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

Lorenzo Beretta, Marta Cossu, Maurizio Marchini, Francesca Cappiello, Andrea Artoni, Giovanna Motta, Raffaella Scorza

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numberR103
JournalArthritis Research and Therapy
Volume10
Issue number5
DOIs
Publication statusPublished - Sep 1 2008

Fingerprint

Receptor, Serotonin, 5-HT2A
Systemic Scleroderma
Platelet Aggregation
Serotonin
Genes
Adenosine Diphosphate
Blood Platelets
Platelet-Rich Plasma
Platelet Activation
Chi-Square Distribution
Nonparametric Statistics
Vasoconstriction
Healthy Volunteers
Fibrosis
Alleles
Odds Ratio
Confidence Intervals
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Rheumatology
  • Immunology
  • Immunology and Allergy
  • Medicine(all)

Cite this

A polymorphism in the human serotonin 5-HT2A receptor gene may protect against systemic sclerosis by reducing platelet aggregation. / Beretta, Lorenzo; Cossu, Marta; Marchini, Maurizio; Cappiello, Francesca; Artoni, Andrea; Motta, Giovanna; Scorza, Raffaella.

In: Arthritis Research and Therapy, Vol. 10, No. 5, R103, 01.09.2008.

Research output: Contribution to journalArticle

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abstract = "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.",
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AU - Beretta, Lorenzo

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AU - Marchini, Maurizio

AU - Cappiello, Francesca

AU - Artoni, Andrea

AU - Motta, Giovanna

AU - Scorza, Raffaella

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N2 - 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.

AB - 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.

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