A novel single nucleotide polymorphism of the neuropeptide Y (NPY) gene associated with alcohol dependence

BACKGROUND: Neuropeptide Y (NPY) is a major endogenous regulator of anxiety-related behaviors and emotionality. Transgenic work with NPY and null-mutant mice have implicated NPY in the control of alcohol consumption, suggesting that genetic variation of the prepro-NPY gene may also contribute to the heritability of alcoholism. The aim of this study was to examine whether polymorphic variants of the NPY gene are associated with the diagnosis of alcohol dependence. METHODS: We compared allele frequencies of 5 NPY polymorphisms (-883-ins/del, -602, -399, -84, and +1128) in a Nordic population of alcohol-dependent individuals (n = 428 males; n = 149 females) and ethnically matched controls (n = 84 males; n = 93 females) for whom alcohol dependence or any diagnosis of substance disorder was excluded. Patients were further subtyped into type I (late-onset) and type II (early-onset) alcoholics. RESULTS: The -602 marker showed a significant association with alcohol dependence (p = 0.0035; OR, 2.3; 95% CI, 1.3-4.0); a trend level association was further observed for the -399 marker (p = 0.058; OR, 1.3; 95% CI, 0.99-1.7) and the +1128 marker (p = 0.053; OR, 1.8; 95% CI, 0.99-3.1). The association for the -602 marker remained and was strengthened when analyzed in type I subjects only, although this association was not seen in type II patients, and there also was a significant association in the female subjects but not in males. The -602 single nucleotide polymorphism was in strong linkage dysequilibrium (r2 = 0.7; p < 0.0001) with the +1128 single nucleotide polymorphism, which has previously been reported to be associated with a diagnosis of alcoholism. Haplotype-based association confirmed these results. CONCLUSIONS: We report a novel polymorphism at position -602 in the 5' region of the NPY gene that is significantly associated with alcohol dependence. We also describe the haplotype frequencies and linkage dysequilibrium pattern of four variations in that region.     

The 3' part of the dopamine transporter gene DAT1/SLC6A3 is associated with withdrawal seizures in patients with alcohol dependence

Background:  Some studies have reported that the A9 allele of the variable nucleotide tandem repeat (VNTR) of the gene which encodes the dopamine transporter ( DAT1/SLC6A3 ) is associated with alcoholism withdrawal symptoms such as alcohol withdrawal seizures (WSs), whereas others did not. We investigated whether polymorphisms within the DAT1 gene are associated with WS taking into account some of the confounding factors such as the severity of alcohol dependence.
Methods:  To further assess the role of this gene in WS, we genotyped the VNTR and 7 single nucleotide polymorphisms (SNPs) encompassing the DAT1 gene in a sample of 250 alcohol-dependent subjects (175 men and 75 women), of whom 24% exhibited WSs, taking into account the severity of alcohol dependence.
Results:  The VNTR is associated with an increased risk of WSs (odd ratio = 3.5; p  = 0.019), even when controlling for confounding factors ( p  = 0.031). As 2 SNPs, in roughly the same location of the gene (namely rs27072 and rs27048), are also associated with WSs, it is possible that the initial association of the VNTR polymorphism was tagging a specific haplotype of this gene. Indeed, in our sample of alcohol-dependent patients, 2 haplotypes were associated with a significantly different risk of WSs.
Conclusions:  The present study adds evidence for a significant role of the 3' part of the DAT1 gene in WS of alcohol-dependent patients, not only because it is in accordance with previous work, but also because of larger statistical power (as relying on a sample over sampled with the studied phenotype), as it gives a more precise analysis of different SNPs within the DAT1 gene, and as it confirms the association when major potentially confounding factors are taken into account in a logistical regression analysis.     

