Genetic Variation of the Ghrelin Signaling System in Females With Severe Alcohol Dependence

Introduction: Central ghrelin signaling is required for the rewarding effects of alcohol in mice. Because ghrelin is implied in other addictive behaviors such as eating disorders and smoking, and because there is co‐morbidity between these disorders and alcohol dependence, the ghrelin signaling system could be involved in mediating reward in general. Furthermore, in humans, single nucleotide polymorphisms (SNPs) and haplotypes of the pro‐ghrelin gene (GHRL) and the ghrelin receptor gene (GHSR) have previously been associated with increased alcohol consumption and increased body weight. Known gender differences in plasma ghrelin levels prompted us to investigate genetic variation of the ghrelin signaling system in females with severe alcohol dependence (n = 113) and in a selected control sample of female low‐consumers of alcohol from a large cohort study in southwest Sweden (n = 212). Methods: Six tag SNPs in the GHRL (rs696217, rs3491141, rs4684677, rs35680, rs42451, and rs26802) and four tag SNPs in the GHSR (rs495225, rs2232165, rs572169, and rs2948694) were genotyped in all individuals. Results: We found that one GHRL haplotype was associated with reports of paternal alcohol dependence as well as with reports of withdrawal symptoms in the female alcohol‐dependent group. Associations with 2 GHSR haplotypes and smoking were also shown. One of these haplotypes was also negatively associated with BMI in controls, while another haplotype was associated with having the early‐onset, more heredity‐driven, type 2 form of alcohol dependence in the patient group. Conclusion: Taken together, the genes encoding the ghrelin signaling system cannot be regarded as major susceptibility genes for female alcohol dependence, but is, however, involved in paternal heritability and may affect other reward‐ and energy‐related factors such as smoking and BMI.     

Association of alcohol dehydrogenase genes with alcohol-related phenotypes in a Native American community sample

Background: Previous linkage studies, including a study of the Native American population described in the present report, have provided evidence for linkage of alcohol dependence and related traits to chromosome 4q near a cluster of alcohol dehydrogenase (ADH) genes, which encode enzymes of alcohol metabolism. Methods: The present study tested for associations between alcohol dependence and related traits and 22 single‐nucleotide polymorphisms (SNPs) spanning the 7 ADH genes. Participants included 586 adult men and women recruited from 8 contiguous Native American reservations. A structured interview was used to assess DSM‐III‐R alcohol dependence criteria as well as a set of severe alcohol misuse symptoms and alcohol withdrawal symptoms. Results: No evidence for association with the alcohol dependence diagnosis was observed, but an SNP in exon 9 of ADH1B (rs2066702; ADH1B*3) and an SNP at the 5′ end of ADH4 (rs3762894) showed significant evidence of association with the presence of withdrawal symptoms (p = 0.0018 and 0.0012, respectively). Further, a haplotype analysis of these 2 SNPs suggested that the haplotypes containing either of the minor alleles were protective against alcohol withdrawal relative to the ancestral haplotype (p = 0.000006). Conclusions: These results suggest that variants in the ADH1B and ADH4 genes may be protective against the development of some symptoms associated with alcohol dependence.     

Stress-induced and cue-induced craving for alcohol in heavy drinkers: Preliminary evidence of genetic moderation by the OPRM1 and CRH-BP genes

