Untranslated Region Single Nucleotide Polymorphisms Research Articles

An individual coding polymorphism and the haplotype of the SPARC gene predict gastric cancer recurrence

The 5-year survival rate for gastric adenocarcinoma (GA) remains only 40% and biomarkers to identify patients at high risk of tumor recurrence are urgently needed. Secreted protein acidic and rich in cysteine (SPARC) is an extracellular matrix glycoprotein that mediates cell matrix interactions, and upregulation of SPARC can promote tumor progression and metastasis. This study investigated whether single-nucleotide polymorphisms (SNPs) in SPARC impact the prognosis of GA. Blood or formalin-fixed, paraffin-embedded tissues were obtained from 137 GA patients at the University of Southern California and Memorial Sloan-Kettering Cancer Center medical facilities. DNA was isolated and five SNPs in the SPARC 3'-untranslated region (UTR) were evaluated by DNA sequencing or PCR-restriction fragment length polymorphism. Associations between SNPs and time to tumor recurrence (TTR) were analyzed using Kaplan-Meier curves, log-rank tests, and likelihood-ratio test within logistic or Cox regression model as appropriate. Patients carrying at least one G allele of the SPARC rs1059829 polymorphism (GG, AG) showed a median TTR of 3.7 years compared with 2.1 years TTR for patients with AA (hazard ratio (HR) 0.57; P=0.033). In a multivariate analysis adjusted for T and N category as covariates and stratified by race, hospital and chemotherapy, patients with at least one SPARC rs1059829 G allele (GG, AG) remained significantly associated with superior TTR than patients with AA genotype (adjusted P=0.026). In addition, patients harboring the G-A-A haplotype had the highest risk of tumor recurrence (HR 1.892; adjusted P=0.016). Our findings suggest that SPARC 3'-UTR SNPs may be useful in predicting GA patients at increased risk of recurrence.

Associations of Fibroblast Growth Factor 21 Gene 3′ Untranslated Region Single-Nucleotide Polymorphisms with Metabolic Syndrome, Obesity, and Diabetes in a Han Chinese Population

Fibroblast growth factor 21 (FGF-21) is a novel regulator for metabolic syndrome (MetS), diabetes, and obesity. However, no study has been performed on the association of these diseases with FGF-21 gene polymorphism. The aim of the study was to investigate the association of 3' untranslated region (UTR) single-nucleotide polymorphisms (SNPs) in the FGF-21 gene with MetS, obesity, and diabetes in the Han Chinese population. A total of 291 subjects were recruited from the Han Chinese population in Sichuan province. The genotypes of FGF-21 were determined by polymerase chain reaction-restriction fragment length polymorphism. The genotypes were confirmed by sequencing. No polymorphisms were found in rs11665841 (1 of 291) and rs3745706 (2 of 291). We did not find an association between genotype frequencies of SNP rs11665896 and lipid concentration, glucose concentration, or blood pressure. The TG/GG genotype relative to the TT genotype had an age- and sex-adjusted odds ratio of 1.41 for MetS (p=0.149), 1.84 (p=0.016) for obesity (body mass index ≥25 kg/m(2)), and 1.19 (p=0.492) for diabetes. Genetic variation of the 3' UTR of the FGF-21 gene was associated with obesity, however, not with MetS or diabetes.

Analysis of multiple polymorphisms in the bovine neuropeptide Y5 receptor gene and structural modelling of the encoded protein