A haplotype of the DRD1 gene is associated with alcohol dependence

Background:  The D1 dopamine receptor has been involved in a number of brain functions, including motor control, inattentive symptoms and reward and reinforcement mechanisms. Indeed, DRD1 antagonists may reduce cocaine-seeking behavior and the acquisition of cocaine-cue associations. The D1.1/r4532 marker of the DRD1 gene has been associated with a large set of phenotypes including addictive behaviors, but none with alcohol dependence per se.
Methods:  We analyzed a population of 134 patients with alcohol dependence, also assessing more homogeneous (severe) phenotypes, comparing this sample with a healthy control population, assessing two SNPs within the DRD1 gene in order to depict the role of DRD1 polymorphisms and haplotypes.
Results:  The T allele of the rs686 polymorphism within DRD1 gene was significantly more frequent in patients with alcohol dependence ( p  = 0.0008), with a larger excess for patients with severe dependence ( p  = 6 × 10⁻⁶), and even more for patients with severe complications such as withdrawal seizures ( p  = 7 × 10⁻⁷). A specific haplotype rs686*T-rs4532*G within the DRD1 gene was significantly more precisely associated with alcohol dependence in our sample ( p  = 5 × 10⁻⁶).
Conclusions:  Even though chance finding cannot be ruled out, convergent evidence is given that the DRD1 gene is a susceptibility gene in alcohol dependence, regarding the fact that relying on more homogeneous phenotypes (i.e., more severe patients) and more informative genetic markers (i.e., haplotypes) reinforce the initial association.     

The tachykinin receptor 3 is associated with alcohol and cocaine dependence

Background:  A broad region on chromosome 4q was previously linked to the phenotype of alcohol dependence in the Collaborative Study on the Genetics of Alcoholism sample. A strong positional candidate gene was identified within this region: tachykinin receptor 3 gene ( TACR3 ), which encodes tachykinin receptor 3 (NK3R), the receptor for the tachykinin 3 (neurokinin B) peptide. Pharmacological studies have provided evidence that the administration of NK3R agonists attenuates the intake of alcohol and NK3R can also mediate the acute and chronic behavioral effects of cocaine.
Methods:  Thirty SNPs were genotyped throughout TACR3 . Family based association analysis was performed in 219 European American families to detect an association with alcohol dependence. Subsequent analyses were performed to evaluate the evidence of association with other definitions of alcohol dependence as well as cocaine dependence.
Results:  Seven of the 9 SNPs in the 3' region of TACR3 provided significant evidence of association with alcohol dependence ( p  ≤ 0.05). Further analyses suggest that the evidence of association is strongest among those subjects with more severe alcohol dependence (defined by ICD-10) and those with co-morbid cocaine dependence. Haplotype analyses further strengthen the evidence of association in the 3' region of the gene.
Conclusions:  These results indicate that sequence variations in TACR3 contribute to the variation in more severe alcohol dependent individuals and those who are also cocaine dependent.     

The frequent and conserved DR3-B8-A1 extended haplotype confers less diabetes risk than other DR3 haplotypes

Aim:  The goal of this study was to develop and implement methodology that would aid in the analysis of extended high-density single nucleotide polymorphism (SNP) major histocompatibility complex (MHC) haplotypes combined with human leucocyte antigen (HLA) alleles in relation to type 1 diabetes risk.
Methods:  High-density SNP genotype data (2918 SNPs) across the MHC from the Type 1 Diabetes Genetics Consortium (1240 families), in addition to HLA data, were processed into haplotypes using P ed C heck and M erlin , and extended DR3 haplotypes were analysed.
Results:  With this large dense set of SNPs, the conservation of DR3-B8-A1 (8.1) haplotypes spanned the MHC (≥99% SNP identity). Forty-seven individuals homozygous for the 8.1 haplotype also shared the same homozygous genotype at four 'sentinel' SNPs (rs2157678 'T', rs3130380 'A', rs3094628 'C' and rs3130352 'T'). Conservation extended from HLA-DQB1 to the telomeric end of the SNP panels (3.4 Mb total). In addition, we found that the 8.1 haplotype is associated with lower risk than other DR3 haplotypes by both haplotypic and genotypic analyses [haplotype: p = 0.009, odds ratio (OR) = 0.65; genotype: p = 6.3 × 10⁻⁵, OR = 0.27]. The 8.1 haplotype (from genotypic analyses) is associated with lower risk than the high-risk DR3-B18-A30 haplotype (p = 0.01, OR = 0.23), but the DR3-B18-A30 haplotype did not differ from other non-8.1 DR3 haplotypes relative to diabetes association.
Conclusion:  The 8.1 haplotype demonstrates extreme conservation (>3.4 Mb) and is associated with significantly lower risk for type 1 diabetes than other DR3 haplotypes.     

