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PubMed2005

TNF-857T, a genetic risk marker for acute anterior uveitis.

PURPOSE: To determine the association between 17 single nucleotide polymorphisms (SNPs) of tumor necrosis factor-alpha, lymphotoxin-alpha, and the TNF-receptors genes (TNF, LTA, and TNFRSF1A and -B) and idiopathic acute anterior uveitis (IAU) and to investigate their association with HLA-B27 and/or the development of visually significant complications. METHODS: Ninety-eight white patients in the United Kingdom were identified (by SL) from the uveitis clinics of Moorfields Eye Hospital (London, UK). Sequence-specific primers with 3' end mismatches were used to identify the presence of specific allelic variants by PCR amplification. RESULTS: There was a significant increase in the frequency of the TNF-857T allele in patients with IAU when compared with control subjects (15.3% vs. 7.3%, P = 0.0006). The frequency of haplotype 4, containing the T allele at nucleotide position -857, was also significantly increased in patients with IAU compared with control subjects (15.4% vs. 7.1%, P = 0.0003, OR 2.4, 95% confidence interval 1.4-4.0). In subgroup analysis, there were significant differences in the frequencies of the uncommon TNFRSF1A-201T and TNFRSF1A-1135T alleles between HLA-B27(+) patients with inflammation-related complications and those without complications (80.0% vs. 33.6%, P = 0.006; 80.0% vs. 36.6%, P = 0.01, respectively). CONCLUSIONS: A significant difference in the frequency of TNF-857T allele was found in patients with IAU. There was a trend toward the development of inflammation-related complications in HLA-B27(+) patients with IAU who were carriers of TNFRSF1A-201T or TNFRSF1A-1135T alleles. Genetic variations in these proinflammatory mediators and their receptors appear to influence the susceptibility and severity of the inflammatory response within the eyes of patients during the development of IAU.

Acute Disease↗
PubMed2025

ABO exon polymorphisms are related to ischemic stroke in a Chinese Han population.

BACKGROUND: Recent research have underscored the relation of ABO blood group system to cerebrovascular disorders predisposition. The present investigation endeavors to delve into the relationship between ABO polymorphisms and ischemic stroke (IS) risk. METHODS: A cohort of 646 IS patients and 649 matched healthy controls was recruited. Genotyping of five SNPs within ABO were conducted by Agena MassARRAY platform. Logistic regression models were employed to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Additionally, SNP-SNP interaction was assessed by multifactor dimensionality reduction (MDR) method. Furthermore, Analysis of Variance (ANOVA) was utilized to explore the association between genotypes and blood lipid profiles. RESULTS: The study identified an elevated IS risk associated with rs8176740 and rs8176720 in the overall population. Notably, ABO rs8176720 emerged as the most informative single-locus model for IS susceptibility. These variants were related to an elevated IS risk, specifically in female subjects, the subgroup aged > 64 years, non-smokers, drinkers or non-drinkers. Moreover, rs8176749 and rs8176745 were associated with red blood cell count levels and total bilirubin levels. CONCLUSION: This study firstly demonstrated the association of ABO rs8176740 and rs8176720 with IS incidence, which increased the understanding regarding the effect of ABO on IS pathogenesis.

Aged↗
PubMed1999

Managing antipsychotic-induced tardive dyskinesia.

Antipsychotic-induced tardive dyskinesia is a common and clinically significant hazard of long term antipsychotic therapy. The arrival of atypical antipsychotics has markedly improved the outlook: atypical antipsychotics are emerging as effective treatments and may also reduce the prevalence and incidence of tardive dyskinesia. In mild cases, careful monitoring of tardive dyskinesia by serial Abnormal Involuntary Movements Scale (AIMS) assessments may be the appropriate course. More severe tardive dyskinesia calls for intervention in order to treat the dyskinesia. Atypical antipsychotics and tocopherol (vitamin E) are effective and generally well tolerated treatment options for tardive dyskinesia. Tardive dyskinesia variants such as tardive dystonia and tardive akathisia tend to be more severe and difficult to treat compared with typical tardive dyskinesia. Prevention of tardive dyskinesia is possible through careful selection of patients for antipsychotic therapy, use of the lowest effective antipsychotic dosages, use of atypical rather than traditional antipsychotics and concurrent tocopherol administration. The clinician can now undertake the management of tardive dyskinesia with growing confidence.