The neuropeptide Y 5 receptor (NPY5R) plays an important role in the regulation of appetite and feeding behaviour in mammals by modulating the effect of the neurotransmitter neuropeptide Y. As single nucleotide polymorphism (SNP) variation in the bovine NPY5R gene is likely to influence the expression and/or function of this gene, the objectives of this study were to identify SNPs in the bovine NPY5R gene and to predict their functional role in the expression and physico-chemical characteristics of the protein product. Nineteen novel SNPs were identified in a 2.1kb genomic region of the NPY5R gene in a total of 419 beef cattle from 13 Bostaurus breeds and eight Bosindicus animals. Four of these SNPs were non-synonymous (Met→Ile, Leu→Phe, Pro→Leu, Arg→Stop codon), while 10 were synonymous. Of particular interest was one non-synonymous SNP (c.1090C>T) that introduced a stop codon in the third intracellular loop of the NPY5R molecule. This stop codon is predicted to create a truncated NPY5R molecule with different physico-chemical properties compared to the native NPY5R protein. A further four SNPs were located in the 5' untranslated region (UTR) and one in the 3'UTR. Two of the 5'UTR SNPs affected putative transcription factor binding sites (GATA binding factor and snRNA-activating protein complex). In conclusion, regulatory and functional SNPs were identified in the bovine NPY5R gene. These include SNPs which potentially modify transcription factor binding sites as well as SNPs that cause amino acid changes and premature termination of the NPY5R protein. Such polymorphisms are likely to play vital physiological roles in the neuropeptide Y mediated appetite, feed intake and energy homeostasis in cattle.

Genetic Variation in an miRNA-1827 Binding Site in MYCL1 Alters Susceptibility to Small-Cell Lung Cancer

Genetic variations in microRNAs (miRNA) that affect control of their target genes may alter individual susceptibilities to cancer. In this study, we took an in silico approach to identify single-nucleotide polymorphisms (SNP) within the 3'-untranslated region (UTR) of miRNA genes deregulated in human small-cell lung cancer (SCLC), and then investigated their associations with SCLC susceptibility in 666 SCLC patients and 758 controls. Odds ratios (OR) were estimated by multivariate logistic regression, and biochemical assays were conducted to investigate SNP functions. We identified 2 SNPs, rs3134615 and rs2291854, which were located in the 3'-UTR of the L-MYC gene MYCL1 and the neuronal development Achaete-Scute Complex homolog ASCL1. Case-control analyses showed that the rs3134615T allele was associated with a significantly increased risk of SCLC, with the OR for carrying the GT or TT genotype being 2.08 (95% confidence interval, 1.39-3.21; P = 0.0004) compared with the GG genotype. In support of the likelihood that these 3'-UTR SNPs may directly affect miRNA-binding sites, reporter gene assays indicated MYCL1 as the target of hsa-miR-1827 and the rs3134615 G>T change resulted in altered regulation of MYCL1 expression. Our findings define a 3'-UTR SNP in the human L-MYC oncogene that may increase susceptibility to SCLC, possibly resulting from attenuated interaction with the miRNA hsa-miR-1827.

Naturally Occurring Variations in the Human Cholinesterase Genes: Heritability and Association with Cardiovascular and Metabolic Traits

Cholinergic neurotransmission in the central and autonomic nervous systems regulates immediate variations in and longer-term maintenance of cardiovascular function with acetylcholinesterase (AChE) activity that is critical to temporal responsiveness. Butyrylcholinesterase (BChE), largely confined to the liver and plasma, subserves metabolic functions. AChE and BChE are found in hematopoietic cells and plasma, enabling one to correlate enzyme levels in whole blood with hereditary traits in twins. Using both twin and unrelated subjects, we found certain single nucleotide polymorphisms (SNPs) in the ACHE gene correlated with catalytic properties and general cardiovascular functions. SNP discovery from ACHE resequencing identified 19 SNPs: 7 coding SNPs (cSNPs), of which 4 are nonsynonymous, and 12 SNPs in untranslated regions, of which 3 are in a conserved sequence of an upstream intron. Both AChE and BChE activity traits in blood were heritable: AChE at 48.8 ± 6.1% and BChE at 81.4 ± 2.8%. Allelic and haplotype variations in the ACHE and BCHE genes were associated with changes in blood AChE and BChE activities. AChE activity was associated with BP status and SBP, whereas BChE activity was associated with features of the metabolic syndrome (especially body weight and BMI). Gene products from cDNAs with nonsynonymous cSNPs were expressed and purified. Protein expression of ACHE nonsynonymous variant D134H (SNP6) is impaired: this variant shows compromised stability and altered rates of organophosphate inhibition and oxime-assisted reactivation. A substantial fraction of the D134H instability could be reversed in the D134H/R136Q mutant. Hence, common genetic variations at ACHE and BCHE loci were associated with changes in corresponding enzymatic activities in blood.

