A polymorphism in the human serotonin 5-HT2A receptor gene may protect against systemic sclerosis by reducing platelet aggregation

Introduction

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).

Conclusion

The His⁴⁵²Tyr substitution may influence susceptibility to systemic sclerosis by altering platelet aggregation in response to serotonin.