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Jadranka Sertić
Department of Medical Biochemistry and Clinical Chemistry, School of Medicine, University of Zagreb
Department of Laboratory Diagnostics, University Hospital Center Zagreb
Zagreb, Croatia
GENETICS AND
METABOLIC DYSFUNCTION
INDO-GLOBAL HEALTHCARE SUMMIT & EXPO 2014, Hayderabad, India
METABOLIC DYSFUNCTION
Environment Genes
CARDIO-CEREBROVASCULAR DISEASE
Atherosclerosis
Obesity Dyslipidemia Diabetes
Metabolic syndrome
Hypertension
HEALTH
MS and CVD are leading cause of morbility and mortality and have genetic component, as risk of
disease and biomarcer of heath.
For genetic prediction of disease risk it is important to identify functional gene variant, polymorphism
in order to established genotype-phenotype correlation.
There are gene-gene and gene –enviroment interaction.
GENOMICS PROTEOMICS
NUTRIGENOMICS
THE WORLD OF "OMICS"
BIOMARKERS
PREDICTIVE, PREVENTIVE AND PERSONALIZED MEDICINE
Today OMNICS technologies allow detection of genetic, biochemical and other relevant biomarkers for
personalized early diagnosis, intervention and treatment.
Biomarker, gene variants is a valuable tool in the prevention of a complex multifactorial disease.
PERSONALIZED MEDICINE
BIOMARKERS: GROWING IMPACT IN LABORATORY MEDICINE
Human Genome Project
Enhanced understanding of molecular basis of disease
Genetics Genomics Proteomics: new possibilities
To predict disease onset Improvement quality of life
To individualize treatment Reduced costs of healthcare
PPPM offer great promise for the future practise of medicine. Essential components of this approach include
utilizing novel diagnostic biomarkers of disease states resulting in a improvement in quality of life and reduced
costs of healthcare
GENES AND ENVIRONMENT
The importance of gene-environment interaction is evident in the fact that its
effect will be so great that premature disease will develop
only when an individual with a high-risk genetic profile moves into a high-risk
environment.
Genetics and environmental factors
(including diet, alcohol and tobacco)
Biological and clinical data
+ lead to application of preventive
medicine in the field of obesity, MS
and CVD
For genetic prediction of disease risk, it is important to identify
functional gene variants (SNPs) in order to establish genotype-
phenotype correlation
SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS)
- MOST COMMON GENE VARIANTS
There are two types of polymorphisms:
good-risk predictors - associated with health (low risk)
poor-risk predictors - related to possible development of disease
(hypercholesterolemia, hypertension, obesity, metabolic syndrome,
cardiovascular disease) (high risk)
NEW TREND IN LABORATORY MEDICINE Genomic,proteomic and nutrigenomic profiling
Genomic, proteomic and nutrigenomic profiling provides a picture of the cell and genes
variants and proteins associated with inflammatory processes, lipid homeostasis, and
hemostatic status,
as well as pathways and biological processes involved in the predisposition, interaction of
genetic risk factors, and pathophysiology of clinical entities like metabolic syndrome, obesity,
atherosclerosis and stroke.