Haplotype-based search for SNPs associated with differential type 1 diabetes risk among chromosomes carrying a specific HLA DRB1–DQA1–DQB1 haplotype

Aim:  The aim of this study was to test chromosomes carrying the same DRB1–DQA1–DQB1 haplotype for single nucleotide polymorphisms (SNPs) in the major histocompatibility complex (MHC) that might mark subgroups of the haplotype with different risks for type 1 diabetes (T1D).
Methods:  Chromosomes from T1D children, their parents and non-diabetic siblings in families of the Type 1 Diabetes Genetics Consortium (T1DGC) were analysed by two haplotype-based methods: (i) logistic regression analysis restricted to phased chromosomes carrying the same DRB1–DQA1–DQB1 haplotype but differentiated by the two alleles at MHC SNPs, which were individually tested for association with T1D and (ii) homozygous parent transmission disequilibrium test (TDT) for biased transmission of a SNP allele to diabetic children from parents who are heterozygous at the SNP but homozygous for the specific DRB1–DQA1–DQB1 haplotype being evaluated.
Results:  A number of SNPs gave nominally significant (p < 0.05) evidence of marking two subsets of the 301–501–201 haplotype that might differ with respect to their diabetogenic potency. However, none of the SNPs achieved experiment-wide significance and hence may be false-positive associations.
Conclusions:  We discuss limitations and possible deficiencies of our study suggesting further work that might yield more robust SNP associations marking two subgroups of a DRB1–DQA1–DQB1 haplotype with different T1D risks.     

Association of alcohol craving with alpha-synuclein (SNCA)

BACKGROUND: Studies have found that genomic variation in the gene SNCA, which encodes the protein alpha-synuclein, may contribute to the variation in alcohol consumption in an inbred rat model of alcohol preference. Studies in humans have provided support for an association between SNCA and craving for alcohol. METHODS: To examine the role of this gene in alcohol dependence and related phenotypes, 30 single nucleotide polymorphisms (SNPs) were genotyped across the SNCA gene in a sample of 219 multiplex alcoholic families of European American descent. Two phenotypes, alcohol dependence and alcohol craving, were analyzed using the pedigree disequilibrium test. RESULTS: There was no evidence of association between any of the SNCA SNPs and alcohol dependence (p>or=0.13). In contrast, 8 SNPs provided evidence of association (p<0.05) with the phenotype of alcohol craving. Haplotype analysis further supported evidence of an association with alcohol craving; a haplotype encompassing SNPs in intron 4 through the region downstream of the gene was overtransmitted to cravers and a second haplotype was overtransmitted to noncravers. CONCLUSIONS: These results suggest that variation in SNCA contributes to alcohol craving, a common, although not uniform, feature of alcohol dependence.     

Association of Markers in the 3' Region of the GluR5 Kainate Receptor Subunit Gene to Alcohol Dependence

Background:  Glutamate neurotransmission plays an important role in a variety of alcohol-related phenomena, including alcohol self-administration by both animals and humans. Because the risk for alcohol dependence (AD) is genetically influenced, genes encoding glutamate receptors are candidates to contribute to the risk for AD. We examined the role of variation in the 3' region of GRIK1 , the gene that encodes the GluR5 receptor subunit of the kainic acid glutamate receptor, on risk for AD. We focused specifically on this gene because topiramate, a glutamate modulator that binds to the GluR5 subunit, has shown robust efficacy in the treatment of AD.
Methods:  We genotyped 7 single nucleotide polymorphisms (SNPs) in the 3'-half of GRIK1 , which includes 3 differentially spliced exons, in a sample of EA control subjects ( n  = 507) and subjects with AD ( n  = 1,057).
Results:  We found nominally significant evidence of association to AD for 3 SNPs (rs2832407 in intron 9, rs2186305 in intron 17, and rs2832387 in the 3'UTR). Empirical p -value estimation revealed that only rs2832407 was significantly associated to phenotype ( p  = 0.043).
Discussion:  These findings provide support for the hypothesis that variation in the 3' portion of the gene encoding the GluR5 kainate receptor subunit contributes to the risk for AD. Further research is needed to ascertain whether this SNP is itself functional or whether the association reflects linkage disequilibrium with functional variation elsewhere in the gene and whether this SNP moderates topiramate's effects in the treatment of AD.     