Antipsychotic Agents↗
PubMed2006

[Factor V Leiden (G1691A) and prothrombin-G20210A alleles among patients with deep venous thrombosis and in the general population from Spain].

BACKGROUND: Factor V leiden and the -G20210A variant of prothrombin gene are associated to a higher risk of deep venous thrombosis. AIM: To assess the frequency of factor V Leiden (G1691A) and prothrombin -G20210A alleles in patients with deep venous thrombosis (DVT) and in the general population from Spain. MATERIAL AND METHODS: Factor V Leiden (g1691a) and prothrombin-g20210a alleles were genotyped in 493 individuals from the Spanish general populations and in 131 patients with DVT. The presence of DVT was confirmed by phlebography. Allelic frequencies and the DVT risk associated with these variants were estimated. RESULTS: Allelic frequencies for the factor V Leiden (G1691A) allele were 0.019 in patients with DVT and 0.010 in the general population (p=0.235). The frequencies for the prothrombin-G20210A allele were 0.027 and 0.026 (p=0.975). After adjustment for age and gender, the odds ratio for DVT, associated with the presence of G1691A allele was 2.41, but not statistically significant (95% confidence intervals 0.63-9.19). CONCLUSIONS: Prothrombin-G20210A allele was more prevelant than factor V Leiden (G1691A) allele in the Spanish population. However, the magnitude of the association between the G20210A and DVT risk is very low. On the contrary, the G1691A allele is associated by itself with a two fold increase in DVT risk in this population although without reaching statistical significance due to its low frequency.

Factor V↗
PubMed2001

Genetic polymorphism of cytochrome P450 2C9 in a Caucasian and a black African population.

AIMS: CYP2C9 is a major enzyme in human drug metabolism and the polymorphism observed in the corresponding gene may affect the therapeutic outcome during treatment with several drugs. The distribution of variant CYP2C9 alleles was therefore investigated in an Italian and an Ethiopian population. METHODS: Allele-specific PCR analysis was carried out in order to determine the frequencies of the two most common variant alleles, CYP2C9*2 and CYP2C9*3 in genomic DNA isolated from 157 Italians and 150 Ethiopians. RESULTS: The frequencies of CYP2C9*1 (80%), CYP2C9*2 (11%) and CYP2C9*3 (9%) found in the Italian population were similar to other Caucasian groups. However in the Ethiopian population CYP2C9*1, CYP2C9*2 and CYP2C9*3 were present at a frequency of 94, 4 and 2% respectively. The 95% confidence intervals in CYP2C9*1, CYP2C9*2 and CYP2C9*3 between Italians and Ethiopians were 0.098, 0.176, 0.040, 0.098 and 0.040, 0.098, respectively. CONCLUSIONS: Our results indicate that the Ethiopian population has a unique relative distribution of the CYP2C9 alleles, which is not similar to any other ethnic group hitherto described.

Adult↗
PubMed2003

Effect of carbocysteine on cough reflex to capsaicin in asthmatic patients.

