Association of a polymorphism of the 5HT2A receptor gene promoter region with alcohol dependence

Abstract

Approximately 10% of Japanese alcoholics develop their disease despite having an inactive form of aldehyde dehydrogenase-2 (ALDH2), 1 known as a genetic deterrent of heavy drinking due to adverse reactions after drinking.2 Such alcoholics are considered to be advantageous in genetic research because they should show reduced heterogeneity and possess genetic factors conferring susceptibility to alcohol dependence. Examination of the −1438 A/G polymorphism of the serotonin 2A (5HT2A) receptor gene in 225 Japanese alcoholics with inactive ALDH2 revealed the presence of significantly more of the G allele than was found in 361 control subjects. The frequency of the G allele in 282 alcoholics with active ALDH2 fell between the G allele frequencies of controls and subjects with inactive ALDH2. These data suggest that although the effect is relatively small, genetic variability in the 5HT2A receptor is involved in the development of alcohol dependence.Genetic factors play pivotal roles in the development of alcohol dependence, as twin, adoption studies consistently show. These factors may involve genetic variation in neurotransmission. Recently, Collier and colleagues 3 reported a positive association between a biallelic polymorphism (−1438 G/A) in the promoter region of the serotonin 2A (5HT2A) receptor gene and anorexia nervosa. They reported that the frequency of an A allele was overrepresented in patients with anorexia nervosa compared with that in controls. However, evidence against these findings 4 makes them controversial.Because (1) several lines of evidence have shown that the function of the serotonergic system is closely related to the alterations in food and ethanol intake in both animals and humans, 5-7 and (2) eating disorders are often coincident with alcohol dependence, 8 we speculate that the 5HT2A receptor gene promoter polymorphism confers genetic susceptibility to alcohol dependence. To explore this hypothesis, we have investigated possible associations between 5HT2A receptor gene promoter polymorphism and alcohol dependence.The most likely model of inherited alcohol dependence involves the interaction of multiple genes that have minor effects and sociocultural factors in the environment, which leads to the development of the disease in genetically susceptible individuals. One of the major obstacles in identifying genes that produce minor effects is the heterogeneity of the disease to be examined. To overcome this problem, we studied alcoholics with inactive aldehyde dehydrogenase-2 (ALDH2), which is encoded by either heterozygous ALDH2*1/2*2 or homozygous ALDH2*2, a welldefined genetic risk factor that lowers the risk for alcohol dependence.2,9,10 The heterogeneity of the disease is considered to be relatively low in this genetically defined subgroup, compared with the entire alcoholic population.In addition, individuals who have become alcoholic despite their inactive ALDH2 probably have one or more factors that increase their susceptibility to alcohol dependence. If 5HT2A receptor gene polymorphis...

Irritable Bowel Syndrome: Methods, Mechanisms, and Pathophysiology. Genetic epidemiology and pharmacogenetics in irritable bowel syndrome

“…The 5-HT 2A receptor gene is expressed in the brain, vagal nuclei, and the gut (11,74). The Ϫ1438 (G/A) polymorphism has been associated with anorexia nervosa, alcohol dependence, obesity, obsessive compulsive disorder, and seasonal affective disorder (33,86). The AA genotype is associated with higher 5-HT 2A gene expression in cell lines endogenously expressing 5-HT 2A (91).…”

5-HT2A promoter polymorphism −1438G/A in children and adolescents with obsessive-compulsive disorders

“…17 The authors discussed that the Aallele could be associated with restrictive behaviour, as opposed to the G-allele, which could be associated with food and alcohol addiction. Aubert et al reported that the −1438 G/A polymorphism may influence food and alcohol intake in French overweights.…”

“…14 The −1438G/A promoter polymorphism of the 5-HT 2A gene seems to be implicated in other neuropsychiatric disorders such as schizophrenia, 15 seasonal affective disorder 16 and alcohol dependence. 17 Especially, AN restricting type has been found to be associated with the A-allele of the −1438G/A promoter polymorphism. 18 However, some studies were not able to confirm this association in AN.…”

The development of functional gastrointestinal diseases: Genetic aspects

“…Так, изуча-лись особенности гена рецепторов 5-HT2A, расположенных в головном мозге, ядре блуждающего нерва и в ЖКТ [25]. Показа-но, что полиморфизм гена 1438 (G/A) ассоциирован с такими на-рушениями, как неврогенная анорексия, алкогольная зависи-мость, обсессивно-компульсивные расстройства, с сезонными аффективными расстройствами [26,27]. В исследовании, прове-денном в Турции у 54 пациентов с СРК и 107 здоровых лиц, по-казано, что при СРК отмечается более высокая статистически значимая частота носительства гомозиготного аллеля С поли-морфизма 102 Т/С и гомозиготного аллеля А полиморфизма 1438 G/A гена рецепторов 5HT2A; при этом отмечено, что генотип ТТ полиморфизма 102 Т/С ассоциировался с более выраженным бо-левым синдромом у пациентов с СРК [28].…”