Individual Variability in the Detoxification of Carcinogenic Arylhydroxylamines in Human Breast

Cytochrome b(5) (b5) and NADH cytochrome b(5) reductase (b5R) detoxify reactive hydroxylamine (NHOH) metabolites of known arylamine and heterocyclic amine mammary carcinogens. The aim of this study was to determine whether NHOH reduction for the prototypic arylamine 4-aminobiphenyl (4-ABP) was present in human breast and to determine whether variability in activity was associated with single nucleotide polymorphisms (SNPs) in the coding, promoter, and 3'untranslated region (UTR) regions of the genes encoding b5 (CYB5A) and b5R (CYB5R3). 4-ABP-NHOH reduction was readily detected in pooled human breast microsomes, with a K(m) (280μM) similar to that found with recombinant b5 and b5R, and a V(max) of 1.12 ± 0.19 nmol/min/mg protein 4-ABP-NHOH reduction varied 75-fold across 70 individual breast samples and correlated significantly with both b5 (80-fold variability) and b5R (14-fold) immunoreactive protein. In addition, wide variability in b5 protein expression was significantly associated with variability in CYB5A transcript levels, with a trend toward the same association between b5R and CYB5R3. Although a sample with a novel coding SNP in CYB5A, His22Arg, was found with low reduction and b5 expression, no other SNPs in either gene were associated with outlier activity or protein expression. We conclude that b5 and b5R catalyze the reduction of 4-ABP-NHOH in breast tissue, with very low activity, protein, and messenger RNA expression in some samples, which cannot be attributed to promoter, coding, or 3'UTR SNPs. Further studies are underway to characterize the transcriptional regulation of CYB5A and CYB5R3 and begin to understand the mechanisms of individual variability in this detoxification pathway.

Haplotype association mapping of acute lung injury in mice implicates activin a receptor, type 1.

Because acute lung injury is a sporadic disease produced by heterogeneous precipitating factors, previous genetic analyses are mainly limited to candidate gene case-control studies. To develop a genome-wide strategy in which single nucleotide polymorphism associations are assessed for functional consequences to survival during acute lung injury in mice. To identify genes associated with acute lung injury, 40 inbred strains were exposed to acrolein and haplotype association mapping, microarray, and DNA-protein binding were assessed. The mean survival time varied among mouse strains with polar strains differing approximately 2.5-fold. Associations were identified on chromosomes 1, 2, 4, 11, and 12. Seven genes (Acvr1, Cacnb4, Ccdc148, Galnt13, Rfwd2, Rpap2, and Tgfbr3) had single nucleotide polymorphism (SNP) associations within the gene. Because SNP associations may encompass "blocks" of associated variants, functional assessment was performed in 91 genes within ± 1 Mbp of each SNP association. Using 10% or greater allelic frequency and 10% or greater phenotype explained as threshold criteria, 16 genes were assessed by microarray and reverse real-time polymerase chain reaction. Microarray revealed several enriched pathways including transforming growth factor-β signaling. Transcripts for Acvr1, Arhgap15, Cacybp, Rfwd2, and Tgfbr3 differed between the strains with exposure and contained SNPs that could eliminate putative transcriptional factor recognition sites. Ccdc148, Fancl, and Tnn had sequence differences that could produce an amino acid substitution. Mycn and Mgat4a had a promoter SNP or 3'untranslated region SNPs, respectively. Several genes were related and encoded receptors (ACVR1, TGFBR3), transcription factors (MYCN, possibly CCDC148), and ubiquitin-proteasome (RFWD2, FANCL, CACYBP) proteins that can modulate cell signaling. An Acvr1 SNP eliminated a putative ELK1 binding site and diminished DNA-protein binding. Assessment of genetic associations can be strengthened using a genetic/genomic approach. This approach identified several candidate genes, including Acvr1, associated with increased susceptibility to acute lung injury in mice.

