A genome-wide scan for preeclampsia in the Netherlands

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Preeclampsia, hallmarked by de novo hypertension and proteinuria in pregnancy, has a familial tendency. Recently, a large Icelandic genome-wide scan provided evidence for a maternal susceptibility locus for preeclampsia on chromosome 2p13 which was confirmed by a genome scan from Australia and New Zealand (NZ). The current study reports on a genome-wide scan of Dutch affected sib-pair families. In total 67 Dutch affected sib-pair families, comprising at least two siblings with proteinuric preeclampsia, eclampsia or HELLP-syndrome, were typed for 293 polymorphic markers throughout the genome and linkage analysis was performed. The highest allele sharing lod score of 1.99 was seen on chromosome 12q at 109.5 cM. Two peaks overlapped in the same regions between the Dutch and Icelandic genome-wide scan at chromosome 3p and chromosome 15q. No overlap was seen on 2p. Re-analysis in 38 families without HELLP-syndrome (preeclampsia families) and 34 families with at least one sibling with HELLP syndrome (HELLP families), revealed two peaks with suggestive evidence for linkage in the non-HELLP families on chromosome 10q (lod score 2.38, D10S1432, 93.9 cM) and 22q (lod score 2.41, D22S685, 32.4 cM). The peak on 12q appeared to be associated with HELLP syndrome; it increased to a lod score of 2.1 in the HELLP families and almost disappeared in the preeclampsia families. A nominal peak on chromosome 11 in the preeclampsia families showed overlap with the second highest peak in the Australian/NZ study. Results from our Dutch genome-wide scan indicate that HELLP syndrome might have a different genetic background than preeclampsia.


  1. 1

    Ness RB, Roberts JM . Heterogeneous causes constituting the single syndrome of preeclampsia: a hypothesis and its implications Am J Obstet Gynecol 1996 175: 1365–1370

  2. 2

    Chesley LC, Cooper DW . Genetics of hypertension in pregnancy: possible single gene control of pre-eclampsia and eclampsia in the descendants of eclamptic women Br J Obstet Gynaecol 1986 93: 898–908

  3. 3

    Arngrimsson R, Bjornsson S, Geirsson RT, Bjornsson H, Walker JJ, Snaedal G . Genetic and familial predisposition to eclampsia and pre- eclampsia in a defined population Br J Obstet Gynaecol 1990 97: 762–769

  4. 4

    Cincotta RB, Brennecke SP . Family history of pre-eclampsia as a predictor for pre-eclampsia in primigravidas Int J Gynaecol Obstet 1998 60: 23–27

  5. 5

    Sutherland A, Cooper DW, Howie PW, Liston WA, MacGillivray I . The incidence of severe pre-eclampsia amongst mothers and mothers-in-law of pre-eclamptics and controls Br J Obstet Gynaecol 1981 88: 785–791

  6. 6

    Cooper DW, Hill JA, Chesley LC, Bryans CI . Genetic control of susceptibility to eclampsia and miscarriage Br J Obstet Gynaecol 1988 95: 644–653

  7. 7

    Lie RT, Rasmussen S, Brunborg H, Gjessing HK, Lie-Nielsen E, Irgens LM . Fetal and maternal contributions to risk of pre-eclampsia: population based study BMJ 1998 316: 1343–1347

  8. 8

    Liston WA, Kilpatrick DC . Is genetic susceptibility to pre-eclampsia conferred by homozygosity for the same single recessive gene in mother and fetus? Br J Obstet Gynaecol 1991 98: 1079–1086

  9. 9

    Arngrimsson R, Bjornsson H, Geirsson RT . Analysis of different inheritance patterns in preeclampsia/eclampsia syndrome Hypertension in Pregnancy 1995 14: 27–38

  10. 10

    Ward K, Hata A, Jeunemaitre X et al. A molecular variant of angiotensinogen associated with preeclampsia Nat Genet 1993 4: 59–61

  11. 11

    Guo G, Wilton AN, Fu Y, Qiu H, Brennecke SP, Cooper DW . Angiotensinogen gene variation in a population case-control study of preeclampsia/eclampsia in Australians and Chinese Electrophoresis 1997 18: 1646–1649

  12. 12

    Arngrimsson R, Hayward C, Nadaud S et al. Evidence for a familial pregnancy-induced hypertension locus in the eNOS-gene region Am J Hum Genet 1997 61: 354–362

  13. 13

    Lewis I, Lachmeijer G, Downing S et al. Failure to detect linkage of preeclampsia to the region of the NOS3 locus on chromosome 7q Am J Hum Genet 1999 64: 310–313

  14. 14

    Chen G, R Wilson, Wang SH, Zheng HZ, Walker JJ, McKillop JH . Tumour necrosis factor-alpha (TNF-alpha) gene polymorphism and expression in pre-eclampsia Clin Exp Immunol 1996 104: 154–159

  15. 15

    Dizon-Townson DS, Major H, Ward K . A promoter mutation in the tumor necrosis factor alpha gene is not associated with preeclampsia J Reprod Immunol 1998 38: 55–61

  16. 16

    Kupferminc MJ, Eldor A, Steinman N et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy N Engl J Med 1999 340: 9–13

  17. 17

    Sohda S, Arinami T, Hamada H, Yamada N, Hamaguchi H, Kubo T . Methylenetetrahydrofolate reductase polymorphism and pre- eclampsia J Med Genet 1997 34: 525–526

  18. 18

    Grandone E, Margaglione M, Colaizzo D et al. Factor V Leiden, C>T MTHFR polymorphism and genetic susceptibility to preeclampsia Thromb Haemostas 1997 77: 1052–1054