Background: Neurobiological theories of addiction have highlighted disruption in stress pathways as a central feature of addictive disorders, and pharmacological treatments targeting stress mechanisms hold great promise. This study examines genetic determinants of stress‐induced and cue‐induced craving in heavy drinkers by testing single‐nucleotide polymorphisms (SNPs) of the corticotrophin‐releasing hormone binding protein (CRH‐BP) gene and the mu‐opioid receptor (OPRM1) gene. Methods: This study combines guided imagery stress exposure and in vivo alcohol cue exposure in a sample of 64 (23 women) non‐treatment‐seeking heavy drinkers. Results: Analyses, uncorrected for multiple comparisons, revealed that a tag SNP of the CRH‐BP gene (rs10055255) moderated stress‐induced craving in this sample. The same SNP predicted greater affective responses to the stress manipulation, including greater levels of subjective tension and negative mood. The Asp40 allele of the OPRM1 was associated with greater cue‐induced alcohol craving following the neutral imagery condition. Conclusions: These initial results extend recent preclinical and clinical findings implicating the CRH‐BP in stress‐related alcoholism and confirm the role of the Asp40 allele of the OPRM1 gene in reward‐driven alcohol phenotypes. Human laboratory models of stress and cue‐induced craving may be useful in pharmacotherapy development targeting dysregulation of stress systems. Larger studies are needed to validate these preliminary findings, which should also be extended to clinical samples.     

Haplotype-based study of the association of alcohol-metabolizing genes with alcohol dependence in four independent populations

Background: Ethanol is metabolized by 2 rate‐limiting reactions: alcohol dehydrogenases (ADH) convert ethanol to acetaldehyde that is subsequently metabolized to acetate by aldehyde dehydrogenases (ALDH). Approximately 50% of East Asians have genetic variants that significantly impair this pathway and influence alcohol dependence (AD) vulnerability. We investigated whether variation in alcohol metabolism genes might alter the AD risk in four non‐East Asian populations by performing systematic haplotype association analyses to maximize the chances of capturing functional variation. Methods: Haplotype‐tagging SNPs were genotyped using the Illumina GoldenGate platform. Genotypes were available for 40 SNPs across the ADH genes cluster and 24 SNPs across the two ALDH genes in four diverse samples that included cases (lifetime AD) and controls (no Axis 1 disorders). The case control sample sizes were the following: Finnish Caucasians: 232, 194; African Americans: 267, 422; Plains American Indians: 226, 110; and Southwestern American (SW) Indians: 317, 72. Results: In all four populations, as well as HapMap populations, 5 haplotype blocks were identified across the ADH gene cluster: (i) ADH5‐ADH4; (ii) ADH6‐ADH1A‐ADH1B; (iii) ADH1C; (iv) intergenic; (v) ADH7. The ALDH1A1 gene was defined by 4 blocks and ALDH2 by 1 block. No haplotype or SNP association results were significant after correction for multiple comparisons; however, several results, particularly for ALDH1A1 and ADH4, replicated earlier findings. There was an ALDH1A1 block 1 and 2 (extending from intron 5 to the 3′ UTR) yin yang haplotype (haplotypes that have opposite allelic configuration) association with AD in the Finns driven by SNPs rs3764435 and rs2303317, respectively, and an ALDH1A1 block 3 (including the promoter region) yin yang haplotype association in SW Indians driven by 5 SNPs, all in allelic identity. The ADH4 SNP rs3762894 was associated with AD in Plains Indians. Conclusions: The systematic evaluation of alcohol‐metabolizing genes in four non‐East Asian populations has shown only modest associations with AD, largely for ALDH1A1 and ADH4. A concentration of signals for AD with ALDH1A1 yin yang haplotypes in several populations warrants further study.     

Variation in genes encoding the neuroactive steroid synthetic enzymes 5α-reductase type 1 and 3α-reductase type 2 is associated with alcohol dependence