Single nucleotide polymorphisms within functional regions of genes implicated in insulin action and association with the insulin resistant phenotype

Type 2 diabetes and insulin resistance (IR) are characterized by severe anomalies in genes expression rate including genes involved in insulin signal transduction. Post-transcriptional regulation of gene expression is crucial for many physiological processes and is mediated mainly by untranslated region (UTR). Present study concentrated on the search for correlation between single nucleotides polymorphisms in UTRs of the INSR, PIK3R1, PTPN1, and SLC2A4 genes and IR. 130 unrelated diabetic patients and 98 healthy controls were analyzed in present study. Genotyping was performed by multiplex minisequencing preceded by multiplex PCR. Two single nucleotide polymorphisms (SNPs) showed significant differences in genotype frequencies between analyzed groups. Statistical significance was received for rs3745551 located in 3'-UTR of the INSR and rs3756668 located in 3'-UTR of the PIK3R1 gene with higher number of G/G genotype in insulin resistant subjects. Furthermore, patients carrying G/G genotype of those SNPs displayed higher BMI value, higher fasting glucose and insulin levels and were more insulin resistant assessed by HOMA-IR and QUICKI. Present study provides evidence for association between SNPs in UTRs of the INSR and PIK3R1 genes and insulin resistant phenotype.

Functional Genetic Variants in the 3′-Untranslated Region of Sulfotransferase Isoform 1A1 (SULT1A1) and Their Effect on Enzymatic Activity

Sulfotransferase isoform 1A1 (SULT1A1) is the most highly expressed hepatic sulfotransferase and is involved in the biotransformation of a wide variety of endo- and xenobiotics. A common single nucleotide polymorphism (SNP) in the coding region of SULT1A1, several proximal promoter SNPs, and copy number variation (CNV) are associated with altered enzymatic activity, but these variants do not fully account for the observed variation of SULT1A1 activity in human populations. In order to identify additional SNPs modulating SULT1A1 activity, we examined the 3'-untranslated region (UTR) of SULT1A1 in 97 liver samples. Direct sequencing revealed that two SNPs in the 3'-UTR (902A > G [rs6839] and 973C > T [rs1042157]) and one SNP in the 3'-flanking region (1307G > A [rs4788068]) were common. These SNPs are in absolute linkage disequilibrium with each other and in tight linkage with SULT1A1 1/2 (linkage coefficient D' 0.83) and are significantly associated with SULT1A1 messenger RNA (p = 0.001, 0.029, 0.021) and enzymatic activity (p = 0.022, 0.012, 0.027). We then examined the collective effects of 3'-UTR SNPs, SULT1A1 1/2, and CNV on SULT1A1 activity in 498 Caucasian and 127 African-American subjects by haplotype analysis. This analysis revealed that SULT1A1 1/2 does not contribute to the variation in SULT1A1 enzymatic activity when the 3'-UTR SNPs are included in the statistical model. Two major haplotypes (ACG and GTA) were significantly correlated with SULT1A1 activity, and when stratified by copy number, the SULT1A1 3'-UTR SNPs remain significantly associated with SULT1A1 enzymatic activity in Caucasians, but not in African-Americans. Subsequent functional characterization revealed that a microRNA, miR-631, regulates SULT1A1 expression in a genotype-specific manner.

Epistasis between CYP19A1 and ESR1 polymorphisms is associated with premature ovarian failure

Because an interaction between CYP19A1 and ESR1 may play a key role in determining the level of circulating E2 by way of the hypothalamus-hypophysis-ovarian axis, the effect of single nucleotide polymorphism (SNP)-SNP interactions between CYP19A1 and ESR1 on the development of premature ovarian failure (POF) was investigated by comparing the polymorphisms of 98 patients with POF and 218 matched controls of Korean ethnicity. A significant association with POF risk was found for the combined genetic effect between the CYP19A1 3'untranslated region (UTR) SNP rs10046 (CT+TT) and the intronic ESR1 SNP rs1569788 (CC) genotype (odds ratio=12.67, 95% confidence interval: 1.61-99.71), and a statistically significant association was also observed between POF and the CYP19A1 3'UTR SNP rs10046 under a dominant model (odds ratio=2.51, 95% confidence interval: 1.33-4.76), suggesting that epistasis between ESR1 and CYP19A1 may be involved in the regulation of folliculogenesis.