AIMS: Cough, one of the main symptoms of bronchial asthma, is a chronic airway inflammatory disease with functionally damaged bronchial epithelium. Recently, we established an animal model with cough hypersensitivity after antigen challenge and clearly showed the protective effect of carbocysteine in this model. This study was designed to investigate the clinical effect of carbocysteine for cough sensitivity in patients with bronchial asthma. METHODS: The effects of the two orally active mucoregulatory drugs, carbocysteine and ambroxol hydrochloride, on cough response to inhaled capsaicin were examined in 14 patients with stable asthma. Capsaicin cough threshold, defined as the lowest concentration of capsaicin eliciting five or more coughs, was measured as an index of airway cough sensitivity. RESULTS: Geometric mean values of the cough threshold at run-in (baseline) and after 4 weeks' treatment of placebo, 1500 mg day-1 of carbocysteine and 45 mg day-1 of ambroxol hydrochloride were 12.8 micro M (95% confidence interval [CI] 5.5, 29.6), 11.0 micro M (95% CI 4.4, 27.5), 21.0 micro M (95% CI 8.8, 50.2) and 11.6 micro M (95% CI 5.8, 23.3), respectively. The cough threshold for carbocysteine was significantly greater than those of ambroxol hydrochloride (P = 0.047) and placebo (P = 0.047), respectively. CONCLUSIONS: These findings indicate that carbocysteine administration may be a novel therapeutic option for asthmatic patients, especially with cough variant asthma.

Adult↗
PubMed2004

Association of the thymidylate synthase polymorphisms with esophageal squamous cell carcinoma and gastric cardiac adenocarcinoma.

Polymorphisms in the untranslated regions (UTRs) of the thymidylate synthase (TS) gene, which may modulate TS transcription and expression, have been associated with susceptibility and prognosis of several tumors. However, their effects on the development and clinical staging of esophageal squamous cell carcinoma (ESCC) and gastric cardiac adenocarcinoma (GCA) have not been assessed so far. In this study, the 28-bp tandem repeat and the G/C single nucleotide polymorphism in the TS 5'UTR, the 6-bp deletion (6 bp-) polymorphism in the TS 3'UTR, were genotyped in 465 cancer patients (232 ESCC, 233 GCA) and 348 control subjects in North China. The genotype and allelotype distribution of the TS variants in ESCC, GCA patients and controls did not show significant difference. However, the frequency of the 6 bp-/2R haplotype in ESCC and GCA patients was marginally or significantly lower than that in controls (P = 0.05 and 0.006, respectively). Thus, the 6 bp-/2R significantly reduced the risk to ESCC and GCA, compared with the 6 bp-/3G haplotype [odds ratio (OR) = 0.61 and 0.48, 95% confidence interval (CI) = 0.37-1.00 and 0.28-0.81, respectively]. In addition, the 6 bp+/3G haplotype in ESCC patients was also significantly less common than in controls (P = 0.002). Compared with the 6 bp-/3G haplotype, the 6 bp+/3G significantly reduced the risk to ESCC (OR = 0.30, 95% CI = 0.14-0.67). Moreover, the TS 2R/3G genotype frequency in ESCC patients with and without lymphatic metastasis was significantly different (27.1 versus 4.9%, P < 0.001). Therefore, the 2R/3G genotype had an approximately 11-fold increase in the risk of lymphatic metastasis of ESCC, compared with the 3G/3G genotype (95% CI = 2.67-49.74). The results suggested that the TS polymorphisms might be associated with the susceptibility to ESCC and GCA, and the 2R/3G genotype might be a candidate marker to predict the potential of lymphatic metastasis in ESCC.

Adenocarcinoma↗
PubMed2004

Polymorphisms of the paraoxonase gene and risk of preterm delivery.