Background: Studies of alcohol effects in rodents and in vitro implicate endogenous neuroactive steroids as key mediators of alcohol effects at GABA_A receptors. We used a case‐control sample to test the association with alcohol dependence (AD) of single nucleotide polymorphisms in the genes encoding two key enzymes required for the generation of endogenous neuroactive steroids: 5α–reductase, type I (5α‐R), and 3α‐hydroxysteroid dehydrogenase, type 2 (3α‐HSD), both of which are expressed in human brain. Methods: We focused on markers previously associated with a biological phenotype. For 5α‐R, we examined the synonymous SRD5A1 exon 1 SNP rs248793, which has been associated with the ratio of dihydrotestosterone to testosterone. For 3α‐HSD, we examined the nonsynonymous AKR1C3 SNP rs12529 (H5Q), which has been associated with bladder cancer. The SNPs were genotyped in a sample of 1,083 non‐Hispanic Caucasians including 552 controls and 531 subjects with AD. Results: The minor allele for both SNPs was more common among controls than subjects with AD: SRD5A1 rs248793 C‐allele (χ²(1) = 7.6, p = 0.006) and AKR1C3 rs12529 G‐allele (χ²(1) = 14.6, p = 0.0001). There was also an interaction of these alleles such that the “protective” effect of the minor allele at each marker for AD was conditional on the genotype of the second marker. Conclusions: We found evidence of an association with AD of polymorphisms in two genes encoding neuroactive steroid biosynthetic enzymes, providing indirect evidence that neuroactive steroids are important mediators of alcohol effects in humans.     

Associations and Interactions Between SNPs in the Alcohol Metabolizing Genes and Alcoholism Phenotypes in European Americans

Background:  Alcohol dependence is a major cause of morbidity and mortality worldwide and has a strong familial component. Several linkage and association studies have identified chromosomal regions and/or genes that affect alcohol consumption, notably in genes involved in the 2-stage pathway of alcohol metabolism.
Methods:  Here, we use multiple regression models to test for associations and interactions between 2 alcohol-related phenotypes and SNPs in 17 genes involved in alcohol metabolism in a sample of 1,588 European American subjects.
Results:  The strongest evidence for association after correcting for multiple testing was between rs1229984, a nonsynonymous coding SNP in ADH1B, and DSM-IV symptom count ( p  =   0.0003). This SNP was also associated with maximum number of drinks in 24 hours ( p  =   0.0004). Each minor allele at this SNP predicts 45% fewer DSM-IV symptoms and 18% fewer max drinks. Another SNP in a splice site in ALDH1A1 (rs8187974) showed evidence for association with both phenotypes as well ( p  =   0.02 and 0.004, respectively), but neither association was significant after accounting for multiple testing. Minor alleles at this SNP predict greater alcohol consumption. In addition, pairwise interactions were observed between SNPs in several genes ( p  =   0.00002).
Conclusions:  We replicated the large effect of rs1229984 on alcohol behavior, and although not common (MAF = 4%), this polymorphism may be highly relevant from a public health perspective in European Americans. Another SNP, rs8187974, may also affect alcohol behavior but requires replication. Also, interactions between polymorphisms in genes involved in alcohol metabolism are likely determinants of the parameters that ultimately affect alcohol consumption.     

Ghrelin: more than a natural GH secretagogue and/or an orexigenic factor

Ghrelin, an acylated peptide produced predominantly by the stomach, has been discovered to be a natural ligand of the growth hormone secretagogue receptor type 1a (GHS‐R1a). Ghrelin has recently attracted considerable interest as a new orexigenic factor. However, ghrelin exerts several other neuroendocrine, metabolic and also nonendocrine actions that are explained by the widespread distribution of ghrelin and GHS‐R expression. The likely existence of GHS‐R subtypes and evidence that the neuroendocrine actions, but not all the other actions, of ghrelin depend on its acylation in serine‐3 revealed a system whose complexity had not been completely explored by studying synthetic GHS. Ghrelin secretion is mainly regulated by metabolic signals and, in turn, the modulatory action of ghrelin on the control of food intake and energy metabolism seems to be among its most important biological actions. However, according to a recent study, ghrelin‐null mice are neither anorectics nor dwarfs and this evidence clearly depicts a remarkable difference from leptin null mice. Nevertheless, the original and fascinating story of ghrelin, as well as its potential pathophysiological implications in endocrinology and internal medicine, is not definitively cancelled by these data as GHS‐R1a null aged mice show significant alterations in body composition and growth, in glucose metabolism, cardiac function and contextual memory. Besides potential clinical implications for natural or synthetic ghrelin analogues acting as agonists or antagonists, there are several open questions awaiting an answer. How many ghrelin receptor subtypes exist? Is ghrelin ‘the’ or just ‘a’ GHS‐R ligand? That is, are there other natural GHS‐R ligands? Is there a functional balance between acylated and unacylated ghrelin forms, potentially with different actions? Within the next few years suitable answers to these questions will probably be found, making it possible to gain a better knowledge of ghrelin's potential clinical perspectives.     

