Please use this identifier to cite or link to this item: doi:10.22028/D291-27629
Title: A meta-analysis about the influence of homozygosity in ADH, ALDH, GABA-A receptor and Dopamine receptor D2 genes on the risk of alcohol dependence
Author(s): Schmitt, Matthias Michael
Language: English
Year of Publication: 2016
Place of publication: Homburg/Saar
SWD key words: Alkoholismus
DDC notations: 610 Medicine and health
Publikation type: Dissertation
Abstract: Alcohol dependence as a common disease all over the world and especially in the Western society is influenced by several factors (Bosron et al., 1989). The results of alcohol dependence are massive and not just limited on the organic damage but also affecting social behaviour and psychological health. Therefore many different studies paid attention to the pathogenesis of developing alcohlism as well as to the impacts on patients, seen from the internistic and the intersocial perspective. This still remains subject of actual research programs because of the complicated metabolism and effects of ethanol on the human organism. So far it became clear that long-term ethanol consumption combined with a steadily increasing amount of consumed ethanol plays an important role in progressing an addiction (Konishi et al., 2003). Moreover the drinking behaviour of people can be influenced by risk factors that lead to the consumption of ethanol, such as peer pressure, life crisis or social exclusion which refers to the environmental significance for alcohol dependence (Bosron et al., 1989). A quite similar importance for understanding the complexity of this multifactorial illness has got the analysis of the patients’ genetics, which became a large field in latest research programs. To evaluate the complex results of different studies, we worked out a meta-analysis about homozygous SNP carriers that have to cope with altered proteins playing a role in the human organism’s reaction to alcohol consumption in comparison to carriers of the wildtype alleles. What is more we evaluated the meaning for their behaviour concerning regular alcohol consumption in regard of their genotype. With our meta-analysis we could make the comparison between these studies more bearable and enable people to identify potential genetic predispositions associated with the progress of alcohol dependence. Although the identification of problematic chromosomal regions influencing the progress of alcoholism isn’t finished at all, there is strong evidence provided for several polymorphisms (Edenberg et al., 2006). Quite often they consist in single nucleotide polymorphisms (SNPs), which emphasizes that even small genetic differences cause big clinical effects, as we also know from lots of other diseases such as mucoviscidosis for example (Smerieri et al., 2014). The modified alleles cause variable proteins that show different interaction with ethanol and might lead to a higher risk of becoming an alcoholic, for example by altered reactions to consumption, different agreeability or withdrawal symptoms (Enoch et al., 2008). The homozygous carriers of mutations theoretically show a bigger difference from the wildtype than the heterozygous ones. This is why we investigated our meta-analysis only with homozygous genotypes. Thus our findings should deliver clear differences between the homozygous wildtype allele carriers and the mutated allele carriers that also might own validity in heterozygous individuals in a probably lower stamping dependent on the way of inheritance. The majority of the studies we analyzed especially focused on the following proteins which are the main objects of our meta-analysis as well: 1. ADH Genes: The alcohol dehydrogenase (ADH) is the ethanol metabolizing enzyme. This redoxreaction leads to the creation of acetaldehyde, a neuro-toxic substance (Matsuo et al., 2007). The ADH is located in mainly the liver cells and in a smaller amount in the stomach. The enzyme plays an outsize role in the metabolism of ethanol and is encoded by genes on chromosome 4 (Edenberg et al., 2006). To be able to oxidize ethanol, the alcohol dehydrogenase is dependent on the availability of the cofactors NAD⁺ and Zn²⁺(Choi et al., 2005). It is obvious that examining the enzyme’s activity is inalienable when considering the genetics of alcohol dependence. The different polymorphisms of the genes encoding for the ADH isoenzymes (ADH1A, ADH1B, ADH1C, ADH2, ADH3, ADH4, ADH5, ADH6, ADH7) have been subject of several case-control studies (Shen et al., 1997) on which results we broach the issue on below. Especially the class I isoenzymes are supposed to be important for the metabolism of ethanol. The speed of the alcohol degradation is also crucial for the withdrawal symptoms as it may enlarge the time the body is under the influence of acetaldehyde (Thomasson et al., 1991). (The same reaction can be catalysed by the MEOS – mitochondrial ethanol oxidizing system – that can be induced by regular drinking (Hubacek et al., 2014). This leads to the resistence towards symptoms such as motor incoordination for example but reveals the problem of an increased level of acetaldehyde that is not recogniable and that leads to cell damage especially in neuronal areas.) 