BACKGROUND: Human paraoxonase (PON) is an enzyme involved in vasodilation and thrombosis. Disruption of blood blow through the placenta could be part of the pathophysiological mechanism leading to preterm delivery. The purpose of this study was to examine the association between polymorphisms in 2 paraoxonase genes (PON1 and PON2) and preterm delivery. METHODS: We conducted a case-control study using infant-parents triads in Anqing, China. Between July 1999 and June 2001, we enrolled the families of 105 infants born at term and 80 infants born preterm. Genotyping was performed for the polymorphisms of PON1 Q192R, PON2 A148G, and PON2 S311C using standard techniques. We used log-linear modeling to analyze the association of PON1 and PON2 gene polymorphisms with the risk of preterm delivery. RESULTS: In the analysis of children's genotypes, the relative risk was 3.6 (95% confidence interval [CI] = 1.3-11) for PON1 RR compared with PON1 QQ. An association was also seen for PON2 CC compared with PON2 SS (relative risk = 4.6; CI = 1.5-14). There was no association between the mother's PON1 and PON2 genotypes and preterm delivery, and we did not observe an interaction between mothers' and children's genotypes. Analysis of control triads suggests Mendelian transmissions of the variant alleles of PON1 192R, PON2 148G, and PON2 311C. CONCLUSION: Infant PON1 RR and PON2 CC genotypes were associated with preterm delivery in our study population, which suggests a possible role for human paraoxonase variability in the etiology of preterm delivery.

Aryldialkylphosphatase↗
PubMed2006

Common variants in RB1 gene and risk of invasive ovarian cancer.

Somatic alteration of the RB1 gene is common in several types of cancer, and germ-line variants are implicated in others. We have used a single nucleotide polymorphism (SNP) tagging approach to evaluate the association between common variants (SNP) in RB1 and risks of invasive ovarian cancer. We genotyped 11 tagging SNPs in three ovarian case-control studies from the United Kingdom, United States, and Denmark, comprising >1500 cases and 4,800 controls. Two SNPs showed significant association with ovarian cancer risk: carriers of the minor allele of rs2854344 were at reduced risk compared with the common homozygotes [odds ratio (OR), 0.73; 95% confidence interval (95% CI), 0.61-0.89; P = 0.0009 dominant model]. Similarly, the minor allele of rs4151620 was found to be associated with reduced risk (rare versus common homozygote; OR, 0.19; 95% CI, 0.07-0.53; P = 0.00005 recessive model). After adjusting for multiple testing, the most significant association (rs4151620) was P = 0.001. A global test comparing common haplotype frequencies in cases and controls was of borderline significance (P(8df) = 0.04). There are no common coding SNPs in the RB1 gene. However, intron 17 of RB1 contains the open reading frame for the P2RY5 gene, and rs4151620 is perfectly correlated with rs2227311, which is located in the 5'-untranslated region of P2RY5 and is predicted to affect P2RY5 transcription. rs2854344 has been reported previously to be associated with breast cancer risk. The possible associations of rs2854344 and rs4151620 with ovarian cancer risk warrant confirmation in independent case-control studies before studies on their biological mode of action.

Case-Control Studies↗
PubMed2026

Survey to inform personalised prescribing in a British South Asian community: pharmacogenomics and traditional medicine use.

BACKGROUND: Pharmacogenomics (PGx) uses genetic information to personalize medication, reducing adverse reactions and improving efficacy. Despite its promise, low public awareness and disparities in PGx acceptability among under-represented groups may exacerbate health inequalities. The objective of this study was to elucidate a British South Asian community's attitudes toward personalised prescribing. METHODS: Adults of Bangladeshi or Pakistani ancestry from the Genes & Health (G&H) study completed a survey. Community feedback guided theme prioritization. Multivariable logistic regression analyses (controlling for age and gender) explored relationships among survey variables, and case-control Genome Wide Association Studies (GWAS) and candidate variant enrichment analysis examined the genetic architecture underlying herbal remedy use. RESULTS: Out of 553 respondents (57% female, mostly aged 25-54), 72% reported medication inefficacy, and 54% experienced side effects. Herbal remedies were widely used (66%), notably Black seed (39%), Turmeric (37%), and Ginger (36%). Participants who reported not using traditional or herbal medicines had higher medication adherence MARS-5 scores (Odds Ratio (OR) 1.10, 95% Confidence Interval (CI) 1.05-1.16, p&#x2009;<&#x2009;0.0002). All three commonly used herbal remedies inhibit the pharmacogenomically variable CYP2C9 enzyme responsible for metabolising commonly used medications. 58% of respondents were willing to provide DNA samples for PGx testing, yet 70% agreed that they would be more likely to take medication as instructed if PGx results suggested the medicine would suit them. Concerns about PGx testing were common (27%), especially among non-English speakers. Most (69%) were concerned about misuse of PGx data, particularly by pharmaceutical companies (82%). Importantly, 87% demanded stronger PGx data protections compared to other health data. CONCLUSIONS: Compared to a national UK population, the surveyed subpopulation reported higher rates of adverse drug reactions (ADRs) and perceived medication inefficacy, yet fewer respondents indicated willingness to undergo PGx testing. This highlights the need for tailored implementation strategies and underscores the importance of engaging underrepresented populations in policy development. The inverse relationship between medication adherence and herbal remedy use indicates an association between cultural health practices and medication behaviours that merits further investigation. Increased awareness of the common use of these CYP2C9 inhibitors and further research into the genetic architecture underlying herbal remedy use are warranted.