Association of IRF5 polymorphisms with systemic lupus erythematosus in a Japanese population: support for a crucial role of intron 1 polymorphisms

OBJECTIVE: To determine whether the IRF5 gene, which encodes interferon regulatory factor 5, is associated with systemic lupus erythematosus (SLE) in a Japanese population. METHODS: A case-control study was performed in 277 SLE patients and 201 healthy controls. Associations between the IRF5 genotype and levels of messenger RNA (mRNA) for interferon (IFN) pathway genes were examined using an mRNA expression database of HapMap samples. RESULTS: Carriers of the rs2004640T single-nucleotide polymorphism (SNP) were slightly increased among SLE patients (58.8%) as compared with controls (50.2%). When data from our Japanese population were combined with previously published data from a Korean population, the T allele frequency was found to be significantly increased in SLE patients (P = 8.3 x 10(-5)). While no association was observed for the rs10954213 SNP or the exon 6 insertion/deletion, significant associations with 3 intron 1 SNPs (-4001, rs6953165, and rs41298401) were found. The allele frequency of rs41298401G was significantly decreased in SLE patients (13.0% versus 18.7% in controls; P = 0.017), and the allele frequency of rs6953165G, which was in absolute linkage disequilibrium with -4001A, was increased in SLE patients (8.8% versus 5.2% in controls; P = 0.034). The Caucasian risk haplotype was not present; instead, a protective haplotype carrying rs2004640G, rs41298401G, the deletion in exon 6, and rs10954213A was identified. SNP rs10954213, but not intron 1 SNPs, was associated with IRF5 at the mRNA level; nevertheless, intron 1 SNPs were also associated with levels of mRNA for several IFN pathway genes, suggesting a functional role. CONCLUSION: IRF5 was found to be associated with SLE in Asian populations. Intron 1 SNPs, rather than exon 6 and 3'-untranslated region polymorphisms, appeared to play a crucial role.     

Human longevity and variation in GH/IGF-1/insulin signaling, DNA damage signaling and repair and pro/antioxidant pathway genes: cross sectional and longitudinal studies

Here we explore association with human longevity of common genetic variation in three major candidate pathways: GH/IGF-1/insulin signaling, DNA damage signaling and repair and pro/antioxidants by investigating 1273 tagging SNPs in 148 genes composing these pathways. In a case-control study of 1089 oldest-old (age 92-93) and 736 middle-aged Danes we found 1 pro/antioxidant SNP (rs1002149 (GSR)), 5 GH/IGF-1/INS SNPs (rs1207362 (KL), rs2267723 (GHRHR), rs3842755 (INS), rs572169 (GHSR), rs9456497 (IGF2R)) and 5 DNA repair SNPs (rs11571461 (RAD52), rs13251813 (WRN), rs1805329 (RAD23B), rs2953983 (POLB), rs3211994 (NTLH1)) to be associated with longevity after correction for multiple testing. In a longitudinal study with 11 years of follow-up on survival in the oldest-old Danes we found 2 pro/antioxidant SNPs (rs10047589 (TNXRD1), rs207444 (XDH)), 1 GH/IGF-1/INS SNP (rs26802 (GHRL)) and 3 DNA repair SNPs (rs13320360 (MLH1), rs2509049 (H2AFX) and rs705649 (XRCC5)) to be associated with mortality in late life after correction for multiple testing. When examining the 11 SNPs from the case-control study in the longitudinal data, rs3842755 (INS), rs13251813 (WRN) and rs3211994 (NTHL1) demonstrated the same directions of effect (p<0.05), while rs9456497 (IGF2R) and rs1157146 (RAD52) showed non-significant tendencies, indicative of effects also in late life survival. In addition, rs207444 (XDH) presented the same direction of effect when inspecting the 6 SNPs from the longitudinal study in the case-control data, hence, suggesting an effect also in survival from middle age to old age. No formal replications were observed when investigating the 11 SNPs from the case-control study in 1613 oldest-old (age 95-110) and 1104 middle-aged Germans, although rs11571461 (RAD52) did show a supportive non-significant tendency (OR=1.162, 95% CI=0.927-1.457). The same was true for rs10047589 (TNXRD1) (HR=0.758, 95%CI=0.543-1.058) when examining the 6 SNPs from the longitudinal study in a Dutch longitudinal cohort of oldest-old (age 85+, N=563). In conclusion, the present candidate gene based association study, the largest to date applying a pathway approach, not only points to potential new longevity loci, but also underlines the difficulties of replicating association findings in independent study populations and thus the difficulties in identifying universal longevity polymorphisms.     

