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Author (up) Johnson, M.P.; Brennecke, S.P.; East, C.E.; Dyer, T.D.; Roten, L.T.; Proffitt, J.M.; Melton, P.E.; Fenstad, M.H.; Aalto-Viljakainen, T.; Makikallio, K.; Heinonen, S.; Kajantie, E.; Kere, J.; Laivuori, H.; Austgulen, R.; Blangero, J.; Moses, E.K. url  doi
  Title Genetic dissection of the pre-eclampsia susceptibility locus on chromosome 2q22 reveals shared novel risk factors for cardiovascular disease Type Journal Article
  Year 2013 Publication Molecular Human Reproduction Abbreviated Journal Mol Hum Reprod  
  Volume 19 Issue 7 Pages 423-437  
  Keywords Australia; Cardiovascular Diseases/*genetics; Chromosomes, Human, Pair 2/*genetics; Female; Genetic Predisposition to Disease/genetics; Genotype; Humans; Polymorphism, Single Nucleotide/genetics; Pre-Eclampsia/*genetics; Pregnancy; Risk Factors; 2q22; cardiovascular disease risk trait; genetic association; pleiotropy; pre-eclampsia  
  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 = 0.0027), a synonymous LRP1B SNP (rs35821928, P = 0.0001), an UTR-3 RND3 SNP (rs115015150, P = 0.0024) and a missense GCA SNP (rs17783344, P = 0.0020). We replicated the LCT SNP association (P = 0.02) and observed a borderline association for the GCA SNP (P = 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 pre-eclampsia and present novel empirical evidence of possible shared genetic mechanisms underlying both pre-eclampsia and other CVD-related risk factors.  
  Address Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX 78227, USA  
  Corporate Author FINNPEC Study Group Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1360-9947 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:23420841; PMC3690803 Approved no  
  Call Number HUNT @ maria.stuifbergen @ Serial 1437  
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Author (up) Johnson, M.P.; Brennecke, S.P.; East, C.E.; Goring, H.H.H.; Kent, J.W.J.; Dyer, T.D.; Said, J.M.; Roten, L.T.; Iversen, A.-C.; Abraham, L.J.; Heinonen, S.; Kajantie, E.; Kere, J.; Kivinen, K.; Pouta, A.; Laivuori, H.; Austgulen, R.; Blangero, J.; Moses, E.K. url  doi
  Title Genome-wide association scan identifies a risk locus for preeclampsia on 2q14, near the inhibin, beta B gene Type Journal Article
  Year 2012 Publication PloS one Abbreviated Journal PLoS One  
  Volume 7 Issue 3 Pages e33666  
  Keywords Australia; Chromosomes, Human, Pair 2/*genetics; Cohort Studies; Computational Biology; Female; Finland; Gene Expression Regulation; Genetic Loci/*genetics; *Genetic Predisposition to Disease; Genome, Human/genetics; *Genome-Wide Association Study; Humans; Inhibin-beta Subunits/*genetics/metabolism; Norway; Polymorphism, Single Nucleotide/genetics; Pre-Eclampsia/*genetics; Pregnancy; Reproducibility of Results; Risk Factors; Sequence Analysis, DNA  
  Abstract Elucidating the genetic architecture of preeclampsia is a major goal in obstetric medicine. We have performed a genome-wide association study (GWAS) for preeclampsia in unrelated Australian individuals of Caucasian ancestry using the Illumina OmniExpress-12 BeadChip to successfully genotype 648,175 SNPs in 538 preeclampsia cases and 540 normal pregnancy controls. Two SNP associations (rs7579169, p = 3.58x10(-7), OR = 1.57; rs12711941, p = 4.26x10(-7), OR = 1.56) satisfied our genome-wide significance threshold (modified Bonferroni p<5.11x10(-7)). These SNPs reside in an intergenic region less than 15 kb downstream from the 3' terminus of the Inhibin, beta B (INHBB) gene on 2q14.2. They are in linkage disequilibrium (LD) with each other (r(2) = 0.92), but not (r(2)<0.80) with any other genotyped SNP +/-250 kb. DNA re-sequencing in and around the INHBB structural gene identified an additional 25 variants. Of the 21 variants that we successfully genotyped back in the case-control cohort the most significant association observed was for a third intergenic SNP (rs7576192, p = 1.48x10(-7), OR = 1.59) in strong LD with the two significant GWAS SNPs (r(2)>0.92). We attempted to provide evidence of a putative regulatory role for these SNPs using bioinformatic analyses and found that they all reside within regions of low sequence conservation and/or low complexity, suggesting functional importance is low. We also explored the mRNA expression in decidua of genes +/-500 kb of INHBB and found a nominally significant correlation between a transcript encoded by the EPB41L5 gene, approximately 250 kb centromeric to INHBB, and preeclampsia (p = 0.03). We were unable to replicate the associations shown by the significant GWAS SNPs in case-control cohorts from Norway and Finland, leading us to conclude that it is more likely that these SNPs are in LD with as yet unidentified causal variant(s).  