Genetic risk factors in patients with acute ischemic stroke
University of Zagreb School of Medicine
Functional genomics and proteomics of the risk factors
of atherosclerosis
Croatian Ministry of Science
•
•
Study is part of a project:
BIOMARKERI
geni proteomici
fizikalni
metabolički
biokemijski
slikovni
fiziološki
anatomski
histološki
zračenje
GENETIC BIOMARKER AN INDICATOR OF NORMAL AND ABNORMAL BIOLOGICAL PROCESSES
AT1R PPARG
MTHFR
ADIPO
ESR
IL-6
BIOMARKERS
ACE
LPL
APOE
We investigated the possible role of gene polymorphisms of ADIPOQ, ESR1, LPL, ApoE, ACE, AT1R IL-6
and PPARG in obesity, MS and acute ischemic stroke in early adulthood
Adiponectin level and gene variablity as obesity and metabolic syndrome markers in a
young population
Gender effects of PPARG, APOE, ACE, LPL, IL-6 and AT1R gene variants on
metabolic syndrome
Genetics risk factors in patients with acute ischemic stroke: The role of PPARG,
IL-6 and AT1R
ESR1, APOE, MTHFR, ACE, IL-6 and LPL in healthy young subjects, and their effect
on biogical variables of the lipid status, hypertension and obesity,
gene - environment interaction as a predictor of early abdominal obesity and
hypertension
•
•
•
•
Genomics and proteomics of the risk
factors of atherosclerosis Croatian Ministry of Science
- obesity is a multifactorial disorder affected by genetic and dietary factors
- obesity s accepted as an important risk factor for development of certain
syndromes and many chronic diseases
- obesity has become an extensive public health concern becuse its prevalence
has increased to epidemic proportions
CONTRIBUTION OF GENE VARIANTS AND DIET TO OBESITY RISK
ESR1, APOE, MTHFR, ACE, IL-6 AND LPL IN HEALTHY YOUNG
INDIVIDUALS, AND THEIR EFFECT ON THE BIOLOGICAL
VARIABLES OF LIPID STATUS AND OBESITY
Sertić J, Juričić L, Ljubić H, Božina T, Lovrić J, Markeljević J, Jelaković B, Merkler
M, Reiner Ž. Variants of ESR1, APOE, LPL and IL-6 loci in young healthy subjects:
association with lipid status and obesity. BMC Res Notes 2009;2:203.
“ - genetic polymorphic variants could represent predictive genetic risk markers for
obesity-related metabolic disorders in young healthy subjects
- Mediteranean type of diet is also an important protective factor against
abdominal obesity ”
105 young healthy subjects aged 20 - 35 years (F 58, M 47),
participated in the study
invited to participate during routine medical check-up
family history of CVD, hypertension, obesity, medications, smoking,
diet was registered through a questionnaire
participants signed informed consent forms
study protocol was approved by the Ethics Committee
Focus of the study is on candidate genes and SNP, and their
association with biological data and demographic and
biochemical characteristics
LABORATORY MEASUREMENTS
Biochemical analyses
blood samples for biochemical analyses (total cholesterol, LDL- and HDL-
cholesterol, glucose, CRP, urate) were taken after overnight fasting
Genetic analyses included the following genes:
ESR1; TA ( 19) - short allele; > 19 repeats - long allele
APOE E2, E3, E4
MTHFR C677T
ACE; I/D
IL-6 174G>C
LPL PvuII
N= 105 young subjects Age: 25-35 Croatian origin
BMI waist/hip ratio
IL-6, ACE, LPL
PCR-RFLP
APOE, MTHFR
Real-time PCR
ESR1
Capillary electrophoresis
GENOTYPING
GENES
Genotypes have been determined by applying PCR/CE/RT-PCR
POPULATION CHARACTERISTICS: AGE, BMI
292.70 +/- 76.35 Urate (mmol/l)
5.03 +/- 0.45 Glucose (mmol/l)
1.34 +/- 1.61 CRP
2.59 +/- 0.85 LDL (mmol/l)
1.45 +/- 0.3 HDL (mmol/l)
4.53 +/- 0.96 Cholesterol (mmol/l)
1.08 +/- 0.55 Triglycerides (mmol/l)
0.81 +/- 0.8 Waist/hip ratio
103.23 +/- 8.32 Hip (cm)
83.61 +/- 12.04 Waist (cm)
23.48 +/- 3.81 BMI
175 +/- 10.53 Height
73.99 +/- 16.09 Weight
25.82 +/- 3.28 Age (yrs)
Mean +/- SD
Subjects' demographic and biochemical characteristics
Basic characteristics: age of the subjects was 25. and metabolic status ,
DIET: CONTINENTAL, MEDITERIAN, MIXED
Feature Frequencies Percent
No 78 74.3 Cardiovascular illness 4 3.8
Somatic illness
Other illnesses 14 14.3 Yes 67 63.8 Smoking No 31 29.5 No 87 82.9 With known effects on investigated features (Contraceptives)
9 3.8
Taking medications
Other medications 4 8.6 No 77 73.3 Raised hepatic enzymes Yes 19 18.1 Continental 75 71.4 Mediterranean 13 12.4
Diet
Mixed 10 9.5 No 25 23.8 Diabetes 12 11.4 Cardiovascular disease 32 30.5 Obesity 2 1.9
Positive family history
More than one 34 32.4 No 79 75.2 Hypertension (>135/85
mmHg) Yes 19 18.1
Positive familiy history was established in 32.4% of subjects.
