Impact of serotonin transporter and catechol-O-methyl transferase genes polymorphism on gastrointestinal dysfunction in Swedish and Japanese familial amyloidotic polyneuropathy patients

Abstract

Background

Differences in the gastrointestinal manifestations have emerged between Swedish and Japanese familial amyloidotic polyneuropathy amyloidogenic transthyretin Valine30Methionine (FAP ATTR Val30Met) patients. To elucidate the cause of the differences, we investigated the associations between serotonin transporter gene-linked polymorphic region (5-HTTLPR) and/or catechol-O-methyl transferase (COMT) gene polymorphism and their gastrointestinal in these patients.

Methods

Twenty-six Swedish and 24 Japanese patients with gastrointestinal disturbances, in whom genetic material was available, were included in the study. The initial gastrointestinal manifestations of the disease were classified as constipation, constipation alternating with diarrhoea, continuous diarrhoea, and nausea/vomiting. 5-HTTLPR and COMT gene polymorphism were assessed by polymerase chain reaction and enzymatic digestion.

Results

A significantly higher L_A allele frequency of 5-HTTLPR was noted in the Swedish population compared with that of the Japanese. Moreover, the L_A allele frequency tended to be lower in the continuous diarrhoea group than in that of the remaining groups of both Swedish and Japanese patients. No association between COMT genotype and initial gastrointestinal symptoms was noted.

Conclusion

A high expression of serotonin transporter induced by L_A allele of 5-HTTLPR may be one of the factors implicated with the inhibition of severe diarrhoea in early stages of Swedish FAP ATTR Val30Met patients.

Introduction

Hereditary transthyretin amyloidosis is a heterogeneous collection of familial diseases marked by a systemic accumulation of amyloid fibrils in various organs, often including the gastrointestinal tract [1], [2]. The most common neuropathic type of the disease is familial amyloidotic polyneuropathy (FAP) caused by an amyloidogenic transthyretin (ATTR) point mutation where valine is replaced by methionine at position 30 (ATTR Valine30Methionine (Val30Met)) [3]. Sporadic families with FAP are present world-wide, whereas endemic areas are found especially in Sweden, Portugal, and Japan.

In FAP ATTR Val30Met, gastrointestinal dysfunction is a common complication [4], [5], [6], [7], [8]. However, differences in the clinical expression of gastrointestinal dysfunction have emerged between endemic areas even though the patients all share the ATTR Val30Met mutation. The initial symptoms in the majority of Swedish cases are pronounced constipation and/or nausea and vomiting, whereas Japanese patients often suffer from diarrhoea at onset [7], [8]. The mechanism leading to the difference between those two populations of patients is not understood.

Recently, attention has been focused on the serotonin transporter and catechol-O-methyl transferase (COMT) genes as potential candidate genes in functional gastrointestinal disorders [9], [10], [11], [12], [13], [14], [15].

The serotonin transporter gene-linked polymorphic region (5-HTTLPR) polymorphism has traditionally been conceptualized as being biallelic, where the long (L) allele and the short (S) allele variants, respectively, correspond to a relatively high or low production of the serotonin transporter protein [16], [17]. Although a relationship between L/S genotype and gastrointestinal symptoms in patients with irritable bowel syndrome (IBS) has been reported [9], [10], [11], [12], [13], a recent meta-analysis failed to confirm this [14]. However, Hu XZ et al. [18] recently disclosed the existence of a low-frequency L single-nucleotide allele variant (L_G) in which adenine was exchanged by guanine in its sequence. The L_G function was comparable to that of the S allele, whereas the L_A (common type) allele was associated with a high production of the serotonin transporter protein. The association of these variants with the gastrointestinal disturbances in FAP ATTR Val30Met has not previously been investigated.

COMT is distributed in all organs and catalyses the transfer of a methyl group to catecholamines, including the neurotransmitters dopamine, adrenaline, and noradrenaline. As the most frequent non-dopaminergic side effect of COMT inhibition is diarrhoea [19], [20], inhibition of COMT may be found in FAP patients suffering from diarrhoea causing an abnormal prolonged action of catecholamines. A Valine158Methionine (Val158Met) (M) allele has been identified in the COMT gene associated with a three-to-four fold decline of the COMT activity compared with that of the non-Val158Met (V) allele [21]. Chong et al. [15] was unable to disclose an association between COMT genotype and gastrointestinal dysfunction in patients with Parkinson's disease who suffered from diarrhoea as a side effect of a selective COMT inhibitor (tolcapone) treatment, but the main systemic effect of tolcapone is not directed towards the intestinal tract. Moreover, the association of COMT polymorphism and gastrointestinal disturbances in FAP ATTR Val30Met has not been investigated.

The aim of the study was to investigate if the different alleles of 5-HTTLPR and/or COMT gene are related to gastrointestinal symptoms in FAP ATTR Val30Met patients, especially if the L_A allele of 5-HTTLPR and/or V allele of COMT gene are decreased in patient populations suffering from diarrhoea (Japanese) compared with those suffering from constipation (Swedish).