Humans↗
PubMed2005

Impact of alphaENaC polymorphisms on the risk of ischemic cerebrovascular events: a multicenter case-control study.

BACKGROUND: Amiloride-sensitive epithelial sodium channels (ENaCs) are important candidates in the development of hypertension, which is a major risk factor for stroke. Two single-nucleotide polymorphisms (SNPs) in the gene that encodes the ENac alpha-subunit (alphaENaC) have been identified. We evaluated those SNPs for a possible association with ischemic cerebrovascular events (ICEs). METHODS AND RESULTS: We genotyped 1399 patients with ICEs [median age, 70 years; interquartile range, 58-78 years; 745 (53%) men] and 1076 control individuals without vascular disease [47 (39-58) years; 557 (52%) men] for the SNPs Trp493Arg and Ala663Thr. The SNP frequencies at nucleotide 3977 (Trp493Arg) in the alphaENaC gene were significantly different in patients and controls. Carriers of 493Arg had a 1.78-fold increased risk (95% confidence interval, 1.02-3.12) for ICEs compared with Trp/Trp carriers. Interaction analysis revealed that the relative risk was even higher in women in the lowest age tertile [adjusted odds ratio, 3.26 (1.10-9.72)]. CONCLUSIONS: Carriers of the 493Arg allele are at increased risk for ICEs compared with Trp/Trp carriers. The effect is independent of traditional vascular risk factors and is particularly evident in younger women. The Trp493Arg variant in alphaENaC may represent an important candidate genetic susceptibility factor in the development of ICEs.

Adult↗
PubMed1979

[IgE concentration in healthy children of various age groups].

Serum IgE was estimated in 181 healthy children aged 2 months-17 years. The concentration of IgE was measured by radioimmunosorbent technique (RIST). To eliminate serum interference the IgE levels were calculated using the correction factors: 0,96 and 0,91 (for the sera diluted respectively 1:10 and 1:5). Statistical calculations were made after logarithmic transformation of the particular results. On the base of the mean geometric values linear and parabolic regression lines have been made. On the grounds of the received regression equations it has been found that parabolic variant of the changes of the IgE concentration with respect to age, shows more accurately the real state. The index of the parabolic correlation (r = 0,98) shows a close and positive relations between IgE concentration and the age of children. The lowest concentrations of IgE were found in the youngest group of infants and then the level increased during childhood. The parabolic regression line and 95% confidence limits for the geometric mean values ar inserted in the paper.

Adolescent↗
PubMed2003

The role of the TSC-22 (-396) A/G variant in the development of diabetic nephropathy.

