GENETIC APPROACH TO ALCOHOLISM.   Term Paper ID:21019 Click to get this paper

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Paper Abstract: Technical analysis of research evidence that disease has biological causes. Paper Introduction: The Genetic Approach to Alcoholism A common human disease, alcoholism may result from a variety of causes. A few of the contributing factors include cultural influences, environmental effects, and heredity. Recent scientific advances in molecular genetics, have focused particular attention on those aspects of the disease which are inherited. Certain researchers claim to have even identified a gene for susceptibility to alcoholism. These assertions have engendered considerable controversy. All sides do agree though, on the fact that the problem is exceedingly complex. Alcoholism is a devastating condition afflicting a substantial segment of the population. It is perhaps one of the most common of the human diseases (3:145). Lifetime risk estimates range from between 3% and 5% among males and between Text of the Paper: The entire text of the paper is shown below. However, the text is somewhat scrambled. We want to give you as much information as we possibly can about our papers and essays, but we cannot give them away for free. In the text below you will find that while disordered, many of the phrases are essentially intact. From this text you will be able to get a solid sense of the writing style, the concepts addressed, and the sources used in the research paper. The general trend of this work seems to indicate that anyanalysis of the Al allele is dependent on the severity of the examinedalcoholism. G.; Madec, A.; Selin, M.; Champiat, J. Despite this variability though, whenthe total alcoholic sample was compared with the total control sample, theAl allelic incidences were found to be 43. 31:229-234; 1993.12. DRD2 is located on human chromosome llq32. Substance abuse represents a major problem for society. In addition, the etiology of alcoholism very complex. Alcoholism in relatives of primarycocaine-dependent patients. J.; Montgomery, A.; Ritchie, T.;Ozkaragoz, T.; Fitch, R. McClearn, G. Because of both the etiologic complexity and the heterogeneity of thealcoholic condition, most researchers have presumed that several differentgenes are involved. Studies have shown thatheavy polysubstance users, while only trending towards a higher Al alleleincidence, do exhibit a significantly higher incidence of the Bl allele.These results are confirmed by meta-analyses of all the research datacombined. More important though, was the fact that 69%of the alcoholic specimens contained the Al allele. Persico, A. 14:1 1 - 1 18; 1992.5. Recent Developments in Alcoholism. Structure and linkage of the D(2)dopamine receptor and neural cell adhesion molecule genes on humanchromosome llq32. 1 :59-67; 1993.3. Over the last few years, the assertions regarding DRD2 have generatedconsiderable debate. J. JAMA. For example, veteran geneticist, Kenneth K.Kidd of Yale University, thinks that the subsequent studies invalidate theoriginal hypotheses. Why there is no gene for alcoholism. Certain researchers claim to have evenidentified a gene for susceptibility to alcoholism. Superimposed upon all of these differentelements is a person's genetic make-up: various inherited characteristicsare thought to result in vulnerability to alcoholism. Culturalinfluences may involve such things as ethnic, religious, or genderattitudes toward alcohol use. Thus,because she examined a less severe population, Bolos obtainednonsignificant results (1 :351). Forexample, the frequencies of the normal alleles have been found to besignificantly higher among alcoholics than among controls. Gelernter, J.; Goldman, D.; Risch, N. Ultimately, this could create a phenotype withfewer dopamine receptor binding sites. Indeed,the heritability of alcoholism among Caucasians has been estimated to be ashigh as 5 %. According to Noble et al. J. More recently, adoption studies, twinstudies, and investigations involving at-risk relatives of alcoholics haveprovided additional evidence for this contention. Therefore, while the allele may represent the mostprominent genetic determinant of susceptibility to alcoholism, thecumulative effects of other genes, as well as cultural and environmentalinfluences may be more important overall (1 :358). Finally, the Al and Bl alleles may also be involved in substanceabuse problems other than alcoholism (12:153). &, and 56.3%, respectively. K.; Civelli, O.;McElligott, D. Horgan, J. (1991) revealed that, in subjects with the Al allele, the number ofdopamine binding sites was reduced by about 3 % as compared to subjectswith the K2 allele. The Genetic Approach to Alcoholism A common human disease, alcoholism may result from a variety ofcauses. Analysis of