Download Hereditary risks associated with preeclampsia

Helsinki Hot Topics, NFOG 6th October 2007
Reynir Tómas Geirsson, MD, PhD, FRCOG, professor,
Chief Editor, Acta Obstet Gynecol Scand
Dept. of Obstetrics and Gynecology,
Landspítali University Hospital,
Reykjavik, Iceland.
Hereditary risks associated with
preeclampsia
Hypertensive disorders of pregnancy....
Phenotypes-ssss...........
Preeclampsia
Diagnostic frontier ?
A scale
of
severity
Gest. hypertension
Normal
pregnant
Not pregnant
Diverse factors affect the risk for preeclampsia
Maternal
Fetal
Environmental
First pregnancy/primipaternity
Paternal antigens
Smoking
Long pregnancy interval
Chronic hypertension
Recurrent/prev. PE/E-pregnancy
Family history of PE/E/Ht
Age <20 or >35 years
PCOS
Renal disease
Collagen vascular disease
Hyperhomocysteinuria
AT3, Protein C + S, FVL
Diabetic states
Overweight/Obesity
Low body mass
Multiple pregnancy
Gamete/embryo donation
Hydatidiform mole
Fetal hydrops
Trisomy 13, triploidy
Confined placental mosacism
Uniparental disomy
Male fetus
IUGR/SGA
Viral/bact. infection
Nutritional factors
Low antioxidants
Preeclampsia syndrome…
the connection between pathology and symptoms
System
Pathological
changes
Symptoms and
signs
Cardiovascular
Increased peripheral resistance
Cardiac output diminished
Lipid alterations/peroxidation
Endothelial damage
Pregnancy hypertension
Renal
Capillary leakage
Glomerular endotheliosis
Generalised edema
Proteinuria
Coagulation
Activation of coagulation system
Reduced platelets/DIC
Raised uric acid
Microvascular thrombosis
Hepatic
Nervous
Placenta
Periportal edema/hemorrhage
Epigastric pain
Cell damage/Infarction
Raised liver enzymes/HELLP
Reduced perfusion/ischemia
Cortical/retinal vasospasm
Cerebral edema/hemorrhage
Trophoblast hypoxia/aponecrosis
Headache
Visual disturbance
Convulsions
Placental insufficiency
Are maternal susceptibility genes involved in
the development of hypertension in
pregnancy and in preeclampsia ?
Yes, there is substantial + clear evidence for a
familial and a genetic component,
relating to all disease forms,
lowering the threshold for developing disease.
Genetic susceptibility: a clue to better predictive,
preventive or ameliorating measures…..
*
How relevant is family
information ?
Original work in the USA (Chesley), and Scotland (Cooper,
Sutherland, Liston) showed that hypertension in pregnancy
(preelampsia) is a disease that is found in families..............
In 1990 the work of Arngrímsson, Geirsson, Walker and
Björnsson confirmed that:
• the disease is familial: x 3 higher prevalence for daughters
than daughters-in-law, both for all hypertensive disease
(p<0.02) and for PE/E (p<0.005)
• first or later born child: same prevalence
• born in a PE/E pregnancy or not: no difference
• inherited to granddaughters through sons and daughters
• compatible with major dominant gene with ~30%
penetrance or multifactorial inheritance
what is the relative risk
in familial disease ?
• Mother affected:
• Sister affected:
• Grandmother affected:
x4-5
x3-4
x2-3
Cnattingius et al., Swedish Birth Registry,
Am J Med Genet 2004
• 244.000 sibling pairs who had 701.000 babies
• Variance in liability to PE:
–
–
–
–
–
35% maternal genetic effects
20% fetal genetics (equal from father and mother)
13% a “couple” efffect
1% shared sibling environment
32% unmeasured factors
*
What is the likely inheritance
mode ?
After combining all existing materials
and comparing likelihood ratios…..
best goodness of fit for
• a major dominant gene with about 30%
penetrance
– (homozygous 1% and heterozygous 10-12%)
or more probably
• multifactorial inheritance = several
linked genes
(Arngrimsson, Geirsson, Björnsson 1995)
• modulated by fetal (paternal) genetic components
and environmental factors
*
What possible molecular
genetic links are there ?
Inherited susceptibility in the genetic pool….
• applies to a majority of cases, but not all
• need not be the same in all families/individuals
• may relate to various aspects of pathogenesis
–
–
–
–
–
–
trophoblast allograft invasion
blood pressure/volume control/vascular reactivity
endothelial function
coagulation
oxidative stress/lipid metabolism /inflammatory response
immunogenetics/immune cells/placental function
Candidate genes at some time positively related to
maternal susceptibility in linkage or association
studies.......
•
Chromosome 1 Renin, Angiotensinogen; FVL,
MTHFR, EPHX
Chromosome 2 LCHAD
•
•
Chromosome 3 AGTR1 (+)
Chromosome 6 HLA-G, HLA-a-A23/29 B44 DR7 haplotype, TNF
•
eNOS3, PAI-I
• Chromosome 8 LPL
• Chromosome 10 LPL, STOX1
•
Chromosome 7
•
•
•
•
Chromosome 11
Chromosome 17
Chromosome 19
Chromosome 20
Prothrombin, GST
ACE
apoE
Thrombomodulin
Differ in different populations, not much accordance
“...like fishing with a rod in a lake....”
