Genetic dissection of the pre-eclampsia susceptibility locus on chromosome 2q22 reveals shared novel risk factors for cardiovascular disease

Matthew P. Johnson, Shaun P. Brennecke, Christine E. East, Thomas D. Dyer, Linda T. Roten, J. Michael Proffitt, Phillip E. Melton, Mona H. Fenstad, Tia Aalto-Viljakainen, Kaarin Mäkikallio, Seppo Heinonen, Eero Kajantie, Juha Kere, Hannele Laivuori, Rigmor Austgulen, John Blangero, Eric K. Moses, Anneli Pouta, Katja Kivinen, Eeva Ekholm & 7 others Reija Hietala, Susanna Sainio, Terhi Saisto, Jukka Uotila, Miira Klemetti, A. I. Lokki, Leena Georgiadis

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Pre-eclampsia is an idiopathic pregnancy disorder promoting morbidity and mortality to both mother and child. Delivery of the fetus is the only means to resolve severe symptoms. Women with pre-eclamptic pregnancies demonstrate increased risk for later life cardiovascular disease (CVD) and good evidence suggests these two syndromes share several risk factors and pathophysiological mechanisms. To elucidate the genetic architecture of pre-eclampsia we have dissected our chromosome 2q22 susceptibility locus in an extended Australian and New Zealand familial cohort. Positional candidate genes were prioritized for exon-centric sequencing using bioinformatics, SNPing, transcriptional profiling and QTL-walking. In total, we interrogated 1598 variants from 52 genes. Four independent SNP associations satisfied our gene-centric multiple testing correction criteria: a missense LCT SNP (rs2322659, P 1/40.0027), a synonymous LRP1B SNP (rs35821928, P 1/4 0.0001), an UTR-3 RND3 SNP (rs115015150, P 1/4 0.0024) and a missense GCA SNP (rs17783344, P 1/4 0.0020).We replicated the LCT SNP association (P 1/4 0.02) and observed a borderline association for the GCA SNP (P 1/4 0.07) in an independent Australian case-control population. The LRP1B and RND3 SNP associations were not replicated in this same Australian singleton cohort. Moreover, these four SNP associations could not be replicated in two additional case-control populations from Norway and Finland. These four SNPs, however, exhibit pleiotropic effects with several quantitative CVD-related traits. Our results underscore the genetic complexity of preeclampsia and present novel empirical evidence of possible shared genetic mechanisms underlying both pre-eclampsia and other CVDrelated risk factors.

Original languageEnglish (US)
Pages (from-to)423-437
Number of pages15
JournalMolecular Human Reproduction
Volume19
Issue number7
DOIs
StatePublished - Jul 2013
Externally publishedYes

Fingerprint

Pre-Eclampsia
Single Nucleotide Polymorphism
Dissection
Cardiovascular Diseases
Chromosomes
Genes
Pregnancy
3' Untranslated Regions
Finland
Norway
Computational Biology
New Zealand
Population
Walking
Exons
Fetus
Mothers
Morbidity
Mortality

Keywords

  • 2q22
  • Cardiovascular disease risk trait
  • Genetic association
  • Pleiotropy
  • Pre-eclampsia

ASJC Scopus subject areas

  • Molecular Biology
  • Embryology
  • Cell Biology
  • Genetics
  • Developmental Biology
  • Reproductive Medicine
  • Obstetrics and Gynecology

Cite this

Johnson, M. P., Brennecke, S. P., East, C. E., Dyer, T. D., Roten, L. T., Proffitt, J. M., ... Georgiadis, L. (2013). Genetic dissection of the pre-eclampsia susceptibility locus on chromosome 2q22 reveals shared novel risk factors for cardiovascular disease. Molecular Human Reproduction, 19(7), 423-437. https://doi.org/10.1093/molehr/gat011

Genetic dissection of the pre-eclampsia susceptibility locus on chromosome 2q22 reveals shared novel risk factors for cardiovascular disease. / Johnson, Matthew P.; Brennecke, Shaun P.; East, Christine E.; Dyer, Thomas D.; Roten, Linda T.; Proffitt, J. Michael; Melton, Phillip E.; Fenstad, Mona H.; Aalto-Viljakainen, Tia; Mäkikallio, Kaarin; Heinonen, Seppo; Kajantie, Eero; Kere, Juha; Laivuori, Hannele; Austgulen, Rigmor; Blangero, John; Moses, Eric K.; Pouta, Anneli; Kivinen, Katja; Ekholm, Eeva; Hietala, Reija; Sainio, Susanna; Saisto, Terhi; Uotila, Jukka; Klemetti, Miira; Lokki, A. I.; Georgiadis, Leena.

In: Molecular Human Reproduction, Vol. 19, No. 7, 07.2013, p. 423-437.

Research output: Contribution to journalArticle

Johnson, MP, Brennecke, SP, East, CE, Dyer, TD, Roten, LT, Proffitt, JM, Melton, PE, Fenstad, MH, Aalto-Viljakainen, T, Mäkikallio, K, Heinonen, S, Kajantie, E, Kere, J, Laivuori, H, Austgulen, R, Blangero, J, Moses, EK, Pouta, A, Kivinen, K, Ekholm, E, Hietala, R, Sainio, S, Saisto, T, Uotila, J, Klemetti, M, Lokki, AI & Georgiadis, L 2013, 'Genetic dissection of the pre-eclampsia susceptibility locus on chromosome 2q22 reveals shared novel risk factors for cardiovascular disease', Molecular Human Reproduction, vol. 19, no. 7, pp. 423-437. https://doi.org/10.1093/molehr/gat011
Johnson, Matthew P. ; Brennecke, Shaun P. ; East, Christine E. ; Dyer, Thomas D. ; Roten, Linda T. ; Proffitt, J. Michael ; Melton, Phillip E. ; Fenstad, Mona H. ; Aalto-Viljakainen, Tia ; Mäkikallio, Kaarin ; Heinonen, Seppo ; Kajantie, Eero ; Kere, Juha ; Laivuori, Hannele ; Austgulen, Rigmor ; Blangero, John ; Moses, Eric K. ; Pouta, Anneli ; Kivinen, Katja ; Ekholm, Eeva ; Hietala, Reija ; Sainio, Susanna ; Saisto, Terhi ; Uotila, Jukka ; Klemetti, Miira ; Lokki, A. I. ; Georgiadis, Leena. / Genetic dissection of the pre-eclampsia susceptibility locus on chromosome 2q22 reveals shared novel risk factors for cardiovascular disease. In: Molecular Human Reproduction. 2013 ; Vol. 19, No. 7. pp. 423-437.
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