cadaver brains by Nobleet al. Genetic linkage occurs as a result of the tendencyfor nearby genes on the same chromosome to be cotransmitted from parent tooffspring together. Dopamine D(2) receptor gene Taq I 'A' locus mapincluding 'A4' variant: relevance for alcoholism and drug abuse. In recent yearsassociation data has also been found to suffer from a "general lack ofdurability" (5:1673). Proponents of the hypotheses maintain that DRD2theory has been corroborated by subsequent research. A number of studies have shown that the mutant metabolic enzymes mayactually exert a protective influence with regard to alcoholism. In contrast, the population association approach to locating loci isbased upon the tendency of closely linked genetic markers to remainassociated during transmission through the generations. These assertions haveengendered considerable controversy. -kb 3' from exon 8 of theDRD2 gene. Because of the heterogeneity of alcoholism, any trait whichdifferentiates a large fraction of alcoholics from nonalcoholics mustalways be suspected of being merely a secondary development resulting fromthe disease. Amadeo, S.; Abbar, M.; Fourcade, M. The accumulation of rese-arch data over the years has alsoenabled summary investigations. Whether or not these observations reflect the influence ofinheritance in the development of alcoholism remains to be determined(3:149). H.; Djabali, M.; Selleri, L.; Grandy, D. Soon after the first DRD2 gene association was announced, a number ofdifferent laboratories attempted to replicate the original work. 11:345-362; 1993.11. With subjects divided into groupsincluding nonalcoholic controls, general population controls (alcoholicsexcluded), all types of alcoholics (less severe and severe), and severealcoholics, Noble et al. By establishing the frequency with which a given traitis coupled with a genetic marker of known location, the locus for thattrait can be identified. Lastly, two miscellaneous biological markers that have shown repeatedassociation with alcoholism involve the enzymes adenylate cyclase (AC) andmonoamine oxidase B (MAOB). (1993), the Bl alleleoccurs in 13.3% of nonalcoholics, in 16.7% of less severe alcoholics, andin 46.9% of severe alcoholics (1 :356). J.; Wood, R.; Finley, O.; Sadlack, F. Epistasis refers to "interaction among multiple genes"(1 :347). Robert Cloninger ofWashington University, has found no linkage between the Al allele andfamilies with high rates of alcoholism. Genetics, systems, and alcohol. Several studies have found reduced AC activityin the platelets of alcoholics and their families. Other researchers, however, refute suchhypotheses. The controversy, however is ongoing. The skeptics,however, are more doubtful. The Al allele at the D(2)dopamine receptor gene and alcoholism. Recent scientific advances inmolecular genetics, have focused particular attention on those aspects ofthe disease which are inherited. The Al alleleoccurs some distance away from the portion of the gene which encodes forprotein. The mutations responsible for these structural anomalies mayoccur somewhere near the Tag I endonuclease restriction site in the 31 non-coding region of the DRD2 gene (1:177). Environmental issues can concern alcoholavailability or peer pressure. These digests were then hybridized with differentalcoholism gene probes (e.g., clones of the gene for DRD2, etc.) in orderto identify different forms of the genes (polymorphisms) (1 :348). F.; Farmer, S.; Gysin, R.; Flanagan, S.D.; Uhl, G. D(2)dopamine receptor gene and alcoholism. 23:119-129; 1993, March.1 . I just don't think the D(2) gene is that component"(7:29). Genomics. These have included 5 studies of Caucasians and 1 of CheyenneIndians, all of which obtained negative results. Subsequent studies over the last few years have similarly arrived atmixed results. One such summary involved 986 Caucasianswho participated in 9 independent studies. With epistasis, a variant form of one gene cannot by itselfcause a disease such as alcoholism. Many years later, Carmelli et al. Recent developments in alcoholism: Genetic transmission. L.; Mallet, J. Statistical analysessubsequently revealed that this difference in the proportion of alcoholicand nonalcoholic subjects possessing the Al allele was significant(1 :348). Several different mechanisms can be proposed to explain theassociation between the Al allele and susceptibility to alcohol. %, 31.8%, 43. Furthermore, thiswide array of contributing factors can vary throughout a given family,across a span of time, and in different populations (6:243-244). L.; Evans, G. Thesesensations are thought to be directly responsible for the reward andreinforcement behaviors associated with many drug-induced addictivedisorders (11:229). Goldman, D. The D(2) dopamine receptor gene: A review of associationstudies in