Hypertension in 18.1%
12.4% of subjects were on Mediterrannean diet
< 25 77 73.3 25.01-30 23 21.9
BMI/km/m2
> 30.01 5 4.8 No 85 83.3 Abdominal obesity (Waist/hip
>90 (Male), >85 (Female) Yes 17 16.7
No 93 88.6 Hypertriglyceridemia (>1.7) Yes 12 11.4 No 81 77.1 Hypercholesterolemia (>5) Yes 24 22.9 No 98 93.3 Low HDL (<1.0) Yes 7 6.7 No 81 77.1 High LDL (>3) Yes 24 22.9 Normal 104 99 Glucose (>6.4) Hyperglycemia 1 1.0 < 1 61 58.1 1-3 34 32.4
CRP levels
> 3 10 9.5 No 93 88.6 Elevated urate levels (>383) Yes 12 11.4
Feature Frequencies Percent
HEALTHY YOUNG SUBJECTS – BMI, WC, CHOL.
BMI values ranging between 25 – 30 were found n 21.9% of subject
Hypertriglyceridemia was detected i 11.4% of subjects
DIFFERENCES IN WEIGHT, BMI AND WAIST OF THE
SUBJECTS WITH REGARD TO THEIR DIET TYPE
0
20
40
60
80
100
120
Weight BMI Waist
Continental Mediterranean Mixed
*
*
*
We found association between BMI and diet type – Mediterranean diet significantly different,
as a factor of environment, has considerable impact on the health of young population
Subjects on Mediterranean diet had the best results
with regard to BMI and WHR
Croatia
ASSOCIATION BETWEEN LIPID PARAMETERS AND
ESR1- AND APO E POLYMORPHISMS
Significant association was found between ESR1 (S allele) and APO E (2,3), and cholesterol
("good-risk factors")
-- Association between estrogen receptor-alfa gene polymorphisms and coronary artery
disease wth familiar hypercholesterolemia was previously reported.
Cholesterol
<5 N=81
Cholesterol
>5 N=24
OR CI Test
Alleles L 42 19 1 1-1
S 54 9 2.714 1.18- 6.26
Χ2=5.123
df = 1
p = 0.023
Genotypes LL 9 7 1 1-1 LS 24 5 3.733 0.94- 14.84
ESR1
SS 15 2 5.833 0.98- 34.44
Χ2=5.328 df = 2
p= 0.0696
Alleles 2 21 1 1 1-1 3 121 33 0.1746 0.02- 1.404
4 14 12 0.055 0.005-0.59
Χ2=12.69 df = 2
p= 0.0017
Genotypes 22 2 0 1 1-1
23 15 0 2.081e+011 9.954e+010-
4.353e+011
24 2 1 1.006e-008 0- 7.707e-008
33 47 12 1.97e-008 0-6.223e-008
34 12 9 0 0-2.319e-008
APO E
44 0 1 0 0-0
Χ2=16.28
df = 5
p= 0.006
RESULTS THAT INDICATE A RISK ASSOCIATED WITH
ABDOMINAL OBESITY
Abdominal obesity was correlated to LPL P+/-, P+/+ genotypes in significant manner
WHR /09 was found good indicator for obesity among heterozygous and homozygous subjects
for LPL genotype
Waist/hip
<0.9 (M);
<0.85 (F),
N=85
Waist/hip
>0.9 (M);
>0.85 (F),
N=17
OR CI Test
Alleles M 87 16 1 1-1
P 65 18 0.6641 0.203- 2.18
Χ2=
1.158
df = 1
p= 0.282
Genotypes MM 25 1 1 1-1
MP 37 14 0.1057 0.01-0.86
LPL
PP 14 2 0.28 0.023-3.37
Χ2=
7.984
df = 2
p = 0.018
GOOD-RISK PREDICTION IN YOUNG HEALTHY POPULATION
Environment factor:
Mediterranean diet
Genetic biomarkers:
ESR1 (TA<19)
APO E (2/3)
LPL Pvu -/-
• Results of examining correlation between weight, BMI and waist/hip ratio, and continental,
Mediterranean and mixed diet showed optimal values in subjects on Mediterranean diet
• Statistically significant correlation was detected for ESR1 short allele and cholesterol
• We also found statistically significant association of APO E 2/3 genotype with lower total- and
LDL-cholesterol levels
• Statistically significant association was observed between LPL and abdominal obesity
GENES & ENVIRONMENT: ORDER OF RELEVANCE??