TSC-22 is a leucine zipper transcriptional factor and expression of the TSC-22 gene is highly induced by TGF-beta treatment. We estimated the frequency of the -396 A/G polymorphism of the TSC-22 gene with an Alu I-Restriction fragment length polymorphism (RFLP) method in 498 Japanese subjects with type 2 diabetes mellitus. We also determined the promoter activity. The diabetic patients with the AA genotype had a significantly higher incidence of the diabetic nephropathy (vs. the AG genotype, P<0.05, odds ratio: 1.95; 95% confidence intervals 1.14-3.33). There was no significant difference in the promoter activity between the fragments with -396A and -396G. These findings suggest that the TSC-22 gene (-396) A allele is associated with an increasing risk of the diabetic nephropathy.

Cell Line, Tumor↗
PubMed2000

The dopamine D2 receptor gene is a susceptibility locus for Parkinson's disease.

The dopamine D2 receptor (DRD2) gene has been proposed as a candidate gene underlying several psychiatric and neurologic disorders. The aim of the present study was to examine if selected polymorphisms in the DRD2 gene are associated with Parkinson's disease (PD). We determined the allelic frequencies for four polymorphisms located in the DRD2 gene in a sample of 135 patients with PD and 202 normal control subjects. No significant difference was observed in the allelic frequencies between patients with PD and control subjects with regard to the -141C Ins/Del and the Ser311/Cys311 variants. On the contrary, the A1 allele of the TaqIA polymorphism and the B1 allele of the TaqIB polymorphism were more frequent in patients with PD than in control subjects (control subjects: TaqIA A1 = 14.6%, TaqIB B1 = 10.6%; patients with PD: TaqIA A1 = 20.7%, TaqIB B1 = 17.4%). Patients carrying the A1 allele or the B allele had an increased risk of developing PD (TaqIA, odds ratio: 1.71, 95% confidence intervals: 1.08-2.73; TaqIB, odds ratio: 1.83, 95% confidence intervals: 1.12-3.02). The TaqIA and TaqIB polymorphisms were in strong linkage disequilibrium, suggesting that these two polymorphisms convey the same information about the risk of presenting with PD. Genetic variation in the DRD2 gene may influence the risk of developing PD, thus confirming that the DRD2 gene is a susceptibility locus for PD.

Aged↗
PubMed1993

Q-T interval as predictor of serum calcium level.

To assess whether measurement of the electrocardiograhic (ECG) Q-T interval is a useful predictor of total serum calcium concentration, 15 uraemic patients were studied (10 female, five male; age range, 25-60 years). Resting ECGs were interpreted by three independent observers without knowledge of the patients' identity or serum calcium. Three variants of measurement of the Q-T interval were analysed, of which Q-aTc, the interval from the beginning of the Q-wave to the apex of the T-wave, was the most consistent (coefficient of variation, 2.7%). This also provided the best correlation with measured serum calcium concentration (P < 0.001). When compared to biochemical measurements, the predicted serum calcium concentration was within 95% confidence limits in 14 of the 15 patients studied. However, the wide confidence limits of this technique mean that it cannot be recommended in routine clinical practice.

Adult↗
PubMed2004

Glutathione S-transferase P1 Ile105Val polymorphism, cigarette smoking and prostate cancer.

The enzyme glutathione S-transferase P1 (GSTP1) detoxifies carcinogenic products of tobacco smoke. This exploratory case-control study evaluates the possible effect modification by the GSTP1 Ile105Val polymorphism (replacement of isoleucine by valine at codon 105) on smoking and prostate cancer. Because the Val variant possesses up to a five-fold greater enzymatic activity towards the carcinogenic metabolites of tobacco smoke, the Ile allele is expected to be related to an increase in the risk of prostate cancer among smokers. GSTP1 genotype and epidemiological data were obtained from 122 cases of prostate cancer and 135 healthy males as controls. A logistic regression model was used to estimate odds ratios and 95% confidence intervals. The adjusted OR of homozygous Ile compared to other genotypes for prostate cancer was 1.21 (95% CI: 0.61-2.83). Smoking was not significantly associated with prostate cancer with an adjusted OR of 1.56 (95% CI: 0.78-3.12). However, among individuals with the Ile/Ile genotype, smoking was strongly associated with an increased risk of prostate cancer with an adjusted odds ratio of 4.09 (95% CI: 1.25-13.35). A potential multiplicative interaction was suggested between GSTP1 and smoking on the risk of prostate cancer with the adjusted OR for the interaction of 4.52 (95% CI: 1.07-19.17). To our knowledge, this is the first time that a potential effect modification by the GSTP1 Ile/Ile genotype on smoking and the risk of prostate cancer is suggested.