alcoholism. This is not tosay that the association studies are flawless though. Oneconsequence of alcohol ingestion is dopamine secretion. The other general line of investigation into the genetics ofalcoholism involves the neurotransmitter, dopamine (1:173). Lifetime risk estimates range from between 3% and5% among males and between .1% and 1% in females. L.; Waksman, G.; Leroux, M. Additionally, alcoholism genetics pioneer, C. (1993) estimated Al allele prevalences to be23. D(2) or not D(2): A barroom brawl over an "alcoholism gene." Scientific American. Drugand Alcohol Dependence. The oxidation of alcohol to acetaldehydeand then, subsequently, to acetic acid requires the enzymes, alcoholdehydrogenase (ADH) and mitochondrial acetaldehyde dehydrogenase (ALDH).In approximately 3 % to 5 % of Orientals, dominant point mutations occur inthe genes which encode for these enzymes. Geneticpredisposition in alcoholism: Association of the D(2) dopamine receptorTaq I Bl RFLP with severe alcoholics. A. Elucidationof the molecular genetic mechanisms responsible for drug dependence mayresult in new methods for managing the associated behaviors. Behavior Genetics.23:223-23 ; 1993, March.9. In fact, causal fields mayarise where the "relative importance of every variable, genetic orenvironmental, is dependent to a greater or a lesser extent on the contextof the other variables in the system" (8:223-229). Thus, the etiologic influences with regard to alcohol use and-abuseconstitute a complex system. This reduction may also be morecharacteristic of certain subtypes of alcoholics. 23:145-151; 1993, March.4. In contrast to this success though, researchers have hadmore difficulty establishing the molecular basis of behavioral disorders.This has been in part due to the fact that psychiatric conditions do nottypically display a clear mode of genetic transmission. References to itsgenetic tendencies can be found as far back as the writings ancient Greekand Chinese civilizations (3:145). With closelylinked markers, nonrandom association (also known as linkagedisequilibrium) between the marker and some nearby structural variantenables its detection and identification (6:239). Other findings also shed doubt on DRD2 hypotheses. This fact is often pointed out by skeptical researchers. Forexample, mutations of the Al allele could exert a direct effect on the genelocus. While this phenomenon could conceivably result frominheritance, it might also be a secondary effect (3:149). W.; Frawley, P. The inheritance ofalcoholism, for example, is characterized by incomplete penetrance andextremely variable clinical expression (1 :346). In addition to susceptibility toalcoholism, the gene has also been circumstantially associated with anumber of other disorders including Parkinson's disease and schizophrenia(4:1 1 -1 16). Moreover, the finding is consistent with an epistatic model ofmultiple gene interaction. Behavior Genetics. For example,researchers studying cerebrospinal fluid homovanillic acid--a dopaminemetabolite and a crude index of brain dopamine function--could find nocorrelation to DRD2 genotype. Still, regardless of these problems, research on the genetics ofalcoholism currently seems to be following two general trends: the firstinvolves the hepatic metabolism of ethanol, whereas the second concernsneurotransmitter systems (1:173). This observation might, however, be discounted by DRD2detractors. These same studies showed that thesons of alcoholics exhibited characteristics such as less intense brain-wave activity and a higher alcohol tolerance--traits which could beinherited. He foundsignificant heritability for average monthly alcohol consumption. The complexity and heterogeneity of thedisease generally make gene localization through linkage analysis extremelydifficult; in fact, most of the genetic linkage findings that have beenreported are either nonreplicated or "problematic" (6:239). % to 35.3%). The symptoms of this reaction may be somewhat unpleasant andinclude facial flushing, nausea, palpitations, and light-headedness(6:24 ). Brain samples were collectedfrom cadavers and frozen. (1992) found that both G enzymeamounts and G enzyme GTP- binding were reduced in the platelets ofalcoholics. (1993) postulates that such findings reveal a strongassociation between the Al allele and alcoholism. Thus far, mutant alleles have beendescribed for such diseases as cystic fibrosis, Huntington's chorea, andcertain cancers. A few of the contributing factors include cultural influences,environmental effects, and heredity. These differences would be determinedby the person's specific genome, and susceptibility to alcohol couldaccordingly be governed by a possible "alcoholism gene." Eventually these hypotheses led to the D(2) dopamine receptor (DRD2)gene. Regarding alcoholism, Kidd says, "I believe