"Genes load the gun, but the environment pulls the
trigger." 1921
Elliot Proctor Joslin (1869-1962)
a physician and a diabetes educator
This has recently been a very frequently used saying: would you agree that both genes and
environment are equally important?
Gender effects of PPARG, APOE, ACE, LPL, IL-6 and AT1 gene variants on metabolic
syndrome
Adiponectin gene variants and MS
Genetics risk factors in patients with acute ischemic stroke: The role of PPARG
IL-6 and AT1R
ESR1, APOE, MTHFR, ACE, IL-6 and LPL in healthy young subjects, and
their effect on biogical variables of the lipid status, hypertension and obesity •
•
•
•
Genomics and proteomics of the risk factors
of atherosclerosis Croatian Ministry of Science
Karmelić I, Lovrić J, Božina T, Ljubić H, Vogrinc Ž, Božina N, Sertić J.
Adiponectin level and gene variability are obesity and
metabolic syndrome markers in a young population.
Arch Med Res 2012;43(2):145-153.
ADIPONECTIN GENE aS A PREDICTOR OF EARLY ABDOMINAL OBESITY
The aim of the study was to establish possible correlation of adiponectin (ADIPOQ)
gene variants and peroxisome proliferator activated receptor (PPAR ) with
development of abdominal obesity, and consequently also of MS in young individuals,
as well as possible association of the variants of this gene with lipid variables.
CORRELATION OF ADIPOQ GENE POLYMORPHISMS WITH MS
Gene/polymorphism
Genotype or
allele
Subjects
without MS
N (%)
Subjects with
MS
N (%)
OR
(95% C.I.)
Pearson’s χ2 test
ADIPOQ
-11377 C>G
CC 59 (86.8) 9 (13.2) 2.93
1.26-6.81
p=0.0128
χ2= 6.523
d.f.=1; p=0.001
CG+GG 49 (64.3) +7
(70.1)
20 (29.9)
+ 5 (35.7)
C 106 (78.5) 29 (21.5) 1.63
0.87-3.05
p=0.128
χ2= 6.523 d.f.=1;
p=0.011
G 56 (69.1) 25 (30.9)
ADIPOQ
-11391 G>A
GG 76 (85.4) 13 (14.6) 3.15
1.43-6.95
p= 0.004
χ2= 8,463 d.f.=1;
p=0.004 GA+AA 38 (66.7) + 1
(33.3)
19 (33.32) + 2
(66.7)
G 115 (77.2) 34 (22.8) 1.91
1-3.65
p=0.05
χ2= 6.523 d.f.=1;
p=0.011
A 39 (65.0) 22 (35.0)
Prevalence of MS in young population is high; from 45% of subjects with increased waist circumference, 65%
also had other MS components.
Statistically significant correlation was found between ADIPOQ -11377GG and ADIPOQ -11391AA genotype,
and abdominal obesity.
CORRELATION OF ADIPOQ GENE POLYMORPHISMS WITH MS COMPONENTS
Characteristic/
ADIPOQ gene polymorphism
Genotype or allele Subjects
without MS
N (%)
Subjects with MS
N (%)
OR
(95% C.I.)