Association of ADH and ALDH genes with alcohol dependence in the Irish Affected Sib Pair Study of alcohol dependence (IASPSAD) sample

Background:  The genes coding for ethanol metabolism enzymes [alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH)] have been widely studied for their influence on the risk to develop alcohol dependence (AD). However, the relation between polymorphisms of these metabolism genes and AD in Caucasian subjects has not been clearly established. The present study examined evidence for the association of alcohol metabolism genes with AD in the Irish Affected Sib Pair Study of alcohol dependence.
Methods:  We conducted a case–control association study with 575 independent subjects who met Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, AD diagnosis and 530 controls. A total of 77 single nucleotide polymorphisms (SNPs) in the seven ADH ( ADH1-7 ) and two ALDH genes ( ALDH1A1 and ALDH2 ) were genotyped using the Illumina GoldenGate protocols. Several statistical procedures were implemented to control for false discoveries.
Results:  All markers with minor allele frequency greater than 0.01 were in Hardy–Weinberg equilibrium. Numerous SNPs in ADH genes showed association with AD, including one marker in the coding region of ADH1C (rs1693482 in exon6, Ile271Gln). Haplotypic association was observed in the ADH5 and ADH1C genes, and in a long haplotype block formed by the ADH1A and ADH1B loci. We detected two significant interactions between pairs of markers in intron 6 of ADH6 and intron 12 of ALDH2 ( p  =   5 × 10⁻⁵), and 5' of both ADH4 and ADH1A ( p  =   2 × 10⁻⁴).
Conclusion:  We found evidence for the association of several ADH genes with AD in a sample of Western European origin. The significant interaction effects between markers in ADH and ALDH genes suggest possible epistatic roles between alcohol metabolic enzymes in the risk for AD.     

Polymorphisms of human vascular endothelial growth factor gene in high-altitude pulmonary oedema susceptible subjects

Background and objective:   Based on the reported biological properties and function of vascular endothelial growth factor (VEGF) in hypoxic conditions, many investigations have studied the hypothesis that VEGF has an important role in the pathogenesis of high altitude sicknesses, including high-altitude pulmonary oedema (HAPE). Unfortunately, the results are inconsistent. Therefore, the association of VEGF gene single nucleotide polymorphisms (SNP) with being susceptible to HAPE was investigated.
Methods:   The study included 53 HAPE-susceptible subjects (HAPE-s) and 69 HAPE-resistant mountaineer controls (HAPE-r). Subjects were Japanese and the two groups were comparable in terms of age and gender. The SNP of the VEGF gene, namely C-2578A, G-1154A and T-460C in the promoter, G + 405C in the 5'-untranslated region and C936T in the 3'-untranslated region, were examined by allele discrimination experiments. In addition, arterial oxygen tension (PaO₂) and pulmonary haemodynamic data were available for 21 of the HAPE-s subjects.
Results:   There were no statistically significant differences in the allele frequencies, genotype distributions or haplotype frequencies of VEGF SNP between the HAPE-s and HAPE-r groups. Furthermore, neither PaO₂ nor pulmonary haemodynamic parameters were associated with the VEGF SNP in the 21 HAPE-s subjects.
Conclusions:   This genetic study did not provide evidence that functional SNP of the VEGF gene are associated with susceptibility to HAPE in a Japanese population.     

Neuropeptide Y receptor genes are associated with alcohol dependence, alcohol withdrawal phenotypes, and cocaine dependence