2. ALDH Genes: The acetaldehyde dehydrogenase (ALDH) is responsible for the oxidation of acetaldehyde, the molecule which is mainly causing hangover symptoms after an excessive alcohol consumption and particularly affecting the neuronal system (Goedde et al., 1992). To process the degradation of acetaldehyde, the enzyme needs NAD(P)⁺ as a hydrogen acceptor. There exist 9 major gene families coding for isoenzymes such as ALDH1, ALDH2, ALDH3-ALDH9 (Ehlers et al., 2012). Above all chromosome 12 contains notable genetic variation according to ALDH genes, particularly for the ALDH2 gene, so that this chromosomal area has an outstanding role analyzing the effects of mutations on the metabolism of acetaldehyde (Husemoen et al., 2008). The ALDH2 has got a low Km and is located in the mitochondria. It is the isoenzyme with the biggest importance for the oxidation of acetaldehyde (Hurley et al., 2012) and its deficiency influences the occurrence of aversive symptoms which also regulate the risk of developing an alcohol addiction. 3. GABA-A Receptor Genes: Several genetic polymorphisms are identified for this pentameric ion channel that is assembled by α, β, γ, δ, ε and ρ subunits (Buck et al., 1996). The loci of the relevant alleles are limited on chromosome 4, 5 and 15 that provide genetic information for the different subunits. Although there is really good evidence for the importance of GABA reception for the metabolism of ethanol and for the fact that alcohol leads to a higher rate of activity of this receptor that causes the decreased central nerval alertness, the precise mechanisms of GABA reception involvement in the pathogenesis of alcoholism remains unknown and are characterized by different reactions in different neuronal areas (Covault et al., 2008). These different reactions caused by diverse neurotransmitter concentration alterations and different receptor efficiencies between the brain regions are dependent on the composition of GABA-A receptors which is influenced by several genetic polymorphisms. In particular the alleles of the α2-subunit were taken into consideration to differ between alcoholic patients and healthy controls, thus being suspicious to increase the individual risk of becoming alcohol dependent by SNPs in that gene (Enoch et al., 2008). What is more the importance of the GABA-A receptors on behavioural effects like motor incoordination, anxiolysis, sedation, withdrawal signs, that are all closely linked with alcohol consumption, are stated (Buck et al., 1996). 4. Dopamine Receptor D2 Genes: The fact that dopamine plays a huge role in neuronal systems is known at the latest since the understanding of Parkinson's disease (Wu et al., 2014). Furthermore the metabolism of dopamine and especially its receptor activity has impact on other physiological and pathological pathways throughout the central nervous system that are also related to the symptoms of alcohol consumption (Bhaskar et al., 2010). Thus the genetic information encoding 5 different types of dopamine receptors (DRD1-DRD5) is regarded to be of major importance for the understanding of the neuronal mechanisms of alcohol. Several alleles particularly in the dopamine receptor D2 (DRD2) have been focused and linked with a predisposition for or a protection from alcoholism (Joe et al., 2008). The TaqIA polymorphisms for example, that lies 10 kb downstream of the DRD2 and contains gentic information for a kinase gene, ANKK1 (ankyrin repeat and kinase domain containing 1), is associated with the density of DRD2 in the human brain (Singh et al., 2013). The receptor density is responsible for interindividual effects of ethanol. Participants with a low density of receptors in the central reward pathway such as the nucleus accumbens or amydala for example require higher amounts of alcohol to achieve benefit feelings or positive emotional effects from ethanol consumption in comparison to those having a higher density of DRD2 receptors (Noble et al., 2003). Additionaly the -141C Ins/Del polymorphism of an intronic region of the DRD2 gene is also considered to influence the density of DRD2 (Ishiguro et al., 1998). That's why we investigated the data especially for these polymorphisms of the DRD2 which are all together located on chromosome 11.
Link to this record: urn:nbn:de:bsz:291-scidok-ds-276291
Advisor: Wagenpfeil, Stefan
Date of oral examination: 20-Jun-2016
Date of registration: 4-Jan-2019
Faculty: M - Medizinische Fakultät
Department: M - Medizinische Biometrie, Epidemiologie und medizinische Informatik
Collections:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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