Pearson’s χ2 test
Waist circumference/
-11377 C>G
CC 39 (49.4) 27 (40.3) 5.29
0.75-2.79
p=0.017
4.68
1.19-18.34
p=0.027
χ2= 6.782; d.f.=2 p=0.03
CG 37 (46.8) 29 (43.3)
GG 3 (3.8) 11 (16.4)
C 76 (96.2) 56 (83.6) 1.36
0.78-2.37
p=0.283
Χ2= 6.6604; d.f.=1; p=0.01
G 40 (50.6) 40 (59.7)
Waist circumference/
-11391 G>A
GG 60 (75.9) 27 (40.3) 4.68
2.30-9.52
p<0.0001
χ2= 19.139; d.f.=1 p<0.001
GA+AA 18 (22.8) +1
(1.3)
38 (56.7) + 2
(3.0)
G 78 (98.7) 65 (97.0) 2.53
1.34-4.78
p=0.004
χ2=19.135;
d.f.=1 p<0.001 A 19 (24.1) 40 (59.7)
Triglycerides/
-11377 C>G
CC 58 (49.6) 9 (29.0) 6.23
2.82-13.73
p<0.0001
χ2= 6.992 d.f.=1;
p=0.008 CG + GG 50 (42.7) +9
(7.7)
22 (54.8) +5
(16.1)
C 108 (92.3) 26 (83.9) 1.54
0.80-2.99
p=0.187
χ2= 4.173; d.f.=1 p=0.041
G 59 (50.4) 22 (71.0)
Triglycerides/
-11391 G>A
GG 75 (64.1) 14 (45.2) 2.17
0.97-4.45
p=0.006
χ2= 3.663 d.f.=1
p=0.05 GA+AA 41 (30.5)
+1 (0.9)
15 (48.4)
+ 2 (6.5)
G 116 (99.1) 29 (93.5) 1.62
0.80-3.25
P=0.174
χ2= 3.668
d.f.=1
p=0.06 A 42 (35.9) 17 (54.8)
Statistically significant correlation was established between ADIPOQ -11377 G allele and hypertriglyceridemia.
ADIPOQ 11377 G and ADIPOQ -11391 A alleles have been found to be significant predictors of MS, with all its
components.
MULTIVARIATE DISCRIMINANT ANALYSIS OF MS PREDICTORS – BIOMARKER AS MODULATORS OF VISCERAL FAT ACCUMULATION???
Method: forward stepwise. Step 10; N variables in a model:8; Grouping: 2 groups (without MetS and with MetS) Wilk’s
Lambda: 0.430 approx. F (10.131)=17.364; p<0,00001
N =149
Wilks’ Lambda Partial Lambda F-remove p-value
Triglycerides (mmol/L) 0.500 0.860 21.34 <0.0001
Blood pressure 0.518 0.831 26.73 <0.0001
HDL-cholesterol (mmol/L) 0.470 0.915 12.18 0.001
ADIPOQ-11391 G>A; allele A 0.444 0.970 4.11 0.045
Glucose (mmol/L) 0.443 0.968 4.32 0.040
PPAR 2 Pro12Ala; alel C 0.442 0.973 3.67 0.058
ADIPOQ -11377 C>G; alel G 0.441 0.974 3.49 0.064
ADIPOQ -11391 G>A; alel G 0.436 0.985 1.96 0.163
Multivariate discriminant analysis was used to confirm all MS components and ADIPOQ -11391
A allele as independent MS predictors.
BIOMARKER- ADIPOQ -11391 A allele as independent MS predictors.
BIOMARKERS
Triglycerides (mmol/L)
Blood pressure
HDL-cholesterol (mmol/L)
ADIPOQ-11391 G>A; allele A
Waist circumference/
-11391 G>A Triglycerides/
-11391 G>A
Gender effects of PPARG, APOE, ACE, LPL, IL-6 and AT1 gene
variants on MS
Adiponectin gene and MS
Genetics risk factors in patients with acute ischemic stroke: The role of PPARG
and IL-6
ESR1, APOE, MTHFR, ACE, IL-6 and LPL in healthy young subjects, and
their effect on biogical variables of the lipid status, hypertension and obesity •
•
•
•
Genomics and proteomics of the risk factors
of atherosclerosis Croatian Ministry of Science
Božina T, Simić I, Lovrić J, Pećin I, Jelaković B, Sertić J, Reiner Z. Effects of
lipoprotein lipase and peroxisome proliferator-activated receptor-gamma
gene variants on metabolic syndrome traits.