Background: Several lines of evidence in both human and animal studies suggest that variation in neuropeptide Y (NPY) or its receptor genes (NPY1R, NPY2R and NPY5R) is associated with alcohol dependence as well as alcohol withdrawal symptoms. Additional studies suggest that cocaine may affect NPY expression. Methods: A total of 39 single nucleotide polymorphisms (SNPs) were genotyped across NPY and its 3 receptor genes in a sample of 1,923 subjects from 219 multiplex alcoholic families of European American descent recruited as part of the Collaborative Studies on the Genetics of Alcoholism (COGA) study. Family‐based association analysis was performed to test the primary hypothesis that variation in these genes is associated with alcohol dependence. Secondary analyses evaluated whether there was an association of these SNPs with symptoms of alcohol withdrawal, cocaine dependence, or comorbid alcohol and cocaine dependence. Results: Although variations in NPY itself were not associated with these phenotypes, variations in 2 NPY‐receptor genes were. SNPs in NPY2R provided significant evidence of association with alcohol dependence, alcohol withdrawal symptoms, comorbid alcohol and cocaine dependence, and cocaine dependence (all p < 0.03). Haplotype analyses strengthened the evidence for these phenotypes (global 0.0004 < p < 0.005). SNPs in NPY5R demonstrated significant association with alcohol withdrawal characterized by seizures (p < 0.05). Conclusion: These results indicate that sequence variations in NPY receptor genes are associated with alcohol dependence, particularly a severe subtype of alcohol dependence characterized by withdrawal symptoms, comorbid alcohol and cocaine dependence, and cocaine dependence.     

Leucine 7 to proline 7 polymorphism in the neuropeptide y gene is associated with retinopathy in type 2 diabetes.

In this study we tested the hypothesis that the Leu7Pro7 polymorphism in prepro neuropeptide Y (NPY) gene could be a risk marker for the development of diabetic retinopathy and analyzed a well characterized cohort of patients with Type 2 diabetes followed-up for 10 years from the time of diagnosis. The frequency of Leu7/Pro7-polymorphism was 9.3% (8 out of 86). At baseline, the frequency of retinopathy in patients with the Leu7/Pro7-polymorphism was 25% (2 out of 8) and in those without it 6.4% (5 out of 78) (p=0.126). At 10-year the respective figures were 88% and 50% (p=-0.040). The odds ratio for Leu7/Pro7-polymorphism in logistic regression analysis adjusted for age, gender and HbA1c was 8.97 (95% confidence intervals 1.09-98.0; p=0.049). Our finding based on elderly Finnish Type 2 diabetic subjects suggests that the Leu7Pro7-genotype in preproNPY gene is associated with the development of diabetic retinopathy.     

The Leu7Pro polymorphism of the neuropeptide Y gene regulates free fatty acid metabolism

The Leu7Pro polymorphism in the signal peptide of the preproneuropeptide Y (NPY) has been associated with dyslipidemias and free fatty acid (FFA) levels during exercise. The association of this polymorphism with insulin sensitivity has not been studied. In this study, the Leu7Pro polymorphism was determined in 2 groups of nondiabetic middle-aged subjects (n [equals] 266 and n [equals] 295). Insulin sensitivity was measured with the hyperinsulinemic euglycemic clamp (n [equals] 266) or with an intravenous glucose tolerance test (IVGTT, n [equals] 295). First-phase insulin secretion was determined as insulin area under the curve (AUC) during the first 10 minutes of the IVGTT. FFAs were measured both in the fasting state and during the hyperinsulinemic clamp. The Leu7Pro polymorphism of the NPY gene was not associated with the rates of whole body glucose uptake, insulin sensitivity index, insulin secretion during the IVGTT, or insulin AUC during the oral glucose tolerance test. However, the Pro7 allele was associated with low FFA levels both in the fasting state (P [equals] .043) and during the hyperinsulinemic clamp (P [equals] .003). In conclusion, the Leu7Pro polymorphism of the NPY gene associates with alterations in FFA metabolism but does not have an impact on insulin sensitivity, insulin secretion, or glucose metabolism. [copy ] 2003 Elsevier Inc. All rights reserved.     