Association of DLG5 variants with inflammatory bowel disease in the New Zealand Caucasian population and meta-analysis of the DLG5 R30Q variant

BACKGROUND: Variants in the DLG5 gene have been associated with inflammatory bowel disease (IBD) in samples from some, but not all populations. In particular, 2 nonsynonymous single-nucleotide polymorphisms (SNPs), R30Q (rs1248696) and P1371Q (rs2289310), have been associated with an increased risk of IBD, and a common haplotype (called haplotype "A") has been associated with reduced risk. METHODS: We genotyped R30Q, P1371Q, and a haplotype A tagging SNP (rs2289311) in a New Zealand Caucasian cohort of 389 Crohn's disease (CD) patients, 406 ulcerative colitis (UC) patients, and 416 population controls. Each SNP was tested for association with disease susceptibility and clinical phenotypes. We also performed a meta-analysis of R30Q data from published association studies. RESULTS: The haplotype A tagging SNP was associated with reduced risk of IBD at the 0.05 significance level (P=0.036) with an allelic odds ratio of 0.83 (95% confidence interval [CI]: 0.69-0.99). Association with haplotype A was strongest (odds ratio approximately 0.57) in UC patients with familial IBD or extraintestinal manifestations. The R30Q and P1371Q polymorphisms were not significantly associated with UC, CD, or IBD. Analysis of male and female data did not find any gender-specific associations. Meta-analysis gave no evidence of association of R30Q with IBD. CONCLUSIONS: Meta-analysis demonstrates that the minor allele of R30Q is not a risk factor for IBD across populations. This study provides some evidence that DLG5 haplotype A is associated with reduced risk of IBD in the New Zealand Caucasian population, but this association will need to be replicated in an independent sample.     

GABRG1 and GABRA2 variation associated with alcohol dependence in African Americans

Background: GABRG1 and GABRA2, genes that encode the γ1 and α2 subunits, respectively, of the GABA‐A receptor, are located in a cluster on chromosome 4p. Association of alcohol dependence (AD) with markers located at the 3′ region of GABRA2 has been replicated in several studies, but recent studies suggested the possibility that the signal may be attributable to the adjacent gene, GABRG1, located 90 kb distant in the 3′ direction. Owing to strong linkage disequilibrium (LD) in European Americans (EAs), the origin, or origins, of the association signal is very difficult to discern, but our previous population‐based study suggested that decreased LD across the GABRG1–GABRA2 region in African Americans (AAs) may be useful for fine mapping and resolution of the association signal in that population. Methods: To examine these associations in greater detail, we genotyped 13 single nucleotide polymorphisms (SNPs) spanning GABRG1 and GABRA2 in 380 AAs with AD and in 253 AA controls. Results: Although there was no association between any individual SNP and AD, a highly significant difference was shown between AD subjects and controls in the frequency of a 3‐SNP GABRA2 haplotype (global p = 0.00029). A similar level of significance was obtained in 6‐SNP haplotypes that combined tagging SNPs from both genes (global p = 0.00994). High statistical significance was also shown with a 6‐SNP haplotype (T‐G‐C‐G‐T‐A), p = 0.0033. The T‐G‐C‐G‐T‐A haplotype contains the most significant GABRA2 3‐SNP haplotype (p = 0.00019), G‐T‐A. Conclusions: These findings reflect the interrelationship between these 2 genes and the likelihood that risk loci exist in each of them. Study of an AA population allowed evaluation of these associations at higher genomic resolution than is possible in a EA population, owing to the much lower LD across these loci in AAs.     

