Med. Surg. J. – Rev. Med. Chir. Soc. Med. Nat., Iaşi 2021, 126(1): 42-50 doi: 10.22551/MSJ.2022.01.

06

INTERNAL MEDICINE - PEDIATRICS ORIGINAL PAPERS

IMPACT OF APOE POLYMORPHISM IN A FAMILIAL

HYPERCHOLESTEROLEMIA POPULATION

Alexandra Maștaleru 1,4, Maria Magdalena Leon Constantin 1,4*, Andra Oancea 1,4 ,
Elena Cojocaru 2, Cristina Rusu 3, Roxana Popescu 3, M. Roca1,4, Irina Abdulan 1,
Diana Apopei 3, Simona Mititelu3, A. Costache 1,4, F. Mitu1,4
“Grigore T Popa” University of Medicine and Pharmacy Iasi
Faculty of Medicine
1. Department of Medical Specialties (I)
2. Department of Morpho-functional Sciences (I)
3. Department of Medical Genetics
4. Clinical Rehabilitation Hospital, Iasi, Romania
*
Corresponding author: e-mail: leon_mariamagdalena@yahoo.com

IMPACT OF APOE POLYMORPHISM IN A FAMILIAL HYPERCHOLESTEROLEMIA

POPULATION (Abstract): Familial hypercholesterolemia is a genetic disease caused by a
mutation in one of the genes implied in the low-density lipoprotein (LDL) catabolism, lead-
ing to increased seric values of LDL and a very high cardiovascular risk. ApoE is a ligand
for the LDL receptor and the polymorphisms at the level of ApoE will alter the lipid profile.
Material and methods: A cross-sectional study was conducted in the Cardiovascular Reha-
bilitation Clinic from Iasi Clinical Rehabilitation Hospital between December 1 st, 2020, and
December 1 st, 2021, including 52 patients with familial hypercholesterolemia in the study
group and 17 patients in the control group. Results: In our research, the patients with Ap-
oE4/E4 had the highest lipid profile concentrations. Statistical significance was observed b e-
tween ApoE2/E3 and ApoE3/E3, ApoE3/E4 and Apo E4/E4 and between ApoE3/E3 and Ap-
oE4/E4 regarding the creatinine clearance in the familial hypercholesterolemia group. In the
same group, statistical significance correlations were observed between ApoE3/E3 and A p-
oE3/E4 for triglycerides concentration, between ApoE3/E3 and ApoE4/E4 for the glycosyl-
ated hemoglobin. Conclusions: For a better understanding of the genetic and environmental
factors in patients with familial hypercholesterolemia, larger studies are needed, in order to
increase their quality of life. Keywords: FAMILIAL HYPERCHOLESTEROLEMIA, AP-
OE, LIPID PROFILE, CARDIO-VASCULAR DISEASE, CREATININE CLEARANCE.

Familial hypercholesterolemia is a ge- part of the gene network involved in famil-

netic disease of the metabolism of lipopro-
teins, causing high levels of low-density
lipoproteins (LDL). The loss of function
mutations in LDLR, APOB, or PCSK9
genes can lead to homozygous or heterozy-
gous familial hypercholesterolemia. Rela-
tively recent research identified APOE as
ial hypercholesterolemia (1, 2). The elevat-
ed serum LDL-C induced by any of these
mutations promotes atherosclerosis and
cardiovascular disease, putting these indi-
viduals at a tenfold increased risk of coro-
nary artery disease compared to those
without FH. Clinical scoring systems for