Disease-Associated Mutations That Alter the RNA Structural Ensemble

Genome-wide association studies (GWAS) often identify disease-associated mutations in intergenic and non-coding regions of the genome. Given the high percentage of the human genome that is transcribed, we postulate that for some observed associations the disease phenotype is caused by a structural rearrangement in a regulatory region of the RNA transcript. To identify such mutations, we have performed a genome-wide analysis of all known disease-associated Single Nucleotide Polymorphisms (SNPs) from the Human Gene Mutation Database (HGMD) that map to the untranslated regions (UTRs) of a gene. Rather than using minimum free energy approaches (e.g. mFold), we use a partition function calculation that takes into consideration the ensemble of possible RNA conformations for a given sequence. We identified in the human genome disease-associated SNPs that significantly alter the global conformation of the UTR to which they map. For six disease-states (Hyperferritinemia Cataract Syndrome, β-Thalassemia, Cartilage-Hair Hypoplasia, Retinoblastoma, Chronic Obstructive Pulmonary Disease (COPD), and Hypertension), we identified multiple SNPs in UTRs that alter the mRNA structural ensemble of the associated genes. Using a Boltzmann sampling procedure for sub-optimal RNA structures, we are able to characterize and visualize the nature of the conformational changes induced by the disease-associated mutations in the structural ensemble. We observe in several cases (specifically the 5′ UTRs of FTL and RB1) SNP–induced conformational changes analogous to those observed in bacterial regulatory Riboswitches when specific ligands bind. We propose that the UTR and SNP combinations we identify constitute a “RiboSNitch,” that is a regulatory RNA in which a specific SNP has a structural consequence that results in a disease phenotype. Our SNPfold algorithm can help identify RiboSNitches by leveraging GWAS data and an analysis of the mRNA structural ensemble.

Genetic variation in CXCL12 and risk of cervical carcinoma: a population‐based case–control study

CXCL12 provides a chemotactic signal-directing leucocyte migration and regulates metastatic behaviour of tumour cells. We conducted a population-based case-control study to test the hypothesis that common genetic variation in CXCL12 individual single nucleotide polymorphism (SNP) alleles and haplotypes] is associated with the risk of cervical carcinoma. Cases (n = 917) were residents of western Washington State diagnosed with invasive squamous cell cervical carcinoma (SCC), invasive adenocarcinoma or adenosquamous carcinoma, or adenocarcinoma in situ of the cervix. Control participants (n = 849) were identified from the source population by random digit telephone dialling and frequency matched to cases on county and age. Nine CXCL12 tagSNPs chosen from the SeattleSNPs database were genotyped. The minor allele of intronic SNP rs266085 was inversely associated with cervical cancer under a recessive genetic effects model (OR = 0.74, 95% CI: 0.56-0.98). Among the ten common haplotypes inferred from the nine tagSNPs, one haplotype defined by minor alleles at 5'-flanking SNP rs17885289 and rs266085, and common alleles at the other seven SNPs occurred among 7.8% of cases and 10.6% of controls (dominant model OR = 0.72, 95% CI: 0.56-0.93; recessive model OR = 0.35, 95% CI: 0.12-0.97; and log-additive model OR = 0.72, 95% CI: 0.57-0.90). A stepwise procedure identified rs17885289, rs266085 and 3'-untranslated region (UTR) SNP rs266093 as the most parsimonious subset of SNPs necessary to define the haplotype inversely associated with cervical cancer risk in our study. A 3'-UTR SNP, rs1801157, previously found to be related to HIV pathogenesis, was not associated with cervical cancer risk. Further population-based studies are warranted to confirm these associations between genetic variation in CXCL12 and cervical cancer risk.

