TaqI-A polymorphism linked to the DRD2 gene and P300 in alcoholic patients

Background and Objectives: Different studies carried out mainly in young non-consuming children of alcoholics show an association of P300 abnormalities with alcoholism and with the TaqI-A1 allele. Since the relationship between P300 and the TaqIA1 allele has not been specifically studied in alcoholic patients, our objective was to investigate whether the association exits in this population. Methods: Our sample consisted of 176 recently detoxified male alcohol-dependent patients. These patients had been alcohol dependent from a mean age of 22.6 years and consumed on average 164.63 (± 142.99) cm3 of alcohol daily. P300 was studied using an auditory paradigm. TaqI-A polymorphism genotyping was performed. The association between P300 and TaqI-A, and correlation with age and alcohol consumption, was studied. Results: The TaqI-A1 allele was found in 38.6% of our patients (n = 68). The latency and amplitude of P300 were 361.64 milliseconds and 17.53 microvolts, respectively. P300 wave latency in alcoholic patients was longer than the reference value obtained from a sample of healthy men of the Event-Related Potentials Unit (p < 0.001). Alcoholic patients who carried the TaqI-A1 allele showed more prolonged P300 latency than non-carriers, and these in turn more than the control subjects. P300 characteristics varied according to age, but an association with amount of alcohol or number of years consuming was not found. Conclusions: There is a relationship between the TaqI-A polymorphism and P300 wave characteristics in alcoholic patients. Further investigations need to be carried out in nonconsuming alcoholic patients and in healthy control subjects to confirm this association and to clarify the possible influence of the neurotoxic effects of alcohol on P300 physiology. Background and Objectives Several studies have related the presence of a lower amplitude or a longer latency of the Event-Related Potentials P300 (P300) with alcoholism (Polich et al. 1986, Cohen et al. 1995, Nacher 2000, Polich and Ochoa 2004). It has been suggested that these alterations of P300 would have a strong genetic load (Anokhina et al. 2000, Enoch et al. 2002) and could represent a risk endophenotype for the development of alcohol dependence (Van der Stelt et al. 1994, Cohen et al. 1997a, Cohen et al. 1998, Berman and Noble 1995, Hesselbrock et al. 2001). In addition, P300 has been associated to a family history of alcoholism (Benegal et al. 1995, Hill et al. 1999a), a family history of antisocial behaviour (Hesselbrock et al. 1993, Preuss et al. 1999, Houston et al. 2004) and with different cognitive alterations related to attentional processes (Berman and Noble 1997, Cohen et al. 1997b, Ratsma et al. 2002). The discovery of P300 abnormalities in patients suffering Parkinson’s disease had suggested that they could be related to a lower dopaminergic activity (Polich et al. 1994); this association was confirmed by later studies (Hansenne 2000, Nacher 2000). These findings justified later investigations of the relationship between P300 alterations and genetic markers related to the dopaminergic system. Amongst them, the importance of the Single Nucleotide Polymorphism (SNP) which constitutes the TaqI-A polymorphism has been highlighted by different studies (Blum et al. 1996, Comings & Blum 2000). The TaqI-A1 allele of this polymorphism, located in the 3 ́ region of the gene which encodes the dopaminergic D2 receptor (DRD2) (Grandy et al. 1989, Blum et al. 1991) has been associated with severe alcoholism in caucasian populations (Blum et al. 1991, Noble, 2003) and with different psychiatric disorders related to addictions and impulsiveness (Blum et al. 2000, Comings y Blum 2000, Ponce et al. 2003, RodriguezJimenez et al. 2005). Although the TaqI-A polymorphism was initially described as a non-functional marker of genetic variations pertaining to DRD2, it is now known that the TaqI-A SNP is a functional polymorphism which belongs to the adjacent gene ANKK1 (Duan et al. 2003, Dubertret et al. 2004) and encodes a kynase protein. Since the TaqI-A1 allele is in linkage disequilibrium with the DRD2 gene and could be involved in dopamine synthesis (Laakso 2005) it is still considered an adequate genetic marker for the study of dopaminergic function. There are few studies which relate the TaqI-A1 allele and alterations of P300. One of them (Blum et al. 1994), carried out on a general psychiatric population, found that subjects with the A1A1 genotype showed significant prolongation of P300 latency compared with A2A2 genotype subjects; no association was found between P300 abnormalities and alcoholism in this population. With respect to alcoholism, there are three studies which analise the relationship between the TaqI-A1 allele and alterations of P300. They were not carried out on alcoholic patients but on non-consuming children of alcoholic subjects (Noble et al. 1994, Hill et al. 1998, Ratsma et al. 2001). The first of these studies found prolongation of the P300 wave latency associated to the presence of the TaqI-A1 allele (Noble et al. 1994); the second found a significantly lower amplitude of P300 in the TaqI-A1 allele group, compared with the TaqI-A2 allele group (Hill et al. 1998). The third study, however, performed on older descendents of alcoholics, could not confirm this association between P300 and TaqI-A (Ratsma et al. 2001). In fact, the influence of age as a confounding factor has been seen in a previous study car46 JIMÉNEZ-ARRIERO ET AL.