42
 Impact of ApoE polymorphism in a familial hypercholesterolemia population
the diagnosis of FH are widely used and
approved, and numerous sets of criteria
have been created, encompassing clinical,
biochemical, and genetic factors. The most
commonly used criteria are Simon Broome,
MedPed and Dutch Lipid Clinic Network
(DLCN), the last one being used predomi-
nantly in the European countries (3, 4).
ApoE is a component of chylomicrons,
very-low-density lipoproteins (VLDL),
intermediate-density lipoproteins (IDL),
LDL, high-density lipoproteins (HDL), and
lipoprotein a (LPa). ApoE regulates the
clearance of these lipoproteins from the
plasma and the homeostasis of tissue lipid
content as a ligand for cell membrane lipo-
protein receptors. ApoE is also involved in
the catabolism of VLDL particles, inhibits
lipoprotein lipase and the triglyceride-rich
lipoprotein lipolysis, but may also increase
the hepatic production of VLDL by activat-
ing the particle assembly cascade. All these
data support the involvement of a dysfunc-
tional apoE in the etiology of dyslipidemia
(5).
The APOE gene is located on 19q13.2
and encodes for a precursor that follows
peptide cleavage and glycosylation, result-
ing in mature apoE that is secreted as a 299
amino acid protein with a relative molecu-
lar mass of 34,200 kDa. According to cur-
rent literature, one of the main factors af-
fecting the lipid profile levels are ApoE
polymorphisms. ApoE2, ApoE3 and ApoE4
are the protein isoforms that are encoded
by the most frequent alleles (ε2, ε3, and
ε4). Among the population, six phenotypes
can be observed: E2/2, E3/2, E3/3, E4/2,
E4/3, and E4/4, each of them with different
prevalence. Up to date, it is known that the
ε2 allele determines a reduction of the cho-
lesterol absorption and also a decrease of
the LDL cholesterol values compared to ε4
allele which correlates with high serum
cholesterol levels (6, 7). Moreover, the
association between dyslipidemia and
chronic kidney disease, to be correlated
with apoE isoforms, suggesting the im-
portance of apoE polymorphisms study for
an accurate prognosis and management
plan (8).
MATERIAL AND METHODS
A cross-sectional study was conducted
in the Cardiovascular Rehabilitation Clinic
from Iasi Clinical Rehabilitation Hospital
between December 1 st, 2020, and Decem-
ber 1 st, 2021. From the 1,499 patients that
were admitted in this period, only 52 adults
were included in the study. Inclusion selec-
tion consisted of patients diagnosed with
familial hypercholesterolemia with a
DLCN score over 8 that signed the in-
formed consent. Exclusion criteria were
considered secondary causes of hypercho-
lesterolemia such as patients diagnosed
with severe liver diseases, hypothyroidism,
severe chronic kidney disease or nephrotic
syndrome, uncontrolled diabetes mellitus
or patients that eat meals with high concen-
trations of saturated and trans-unsaturated
fatty acids. The 52 patients were compared
to a control group that included 17 adult
patients with normal lipid profile who
signed the informed consent.
The participants in the study group had
a clinical diagnosis of FH, as determined
by a DLCN score greater than 8, and were
included in the study. A score below 3
points is considered improbable, between 3
and 5 is possible, probable between 6 and 8
points, and more than 8 is considered as a
definite clinical diagnosis for familial hy-
percholesterolemia. One of the criteria used
in the diagnosis score is the LDL value,
which was adjusted for the patients who
43
 Alexandra Maștaleru et al.
underwent in the last 6 months treatment
with statins or ezetimibe. This correction
factor was described by Haralambos et al.
based on a review of 71 original papers
gathered prior to the establishment of FH
criteria.
A single investigator conducted the an-
amnesis and physical examination, record-
ing the patients’ medical history, body
mass index, blood pressure, and heart rate
as well as the drug history (including the
lipid-lowering therapy and antiaggregant
drugs). Regarding the laboratory tests, we
included the lipid profile (total cholesterol,
LDL, HDL, triglycerides), uric acid, urea,
creatinine, blood glucose, and glycated
hemoglobin.
DNA was prepared from peripheral
blood cells using PureLink ® Genomic DNA
Kit (Thermo Fisher Scientific). We evalu-
ated relevant mutations in PAI-1 (4G/5G),
MTHFR (C677T, A1298C), ACE I/D,
apolipoprotein B (R3500Q), and apolipo-
protein E (Apo E) E2/E3/E4 by reverse-
hybridization using CVD StripAssay kit
(ViennaLab Diagnostics, Vienna, Austria).
After PCR amplification with biotinyl-
ated primers, PCR products were hybrid-
ized directly on the StripAssay ® test strips,
which contain allele-specific oligonucleo-
tide probes immobilized as parallel lines.
The presence of a wild type or/and mutant
alleles was visualized by an enzymatic
color reaction visible on the strip.
Positively stained lines were analyzed
using the online tool StripAssay ® Online
Calculator (ViennaLab Diagnostics) and
for each targeted gene were identified un-
derlying genotypes.
The informed consent was collected
from all the patients included in the study
and the ethics committee approval was
obtained from both “Grigore T. Popa” Uni-
44
versity of Medicine and Pharmacy Iasi
(certificate of approval dated 15 th June
2020) and Iasi Clinical Rehabilitation Hos-
pital (certificate of approval dated 25 th
November 2020).
The data analysis was realized using
SPSS 20.0 (Statistical Package for the So-
cial Sciences, Chicago, Illinois). For con-
tinuous variables, the data were presented
as median with interquartile range or as
mean±standard deviation (SD). For cate-
gorical variables, the data were presented
as the number of cases with percent fre-
quency. Continuous normally distributed
variables were compared by Independent
Samples t-Test in case of two samples, or
by One-Way ANOVA, in case of compari-
sons of more than two samples. Categorical
comparisons were performed by Fisher's
exact test or by Chi-square test. In the cas-
es where the distribution of the continuous
variables didn’t satisfy the assumption of
normality, we applied the Mann-Whitney U
test. Spearman correlation coefficient was
calculated when evaluating the correlations
between continuous variables. A statistical
significance was considered at a two-sided
p-value < 0.05.
RESULTS
In this research were enrolled 52 pa-
tients that were clinically diagnosed with
familial hypercholesterolemia and 17
healthy controls. More than half of the
included patients were females (63.5%),
with a mean age of 55.5±12.8. Regarding
the males, they had a lower mean age of
detection 38.88±11.72. Regarding educa-
tion, most of the patients finished universi-
ty studies (38.5% from the FH group and
70.5% from the control group) followed by
patients that have a bachelor’s degree
(34.6% vs. 11.8%). The patients included
 Impact of ApoE polymorphism in a familial hypercholesterolemia population