there isa genetic component. They consisted of the Al (6.6-kb) and A2 (3.7-kb)alleles. % and 25.7%, respectively--adifference which is statistically significant (1 :354). Thus, Goldman (1993)claims that "taken together, association studies performed outside thegroup who originally reported the finding do not confirm a DRD2 associationto alcoholism" (6:242). In the last few years, advances in technology--and, in particular,advances in molecular genetics--have made it possible to search the humangenome for disease-causing genes. The Al and the A2 alleles start about 9. With regard to the prevalence of alcoholism inOriental populations, these scientists also note the paucity of dataconcerning cultural, environmental, and additional genetic contributions(6:24 ). They include the sequence variants, A3 (14.2-kb) and A4 (8.6-kb) (11:23 ). The specimens were classified as either"alcoholic" or "nonalcoholic" according to recorded data available and DSM-III-R criteria (9:121). Alcoholism is a devastating condition afflicting a substantialsegment of the population. Ozawa et al. These receptors generally are found in the central nervoussystem. In the nonalcoholic brain samples, 2 % were found to have the Alallele, whereas 8 % did not. Journal of Psychiatric Research. Each component acts toinfluence--or is influenced by--the other elements. Moreover, two alleles for the locus have beenidentified: Bl (4.6-kb) and B2 (4.1-kb). 266:29, 32; 1992, April.8. Suchprevention and treatment approaches could one day serve to minimize thesediseases devastating effects. Recent Developments in Alcoholism. This study analyzed the association of various genes with asubtype of alcoholism that results in death. Inthese Orientals, the metabolic abnormality leads to a pronounced flushingreaction. In addition, the activity of the MOAB enzyme appears to be reduced inthe platelets of alcoholics. The prevalence of each of these alleles has been measured in bothalcoholics and controls. Of the several DNA probes actually employed, only the lambdahD(2)Glprobe for DRD2 showed polymorphism significantly associated withalcoholism. 269:1673- 1677; 1993.6. In alcoholism research, for instance, there existseveral previously reported,positive population associations which are nolonger thought to be valid. E. Noble, E. In the research on alcoholism, association studies have seemed to befavored over linkage studies. Subsequent to processing for high-molecular-weightgenomic DNA, the samples were digested with four separate restrictionendonucleases. It was found that majorvariation occurred as far as the incidence of the Al allele both in"heterogenous groups of alcoholics" (19.1% to 63.6%) and "heterogenousgroups of controls" (12. Since these initial observations, other restriction fragment lengthpolymorphisms (RFLPS) at the DRD2 locus have additionally been identified.These RFLPs have been found by hybridizing different-sized restrictionfragments of the endonuclease, Taq I, with CDNA probes derived from theDRD2's 3' flanking sequence. Thus someresearchers have surmised that the genes encoding for these enzymesinteract with and modify any influence which might be exerted by genes foralcoholic susceptibility (6:24 ). R. In an extremelycomplicated system, such as that of alcoholism, multiple variables make itdifficult to delineate any specific causation. Noble et al. Blum, K.; Noble, E. P.; Paredes, A. A system can be defined as a "partiallyinterconnected set of components" (8:223-229). 11:231- 248; 1993.7. Theyargue that "no direct molecular evidence links the Al alleles to anyvariation in the expression of the D2 gene." Supporters of the DRD2hypotheses, however, respond by noting that more recently discoveredmarkers occur more proximal to the coding region of the gene (7:32). The map of DRD2spans over 1.2 mb of chromosome. One region of the brain where they normally occur in highconcentrations is the caudate nucleus. Itcontains exons 2-7. This new clone occurs in the 51 region of the DRD2 gene. (1992) thinks thatthe "weight of the evidence appears to favor the position that DRD2 is amarker of severity of alcoholism but is not, of itself, contributing torisk" (3:148). These data indicate thatalcoholism severity can be correlated with Al allele incidence (1 :351-356). BehaviorGenetics. P.; Sheridan, P. It extends over 27 -kband includes an intron of approximately 25 -kb separating the first exonfrom the exons which encode for the receptor protein. Additionally, in 1992, a positive association was made betweenalcoholism and another Tag I site of polymorphism, genomic fragmentlambdahD2G2. Lastly, within familieswith low MOAB activity, significantly higher rates of alcoholism have beenfound to occur. Either throughincreases in the rate of synthesis or decreases in rate of metabolism,blood levels of acetaldehyde