title: Primary pulmonary hypertension may be a heterogeneous disease with a second locus on chromosome 2q31.
abstract: OBJECTIVE
  The aim of our study was to identify genetic causes of primary pulmonary hypertension (PPH), to estimate the proportion of families with mutations in the BMPR2 (bone morphogenetic protein receptor type 2) gene, and to examine whether genetic heterogeneity might play a role.
  
  
  BACKGROUND
  The BMPR2 mutations have been identified in a substantial portion of patients with familial or sporadic PPH. However, the genetic cause of PPH remains unclear in at least 45% of families.
  
  
  METHODS
  We investigated 130 members of 10 families with at least 1 PPH patient, recruited without selection for familial disease. Manifest PPH was documented in 21 individuals. An increase in pulmonary artery systolic pressure (PASP) above 40 mm Hg during supine bicycle exercise was found in 46 healthy individuals. Their PASP increased from 21.0 +/- 4.6 mm Hg at rest to 54.0 +/- 9.8 mm Hg during exercise. In 51 relatives, PASP values were normal at rest and during exercise, and 12 members were classified as status unknown.
  
  
  RESULTS
  Two families showed a mutation in the BMPR2 gene. Three families with no BMBR2 mutation showed evidence for linkage to a more proximal location on chromosome 2q31 (odds ratio [OR] for linkage 1.1.10(6):1). This locus, designated PPH2, maps in-between the markers D2S335 and D2S2314. We obtained significant support for heterogeneity in PPH with an OR of 2.8.10(11).
  
  
  CONCLUSIONS
  We conclude that PPH may be a genetically heterogeneous disorder with at least two-and possibly more-causative genes.
authors.affiliation: Institute of Human Genetics, University of Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Rindermann
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Grünig
authors.forename: Albrecht
authors.initials: A
authors.lastname: von Hippel
authors.forename: Rolf
authors.initials: R
authors.lastname: Koehler
authors.forename: Gabriel
authors.initials: G
authors.lastname: Miltenberger-Miltenyi
authors.forename: Derliz
authors.initials: D
authors.lastname: Mereles
authors.forename: Karlin
authors.initials: K
authors.lastname: Arnold
authors.forename: Michael
authors.initials: M
authors.lastname: Pauciulo
authors.forename: William
authors.initials: W
authors.lastname: Nichols
authors.forename: Horst
authors.initials: H
authors.lastname: Olschewski
authors.forename: Marius M
authors.initials: MM
authors.lastname: Hoeper
authors.forename: Jörg
authors.initials: J
authors.lastname: Winkler
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kübler
authors.forename: Claus R
authors.initials: CR
authors.lastname: Bartram
authors.forename: Bart
authors.initials: B
authors.lastname: Janssen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001794:Blood Pressure / Q000502:physiology; D052006:Bone Morphogenetic Protein Receptors, Type II; D002648:Child; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D005080:Exercise Test; D005260:Female; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000235:genetics* / Q000503:physiopathology; D019901:Locus Control Region / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011651:Pulmonary Artery / Q000503:physiopathology
chemical_list: D017346:Protein Serine-Threonine Kinases; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II