were predominantly married (78.8% from
the FH group and 58.8% from the control
group). When compared to the control
group, the patients diagnosed with FH had
more associated pathologies such as ather-
osclerosis, heart failure, metabolic syn-
drome, or chronic kidney disease. The first
table summarize the general characteristics
of the patients included in the study.
Apo E3/E3 was the most frequent gen-
otype observed in our study in both groups
(80.8% in the FH group and 64.7% in the
control group), followed by Apo E3/E4
form (9.6% in the FH group and 0% in the
control group). Apo E2/E3 had a lower
frequency (5.8% in the FH group and
23.5% in the control group) and Apo
E4/E4 had the lowest frequency (3.8% in
the FH group and 11.8% in the control
group).

TABLE I.
General characteristics of the patients included in the study
Patients characteristics FH Controls p value
Gender, n (%) Females 33 (63.5) 11 (64.7) 0.927
Gender, n (%) Males 19 (36.5) 6 (35.3)
Age, years (mean±SD) 55.5±12.80 38.88±11.72 0.000
BMI , kg/m2 (mean±SD) 28.71±5.22 23.99±5.89 0.003
Lipidic profile, mg/dL (mean±SD)
Total cholesterol 286.93±55.10 207.24±42.15 0.000
HDL cholesterol 58.52±17.51 46.34±11.12 0.009
Non-HDL cholesterol 228.40±57.52 160.90±43.39 0.000
LDL cholesterol 202.41±45.86 129.62±40.05 0.000
Corrected LDL cholesterol 312.73±91.67 129.62±40.05 0.000
Triglycerides 185.88±120.05 178.07±276.96 0.871
Uric acid, mg/dL (mean±SD) 4.44±1.57 4.45±1.37 0.971
Urea, mg/dL (mean±SD) 36.12±14.50 32.51±7.17 0.328
ATS, n (%) 25 (48.1) 3 (17.6) 0.045
HF, n (%) 10 (19.2) 2 (11.8) 0.024
CKD, n (%)
Stage 1 12 (23.1) 8 (47.1) 0.009
Stage 2 25 (48.1) 9 (52.9)
Stage 3A 13 (25.0) 0 (0)
Stage 3B 2 (3.8) 0 (0)
ATS – atherosclerosis; BMI – body mass index; CKD – chronic kidney disease; FH – familial hypercholesterol-
emia; HDL – high density lipoprotein; HF – heart failure; LDL – low density lipoprotein.

45
 Alexandra Maștaleru et al.

Regarding the ApoE genotype (tab.
II), statistical significance correlations
were observed between Apo E3/E3 and
Apo E3/E4 for triglycerides concentra-
tion, between Apo E3/E3 and Apo E4/E4
for the glycosylated hemoglobin, urea
and creatinine clearance value and be-
tween Apo E3/E4 and Apo E2/E3 for the
creatinine clearance and also when com-
paring with the gender. In addition, a p
value < 0.05 was observed for the creati-
nine concentration and for the clearance
of creatinine between Apo E3/E3 and
Apo E2/E3 and only for the creatinine
clearance between Apo E2/E3 and Apo
E4/E4.