Glutamate decarboxylase genes and alcoholism in Han Taiwanese men

Objective: Glutamate decarboxylase (GAD), the rate-limiting enzyme in the synthesis of γ -aminobutyric acid (GABA), may be involved in the development of alcoholism. This study examined the possible roles of the genes that code for 2 forms of GAD (GAD1 and GAD2) in the development of alcoholism.
Method: An association study was conducted among 140 male alcoholic subjects meeting the DSM-III-R criteria for alcohol dependence and 146 controls recruited from the Han Taiwanese in community and clinical settings. Psychiatric assessment of drinking conditions was conducted using a Chinese version of the Schedules for Clinical Assessment in Neuropsychiatry. The SHEsis and Haploview programs were used in statistical analyses.
Results: Nine single-nucleotide polymorphisms (SNPs) at the GAD1 gene were valid for further statistics. Between alcoholic subjects and controls, significant differences were found in genotype distributions of SNP1 ( p =0.000), SNP2 ( p =0.015), SNP4 ( p =0.015), SNP5 ( p =0.031), SNP6 ( p =0.012), and SNP8 ( p =0.004) and in allele distributions of SNP1 ( p =0.001), SNP2 ( p =0.009), and SNP8 ( p =0.009). Permutation tests of SNP1, SNP2, and SNP8 demonstrated significant differences in allele frequencies but not in 2 major haplotype blocks. Three valid SNPs at the GAD2 gene demonstrated no associations with alcoholism. Further permutation tests in the only 1 haplotype block or individual SNPs demonstrated no significant differences.
Conclusions: This is the first report indicating a possible significant role of the GAD1 gene in the development of alcohol dependence and/or the course of alcohol withdrawal and outcome of alcoholism.     

The Leu7Pro polymorphism of preproNPY is associated with decreased insulin secretion, delayed ghrelin suppression, and increased cardiovascular responsiveness to norepinephrine during oral glucose tolerance test

CONTEXT: Neuropeptide Y (NPY) plays a role in angiogenesis, cardiovascular regulation, and hormone secretion. The leucine7 to proline7 (Leu7Pro) polymorphism of preproNPY is associated with vascular diseases and has an impact on hormone levels in healthy subjects. OBJECTIVE: The current study investigated the role of the Leu7Pro polymorphism in metabolic and cardiovascular autonomic regulation. DESIGN AND SUBJECTS: A 5-h oral glucose tolerance test was performed on 27 healthy volunteers representing two preproNPY genotypes (Leu7/Pro7 and Leu7/Leu7) matched for age, sex, body mass index and physical activity. MAIN OUTCOME MEASURES: Simultaneously we performed cardiovascular autonomic function tests and plasma measurements of sympathetic transmitters, glucose, insulin, and ghrelin. RESULTS: The subjects with Leu7/Pro7 genotype had decreased plasma NPY, norepinephrine (NE), and insulin concentrations and insulin to glucose ratios. The suppression of ghrelin concentrations after glucose ingestion was delayed in these subjects. They also had increased heart rate variability indices and baroreflex sensitivity. However, they displayed significant negative association of NE concentration with variability of low-frequency R-R-intervals and with baroreflex sensitivity. CONCLUSIONS: The Leu7Pro polymorphism of preproNPY is related to decreased level of basal sympathetic activity, decreased insulin secretion, and delayed ghrelin suppression during oral glucose tolerance test. The increased responsiveness of autonomic functions to NE associated with the polymorphism may be connected to increased cardiovascular vulnerability.     

血管紧张素原基因多态性与高血压血尿醛固酮水平相关

目的研究血管紧张素原(Angiotensinogen,AGT)基冈5个单核苷酸多态性(single nucleotide polymorphisms,SNPs)及其构成的单倍型在中国汉族人群中与原发性高血压的相关性及各SNP与高血压患者血浆肾素活性(PRA)、血管紧张素Ⅱ(AngⅡ)、血浆和尿醛固酮(Ald)水平的关系。方法采用MassARRAYTM系统质谱检测技术,在500例原发性高血压患者和500名正常对照者中,对AGT基因启动子区域的C-532T、A-20C、G-6A及编码区的T174M和M235T进行基因分型。用放免法检测高血压患者PRA、AngⅡ、血尿Ald水平。结果5种SNP的等位基因频率和单倍型分布在原发性高血压组和对照组中均无显著差异(P>0．05);男性高血压患者中C-532T多态CT TT基因型个体尿Ald水平显著高于CC型个体(6．52 vs 5．19μg／d,P=0．03);女性高血压患者G-6A多态GG GA基因型个体血Ald水平显著高于AA型个体(78．63 vs 58．86 pg/ml,P=0．015);女性高血压患者M235T多态MM MT基因型个体血Ald水平显著高于TT型个体(78．73 vs 58．81 pg／ml,P=0．03); A-20C多态AC CC基因型与G-6A多态GG GA基因型联合者尿Ald水平(P<0．05)、体重指数(P <0．01)显著高于其他联合基因型。结论AGT基因5个SNP及单倍型分布在高血压患者和正常血压对照之间无显著差异,AGT基因的SNP分布与原发性高血压患者血尿醛固酮水平有关。     

