damage has been associated
with the ε2 allele.40 The role of ε2
on renal remodeling merits further study.
Our results corroborate findings that ε4 protects persons with
diabetes from progressing to ESRD.21 The ε4
allele is associated with higher levels of HDL and lower levels of triglycerides,5 a lipid profile that decreases risk of CKD.4 In addition, the protein produced by ε4 shows
far less intracellular accumulation than that of ε2 or ε3.41 Perhaps higher extracellular levels of the ε4
protein can hinder the cycle of further renal tissue deterioration through
induction of matrix HSPG. The relationship of APOE and
CKD mirrors that of APOE and age-related maculopathy
in which ε4 also demonstrates a protective effect while ε2 increases
This study has several limitations. Because CKD is heterogeneous, the
influence of APOE on specific kidney disease etiologies
may not be directly inferred. However, the degree of sensitivity afforded
by our definition provides sufficient power to examine the disease in a longitudinal,
community-based setting that demonstrates that APOE affects
overall CKD risk, not just hypertensive or diabetic kidney disease. While
creatinine-based definitions of CKD progression can be insensitive, they should
be specific and show the expected association with traditional risk factors.4 Additionally, the relationship of APOE with CKD is consistent across the various renal disease outcomes
examined in our subsidiary analyses. Hospitalization or death with a CKD diagnosis
code does not allow for quantification of the amount of kidney disease progression.
However, among individuals without hypercreatinemia at baseline, such a diagnosis
likely denotes a substantial increase in serum creatinine. Treating these
events as outcomes also decreases bias due to censoring, since sick individuals
are less likely to return for a subsequent clinic visit.
Another limitation is that the APOE and CKD
association could be due to differential losses to follow-up by genotype,
specifically due to increased mortality and nonrenal vascular events associated
with the ε4 allele. However, the association with CKD was neither due
to genotype-specific losses to follow-up, nor could it be explained by increased
CHD risk among those with ε4. The magnitude of the association cannot
be compared directly with previous studies due to variation in design and
outcome definition. However, whenever an association of APOE alleles with CKD was found, directions have been remarkably consistent.
Finally, the use of the APOE summary score may be
oversimplifying. This score assumes a codominant model with opposite but equal
effects for ε2 and ε4, which is supported by the data in this
study, and provides a more powerful test of the overall impact of APOE genetic variation. However, the power to test deviations from
these assumptions, particularly for rare genotypes such as ε2/ε2, ε2/ε4,
and ε4/ε4, is limited. In our study, risk associated with ε2/ε4
is least certain, but exclusion of this genotype had no impact on our results.
In summary, APOE variation affects CKD progression,
independent of major CKD risk factors and independent of the well-described
effect of APOE variation on serum cholesterol and
triglycerides. The modest size of the risk associated with APOE variation limits utility for screening, risk stratification, and
individualized therapy. However, if multiple genes of small and moderate effect
on CKD are identified, they may compose panels for risk assessment. Consistency
of the finding across participants with and without diabetes and hypertension
supports the hypothesis that much of CKD is multifactorial with common pathways
across different diagnostic settings. Studying the pathways mediating this
association, which has consistently been in the opposite direction to the
CHD and Alzheimer disease associations, may shed light on novel pathways and
therapeutic targets in the pathophysiology of CKD.
Corresponding Author: Josef Coresh, MD,
PhD, Welch Center for Prevention, Epidemiology, and Clinical Research, The
Johns Hopkins Medical Institutions, 2024 E Monument St, Suite 2-600, Baltimore,
MD 21205-2223 (email@example.com).
Author Contributions: Dr Coresh had full access
to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: Hsu, Kao, Coresh.
Acquisition of data: Coresh, Boerwinkle, Bray.
Analysis and interpretation of data: Hsu, Kao,
Coresh, Pankow, Marsh-Manzi.
Drafting of the manuscript: Hsu.
Critical revision of the manuscript for important
intellectual content: Hsu, Kao, Coresh, Pankow, Marsh-Manzi, Boerwinkle,
Statistical analysis: Hsu, Kao, Marsh-Manzi.
Obtained funding: Hsu, Coresh, Marsh-Manzi,
Administrative, technical, or material support:
Kao, Coresh, Pankow, Boerwinkle, Bray.
Study supervision: Kao, Coresh.
Financial Disclosures: None reported.
Funding/Support: The Atherosclerosis Risk in
Communities Study was supported by contracts N01-HC-55015, N01-HC-55016, N01-HC-55018,
N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022 with the National
Heart, Lung, and Blood Institute. This work was also supported by National
Institutes of Health grant HL73366 and the Centers for Disease Control and
Prevention grant UR6/CCU617218 (Dr Bray), grant 5T32HL007024 (Dr Marsh-Manzi),
the Medical Scientist Training Program (Dr Hsu), the American Diabetes Association
Medical Scholars Award (Dr Hsu), and the American Heart Association Established
Investigator Award 01-4019-7N (Dr Coresh).
Role of the Sponsors: Except NHLBI input through
the ARIC contract, the organizations funding this study had no role in the
design and conduct of this study; the analysis and interpretation of the data;
or the preparation, review, or approval of the manuscript.
Acknowledgment: We are indebted to the staff
and participants in the Atherosclerosis Risk in Communities Study for their