TABLE II.
Correlations between ApoE genotypes variants in the FH group
Apo E3/E3 Apo E3/E4 Apo E2/E3 Apo E4/E4 P1 P2 P3 P4 P5
Gender (Females) 26 (78.8%) 5 (15.2%) 1 (3%) 1 (3%)
0.150 0.555 0.035* 1.000 1.000
Gender (Males) 16 (84.2%) 0 (0%) 2 (10.5%) 1 (5.3%)

TC 289.91±53.66 251.80±76.84 284.33±45.44 316.00±28.28 0.718 0.996 0.873 0.699 0.781

LDL 203.45±45.50 175.70±58.63 209.53±29.07 236.70±29.13 0.746 0.985 0.710 0.599 0.756

C-LDL 318.25±93.79 252.06±56.73 308.03±78.43 355.55±138.95 0.196 0.996 0.723 0.975 0.964

HDL 58.50±17.83 64.22 ±19.66 46.30±9.36 63.10±15.13 0.921 0.344 0.385 0.968 0.621

Non-HDL 231.40±57.81 187.58±62.98 238.03±52.35 252.90±13.15 0.510 0.996 0.641 0.449 0.960

TG 198.74±125.58 112.72±40.02 174.16±128.30 116.35±72.61 0.022* 0.986 0.849 0.602 0.912

Glucose 133.77±160.72 110.02±15.15 106.00±12.66 93.80 ±3.53 0.792 0.707 0.976 0.388 0.517

HbA1c 5.82±1.34 5.65±0.85 5.75±0.48 5.11±0.04 0.978 0.996 0.997 0.007* 0.333

IFG 20 (80%) 3 (12%) 2 (8%) 0 (0%) 0.666 0.608 1.000 0.493 0.400

BMI 29.07±5.14 26.11±5.04 29.30±8.16 26.60±4.47 0.632 1.000 0.922 0.870 0.960

MS 18 (85.7%) 1 (4.8%) 2 (9.5%) 0 (0%) 0.635 0.577 0.464 0.505 0.400

ATS 23 (92%) 2 (8%) 0 (0%) 0 (0%) 0.654 0.109 0.464 0.222 1.000

Uric acid 4.64±1.52 3.19±1.61 3.88±1.88 4.02±1.62 0.333 0.894 0.948 0.940 1.000

Urea 37.29±15.70 32.94±6.55 32.06±5.40 25.65±0.07 0.671 0.587 0.997 0.000* 0.391

Creatinine 1.03±0.25 0.95±0.10 0.87±0.04 0.96±0.16 0.569 0.009* 0.463 0.916 0.896

Creatinine
70.61±17.86 72.00 ±10.79 93.66±3.21 80.50±2.12 0.994 0.000* 0.030* 0.030* 0.036*
clearance
ATS – atherosclerosis; BMI – body mass index; C- LDL – corrected LDL; HDL – high density lipoprotein; IFG –
impaired fasting glucose; LDL – low density lipoprotein; MS – metabolic syndrome; TC – total cholesterol; TG –
triglycerides; P1 – statistical significance between ApoE3/E3 and Apo E4/E4; P2 – statistical significance between
ApoE3/E3 and ApoE2/E3; P3 – statistical significance between ApoE3/E4 and ApoE2/E3; P4 – statistical signifi-
cance between ApoE3/E3 and ApoE4/E4; P5 – statistical significance between ApoE2/E3 and ApoE4/E4.

46
 Impact of ApoE polymorphism in a familial hypercholesterolemia population

Regarding the patients with FH and Apo
E3/E3 genotype, most patients (45.2%)
were diagnosed with third-degree hyperten-
sion, 11.9% (5 patients) had second-degree
hypertension, and only 4 patients (9.5%)
presented first-degree hypertension. From
the ones who presented Apo E3/E4 geno-
type, 3 (60%) had first degree hypertension
and 1 (20%) had second degree hyperten-
sion. When referring to the patients with
Apo E2/E3, there was one patient (33%)
with second and third-degree of hyperten-
sion. A significant correlation between the
hypertension and the ApoE genotype has
been observed (p = 0.014).
In table III it can be observed the sta-
tistically significant correlation between
Apo E3/E3 and Apo E4/E4 for the BMI
value in the patients from the control
group.