Associations Among GABRG1, Level of Response to Alcohol, and Drinking Behaviors

Background:  Recent studies of the genetics of alcoholism have focused on a cluster of genes encoding for γ-aminobutyric acid (GABA_A) receptor subunits, which is thought to play a role in the expression of addiction phenotypes. This study examined allelic associations between 2 single nucleotide polymorphisms (SNPs) of the GABRG1 gene (rs1391166 and rs1497571) and alcohol phenotypes, namely level of response to alcohol, alcohol use patterns, and alcohol-related problems.
Method:  Participants were non-treatment-seeking seeking hazardous drinkers ( n  = 124) who provided DNA samples, participated in a face-to-face interview for level of response to alcohol, and completed a series of drinking and individual differences measures.
Results:  Analyses revealed that a SNP of the GABRG1 gene (rs1497571) was associated with level of response to alcohol and drinking patterns in this subclinical sample. Follow-up mediational analyses were also conducted to examine putative mechanisms underlying these associations.
Discussion:  These findings replicate and extend recent research suggesting that genetic variation at the GABRG1 locus may underlie the expression of alcohol phenotypes, including level of response to alcohol.     

NPY Leu7Pro and alcohol dependence in Finnish and Swedish populations

BACKGROUND: Neuropeptide Y (NPY) is a modulator of alcohol intake in animal models of alcoholism, and is potentially involved in alcohol dependence. A coding Leu7Pro polymorphism in the signal peptide of preproNPY has been described, and the Pro7 allele has been reported to correlate with increased alcohol consumption in non-dependent Finnish males. Recently, this polymorphism was also reported to be associated with an actual diagnosis of alcohol dependence. METHODS: We compared Pro7 allele frequencies in one Finnish (n = 135) and one Swedish (n = 472) population of alcohol dependent individuals, and ethnically matched controls (Finns: n = 213; Swedes: n = 177) in whom alcohol dependence was established, or any diagnosis of substance disorder was excluded, respectively, through the use of structured face-to-face interviews. RESULTS: Pro7 frequencies in alcoholics were 5.2 and 4.1% in Finns and Swedes, respectively, similar to the 5.0-5.5% recently reported in European Americans in a Yale study. However, corresponding frequencies in the control populations were similar, at 6.1 and 5.9% in Finns and Swedes, respectively, yielding no association, in contrast with the Yale study, where an association was reported based on a 2.0% Pro7 frequency in European American controls. A meta-analysis of available data yields Pro7 frequencies of 4.7% both in Caucasian alcoholics and Caucasian controls. CONCLUSIONS: Pro7 does not seem to be associated with a diagnosis of alcoholism in Caucasian populations.     

Enhanced exercise-induced GH secretion in subjects with Pro7 substitution in the prepro-NPY.

The leucine 7 to proline 7 (Leu7Pro) polymorphism in the signal peptide of NPY is associated with high blood lipid concentrations and accelerated rate of atherosclerosis as well as diabetic retinopathy. Also, healthy subjects with this polymorphism have increased NPY secretion during sympathetic stimulation. Because NPY may regulate GH release and ghrelin may regulate NPY formation, we studied the effects of the Leu7/Pro7 genotype on GH, ghrelin, and IGF-I secretion during standardized cycle-ergometer exercise. Furthermore, we studied the effect of the Leu7/Pro7 genotype on diurnal GH secretion in rest in a separate study. The subjects with Leu7/Pro7 genotype had 54% higher maximal increases in the plasma GH concentrations than the controls during exercise. There were no significant differences in the ghrelin or IGF-I concentrations during exercise among the groups. Furthermore, there were no differences in diurnal GH secretion between the genotypes. The results indicate that the prepro-NPY genotype has an influence on GH response during exercise in humans. The clinical significance of this finding is not known, and further studies are needed to evaluate whether the observed change in GH secretion during exercise could play a role in promoting diseases.