Association between genetic variants of the ADD1 and GNB3 genes and blood pressure response to the cold pressor test in a Chinese Han population: the GenSalt Study

Genetic factors influence blood pressure (BP) response to the cold pressor test (CPT), which is a phenotype related to hypertension risk. We examined the association between variants of the α-adducin (ADD1) and guanine nucleotide binding protein (G protein) β-polypeptide 3 (GNB3) genes and BP response to the CPT. A total of 1998 Han Chinese participants from the Genetic Epidemiology Network of Salt Sensitivity completed the CPT. The area under the curve (AUC) above the baseline BP during the CPT was used to measure the BP response. Twelve single-nucleotide polymorphisms (SNPs) of the ADD1 and GNB3 genes were selected and genotyped. Both single-marker and haplotype association analyses were conducted using linear mixed models. The rs17833172 and rs3775067 SNPs of the ADD1 gene and the rs4963516 SNP of the GNB3 gene were significantly associated with the BP response to CPT, even after adjusting for multiple testing. For the ADD1 gene, the AA genotype of SNP rs17833172 was associated with lower systolic BP (SBP) reactivity (P<0.0001) and faster BP recovery (P=0.0003). The TT genotype of rs3775067 was associated with slower SBP recovery (P=0.004). For the GNB3 gene, the C allele of SNP rs4963516 was associated with faster diastolic BP recovery (P=0.002) and smaller overall AUC (P=0.003). Haplotype analysis indicated that the CCGC haplotype of ADD1 constructed by rs1263359, rs3775067, rs4961 and rs4963 was significantly associated with the BP response to CPT. These data suggest that genetic variants of the ADD1 and GNB3 genes may have important roles in BP response to the CPT. Future studies aimed at replicating these novel findings are warranted.     

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.     

Limited associations of dopamine system genes with alcohol dependence and related traits in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD)

Background: Over 50 years of evidence from research has established that the central dopaminergic reward pathway is likely involved in alcohol dependence (AD). Additional evidence supports a role for dopamine (DA) in other disinhibitory psychopathology, which is often comorbid with AD. Family and twin studies demonstrate that a common genetic component accounts for most of the genetic variance in these traits. Thus, DA‐related genes represent putative candidates for the genetic risk that underlies not only AD but also behavioral disinhibition. Many linkage and association studies have examined these relationships with inconsistent results, possibly because of low power, poor marker coverage, and/or an inappropriate correction for multiple testing. Methods: We conducted an association study on the products encoded by 10 DA‐related genes (DRD1‐D5, SLC18A2, SLC6A3, DDC, TH, COMT) using a large, ethnically homogeneous sample with severe AD (n = 545) and screened controls (n = 509). We collected genotypes from linkage disequilibrium (LD)‐tagging single nucleotide polymorphisms (SNPs) and employed a gene‐based method of correction. We tested for association with AD diagnosis in cases and controls and with a variety of alcohol‐related traits (including age‐at‐onset, initial sensitivity, tolerance, maximum daily drinks, and a withdrawal factor score), disinhibitory symptoms, and a disinhibitory factor score in cases only. A total of 135 SNPs were genotyped using the Illumina GoldenGate and Taqman Assays‐on‐Demand protocols. Results: Of the 101 SNPs entered into standard analysis, 6 independent SNPs from 5 DA genes were associated with AD or a quantitative alcohol‐related trait. Two SNPs across 2 genes were associated with a disinhibitory symptom count, while 1 SNP in DRD5 was positive for association with the general disinhibitory factor score. Conclusions: Our study provides evidence of modest associations between a small number of DA‐related genes and AD as well as a range of alcohol‐related traits and measures of behavioral disinhibition. While we did conduct gene‐based correction for multiple testing, we did not correct for multiple traits because the traits are correlated. However, false‐positive findings remain possible, so our results must be interpreted with caution.     