TABLE III.
Correlations between ApoE genotypes variants in the control group
Apo E3/E3 Apo E2/E3 Apo E4/E4 P1 P2 P3
Gender (F) 7 (63.6%) 2 (18.2%) 2 (18.2%)
1.000 1.000 0.467
Gender (M) 4 (66.7%) 2 (33.3%) 0 (0%)
TC 205.03±41.71 222.70±55.61 188.50±6.36 0.838 0.457 0.520
LDL/C-LDL 139.71±32.68 107.42±62.28 118.50±1.97 0.625 0.131 0.934
HDL 47.90±10.84 40.42±14.08 49.65±4.45 0.632 0.923 0.517
Non-HDL 157.13±36.05 182.27±68.74 138.85±1.90 0.779 0.262 0.502
TG 111.82±40.95 398.37±564.67 101.80±0.56 0.619 0.705 0.601
Glucose 99.05±8.88 101.00±7.57 91.65±2.75 0.909 0.141 0.187
HbA1c 5.27±0.32 5.22±0.39 5.00±0.11 0.971 0.171 0.595
IFG 2 (66.7%) 1 (33.3%) 0 (0%) 1.000 - -
BMI 24.26±5.82 26.14±6.49 18.17±1.59 0.817 0.049* 0.174
MS 1 (50%) 1 (50%) 0 (0%) - - -
ATS 2 (66.7%) 1 (33.3%) 0 (0%) 1.000 - -
Uric acid 4.30±1.00 5.01±2.37 4.15±1.22 0.838 0.985 0.835
Urea 33.37±6.57 28.10±9.34 36.65±3.04 0.593 0.563 0.326
Creatinine 0.92±0.13 0.95±0.11 0.94±0.02 0.905 0.870 0.991
Creatinine
87.36±17.89 88.75±19.08 81.00±2.82 0.991 0.530 0.730
clearance
ATS – atherosclerosis; BMI – body mass index; C- LDL – corrected LDL; HDL – high density lipoprotein;
IFG – impaired fasting glucose; LDL – low density lipoprotein; MS – metabolic syndrome;
TC – total cholesterol; TG – triglycerides; P1 – statistical significance between ApoE3/E3 and ApoE2/E3;
P2 - statistical significance between ApoE3/E3 and ApoE4/E4;
P3 - statistical significance between ApoE2/E3 and ApoE4/E4.

47
 Alexandra Maștaleru et al.
In table IV are compared the lipid pro-
file, and the Apo E genotypes in the FH
group. We can observe that the lowest val-
ues of the total cholesterol, LDL, corrected
LDL, triglycerides and non-HDL are in the
TABLE IV
Lipid profile and Apo E genotypes in the FH group
Apo E3/E3
Total cholesterol (mean±SD) 289.91±53.66
LDL (mean±SD) 203.45±45.50
Corrected LDL (mean±SD) 318.25±93.79
Triglycerides (mean±SD) 198.74±125.58
HDL (mean±SD) 58.50±17.83
Non-HDL (mean±SD) 231.40±57.81
DISCUSSION
Almigbal et al. recently published a
study in which they evaluated the role of
apolipoprotein E in patients with familial
hypercholesterolemia. Regarding the fre-
quency of the studied genotypes, our re-
sults are consistent with their study, the
most frequent being Apo E3/3 and Apo
E3/E4 (9).
Regarding the lipid profile and the Apo
E genotypes, Liu et al. published in 2021
an article that described the fact that Apo
E2/E3 had lower values of total cholester-
ol and LDL cholesterol compared to Apo
E3/E3 and Apo E4/E4, results obtained
also by us. The authors describe also that
Apo E2/E3 has lower lipid profiles when
compared to Apo E3/E4, these results
being in contradiction to ours (10). Ro-
drigues et al. studied the relationship be-
tween Apo E genotypes and dyslipidemia
in six main regions of Portugal. The study
included 778 men and 1153 women be-
tween the ages of 15 and 74. The authors
have shown that there is a relationship
between E4 allele and high cholesterol
blood levels (11).
48
patients with Apo E3/E4. Slightly increased
values compared to this form can be seen in
Apo E2/E3, followed by Apo E3/E3. The
highest values of the lipid profile can be
observed in the Apo E4/E4 form.
Apo E3/E4 Apo E2/E3 Apo E4/E4
251.80±76.84 284.33±45.44 316.00±28.28
175.70±58.63 209.53±29.07 236.70±29.13
252.06±56.73 308.03±78.43 355.55±138.95
112.72±40.02 174.16±128.30 116.35±72.61
64.22±19.66 46.30±9.36 63.10±15.13
187.58±62.98 238.03±52.35 252.90±13.15
In our study, we have observed a statis-
tical significance between E3/E3 and E4/E4
for glycated hemoglobin in the patients
diagnosed with familial hypercholesterole-
mia. Ukola et al. performed a study on 271
Caucasian patients diagnosed with diabetes
to examine whether there was a link be-
tween Apo E polymorphisms and the onset
of diabetic complications. The authors
observed that the E4-bearing genotypes had
a higher risk of developing micro and
macrovascular complications in patients
diagnosed with non-insulin-dependent
diabetes mellitus, regardless the gender,
when compared to the carriers of E2 geno-
type (12).
Our research described a statistical sig-
nificance regarding the creatinine clearance
between Apo E2/E3 and Apo E3/E3, Apo
E3/E4 and between Apo E4/E4. Studies
suggest that patients with Apo E2 genotype
have a low glomerular filtration rate when
compared to Apo E3 or Apo E4 carriers,
also associating a high concentration in the
serum creatinine (13). A recently published
review illustrates the existence of Apo E2
homozygote glomerulopathy associated
 Impact of ApoE polymorphism in a familial hypercholesterolemia population