  19. 19

    Lachmeijer AM, Arngrimsson R, Bastiaans EJ et al. Mutations in the gene for methylenetetrahydrofolate reductase, homocysteine levels, and vitamin status in women with a history of preeclampsia Am J Obstet Gynecol 2001 184: 394–402

  20. 20

    Hayward C, Livingstone J, Holloway S, Liston WA, Brock DJ . An exclusion map for pre-eclampsia: assuming autosomal recessive inheritance Am J Hum Genet 1992 50: 749–757

  21. 21

    Harrison GA, Humphrey KE, Jones N et al. A genomewide linkage study of preeclampsia/eclampsia reveals evidence for a candidate region on 4q Am J Hum Genet 1997 60: 1158–1167

  22. 22

    Arngrimsson R, Sigurdardóttir S, Frigge ML et al. A genome-wide scan reveals a maternal susceptibility locus for pre-eclampsia on chromosome 2p13 Hum Mol Genet 1999 8: 1799–1805

  23. 23

    Lander E, Kruglyak L . Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results Nat Genet 1995 11: 241–247

  24. 24

    Moses EK, Lade JA, Guo G et al. A genome scan in families from Australia and New Zealand confirms the presence of a maternal susceptibility locus for pre-eclampsia, on chromosome 2 Am J Hum Genet 2000 67: 1581–1585

  25. 25

    Broman KW, Murray JC, Sheffield VC, White RL, Weber JL . Comprehensive human genetic maps: individual and sex-specific variation in recombination Am J Hum Genet 1998 63: 861–869

  26. 26

    Ott J: . in Ott J (ed): Analysis of Human Genetic linkage The Johns Hopkins University Press, Baltimore 1999 pp 272–296

  27. 27

    Kong A, Cox NJ . Allele-sharing models: LOD scores and accurate linkage tests Am J Hum Genet 1997 61: 1179–1188

  28. 28

    Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES . Parametric and nonparametric linkage analysis: a unified multipoint approach Am J Hum Genet 1996 58: 1347–1363

  29. 29

    Gudbjartsson DF, Jonasson K, Frigge ML, Kong A . Allegro, a new computer program for multipoint linkage analysis Nat Genet 2000 25: 12–13

  30. 30

    Whittemore AS, Halpern J . A class of tests for linkage using affected pedigree members Biometrics 1994 50: 118–127

  31. 31

    Brown MA, Hague WM, Higgins J et al. The detection, investigation and management of hypertension in pregnancy: full consensus statement Aust N Z J Obstet Gynaecol 2000 40: 139–155

  32. 32

    Redman CW . Current topic: pre-eclampsia and the placenta Placenta 1991 12: 301–308

  33. 33

    Boyd PA, Lindenbaum RH, Redman CW . Pre-eclampsia and trisomy 13: a possible association Lancet 1987 2: 425–427

  34. 34

    Newman RB, Eddy GL . Association of eclampsia and hydatidiform mole: case report and review of the literature Obstet Gynecol Surv 1988 43: 185–190

  35. 35

    Treloar SA, Cooper DW, Brennecke SP, Grehan MM, Martin NG . An Australian twin study of the genetic basis of preeclampsia and eclampsia Am J Obstet Gynecol 2001 184: 374–381

  36. 36

    Salonen RH, Lichtenstein P, Lipworth L, Cnattingius S . Genetic effects on the liability of developing pre-eclampsia and gestational hypertension Am J Med Genet 2000 91: 256–260

  37. 37

    Kilpatrick DC . Cohabitation and pregnancy-induced hypertension Lancet 1994 344: 1634 discussion 163–165

  38. 38

    Robillard PY, Dekker GA, Hulsey TC . Primipaternities in families: is the incidence of pregnancy-induced hypertensive disorders in multigravidas an anthropological marker of reproduction? Aust N Z J Obstet Gynaecol 1998 38: 284–287

  39. 39

    Tubbergen P, Lachmeijer AM, Althuisius SM, Vlak ME, van GH, Dekker GA . Change in paternity: a risk factor for preeclampsia in multiparous women? J Reprod Immunol 1999 45: 81–88

  40. 40

    Barker DJ . Maternal nutrition, fetal nutrition, and disease in later life Nutrition 1997 13: 807–813

  41. 41

    Innes KE, Marshall JA, Byers TE, Calonge N . A woman's own birth weight and gestational age predict her later risk of developing preeclampsia, a precursor of chronic disease Epidemiology 1999 10: 153–160

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This study was financially supported by The Netherlands Organisation for Scientific Research (NWO; Grant no. 950-10-612), Health Research and Development Council (Grant no. 28-2593), Wellcome Trust, UK, Icelandic Research Council, University of Iceland Research Fund, and deCODE Genetics Inc. We wish to thank professor R.T. Geirsson MD PhD, Department of Obstetrics and Gynaecology of the University Hospital in Reykjavik, Iceland for his kind support and advice throughout the study and preparation of the manuscript. We also wish to thank Barry Pieters, Guido van de Berk, Soe Janssens and Bibi de Leeuw for their enthusiastic help in collecting family data and drawing blood from participants, and all gynaecologists of the 21 Dutch Hospitals that were willing to facilitate our recruitment of families. Finally, we gratefully acknowledge all families for their participation in this study.

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Correspondence to Augusta MA Lachmeijer or Kári Stéfansson.

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Lachmeijer, A., Arngrímsson, R., Bastiaans, E. et al. A genome-wide scan for preeclampsia in the Netherlands. Eur J Hum Genet 9, 758–764 (2001) doi:10.1038/sj.ejhg.5200706

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  • preeclampsia
  • genetics
  • linkage
  • genome-wide scan
  • polymorphic markers
  • sib-pair

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