Adult↗
PubMed2002

BRCA2 gene mutations in families with aggregations of breast and stomach cancers.

Stomach cancer ranks second to lung cancer in the global cancer burden. It is estimated that 25% of families meeting the criteria for hereditary diffuse gastric carcinoma (HDCG) will have germline mutations in the E-cadherin gene. Evidence suggests that stomach cancer might also be a malignant manifestation of other inherited predispositions to disease. Recently, it has been reported that the incidence of stomach cancer is significantly increased in BRCA2 gene mutation carriers. We analysed by direct sequencing the BRCA2 gene in 29 breast cancer patients derived from 29 families with an aggregation of at least one female breast cancer diagnosed before the age of 50 years and one male stomach cancer diagnosed before the age of 55 years. In all but one of these families at least one additional relative was also affected by a malignant tumour. We identified three frameshift mutations and three sequence variants - potentially missense mutations, in six unrelated patients representing 20.7% (six out of 29) of the families investigated. Our results confirm that BRCA2 gene mutations are also associated with familial aggregations of not only breast but also of stomach cancer. In comparison to the number of cancers expected in the study population compared to the general population there is an over-representation of several cancers with significant confidence intervals to suggest that the associations are real and not a selection artefact.

Adult↗
PubMed2000

Reward deficiency syndrome: a biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors.

The dopaminergic system, and in particular the dopamine D2 receptor, has been implicated in reward mechanisms. The net effect of neurotransmitter interaction at the mesolimbic brain region induces "reward" when dopamine (DA) is released from the neuron at the nucleus accumbens and interacts with a dopamine D2 receptor. "The reward cascade" involves the release of serotonin, which in turn at the hypothalmus stimulates enkephalin, which in turn inhibits GABA at the substania nigra, which in turn fine tunes the amount of DA released at the nucleus accumbens or "reward site." It is well known that under normal conditions in the reward site DA works to maintain our normal drives. In fact, DA has become to be known as the "pleasure molecule" and/or the "antistress molecule." When DA is released into the synapse, it stimulates a number a DA receptors (D1-D5) which results in increased feelings of well-being and stress reduction. A consensus of the literature suggests that when there is a dysfunction in the brain reward cascade, which could be caused by certain genetic variants (polygenic), especially in the DA system causing a hypodopaminergic trait, the brain of that person requires a DA fix to feel good. This trait leads to multiple drug-seeking behavior. This is so because alcohol, cocaine, heroin, marijuana, nicotine, and glucose all cause activation and neuronal release of brain DA, which could heal the abnormal cravings. Certainly after ten years of study we could say with confidence that carriers of the DAD2 receptor A1 allele have compromised D2 receptors. Therefore lack of D2 receptors causes individuals to have a high risk for multiple addictive, impulsive and compulsive behavioral propensities, such as severe alcoholism, cocaine, heroin, marijuana and nicotine use, glucose bingeing, pathological gambling, sex addiction, ADHD, Tourette's Syndrome, autism, chronic violence, posttraumatic stress disorder, schizoid/avoidant cluster, conduct disorder and antisocial behavior. In order to explain the breakdown of the reward cascade due to both multiple genes and environmental stimuli (pleiotropism) and resultant aberrant behaviors, Blum united this hypodopaminergic trait under the rubric of a reward deficiency syndrome.

Behavior, Addictive↗