A 3′ UTR transition within DEFB1 is associated with chronic and aggressive periodontitis

Periodontal diseases are complex inflammatory diseases and affect up to 20% of the worldwide population. An unbalanced reaction of the immune system toward microbial pathogens is considered as the key factor in the development of periodontitis. Defensins have a strong antimicrobial function and are important contributors of the immune system toward maintaining health. Here, we present the first systematic association study of DEFB1. Using a haplotype-tagging single nucleotide polymorphism (SNP) approach, including described promoter SNPs of DEFB1, we investigated the associations of the selected variants in a large population (N=1337 cases and 2887 ethnically matched controls). The 3' untranslated region SNP, rs1047031, showed the most significant association signal for homozygous carriers of the rare A allele (P=0.002) with an increased genetic risk of 1.3 (95% confidence interval: 1.11-1.57). The association was consistent with the specific periodontitis forms: chronic periodontitis (odds ratio=2.2 (95% confidence interval: 1.16-4.35), P=0.02), and aggressive periodontitis (odds ratio=1.3 (95% confidence interval 1.04-1.68), P=0.02). Sequencing of regulatory and exonic regions of DEFB1 identified no other associated variant, pointing toward rs1047031 as likely being the causative variant. Prediction of microRNA targets identified a potential microRNA-binding site at the position of rs1047031.

Genetic Variation in Immune Regulation and DNA Repair Pathways and Stomach Cancer in China

The incidence of stomach cancer is high in certain parts of the world, particularly in China. Chronic Helicobacter pylori infection is the main risk factor, yet the vast majority of infected individuals remain unaffected with cancer, suggesting an important role of other risk factors. We conducted a population-based case-control study including 196 incident stomach cancer cases and 397 matched controls to test the hypothesis that adverse single nucleotide polymorphism (SNP) genotypes and haplotypes within genes of the DNA repair and immune regulatory pathways are associated with increased stomach cancer risk. Genomic DNA isolated from blood samples was used for genotyping, and results were obtained for 57 putatively functional SNPs in 28 genes. Odds ratios (OR) and 95% confidence intervals (95% CI) were obtained from adjusted logistic regression models. For PTGS2, a gene involved in the inflammatory response, associations with stomach cancer risk were observed for TC genotype carriers of rs5279 (OR, 0.24; 95% CI, 0.08-0.73), CT genotype carriers of the 3'-untranslated region SNP rs689470 (OR, 7.49; 95% CI, 1.21-46.20), and CTTC haplotype carriers of rs5277, rs5278, rs5279, and rs689470 (OR, 0.41; 95% CI, 0.18-0.95). For ERCC5, a gene involved in nucleotide excision repair, TC genotype carriers of rs1047768 (OR, 0.65; 95% CI, 0.41-1.03), GC genotype carriers of the nonsynonymous SNP rs2227869 (OR, 0.30; 95% CI, 0.13-0.67), and CCG haplotype carriers of rs1047768, rs17655, and rs2227869 (OR, 0.45; 95% CI, 0.20-1.04) were associated with reduced stomach cancer risk. In conclusion, PTGS2 and ERCC5 were associated with stomach cancer risk in a Chinese population.

Novel Sequence Variations in the Brain-Derived Neurotrophic Factor Gene and Association With Major Depression and Antidepressant Treatment Response

Variations in the brain-derived neurotrophic factor gene (BDNF) have been associated with psychiatric disorders. Deep sequencing of the BDNF gene may identify new variations and bring further insight into psychiatric genetics. To better characterize sequence variability in the BDNF gene by resequencing a genomic DNA region of 22 kilobases that contained all BDNF exons and their flanking regions. Case-control study. University of California, Los Angeles, and University of Miami. Two hundred sixty-four controls and 272 Mexican Americans with major depressive disorder (MDD) from Los Angeles who were assessed by the same bilingual clinical research team. Identification of novel genetic polymorphisms in the BDNF gene and assessment of their frequencies and associations with MDD or antidepressant response. We identified 83 novel single-nucleotide polymorphisms (SNPs): 30 in untranslated regions, 4 in coding sequences, 37 in introns, and 12 in upstream regions; 3 of 4 rare novel coding SNPs were nonsynonymous. Association analyses of patients with MDD and controls showed that 6 SNPs were associated with MDD (rs12273539, rs11030103, rs6265, rs28722151, rs41282918, and rs11030101) and 2 haplotypes in different blocks (one including Val66, another near exon VIIIh) were significantly associated with MDD. One recently reported 5' untranslated region SNP, rs61888800, was associated with antidepressant response after adjusting for age, sex, medication, and baseline score on the 21-item Hamilton Depression Rating Scale. Our data support the concept that extensive resequencing of key candidate genes can lead to the discovery of substantial numbers of new variants. Further studies using larger independent samples are needed to confirm the association of the rs61888800 SNP with antidepressant response. clinicaltrials.gov Identifier: NCT00265291.