increase rapidly upon ingestion alcohol. Studies involving human alcoholics and rat lines which preferdrinking alcohol have both exhibited reduced numbers of dopamine receptorsites (1:177). Recent developments in alcoholism: molecular biology and-behavior. Lastly, Merikangas (199 ) observed that first-degreerelatives of persons suffering from the disease have a sevenfold increasedrisk for becoming alcoholics (6:232). All sides do agree though, on thefact that the problem is exceedingly complex. Alcohol. His observations that "somecarriers are not alcoholics and some alcoholics are not carriers" has ledthe scientist to conclude that the allele is neither "a necessary nor asufficient cause of alcoholism." However, Cloninger does concede that theAl allele may "exacerbate the course of the disorder" (7:29). Noble, E. During the 197 s, forexample, researchers showed that children of alcoholics who were adopted bynonalcoholics had a higher probability of becoming alcoholics themselvesthan did their step-siblings (7:29). The A3 allele, in contrast, spansthe A2 sequence and then extends out in the 51 direction; A4 spans theentire Al sequence (11:232). The observed two alleles had been previously described in thegeneral population. These data indicate that the most severe substance abusers areup to three times more likely to display Al and Bl alleles as compared tononaddicted control populations (1 :358). M.; O'Hara, B. Journal of Substance Abuse Treatment. The researchers insistthat variations in prevalence result from the different alcoholicclassification schemes employed. The result of this is alteredenzymatic activity in affected the person's liver (3:148). 27:173-179; 1993.2. Moreover, as Goldman (1993) notes, fourfoldinterpopulational differences in DRD2 allele frequencies are known to.exist: for instance, Al frequencies have been measured at .18- .2 inCaucasians, .38 in American blacks, and .63- .8 in two North AmericanIndian populations (6:242). In the centralnervous system, dopamine activates the mesolimbic/mesocortical dopaminergiccircuits, thus resulting in feelings of pleasure and euphoria. C.; Brethome, A.; LeClaire, Y.; Castelnau, D.; Venisse, J. Such variation could easily alter any resultsobtained from ethnically heterogenous alcoholic and control groups.Finally, rather than corroborating the hypotheses, Goldman (1993) maintainsthat subsequent studies have diminished the strength of the DRD2association. Indeed, calculations based on DRD2 variants find that only27% of the associated risk for severe substance abuse can be attributed tothe Al allele. It is perhaps one of the most common of thehuman diseases (3:145). This phenomenon couldresult from the inheritance of a mutant allele for the stimulatory Gprotein, G(alpha sigma). Eubanks, J. Smith, J. Such observations have focused researcher's attention on the dopaminereceptor genes. Thus, it may beinaccurate to argue that there is or is-not a gene that causes alcoholism.The occurrence of genetic susceptibility to the disease is actually onlyone single aspect of its complete, multifactorial etiology. 9:153-155; 1992.----------------------- 1 Instead, mutant alleles can onlymodify the gene expression of the group as a whole (1 :347). Works Cited1. (199 ) examined severalthousand pairs of monozygotic and dizygotic male twins. Proponents of the DRD2 theory,however, pointed out that Bolos used an exclusionary criterion whichprecluded the examination of severely medically ill alcoholics. Two strategies which can be employed to identify the genetic locusfor a given disease are genetic linkage approach and the populationassociation approach. Additionally, the allele may only serve as a marker associated withsome specific DRD2 mutation--or, more probably, a series of mutations.Such a variant could conceivably result in lower rates of DRD2 MRNAtranscription or stability. They point out that while alcohol metabolic enzyme variantsmay be important in determining genetic risk, observed interpopulationaldifferences in the prevalence of alcoholism could also result from anynumber of other factors. Devor, E. It was hypothesized that perhaps individual differences inthe function of the dopamine receptors might influence a person'svulnerability to alcoholism (2:59). Rather than being actual variants for theDRD2 gene, these alleles are actually only genetic markers. Oneinvestigation by Bolos and her colleagues failed to show any associationbetween the DRD2 gene and alcoholism. The first investigation of the link between DRD2 and alcoholism tookplace in 1988. Uhl et al. Despite this scenario though, it is still probably fair to callalcoholism the most common human hereditary disease. If this paper is not what you are looking for, you can search again: Search for: or Click here to request an essay written just for you.