“Combing” the genetic pool: Genome-wide scanning
“...pulling a net through the lake.....”
• Suggestive LOD score (2.2-3.6) or *study overlap on
chromosomes 1*, 2q, 3*, 3p, 4q*, 9p*, 10q, 11, 12q (HELLP),
15q, 18, 22 from Scotland, Australia/New Zealand,
Netherlands, Iceland, Japan, Finland.
• Significant LOD score (4.77) on chromosome 2p13
(Arngrimsson et al. 1999): Susceptibility gene between 88.15
and 99.41 cM; mostly from the 2 largest families
– Independent Au/NZ validation - 51 cM distance difference (PREG1)
– Finnish gene nearby
• Chr. 2 harbours a highly penetrant haplotype variant, not very
common in the population, responsible for cases with strong
familial component
Genetic
information:
a key to the
door ?
Accurate
phenotyping is
necessary to
make sense of
the genetics in
multifactorial
disorders..….
i.a. Kenneth Ward 2007
Different phenotype definitions affect linkage, - locus on
chromosome 2p changes as a result of changing the phenotype
definition.
• More phenotype information to to study phenotype/genotype
correlation
– the different forms of hypertensive disorder in pregnancy.
• Framework marker set of 1100 microsatellite markers + high
resolution scan on chromosome 2 with additional markers
– genome-wide association studies
• Multipoint allele-sharing method to assess linkage followed by
SNP-analysis/closer association studies.
LOD 2.8 in 458 patients + relatives, 153 families
Preliminary results show sensitivity of
phenotype/genotype analyses.........
• Patients with chronic hypertension do not contribute
to major locus on Chr. 2p
• Restricting analysis to severe forms of disease:
preeclampsia, superimposed preeclampsia and
eclampsia, does not reveal a separate major locus, only when combined with the gestational
hypertension do they contribute to the LOD score for
Chr. 2p.
• New locus on Chr. 5q, seen with severe phenotype
but not gestational hypertension. ? MI link
*
Is there a link to later
cardiovascular diseases ?
Is hypertension in pregnancy, particularly the
more severe forms, a marker of persisting
endothelial damage
or
of an inherited susceptibility ?
- which connects to a raised risk of later hypertension,
to ischemic heart disease and cerebrovascular death
in later life ?
Impaired microvascular regulation in resistance vessels, related to aberrant
insulin resistance, obesity and low plasma volume could be forerunners of
cardiovascular disorder
(Ness and Roberts 1996, Chambers et al. 2001, Ramsey et al 2003, Aardenburg et al. 2003).
Nine different studies:
•
Jónsdóttir LS et al. Acta Obstet Gynecol Scand 1995
–
•
Hannaford et al. Heart 1997
–
•
RR for later hypertension 2.35, myocardial infarction 2.24, chronic ischemic heart disease 1.74
Smith et al. Lancet 2001
–
•
RR for of death from ischemic heart disease 1.47
RR of 2.0 for mothers with a low birthweight baby + preeclampsia
Irgens et al. BMJ 2001
–
OR 1.65 risk of death for women with term preeclampsia
• preeclampsia and preterm delivery = OR 8.12 for cardiovascular disease
•
Wilson et al. BMJ 2003
–
increased RR for later hypertension (1.13-3.98), stroke (3.59) and ischemic heart disease (N.S).
•
Funai et al. Epidemiology 2005.
- RR of death after PE was 2.1 - most excess death from cardiovascular causes
•
Ray et al. Heart 2005
- RR later hypertension 2.35, myocardial infarction 2.24
• Wikström AK et al. BJOG & Acta Obstet Gynecol Scand 2005, BJOG 2007
- RR for all MI: 1.6 gestational ht, 1.9 mild PE, 2.8 severe PE
Survival Functions
1,2
1,0
Long mean
follow-up
,8
Reference
cancer death
hópur
Worse
,6
prognosis
kontról hópurafter
more severe
kontról hópur
disease
in
-censored
pregnancy
Cum Survival
,4
,2
0,0
-10
0
follow up
10
20
30
40
50
60
70
indexand
hópur
Age
parity
matter
index hópur-censored
somewhat
Study from Israel March 2005;
Funai et al. Epidemiology.
RR of death after PE 2.1
Most of the excess from
cardiovascular causes
Used primiparous women
with subsequent normotensive
pregnancy
PE promotes or hastens
systemic vascular disease
links to insulin resistance and lipid abnormalities...