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.     

Genetic polymorphisms of the endocannabinoid system in obesity and diabetes

The endocannabinoid system (ECS) is involved in many physiological processes including fertility, pain and energy regulation. The aim of this systematic review was to examine the contribution of single nucleotide polymorphisms (SNPs) of the ECS to adiposity and glucose metabolism. Database searches identified 734 articles, of which 65 were included; these covered 70 SNPs in genes coding for cannabinoid receptors 1 and 2 (CB₁, CB₂), fatty acid amide hydrolase (FAAH) and N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD). No studies included SNPs relating to monoacylglycerol lipase or diacylglycerol lipase. The CB₁ receptor SNP rs1049353 showed 17 associations with lower body mass index (BMI) and fat mass (five studies). It also showed three associations with lower insulin levels (one study). Conversely, the CB₁ receptor SNP rs806368 was associated with increased BMI and waist circumference (two studies). The FAAH SNP rs324420 was associated with increased obesity (three studies). A haplotype of NAPE-PLD was associated with decreased BMI (one study). A total of 60 SNPs showed no association with any measured outcome. This review suggests a complex but important role of ECS SNPs in energy and glucose metabolism.     

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

Background/Aims: 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 α_V (ITGAV) in a Korean population were associated with chronic hepatitis B virus (HBV) infection and HBV‐infected hepatocellular carcinoma (HCC). Patients and Methods: 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. Results: 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) Conclusion: ITGAV SNPs and haplotypes may be genetic factors that increase the susceptibility of Koreans to chronic HBV infection and HBV‐infected HCC.     

Study of the association between the CAPSL-IL7R locus and type 1 diabetes

AIMS/HYPOTHESIS: In the past few years, several genes outside the MHC region have been described as new susceptibility genetic factors to type 1 diabetes. An association between CAPSL-rs1445898 and type 1 diabetes was reported in a large white population and corroborated in a genome-wide analysis, which also found an association with IL7R, which is located adjacent to CAPSL. The aim of this study was to replicate the aforementioned associations in independent cohorts. METHODS: We analysed two CAPSL (rs1010601 and rs1445898) and three IL7R (rs6897932, rs987106 and rs3194051) polymorphisms. All these single nucleotide polymorphisms (SNPs) were genotyped using TaqMan minor groove binder chemistry in 301 unrelated Spanish type 1 diabetes patients and 646 healthy controls. Additionally, the associated CAPSL SNP rs1445898 was genotyped in a Dutch cohort consisting of 429 type 1 diabetes patients and 720 healthy controls. RESULTS: The homozygous mutant genotype of the CAPSL SNP rs1445898 showed a trend towards a protective effect in the overall Spanish cohort (OR [95% CI] 0.70 [0.44-1.09]; p = 0.09) and in the Dutch cohort (OR [95% CI] 0.74 [0.51-1.05]; p = 0.09). Pooling of both cohorts was performed, yielding a statistically significant difference (Mantel-Haenszel OR 0.71; p = 0.005). This protective effect was significantly different in early-onset vs late-onset Spanish patients (OR [95% CI] 0.26 [0.10-0.65]; p = 0.001). Similarly, in the early-onset subgroup, the homozygous mutant genotype of the IL7R SNP rs6897932 showed a similar protective effect (OR [95% CI] 0.18 [0.02-0.94]; p = 0.02). CONCLUSIONS/INTERPRETATION: In summary, we describe an independent replication of the association between the CAPSL-IL7R locus and type 1 diabetes, especially for early-onset type 1 diabetes patients.