Coll Antropol. 2013;37(3):801-808.
Božina T, Sertić J, Lovrić J, Jelaković B, Simić I, Reiner Z. Interaction of Genetic
Risk Factors Confers Increased Risk for Metabolic Syndrome: The Role of
Peroxisome Proliferator-Activated Receptor Genet Test Mol Biomarkers
2014; 18(1): 32-40.
GENDER-SPECIFIC EFECTS OF
PPARG, APOE, ACE, AT1R, LPL AND IL-6
GENE VARIANTS ON
METABOLIC SYNDROME TRAITS
We aimed to perform analysis of the possible role of gene polymorphisms of PPARG (Pro12Ala), ApoE
(ε2, ε3, ε4), ACE (I/D), LPL (P+/-) and IL-6 (-174G>C) in MS.
A cohort of 527 individuals (343 female, 184 male) were investigated including 263 patients with MS and
264 subjects without MS criteria.
Measurements included: fasting glucose in blood, total cholesterol, triglycerides, LDL-C, HDL-C, CRP,
blood pressure (BP), waist circumferences (WC) and measurements of weight and height for body mass
index (BMI) calculations.
Genotyping was performed for ApoE by Real-time PCR, for PPARG, LPL and IL-6 by PCR-RFLP, for ACE
by PCR based method.
• Metabolic syndrome is a cluster of modifiable risk factors including hypertension, abdominal obesity,
dyslipidemia and insulin resistance, associated with nonmodifiable risk factors, such as age, sex and genetic
background.
• PPARG (PPARG Pro12Ala (CCA – GCA) is a transcription factor with a crucial role in the expression of
key genes involved in adipogenesis, lipid and glucose metabolism, atherosclerosis, inflammation and
immunity.
• The presence of genetic variants is likely to affect expression levels of different target genes. LPL, IL-6,
ApoE and ACE.
MS
An individual with a combination of any three or more of the
following risk factors was classified as having MS:
• waist circumference, male >102 cm, female >88 cm
• TG 1.7 mmol/L
• HDL-C <1.0 in men and <1.3 mmol/L in women
• systolic blood pressure (SBP) or diastolic blood pressure (DBP)
130/85 mm Hg
• and fasting blood glucose 6.1 mmol/L
RESULTS
Patients with MS and control group did not differ significantly with respect to age and sex. Patients had significantly higher blood pressure, BMI and waist circumferences and higher levels of TG, total cholesterol, CRP and glucose and lower levels of HDL-C compared to controls.
Clinical features of study participants
Association of gene variants and components of MS in males and females
- In female group associations were found for: PPAR and LPL with BP; LPL with Chol. and LDL
- For male we found associations of: LPL variants with MS, BMI and WC;
- PPAR, LPL and apoE with BMI,
- IL-6 with CRP
Genotype: prediction - odds ratio (OR)
Feature Genotype high
n (%)
normal
n (%) OR (95% CI)
WC IL6 (controls)
GG 13 (31.7) 70 (38.0) 1
GC 18 (43.9) 94 (51.1) 1.03 (0.47-2.24)
CC 10 (24.4) 20 (10.9) 2.69 (1.03-7.05)
WC PPARγ (controls)
CC 27 (65.9) 142 (77.2) 1
CG/GG 14 (34.1) 42 (22.8) 3.86 (1.24-12.06)
TG AT1R (controls)
AA 8 (26.7) 112 (53.1) 1
AC or CC 22 (73.3) 99 (46.9) 3.11 (1.33-7.30)
Glucose AT1R (cases)
AA 3 (27.3) 115 (50.9) 1
AC 5 (45.5) 97 (42.9) 1.98 (0.46-8.48)
CC 3 (27.3) 14 (6.2) 8.21 (1.51-44.68)
•Healthy participants with IL6 CC genotype had more than 2.5 larger risk (odds) of having high waist circumference compared to those with IL6 GG genotype.
•PPAR CG or GG genotype carriers had almost 4 times larger risk (odds) of having high waist circumference compared to those with PPAR CC genotype carriers.
