A polymorphism in the human serotonin 5-HT2A receptor gene may protect against systemic sclerosis by reducing platelet aggregation.
BACKGROUND
Platelet aggregation may contribute to the pathogenesis of systemic sclerosis: following activation, platelets release significant amounts of serotonin - which promotes vasoconstriction and fibrosis, and further enhances aggregation. The C+1354T polymorphism in the exonic region of the serotonin 2A receptor gene determining the His452Tyr substitution was associated with blunted intracellular responses after serotonin stimulation, and may have a role in susceptibility to scleroderma.


METHODS
One hundred and fifteen consecutive systemic sclerosis patients and 140 well-matched healthy control individuals were genotyped by sequence-specific primer-PCR for the His452Tyr substitution of the serotonin 2A receptor gene, and associations were sought with scleroderma and its main clinical features. The functional relevance of the His452Tyr substitution was also assessed by evaluating the aggregation of platelet-rich plasma from His452/His452 and His452/Tyr452 healthy individuals after stimulation with adenosine diphosphate +/- serotonin.


RESULTS
The T allele of the C+1354T polymorphism was underrepresented in scleroderma patients compared with control individuals (5.2% versus 12.4%, P < 0.001, chi-square test and 1,000-fold permutation test) and its carriage reduced the risk for systemic sclerosis (odds ratio = 0.39, 95% confidence interval = 0.19 to 0.85, P < 0.01). Platelets from His452/Tyr452 healthy subjects more weakly responded to serotonin stimulation compared with platelets from His452/His452 individuals (3.2 +/- 2.6-fold versus 9.6 +/- 8.6-fold increase in aggregation, P = 0.017 by Kolmogorov-Smirnov test and P = 0.003 after correction for baseline adenosine diphosphate-induced aggregation values).


CONCLUSIONS
The His452Tyr substitution may influence susceptibility to systemic sclerosis by altering platelet aggregation in response to serotonin.
Beretta
Lorenzo
L
Referral Center for Systemic Autoimmune Diseases, University of Milan & Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Via Pace 9, 20122 Milan, Italy. lorberimm@hotmail.com
Cossu
Marta
M
Marchini
Maurizio
M
Cappiello
Francesca
F
Artoni
Andrea
A
Motta
Giovanna
G
Scorza
Raffaella
R