  Address Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, United States of America  
  Corporate Author FINNPEC Study Group Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1932-6203 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:22432041; PMC3303857 Approved no  
  Call Number HUNT @ maria.stuifbergen @ Serial 1534  
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Author (up) Thomsen, L.C.V.; McCarthy, N.S.; Melton, P.E.; Cadby, G.; Austgulen, R.; Nygard, O.K.; Johnson, M.P.; Brennecke, S.; Moses, E.K.; Bjorge, L.; Iversen, A.-C. url  doi
  Title The antihypertensive MTHFR gene polymorphism rs17367504-G is a possible novel protective locus for preeclampsia Type Journal Article
  Year 2017 Publication Journal of Hypertension Abbreviated Journal J Hypertens  
  Volume 35 Issue 1 Pages 132-139  
  Keywords Adolescent; Adult; Alleles; Australia; Case-Control Studies; Female; Gene Frequency; Genetic Pleiotropy; Genome-Wide Association Study; Genotype; Humans; Hypertension/genetics; Inflammation/genetics; Methylenetetrahydrofolate Reductase (NADPH2)/*genetics; Norway; Polymorphism, Single Nucleotide; Pre-Eclampsia/*genetics; Pregnancy; Protective Factors; Young Adult  
  Abstract OBJECTIVE: Preeclampsia is a complex heterogeneous disease commonly defined by new-onset hypertension and proteinuria in pregnancy. Women experiencing preeclampsia have increased risk for cardiovascular diseases (CVD) later in life. Preeclampsia and CVD share risk factors and pathophysiologic mechanisms, including dysregulated inflammation and raised blood pressure. Despite commonalities, little is known about the contribution of shared genes (pleiotropy) to these diseases. This study aimed to investigate whether genetic risk factors for hypertension or inflammation are pleiotropic by also being associated with preeclampsia. METHODS: We genotyped 122 single nucleotide polymorphisms (SNPs) in women with preeclampsia (n = 1006) and nonpreeclamptic controls (n = 816) from the Norwegian HUNT Study. SNPs were chosen on the basis of previously reported associations with either nongestational hypertension or inflammation in genome-wide association studies. The SNPs were tested for association with preeclampsia in a multiple logistic regression model. RESULTS: The minor (G) allele of the intronic SNP rs17367504 in the gene methylenetetrahydrofolate reductase (MTHFR) was associated with a protective effect on preeclampsia (odds ratio 0.65, 95% confidence interval 0.53-0.80) in the Norwegian cohort. This association did not replicate in an Australian preeclampsia case-control cohort (P = 0.68, odds ratio 1.05, 95% confidence interval 0.83-1.32, minor allele frequency = 0.15). CONCLUSION: MTHFR is important for regulating transmethylation processes and is involved in regulation of folate metabolism. The G allele of rs17367504 has previously been shown to protect against nongestational hypertension. Our study suggests a novel association between this allele and reduced risk for preeclampsia. This is the first study associating the minor (G) allele of a SNP within the MTHFR gene with a protective effect on preeclampsia, and in doing so identifying a possible pleiotropic protective effect on preeclampsia and hypertension.  
  Address aDepartment of Gynecology and Obstetrics, Haukeland University Hospital bDepartment of Clinical Science, University of Bergen, Bergen, Norway cCentre for Genetic Origins of Health and Disease, University of Western Australia, Perth, Australia dDepartment of Cancer Research and Molecular Medicine, Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim eDepartment of Heart Disease, Haukeland University Hospital, Bergen, Norway fSouth Texas Diabetes and Obesity Institute, School of Medicine, University of Texas Rio Grande Valley, Brownsville, Texas, USA gDepartment of Obstetrics and Gynaecology, University of Melbourne, Parkville hPregnancy Research Centre, Department of Maternal-Fetal Medicine, Royal Women's Hospital, Parkville, Victoria iFaculty of Health Sciences, Curtin University, Perth, Western Australia, Australia  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0263-6352 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:27755385; PMCID:PMC5131692 Approved no  
  Call Number HUNT @ maria.stuifbergen @ Serial 1996  
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