Association of Variants in MANEA With Cocaine-Related Behaviors

Cocaine dependence (CD) and related behaviors are highly heritable, but no genetic association has been consistently demonstrated. A recent genome-wide study of drug dependence identified an association between cocaine-induced paranoia (CIP) and a single-nucleotide polymorphism (SNP) in the alpha-endomannosidase (MANEA) locus in a family-based sample of European Americans and African Americans. To conduct a comprehensive genetic association study of the MANEA locus with CD and CIP. Genome-wide association study. Four university hospitals. A total of 3992 individuals from 2 family-based and 2 case-control samples. Participants were classified as having CD or CIP or as a control using the Semi-Structured Assessment for Drug Dependence and Alcoholism. They were genotyped for 11 SNPs spanning MANEA and its surrounding region. Association of CD and CIP with individual SNPs and haplotypes. Cocaine-induced paranoia was associated with 6 SNPs in the European American families and 9 SNPs in the African American families. The strongest evidence in the total sample of families was observed in 3 markers located in the promoter and 3' untranslated regions (P < .001). The association of MANEA SNPs with CD in both family samples was much weaker. In the African American case-control sample, multiple markers were significantly associated with CIP and CD; CIP and CD were also significantly associated with a 2-SNP haplotype in the European American case-control sample. The A allele of the 3' untranslated region SNP rs9387522 was associated with increased risk of CIP in all 4 data sets. Our findings suggest that CD and associated behaviors may involve biological pathways not typically thought to be associated with brain metabolism.

Integrin alpha V polymorphisms and haplotypes in a Korean population are associated with susceptibility to chronic hepatitis and hepatocellular carcinoma

Integrins are cell surface receptors for extracellular matrix (ECM) proteins that initiate signalling pathways that modulate proliferation, survival, invasion or metastasis. Consequently, integrins are potential targets for the treatment of cancer. In this study, we investigated whether single nucleotide polymorphisms (SNPs) in integrin alpha(V) (ITGAV) in a Korean population were associated with chronic hepatitis B virus (HBV) infection and HBV-infected hepatocellular carcinoma (HCC). Thirteen ITGAV SNPs in 111 cases of chronic HBV infection, 86 cases of HBV-infected HCC and 107 cases of acute self-limited HBV infection were genotyped using Illumina's Sentrix array matrix (SAM) chip. The ITGAV intron SNPs rs9333289 and rs11685758, the 3'-untranslated region SNP rs1839123 and haplotype 3 (T-T-A) were associated with enhanced susceptibility to HBV-infected HCC (OR=1.75-2.42; P=0.02-0.05), while the intron SNP rs2290083 was associated with both chronic infection and HBV-infected HCC (OR=1.73-2.01; P=0.01-0.04). In addition, both rs2290083 and ht1 (C-C-G) were associated with the age at which chronic infection occurred, as determined by Cox relative hazard analysis (RH=1.39-1.62, P=0.04-0.01) ITGAV SNPs and haplotypes may be genetic factors that increase the susceptibility of Koreans to chronic HBV infection and HBV-infected HCC.

Peroxisome proliferator–activated receptor α genetic variation interacts with n−6 and long-chain n−3 fatty acid intake to affect total cholesterol and LDL-cholesterol concentrations in the Atherosclerosis Risk in Communities Study

