SU111 - EFFECT OF DINUCLEOTIDE POLYMORPHISM (RS67175440) OF DAT1 GENE: INCREASED RISK OF CLONINGER TYPE II ALCOHOLISM IN SEX-SPECIFIC MANNER

Abstract

Background The role of dopamine in the addictions’ development, including alcoholism, is well shown. The Dopamine Transporter (DAT) regulates the dopamine levels in the synapse. In some studies, using autoradiography, a DAT density was higher in patients with Cloninger type II alcoholism, which may be due to genetic influence (Tupala E. et’al 2006, Karkkainen O. et’al 2013). The dinucleotide polymorphism RS67175440 (A allele - AG, B allele - GA) is located in intron 1 of the SLC6A3 gene and can be within the regulatory region of the gene, which is interesting for studying its effect on the alcoholism risk. This locus is presumably involved in cocaine dependence risk (Zhou Y. et’al 2014). We attempted to assess the influence of RS67175440 on the probability of development of alcoholism, including patients with the presence of Cloninger type II. Methods Our sample consisted of 1200 patients with alcoholism (mean age 42.94±11.001 years, 277 females) and 536 controls (mean age 43.65±4.318 years, 165 females), all ethnic Russians. The clinical variables (age at first alcohol use, age of onset and term of formation of alcohol abuse, age and term of alcohol withdrawal syndrome, age of first hospitalization, family history (FH) of alcoholism) were assessed by a clinical interview patient and close relative (more often mother). For each individual, RS67175440 was genotyped by PCR-RFLP method using BseRI. The observed genotype distributions didn’t deviate from Hardy-Weinberg equilibrium (Patients: 330AA, 596AB, 274BB, P=0.88, Control: 146AA, 253AB, 137BB, P=0.20). For comparison of groups the chi-squared test with Bonferroni correction for multiple comparisons, logistic regression and Mann-Whitney U-test were used. Results According to the logistic regression, the general group of patients has the influence of the combination GenderxGenotype in relation to the alcoholism risk, but this effect was provided by a group of patients with Cloninger type II alcoholism (age of onset of abuse ≤ 25 years) with the presence of FH (TypeII+FH) for other patients this effect is not revealed. In men, the AA genotype increases the risk of AD by 41.3% in the overall comparison (95%CI 1.07–1.866, P=0.015), and by 48.7% for the group Type II+FH (1.223–2.402; P=0.002); the AB genotype increases the risk by 47.6% in the overall comparison (1.173–1.857, P=0.001) and 71.4% for the group TypeII+FH (1.418–2.486; P=0.000). In women, the AA genotype reduces the risk by 71.3% for the group TypeII+FH (0.164–0.539; P=0.000); the AB genotype reduces the risk by 31.2% in the overall comparison (0.51–0.927, P=0.014), and by 52% for the group TypeII+FH (0.321–0.717; P=0.000). The independent effect of gender was identical: for men, the risk was 48.2% higher than for women in the overall comparison (1.181–1.86; P=0.001); and 48.7% higher for the group TypeII+FH (0.808–2.738; P=0.000). Discussion There were no differences in genotype or allele frequencies between patients and control using the dominant and recessive models. It can be assumed that the differences in the general group are provided by the influence of Cloninger type II, in particular, hereditary factors. Our results indicate that the locus RS67175440 in the DAT gene in men with the presence of Cloninger type II alcoholism with family history increases, while in women reduces alcoholism risk with an early onset, but doesn’t effect on the dynamics of alcoholism and clinical variables.