Альманах клинической медицины. 2019; 47: 496-504
Функциональный полиморфизм транспортера обратного захвата серотонина гена SLC6A4 при различных клинических вариантах синдрома раздраженного кишечника
https://doi.org/10.18786/2072-0505-2019-47-072Аннотация
Актуальность. Синдром раздраженного кишечника (СРК) относится к многофакторным заболеваниям, генетический аспект которых находится в фокусе внимания исследователей.
Цель – изучить функциональный полиморфизм транспортера обратного захвата серотонина гена SLC6A4 при разных формах СРК.
Материал и методы. Проведено поперечное (одномоментное) одноцентровое исследование. Основную группу составили 79 пациентов европеоидной расы с диагнозом СРК (установлен в соответствии с Римскими критериями IV пересмотра), которых распределили на 2 подгруппы: СРК с преобладанием диареи (СРК-Д, n = 45) и СРК с преобладанием запоров (СРК-З, n = 34). В контрольную группу вошли 59 пациентов европеоидной расы гастроэнтерологического профиля без СРК. Всем включенным в исследование пациентам проводился генетический анализ с целью оценки полиморфизма 5-HTTLPR гена SLC6A4. В основной группе также определяли уровень содержания серотонина в крови, проводили психологическое тестирование с оценкой реактивной и личностной тревожности с использованием опросника Спилбергера – Ханина, оценивали качество жизни с помощью опросников SF-36 и GSRS, выраженность астении с помощью шкалы астенического состояния, интенсивность боли по визуальной аналоговой шкале.
Результаты. У пациентов с СРК-Д частота носительства мутантного аллеля S составила 77,8% (35 пациентов из 45), что оказалось статистически значимо выше, чем в группе СРК-З (р = 0,002) и в контрольной группе (р = 0,005). Между группой пациентов с СРК-З и контролем не получено статистически значимых различий (р = 0,54) в частоте обнаружения гомозиготного генотипа по нормальному аллелю (LL) и гетерои гомозиготного генотипа с мутантным аллелем (SL и SS). В группе СРК-Д выявлено гендерное различие: гомозиготный генотип по мутантному аллелю (SS) 5-HTTLPR статистически значимо чаще определялся у женщин (p = 0,0147); у пациентов c СРК-З и контрольной группы статистически значимых гендерных различий в распределении генотипа не было. Уровень серотонина в крови пациентов с СРК в зависимости от генотипа 5-HTTLPR не различался (p = 0,086) и был в пределах референсных значений, однако следует отметить тенденцию к снижению уровня серотонина у носителей LL по сравнению с носителями полиморфизмов SS/SL. Анализ гастроэнтерологического опросника GSRS показал статистически значимое (p = 0,013) повышение суммарного балла констипационного синдрома у пациентов с гомозиготным LL полиморфизмом 5-HTTLPR по сравнению с генотипом SS/SL.
Заключение. Выявленные особенности могут быть обусловлены сниженной экспрессией гена SLC6A4 у носителей мутантного аллеля в промоторе 5-HTTLPR и как результат – замедленной скоростью поглощения серотонина, который оказывает стимулирующее влияние на желудочно-кишечный тракт. Полиморфизм транспортера обратного захвата серотонина гена SLC6A4 заслуживает дальнейшего изучения как потенциальный ген-кандидат в патофизиологии СРК.
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Almanac of Clinical Medicine. 2019; 47: 496-504
Functional polymorphism of the serotonin reuptake transporter SLC6A4 gene in various clinical variants of irritable bowel syndrome
https://doi.org/10.18786/2072-0505-2019-47-072Abstract
Rationale: Irritable bowel syndrome (IBS) is a multifactorial disease, the genetic aspect of which is being actively studied.
Aim: To investigate functional polymorphism of the serotonin reuptake transporter (SERT) SLC6A4 gene of various clinical variants of IBS.
Materials and methods: We performed a cross-sectional single center study in 79 Caucasian patients with IBS (according to the Rome criteria IV). The patients were divided into two groups: group 1, IBS with diarrhea (IBS-D, n = 45) and group 2, IBS with constipation (IBS-C, n = 34). The control group included 59 Caucasian patients with gastrointestinal disorders without IBS. Polymorphism 5-HTTLPR of the SLC6A4 gene was assessed in all subjects. In group 1 patients, blood serotonin levels were measured and psychological tests were performed, including Spielberger's State / Trait Anxiety Inventory, quality of life by SF36 and GSRS, Asthenia scale, VAS scores for pain intensity.
Results: Thirty-five of 45 (77.8%) patients with IBS-D carried the mutant S allele, which was significantly more frequent than in the IBS-C group (p = 0.002) and in the control group (p = 0.005). There were no statistically significant differences (p = 0.54) in the frequency of detection of the homozygous LL genotype (normal allele) and the heteroand homozygous mutant alleles (SL and SS) genotype between the IBS-C and control patients. In the IBS-D group, a gender difference for the mutant SS allele of 5-HTTLPR was found, with significantly higher frequency in female patients (p = 0.0147). No significant gender differences in the genotype distribution between the patients with IBS-C and the control group were found. There were also no differences in blood serotonin levels in the IBS patients with various 5-HTTLPR types (p = 0.086); they were all in the reference range. However, there was a trend towards lower serotonin levels in the LL genotype carriers compared to those with the SS/SL polymorphisms. The Gastroenterological inventory GSRS demonstrated significantly higher total score for the constipation syndrome in the patients with homozygous LL 5-HTTLPR polymorphism, compared to that in the patients with the SS/SL genotype (p = 0.013).
Conclusion: The results may be related to lower expression of the SLC6A4 gene in the carriers of the mutant allele in the 5-HTTLPR promoter and subsequent decreased rate of serotonin uptake, with resulting stimulation of the gastrointestinal tract. The SERT polymorphism of the SLC6A4 gene is worth further investigation as a potential candidate gene in the IBS pathophysiology.
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