BackgroundPeroxisome proliferator–activated receptor-α (PPARA) regulates the expression of genes involved in lipid metabolism. The binding of polyunsaturated fatty acids (PUFAs) to PPARA results in rapid changes in the expression of genes involved in lipid oxidation, with long-chain n−3 fatty acids being potent activators of PPARA. ObjectiveWe evaluated the potential effect modification of PPARA genetic variation on the association between PUFA intake, specifically n−6 and long-chain n−3 fatty acid intakes, and multiple lipid measures in the large biethnic Atherosclerosis Risk in Communities (ARIC) Study. DesignStudy participants (10 134 whites and 3480 African Americans) were selected from the ARIC Study—a prospective investigation of atherosclerosis and its clinical sequelae. Multiple linear regression models were used to assess the relation between PPARA genotypes, as well as dietary fatty acid intake, and baseline lipid measures. PPARA-specific effects of variation were assessed by including genotype-by-fatty acid interaction terms in each statistical model. ResultsPPARA genotype frequencies were significantly different between whites and African Americans. No significant associations between lipid measures and PPARA genotype were observed in either whites or African Americans. Significant genotype-by-n−6 fatty acid intake interactions were observed only in whites for the 3′untranslated region (UTR) G→A single nucleotide polymorphism (SNP) and total cholesterol (P = 0.03) and LDL cholesterol (P = 0.03). Significant genotype-by-long-chain n−3 fatty acid intake interactions were observed only in African Americans for the 3′UTR C→T SNP and total cholesterol (P = 0.03) and LDL cholesterol (P = 0.02). ConclusionsFindings from the current study suggest that PPARA 3′UTR SNPs modulate the association between lipid concentrations and dietary n−6 fatty acid intake (in whites) and long-chain n−3 fatty acid intake (in African Americans) such that persons with homozygous variant genotypes have significantly lower total cholesterol and LDL-cholesterol measures when consuming higher quantities of n−6 or long-chain n−3 fatty acids.

Integrin alpha V polymorphisms and haplotypes were associated with susceptibility to chronic hepatitis B and hepatocellular carcinama in Korean population

Integrins and ECM proteins are highly expressed in chronic liver disease including chronic hepatitis (CH), liver cirrhosis, and hepatocellular carcinoma (HCC). Integrins are cell surface receptors for the extracellular matrix (ECM) proteins, which has been identified as regulators of cancer progression and potent candidate for a cancer treatment. In this study, we investigated whether single nucleotide polymorphisms (SNPs) of integrin alpha V (ITGAV) are associated with CH and HCC in Korean population. Thirteen SNPs of ITGAV were genotyped using Illumina Golden‐gate genotyping assays by allele specific extension. We found that ITGAV intron SNP, 3′ untranslated region SNP, and three haplotypes were significantly associated with the susceptibility of CH or HCC in genetic models (P=0.017~0.048). Whereas, the ht 1 was significantly associated with insusceptibility in CH (P=0.015) but was not HCC. Our results suggest that ITGAV SNPs and haplotype might be associated with the susceptibility of CH and HCC.

Polymorphisms in theCD3ZGene Influence TCRζ Expression in Systemic Lupus Erythematosus Patients and Healthy Controls

TCRzeta (CD247) functions as an amplification module in the TCR signaling cascade and is essential for assembly and surface expression of the TCR/CD3 complex. The TCRzeta-chain is down-regulated in many chronic infectious and inflammatory diseases, including systemic lupus erythematosus (SLE). It is unclear whether reduced TCRzeta expression is a cause or a consequence of chronic inflammatory responses. We have addressed this question by adopting a combined genetic and functional approach. We analyzed TCRzeta protein expression using a FACS-based expression index and documented considerable, but longitudinally stable, variation in TCRzeta expression in healthy individuals. The variation in TCRzeta expression was associated with polymorphisms in the CD3Z 3'-untranslated region (UTR) in SLE patients and healthy controls. Detailed mapping of the 3'-UTR revealed that the minor alleles of two single nucleotide polymorphisms (SNPs) in strong disequilibrium (rs1052230 and rs1052231) were the causal variants associated with low TCRzeta expression (p=0.015). Using allelic imbalance analysis, the minor alleles of these 3'-UTR SNPs were associated with one-third of the level of mRNA compared with the major allele. A family-based association analysis showed that the haplotype carrying the low-expression variants predisposes to SLE (p=0.033). This suggests that a genetically determined reduction in TCRzeta expression has functional consequences manifested by systemic autoimmunity.