•
•
•
Finnish women with PE:
mild insulin resistance
leptin + free fatty acid + triglyceride
HDL2 cholesterol
17 years later: insulin resistance persists
testosterone levels higher
(Laivuori et al. 1996 )
Icelandic women with E: 30 yaers later
LDL size smaller (endothelial dysfunction)
Apolipoprotein B
Total cholesterol : HDL cholesterol ratio
Tendency for higher FFA, cholesterol,
triglycerides, insulin, glucose
Damage in the
affected
pregnancy
or
genetic
susceptibility?
Clues might be
seen in the
offspring !
1
Fatal and non-fatal MIfree survival among
sons; significant
RR of 1.9.......
MI free survival
0,95
0,9
Control
Case
0,85
0,8
0,75
0,7
50
60
70
Age
80
90
What about the genetic background to adult hypertension ?
•
Complex issue: multitude of potential genes for many components interacting
with external modulators
•
A large number of association studies: Conflicting evidence
•
Essential hypertension: Mutations in 17 genes; 8/17 in rare Mendelian
forms of hypertension ( = 0.5%)
– From association studies with replication = 2 candidate genes
• angiotensinogen gene 1q42
• alpha-adducin gene 4p16
– From genome-wide linkage studies
• 2q 14-q23
• 3 (near Agt. II receptor)
• 18q (not fine-mapped, lod score 4.6)
»
Kristjansson et al. Hypertension June 2002
...... and the genetic background of other cardiovascular disease ?
(MI, CVD, POVD)
•
Complex issues with multifactorial gene and environmental interaction
•
SNPs in candidate genes tested for association : not replicated or confer only a modest
risk
•
Case-control association studies = several pro-inflammatory genes with variants
consistent with raised risk or protection
• MI = 4 genome-wide scans with significant peaks (16p, 3 q, 2, X) with in part unknown
or transscription genes in large families: explain < 2%
– a large genome-wide study shows a 13q12-13 site coding for a protein regulator of leukotriene
synthesis significantly associated with MI in men and early MI in women and with ischemic
stroke in males: RR 2.0, replicated in 3 populations, common in the population (18-29%).
Helgadottir et al. Nat Genet 2004
•
CVD (stroke) genome-wide scan shows locus on 5q12 (Lod 4.4) encoding for PDE4D,
16% of the population carry the at risk haplotype (heterozygote)(RR 1.8) and 0.8% are
homozygous (RR 3.8 ) - regulates cAMP in immune cells and smooth muscle which
affects plaque formation
Gretarsdottir et al Nat Genet 2003
What does it mean to the medical care-givers ?
We have to consider a risk of cardiovascular
disease, perhaps for two generations.......
......a likely genetic influence, but vascular damage not
excluded.....
• A new role in preventive medicine/public health
–
–
–
–
Advise women on blood pressure, cardiovascular check-ups
On smoking
On healthy life styles
On OC/HRT
• and consider their offspring...........
The hypertensive disorders in pregnancy are of
concern as a lifelong threat to health !
Thank you for your attention !
the collaborators old and new…..
Iceland
Univ. Clinic:
Reynir T. Geirsson
Reynir Arngrímsson*
Hólmgeir Björnsson *
Ásdís Baldursdóttir*
Sigrún Hjartardóttir
Ragnheidur Inga Bjarnadóttir*
Lilja S. Jónsdóttir*
Gerdur Å Árnadóttir
Sunna Snaedal*
Björn Geir Leifsson
UK
James J Walker
Stein Björnsson*
Alexander Cooke*
Mike Connor* and others*
France
Florent Soubrier*
USA
DeCode Genetics:
Carl Hubel
James Roberts*
Jeff Gulcher*
Mike Frigge*
Augusta MA Lachmeijer*
Kári Stefánsson
Valgerdur Steinthórsdóttir
Augie Kong
Netherlands
* not presently involved
Paternal/fetal genes involved ?
What cardiovascular diseases affect them ?
Cases
Hypertension
Daughters
Sons
Myocardial infarction
Daughters
Sons
NIDDM
Daughters
Sons
Stroke
Daughters
Sons
Controls
Relative
risk
RR
N
RR
N
2.05
2.02
37
42
1.17
1.60
41
64
1.75
1.26
0.87
1.37
8
48
0.70
0.94
12
63
1.25
1.46
2.02
1.59
8
11
1.28
1.25
10
17
1.77
1.43
6
8
1.14
1.49
8
16
The preliminary news.......
•
Cases
Children
1111 (3.43/woman) 2251 (3.64/woman)
Sons
Daughters
561 (50.5%)
550 (49.5%)
1118 (49.7%)
1133 (50.3%)
Died
Sons
Daughters
173 (15.6%)
111 (19.8%)
62 (11.3%)
281 (12.5%)
157 (14.0%) (58% more)
124 (10.9%)
Controls
Study from Iceland: Arnadóttir et al. BJOG March 2005.....
325 cases and 629 controls delivering now 55-75 years ago......
Age
(years)
Cause of
death
CI
95%
RR
<64
IHD
CVA
Ht
1.16-5.02
2.58-27.28
4.78-23.40
2.4
8.4
10.6
>65
IHD
CVA
Ht
1.15-2.08
0.53-1.57
1.84-4.95
1.5
0.9
3.0