title: Association study of serotonin transporter gene (SLC6A4) in systemic sclerosis in European Caucasian populations.
abstract: OBJECTIVE
  Serotonin is a key contributing factor in pulmonary arterial hypertension (PAH) by inducing pulmonary arterial smooth muscle cell (PA-SMC) proliferation. This relates specifically to the internalization process in PA-SMC of the serotonin transporter (SLC6A4 or 5-HTT). A long (L)/short (S) (44 base pair insertion) functional polymorphism within the promoter of the transporter SLC6A4 gene has been reported to be associated with familial and idiopathic PAH. Our objective was to determine whether polymorphisms of SLC6A4 confer susceptibility to SSc and its vascular phenotype.
  
  
  METHODS
  Three Tag single-nucleotide polymorphisms (SNP) (rs2066713, rs1042173, rs6354) chosen using Hapmap and linkage disequilibrium data were genotyped in a total cohort of 667 SSc patients (56 with PAH, 207 with digital ulcerations) and 447 controls. All individuals were of French Caucasian origin. L/S polymorphism genotyping was determined by polymerase chain reaction in a random subgroup of 364 SSc patients (34 with PAH, 138 with digital ulcerations) and 218 controls.
  
  
  RESULTS
  Three polymorphisms (L/S, rs2066713, rs1042173) were in Hardy-Weinberg equilibrium in the control population, but rs6354 deviated. Allelic and genotypic frequencies for these 3 polymorphisms were similar in SSc patients and controls. Subphenotype analyses of subsets with PAH and digital ulceration did not detect any difference between SSc patients compared to controls.
  
  
  CONCLUSIONS
  These results from a large cohort of European Caucasian SSc patients do not support the implication of SLC6A4 in the pathogenesis of SSc and its vascular subphenotypes. However, serotonin pathways remain good candidates to contribute to the vasculopathy of SSc.
authors.affiliation: Service de Rhumatologie A, Hôpital Cochin, 27 rue du Faubourg St Jacques, 75014 Paris, France. julienwipff@cch.aphp.fr
authors.forename: Julien
authors.initials: J
authors.lastname: Wipff
authors.forename: Pierre
authors.initials: P
authors.lastname: Bonnet
authors.forename: Barbara
authors.initials: B
authors.lastname: Ruiz
authors.forename: Philippe
authors.initials: P
authors.lastname: Dieude
authors.forename: Jerome
authors.initials: J
authors.lastname: Avouac
authors.forename: Kiet
authors.initials: K
authors.lastname: Tiev
authors.forename: Eric
authors.initials: E
authors.lastname: Hachulla
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Cracowski
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Diot
authors.forename: Jean
authors.initials: J
authors.lastname: Sibilia
authors.forename: Luc
authors.initials: L
authors.lastname: Mouthon
authors.forename: Olivier
authors.initials: O
authors.lastname: Meyer
authors.forename: Andre
authors.initials: A
authors.lastname: Kahan
authors.forename: Catherine
authors.initials: C
authors.lastname: Boileau
authors.forename: Yannick
authors.initials: Y
authors.lastname: Allanore
mesh_terms: D015331:Cohort Studies; D005260:Female; D005602:France / Q000453:epidemiology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D006976:Hypertension, Pulmonary / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011928:Raynaud Disease / Q000150:complications / Q000453:epidemiology / Q000235:genetics*; D012595:Scleroderma, Systemic / Q000150:complications / Q000453:epidemiology / Q000235:genetics*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D012883:Skin Ulcer / Q000453:epidemiology / Q000209:etiology / Q000235:genetics; D044465:White People
chemical_list: C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins