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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