•Participants with AT1 AC or CC genotype were more than 3 times more likely to have high triglycerides compared to those with AT1 AA genotype.
•Participants with AT1 CC genotype had more than 8 times larger odds of having high levels of fasting blood glucose compared to those with AT1 AA genotype.
Overall predictive model for MS
Interactions / feature Genotypes cases
n (%)
controls
n(%) ORmv (95% CI) P
LPLxPPARγ / MS
LPL if PPAR CG or
GG
M/M 12 (18.5) 19 (30.2) 1
M/P or P/P 53 (81.5) 44 (69.8) 5.98 (1.46-24.47) 0.013
IL6xPPARγ / glucose
PPAR if IL6 GC/CC
CC 39 (62.9) 90 (78.3) 1
CG / GG 23 (37.1) 25 (21.7) 2.39 (1.11-5.17) 0.026
LPLxPPARγ / HDL-males
LPL if PPAR CG/GG
M/M 1 (6.3) 2 (16.7) 1
M/P or P/P 15 (93.8) 10 (83.3) 38.62 (1.72-867.06) 0.021
ACExPPARγ / BMI
PPAR if ACE DD
CC 32 (64.0) 20 (90.9)
CG / GG 18 (36.0) 2 (9.1) 9.98 (1.18-84.14) 0.034
•In the group of patients with PPARG CG or GG genotype, carriers of LPL M/P or P/P genotype have about 6 times greater risk (odds) for developing MetS compared to PPARG CC genotype carriers.
•In the group of patients with MetS carriers of combination of genotypes IL-6 -174 GC or CC with PPARG CG or GG have almost 2.5 times larger odds of having high glucose compared to PPARG CC genotype carriers.
•In the group of patients with PPAR CG or GG genotypes, those with LPL M/P or P/P genotype had 38.62 times greater risk ( odds) for low HDL cholesterol.
•In the group of patients with ACE DD genotype, those with PPAR CG or GG genotype had about 10 times greater risk for obesity.
Haplotypes :Effects of gene-gene interactions on MS syndrome traits in males
Signifikant gene interaction observed between :PPAR & APOE with cholesterol; PPARG & IL-6 with Ch.;
IL-6, PPARG, with LDL and HDL; LPL & PPAR with HDL; PPAR &APOE with CRP;LPL & ACE with CRP
Haplotypes: effects of gene-gene interactions on MS traits in females
-Signifikant gene interaction - haplotypes observed in females between :
- PPARG and LPL with Triglycerides;
- PPARG and APOE with BMI;
- ACE and APOE with BMI
Gender-based dimorphism -
PPARG and LPL- possible explanations include:
possible interaction of LPL with either sex linked genes and/or sexual
hormon effects
the effects of differentially expressed autosomal genes in male and female
differential fat distribution patterns betwen genders
differential gene-environment and gene-gene interaction
although PPAR variant show no influence on MS or its traits when tested
separetly, its inteaction with LPL variants seems to be relevant at least for
HDL-C levels in male population
transcriptional regulation – LPL promotor less efficiently transactiveited in
the presence of the PPARG Ala allele.PPARGAla /Pvu(+), 1.8 times higher
risk for lower HDL-C values in males
Gender-specific effects of PPARG, APOE, ACE, AT1R, LPL and IL-6 gene variants on metabolic syndrome traits
CONCLUSION
- gene variants of PPARG, APOE, LPL, ACE and IL-6 could be
susceptibility factors of obesity, lipid status, and glucose intolerance
- PPARG gene variant interact with target gene contribute to the
variable susceptibility to developed MS ?
-- although further studies are needed to confirm the gender specificity
of genes interaction, they interplay betwen genes and gender seems to be
significant and could point to the personalized recommendation for
prevention of metabolic and cardiovascular diseases
Linkage polymorphism of AT1R with the incidence of stroke in early
adulthood
Genetic risk factors in patients with acute ischemic
stroke:The role of PPARG and IL-6 •
•
The role of genetics markers in the
development of atherosclerosis and stroke University of Zagreb, School of Medicine
GENE VARIANTS IN THE RENIN-
ANGIOTENSIN SYSTEM AND INCREASED
RISK OF EARLY ONSET OF
ISCHEMIC STROKE
Stroke is a multifactorial atherothrombotic disease.
