Association study of serotonin transporter gene (SLC6A4) in systemic sclerosis in European Caucasian populations.
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.
Wipff
Julien
J
Service de Rhumatologie A, Hôpital Cochin, 27 rue du Faubourg St Jacques, 75014 Paris, France. julienwipff@cch.aphp.fr
Bonnet
Pierre
P
Ruiz
Barbara
B
Dieude
Philippe
P
Avouac
Jerome
J
Tiev
Kiet
K
Hachulla
Eric
E
Cracowski
Jean-Luc
JL
Diot
Elizabeth
E
Sibilia
Jean
J
Mouthon
Luc
L
Meyer
Olivier
O
Kahan
Andre
A
Boileau
Catherine
C
Allanore
Yannick
Y
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
C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins