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

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.

Major Depression and Psoriasis: A Psychodermatological Phenomenon

“…Therefore, we believe a possible connection between the two conditions exists. This notion is also supported by many other authors in various research articles [67]. Furthermore, genetic variations of the serotonergic system have been described, including a variable number of tandem repeat polymorphisms in intron 2 of the 5-HTT gene and polymorphism of serotonin receptors, which could play a role in the pathogenesis of psoriasis and depressive symptoms in psoriasis patients [67].…”

5HT2A polymorphism His452Tyr in a German Caucasian systemic sclerosis population – authors' response

“…The variance of results between our recent article [ 1 ] and the replication study by Kirsten and colleagues [ 2 ] in German patients may prompt the reader to ask the simple question: what conclusion can be drawn from these contradictory results?…”

“…This is consistent with a general overestimate of the role of a gene in the first association study of it [ 3 ] and, indeed, we have always been aware of the possibility of false positive findings. Hence, we provided the reader a mean (for example, the false probability report probability) with which to gauge the strength of the association and the chance of having described a spurious result [ 1 ].…”

“…Moreover, the prevalence of females in our population was much higher (93.9% versus 50%) and it is well-known that platelets differently aggregate in males and females due to hormonal and gender-specific influences [ 6 ]. As we hypothesized that the rs6314 polymorphism does not act as a causative genetic mutation per se , but rather it is important in amplifying SSc-causative and coagulative pathological processes once they have already been triggered by other factors [ 1 ], all the above-mentioned and other hidden differences in the genetic background are likely to be of particular relevance. In this sense, it is reductive to consider the importance of the studied single nucleotide polymorphism on SSc susceptibility only for its main independent effect, but it should more appropriately be viewed in the context of a broader gene-gene or gene-environmental frame.…”

5HT2A polymorphism His452Tyr in a German Caucasian systemic sclerosis population

“…Recently, Beretta and colleagues [ 1 ] reported a protective association of the serotonin 5-HT 2A receptor gene polymorphism His452Tyr (C+1354T, rs6314) with systemic sclerosis (SSc) in an Italian population. 5HT 2A accounts for most vasoconstrictive and platelet aggregation due to serotonin activity [ 2 ].…”