title: Variation in endoglin pathway genes is associated with preeclampsia: a case-control candidate gene association study.
abstract: BACKGROUND
  Preeclampsia is a hypertensive, multi-system pregnancy disorder whose pathophysiology remains unclear. Elevations in circulating soluble endoglin (sENG) and placental/blood ENG mRNA expression antedate the clinical onset of preeclampsia. This study investigated if endoglin (ENG) pathway genetic variation was also associated with the development of preeclampsia.
  
  
  METHODS
  We used a case-control candidate gene association design. Data from 355 white (181 preeclampsia cases/174 controls) and 60 black (30 preeclampsia cases/30 controls) women matched on ancestry, age, and parity were analyzed. Tagging single nucleotide polymorphisms (tSNPs) and potentially functional SNPs in ENG, TGFβ1, TGFβR1, ALK1, and TGFβR2 were genotyped with iPLEX® and TaqMan®. Chi-square or Fisher's exact tests were used to conduct allele/genotype/haplotype tests in white/black subgroups separately. Odds ratios were computed with binary logistic regression for tSNPs with significant genotype tests.
  
  
  RESULTS
  Of the 49 SNPs evaluated, variation in two ENG tSNPs (rs11792480, rs10121110) and one TGFβR2 tSNP (rs6550005) was associated with preeclampsia in white women (P <0.05, each). In black women, variation in two TGFβ1 tSNPs (rs4803455, rs4803457), one TGFβR1 tSNP (rs10739778), and three TGFβR2 tSNPs (rs6550005, rs1346907, rs877572) was associated with preeclampsia (P <0.05, each). Further evaluation of ENG tSNP rs10121110 revealed that white women inheriting the AA genotype were 2.29 times more likely to develop preeclampsia compared to the GG genotype (P = 0.008, [99% CI: 1.02 to 5.13]). For black women, similar evaluation of TGFβ1 tSNP rs4803457 revealed women inheriting the CT genotype were 7.44 times more likely to develop preeclampsia than those with the CC genotype (P = 0.005, [99% CI: 1.19 to 46.41]).
  
  
  CONCLUSIONS
  ENG pathway genetic variation is associated with preeclampsia. Different ENG pathway genes may be involved in preeclampsia development among white and black women. Additional studies are needed to validate these findings and to determine if genetic variation in ENG pathway genes impacts ENG and sENG levels in preeclampsia.
authors.affiliation: University of Pittsburgh School of Nursing, 3500 Victoria Street, 440 Victoria Building, Pittsburgh, PA 15261, USA. mjb111@pitt.edu
authors.forename: Mandy J
authors.initials: MJ
authors.lastname: Bell
authors.forename: James M
authors.initials: JM
authors.lastname: Roberts
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Founds
authors.forename: Arun
authors.initials: A
authors.lastname: Jeyabalan
authors.forename: Lauren
authors.initials: L
authors.lastname: Terhorst
authors.forename: Yvette P
authors.initials: YP
authors.lastname: Conley
mesh_terms: D030301:Activin Receptors, Type II / Q000235:genetics; D000328:Adult; D015703:Antigens, CD / Q000235:genetics*; D044383:Black People / Q000235:genetics*; D016022:Case-Control Studies; D000071063:Endoglin; D005260:Female; D015870:Gene Expression; D006239:Haplotypes; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011225:Pre-Eclampsia / Q000208:ethnology / Q000235:genetics*; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D011956:Receptors, Cell Surface / Q000235:genetics*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D044465:White People / Q000235:genetics*; D055815:Young Adult
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II
references.citation: J Biol Chem. 2001 Sep 14;276(37):34486-94
references.pmid: 11432852
references.citation: Br J Obstet Gynaecol. 1984 Feb;91(2):128-32
references.pmid: 6696858
references.citation: Placenta. 2009 Mar;30 Suppl A:S32-7
references.pmid: 19070896
references.citation: Lancet. 2001 Jan 6;357(9249):53-6
references.pmid: 11197372
references.citation: Nucleic Acids Res. 2011 Jan;39(Database issue):D876-82
references.pmid: 20959295
references.citation: Prenat Diagn. 2008 Oct;28(10):956-61
references.pmid: 18792924
references.citation: Nat Med. 2006 Jun;12(6):642-9
references.pmid: 16751767
references.citation: Obstet Gynecol. 2002 Jan;99(1):159-67
references.pmid: 16175681
references.citation: Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3479-84
references.pmid: 10725360
references.citation: Hypertension. 2007 Jul;50(1):137-42
references.pmid: 17515455
references.citation: Hum Mutat. 2006 Jul;27(7):667-75
references.pmid: 16752392
references.citation: FASEB J. 2004 Mar;18(3):609-11
references.pmid: 14734648
references.citation: Am J Obstet Gynecol. 2010 Dec;203(6):575.e1-7
references.pmid: 20934680
references.citation: Am J Hum Genet. 2007 Sep;81(3):559-75
references.pmid: 17701901
references.citation: Am J Obstet Gynecol. 2010 May;202(5):445.e1-11
references.pmid: 20223440
references.citation: Blood. 1998 Dec 15;92(12):4677-90
references.pmid: 9845534
references.citation: J Biol Chem. 2002 Aug 9;277(32):29197-209
references.pmid: 12015308
references.citation: Endocrinology. 1997 Nov;138(11):4977-88
references.pmid: 9348229
references.citation: Am J Pathol. 2012 Mar;180(3):888-894
references.pmid: 22296769
references.citation: Am J Obstet Gynecol. 2000 Jul;183(1):S1-S22
references.pmid: 10920346
references.citation: Circ Res. 2005 Apr 1;96(6):684-92
references.pmid: 15718503
references.citation: J Biol Chem. 1990 May 25;265(15):8361-4
references.pmid: 1692830
references.citation: BJOG. 2010 Apr;117(5):557-64
references.pmid: 20121832
references.citation: Endocrinology. 2011 Nov;152(11):4386-94
references.pmid: 21914777
references.citation: Placenta. 2011 Feb;32(2):175-82
references.pmid: 21183218
references.citation: Cancer Res. 2010 May 15;70(10):4141-50
references.pmid: 20424116
references.citation: Reprod Sci. 2009 Sep;16(9):857-64
references.pmid: 19474289
references.citation: J Biol Chem. 1992 Sep 25;267(27):19027-30
references.pmid: 1326540
references.citation: Biol Reprod. 1994 Sep;51(3):405-13
references.pmid: 7528549
references.citation: Placenta. 2009 May;30(5):424-33
references.pmid: 19249095