We recently showed that a trinucleotide polymorphism within the coding region of the androgen receptor (AR) is linked to craving in alcohol withdrawal, an effect that was mostly mediated by leptin.
In this study, we examined the genetic variant -45 C to T substitution of the CCK gene promoter region among 195 healthy Japanese and 174 patients with alcohol withdrawal syndrome (52 delirium tremens, 39 hallucinosis, 20 seizures, and 92 lack of these symptoms) by using polymerase chain reaction-based single-strand conformational polymorphism analysis.
To investigate the relevance of these findings for human alcoholism, we resequenced 46 exons, exon-intron boundaries, and 2 kilobases in the 5' region of the human MPDZ gene in 61 subjects with a history of alcohol withdrawal seizures (AWS), 59 subjects with a history of alcohol withdrawal without AWS, and 64 Coriell samples from self-reported nonalcoholic subjects [all European American (EA) ancestry] and compared with the Mpdz sequences of 3 mouse strains with different propensity to AWS.
In vivo availability of striatal dopamine transporter (DAT) protein has been reported to be reduced among alcoholics, and allelic variation of the DAT gene (SLC6A3) has been associated with severity of alcohol withdrawal.
Based on our data, the impact of the 9-repeat allele of the dopamine transporter gene in alcoholism and the severity of alcohol withdrawal symptoms is putatively not substantial.
Our results suggest that the A9 allele of the DAT gene is involved in vulnerability to alcohol withdrawal complications in women, but that these complications differ from those associated with this polymorphism in alcohol-dependent men.
The A9 allele of the dopamine transporter gene is associated with more severe effects of alcohol withdrawal, possibly because of modifications of the brain's capacity to compensate for long-term effects of ethanol on cerebral function.
The top association signal for AW severity was in sortilin family neurotrophin receptor gene SORCS2 on chromosome 4 (European American meta-analysis n = 1,478, p = 4.3 × 10<sup>-9</sup> ).
A quantitative trait loci study indicated that genes localized to 11p13, where the BDNF gene is mapped (11p13-15), increase the risk for severe alcohol withdrawal.
Our results suggest that the long variant of the 5-HTTLPR polymorphism is associated with higher compulsive alcohol craving at the beginning of alcohol withdrawal.
Our results show statistically significant associations between SNP in exon 8 A/G in the DRD2 gene and alcohol withdrawal syndrome with seizures, and between SNP in promoter -141 C I/D in the DRD2 gene and early onset of alcohol dependence (AD).