The renin-angiontensin system has an important role in cerebrovascular disease
through a variety of processes.
The angiotensin-converting enzyme (ACE) converts angiotensin I into
angiotensin II, which binds the angiotensin II type-1 receptor (AT1R), and is a
potent vasoconstrictor.
Both ACE and AT1R display polymorphisms that can alter their functions.
The aim of our study was to investigate ACE I/D and AT1R A1166C
polymorphisms and the risk of early onset of ischemic stroke.schemic stroke is
multifactorial disease which include interactionn among various genetic and
environmental factors
Božina T, Bazina A, Lovrić T, Poljaković Z, Sertić J.
Gene variants in the RAS and increased risk of early onset of ischemic stroke.
7th Croatian Congress of Pharmacology, Zagreb, Croatia 2014.
GENE VARIANTS IN THE RENIN-ANGIOTENSIN SYSTEM AND
INCREASED RISK OF EARLY ONSET OF
ISCHEMIC STROKE
Clinical data and genetic and biochemical parameters of 114 patients, aged 18 to
55 years, with acute ischemic stroke were analyzed.
A total of 187 controls were matched for anthropometric parameters, but
were carotid ultrasonography alterations-free, and without history of stroke
before age of 70 in two generations.
DNA was genotyped for ACE I/D and AT1R A1166C polymorphism by means of
PCR-RFLP methods.
GENE VARIANTS IN THE RENIN-ANGIOTENSIN SYSTEM AND INCREASED
RISK OF EARLY ONSET OF
ISCHEMIC STROKE
Statistically significant difference was found in prevalence of particular
AT1R genotype (P=0.004) where AA genotype was more frequent in
patient group
Participants with AT1R 1166AA genotype are two times more likely to
belong to patient group than participants with AC or CC genotypes
(OR=2.0; 95% CI:1.2-3.2)
AT1R genotypes were statistically significant associated with type of
stroke (P=0.046)
Anterior stroke was more frequent among participants with AC or CC
genotype, while posterior stroke was more frequent among participants
with AA genotype
GENE VARIANTS IN THE RENIN-ANGIOTENSIN SYSTEM
AND INCREASED RISK OF EARLY ONSET OF
ISCHEMIC STROKE
ACE I/D polymorphism did not yield a risk of ischemic stroke.
AT1R A1166C polymorphism could be risk factor for early
occurrence of stroke.
Genetic risk factors in patients with acute ischemic stroke:The
role of PPARG and IL-6
•
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The role of genetics markers in the development
of atherosclerosis and stroke University of Zagreb, School of Medicine
Linkage polymorphism of AT1R with the incidence of stroke in
early adulthood
Bazina A, Mišmaš A, Božina N, Skorić MK, Poljaković Z, Sertić J.
Genetic risk factors in patients with acute ischemic stroke:
The role of PPARG. EFNS-ENS, Istanbul, Turkey 2014.
GENETIC RISK FACTORS IN
PATIENTS WITH ACUTE ISCHEMIC
STROKE:
THE ROLE OF PPARG AND IL-6
Ischemic stroke is multifactorial disease which include interactionn among
various genetic and environmental factors
The aim of our study was to estimate possible associations of two
analyzed gene PPARG and IL-6 and their gene variability on ischemic
stroke development in in early adulthood.
Genetic risk factors in patients with acute ischemic stroke: The
role of PPARG and IL-6
Study included 301 subjects, (114 patients and 187 healthy control)
PPARG CC, IL-6 -174 GC were statistically more frequent in the
patient's group
Patients had significantly higher BMI, higher blood pressure, and higher
level of total cholesterol, LDL, triglycerides, lowered level of HDL, and
elevated level of CRP
PPARG CC and IL-6 174 GC gene polymorphism variants could be
susceptibility factors for ischemic stroke development in patient
group, particularly in males, in presence of hypertension and
elevated CRP levels
GENETICS AND METABOLIC DYSFUNCTION
GENETIC BIOMARKERS
PERSONALIZED MEDICINE
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