with the mutations of the apolipoprotein E. CONCLUSIONS

A possible explanation for this can be the
internalization of the lipoproteins by the
macrophages into the cytoplasm, being
therefore responsible for the accumulation
in the glomerulus of lipoproteins (14).
Thus, our results are in accordance with the
ones already published.
When referring to the control group, a
statistical significance regarding the BMI
can be observed between Apo E3/E3 and
Apo E4/E4. Tabatabaei-Malazy et al.
described that the Apo E4 allele had a
significant impact on the central obesity
(15). According to the Atherosclerosis
Risk in Communities (ARIC) study, the
most common Apo E genotype that was
related to BMI was the Apo E4 form (16).
Another study found also that the E4-
bearing genotypes (Apo E3/E4 and Apo
E4/E4) were correlated with higher waist
circumference and obesity in elderly
women with a family history of diabetes
(17).
Common ApoE variants are well known
to be associated with different concentra-
tions of the parameters included in the lipid
profile. In our study, the patients with Ap-
oE4/E4 had the highest lipid profile con-
centrations. In addition, we observed a low
creatinine clearance in patients with Apo
E2 genotype when compared to Apo E3
and Apo E4.
Despite the fact that these data are sta-
tistically significant, larger studies are
needed in order to have a better under-
standing of the impact of the genetic fac-
tors in patients with familial hypercholes-
terolemia. These findings could improve
the quality of life of these patients, with a
decrease in morbidity and mortality.
CONFLICT OF INTEREST
AND FUNDING
The authors declare that there is no con-
flict of interest, and they received no specific
funding regarding the scientific research.

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NOUTĂȚI
NEWS

PROENKEPHALIN CORRELATES WITH THE SEVERITY OF SEPSIS-ASSOCIATED

ACUTE KIDNEY INJURY

In this study, 215 patients were enrolled. They were diagnosed as having sepsis (N=109,
50.7%) or septic shock (N=106, 49.3%) according to the Sepsis-3 criteria. The PENK levels
were significantly higher in the septic shock group than in the sepsis group (118.7 pmol/L
vs. 75.7 pmol/L, p=0.02). The PENK levels were also significantly higher in patients with
vasopressor use than in those without vasopressor use (116.9 pmol/L vs. 72.7 pmol/L,
p=0.007) and in the non-survivors than in the survivors (171.5 pmol/L vs. 79.8 pmol/L,
p<0.001). PENK levels gradually increased according to the increased SOFA renal sub
scores and CKD-EPI eGFR categories; this significance was constantly observed across each
group (P<0.05, post-hoc test), except for eGFR categories G3a and G3b. Another noticeable
finding in this study was the significant association between the PENK quartile and 30 -day
mortality rate. The present data also support the use of a clinical cut-off for PENK (80
pmol/L). In the groups with poor clinical status or outcomes, including septic shock, vas o-
pressor use, and non-survivors, the median value of PENK levels was higher than the clini-
cal cut-off. PENK could thus be an objective and reliable marker that has the potential to
substitute for or augment the current role of the SOFA scoring system in critically ill septic
patients. (Hanah K, et al. Proenkephalin Predicts Organ Failure, Renal Replacement Thera-
py, and Mortality in Patients With Sepsis. Ann Lab Med 2020; 40(6): 466-473).

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