Manganese level and cognitive decline in older adults with the APOE e4 allele: a preliminary study.

This study examined the relationship between serum manganese level and cognition, and the moderating effect of apolipoprotein E ε4 (APOE4) on this relationship. A total of 164 non-demented participants underwent clinical assessments including serum manganese level and cognition [episodic memory score (EMS), non-memory score (NMS) for executive function/attention/language/ visuospatial skill, and total score (TS)]. Serum manganese × APOE4 interaction had a significant effect on EMS and TS. Serum manganese level was inversely associated with EMS and TS in APOE4-positive but not APOE4-negative participants. APOE4 should be considered a key component in Alzheimer's disease studies that included manganese imbalance as a risk factor.

High-intensity walking in midlife is associated with improved memory in physically capable older adults.

BACKGROUND: Little is known about the associations of midlife- and late life-initiated walking with Alzheimer's disease (AD)-related cognitive decline in humans. We aimed to investigate whether high-intensity, prolonged, midlife-initiated walking is associated with changes in AD-related cognitive decline in physically capable older adults. METHODS: We studied 188 physically capable participants aged 65-90 years without dementia who underwent comprehensive clinical assessment, including of their walking modality (i.e., intensity, duration, midlife- or late life-onset), memory- or non-memory and total cognitive performance, and blood or nutritional biomarkers. RESULTS: The walking group showed better episodic memory (B = 2.852, SE = 1.214, ß = 0.144, p = 0.020), but not non-memory cognition, than the non-walking group. High-intensity walking starting in midlife was significantly associated with better episodic memory (B = 9.360, SE = 3.314, ß = 0.446, p = 0.005) compared to the non-walking group. In contrast, there were no differences in cognition according to walking duration, regardless of the onset time. The walking group also showed a similar association with overall cognition. CONCLUSIONS: Among physically capable older adults without dementia, walking, particularly at high intensity and starting in midlife, is associated with improved episodic memory, an AD-related cognitive domain. Further attention should be paid to the role of walking in terms of AD prevention.

Association between physical activity and episodic memory and the moderating effects of the apolipoprotein E ε4 allele and age.

Background: An abundance of evidence indicates that physical activity may protect against Alzheimer's disease (AD) and related cognitive decline. However, little is known about the association between physical activity and AD-related cognitive decline according to age and the apolipoprotein E (APOE) ε4 allele (APOE4) as major risk factors. Therefore, we examined whether age and APOE4 status modulate the effects of physical activity on episodic memory as AD-related cognition in non-demented older adults. Methods: We enrolled 196 adults aged between 65 and 90 years, with no dementia. All participants underwent comprehensive clinical assessments including physical activity evaluation and APOE genotyping. The AD-related cognitive domain was assessed by the episodic memory, as the earliest cognitive change in AD, and non-memory cognition for comparative purposes. Overall cognition was assessed by the total score (TS) of the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery. Results: We found significant physical activity × age and physical activity × APOE4 interaction effects on episodic memory. Subgroup analyses indicated that an association between physical activity and increased episodic memory was apparent only in subjects aged > 70 years, and in APOE4-positive subjects. Conclusion: Our findings suggest that physical activity has beneficial effects on episodic memory, as an AD-related cognitive domain, in individuals aged > 70 years and in APOE4-positive individuals. Physicians should take age and APOE4 status account into when recommending physical activity to prevent AD-related cognitive decline.

Spicy food intake predicts Alzheimer-related cognitive decline in older adults with low physical activity.

A plausible association exists among spicy food consumption, physical activity, and Alzheimer's disease (AD) or cognitive decline, but it remains poorly investigated. We aimed to examined the association between spicy food and AD-related memory decline or global cognitive decline in older adults under the moderating effect of physical activity. Total 196 non-demented older adults were included. Participants underwent comprehensive dietary and clinical assessments including spicy food intake, AD-related memory, global cognition, and physical activity. The strength of spicy food was stratified into three categories: 'not spicy' (reference), 'low spiciness', and 'high spiciness'. Multiple linear regression analyses were performed to examine the relationships between spicy level and cognition. The spicy level was the independent variable in each analysis; it was entered as a stratified categorical variable using the three categories. We found a significant association between a high level of spiciness in food and decreased memory ([Formula: see text] - 0.167, p < 0.001) or global cognition ([Formula: see text] - 0.122, p = 0.027), but not non-memory cognition. To explore the moderating effects of age, sex, apolipoprotein E ε4 allele-positivity, vascular risk score, body mass index, and physical activity on the associations between spicy level and memory or global cognition, the same regression analyses were repeated including two-way interaction terms between the spicy level and each of the six variables as an additional independent variable. An interactive effect was detected between a high level of spiciness in food and physical activity on the memory ([Formula: see text] 0.209, p = 0.029) or global cognition ([Formula: see text] 0.336, p = 0.001). Subgroup analyses showed that the association between a high level of spiciness in food and a lower memory ([Formula: see text] - 0.254, p < 0.001) and global score ([Formula: see text] - 0.222, p = 0.002) was present only in older adults with low physical activity, but not in older adults with high physical activity. Our findings suggest that spicy food intake is predictive of AD-related cognitive decline, i.e., episodic memory; this relationship is worsened by physically inactive lifestyle.

Ginseng intake and Alzheimer disease-specific cognition in older adults according to apolipoprotein ε4 allele status.

Background: The probable association among ginseng intake, Alzheimer's disease (AD)-specific cognition, and apolipoprotein ε4 (APOE4) remains poorly investigated. Hence, we examined the association between ginseng intake and AD-specific cognition in older adults under the moderating effect of APOE4 status. Methods: This study enrolled 160 adults aged 65-90 years without dementia. All participants underwent comprehensive dietary and clinical assessments including ginseng intake, AD-related cognition (i.e., delayed episodic memory, as the earliest cognitive change in AD), and non-memory cognition for comparative purposes. Results: Ginseng intake was associated with higher delayed episodic memory, but not non-memory cognition, compared to no ginseng intake. The interaction between ginseng intake and APOE4 status had a significant effect on delayed episodic memory. Subgroup analyses showed that ginseng intake was associated with higher delayed episodic memory in the APOE4-negative but not the APOE4-positive subgroup. The benefits of ginseng intake on delayed episodic memory were prominent in the high duration (≥5 years) and midlife onset (<65 years) groups. Conclusion: Our study of older adults with no dementia suggests that ginseng intake (with high duration and midlife onset) had a beneficial effect on AD-specific cognitive decline, i.e., the delayed episodic memory. In addition, APOE4 status moderates the association between ginseng intake status and AD-specific cognitive decline.

A combination of midlife diabetes mellitus and the apolipoprotein E ε4 allele increase risk for cognitive decline.

Background: It has been suggested that diabetes mellitus (DM) and the apolipoprotein E (APOE) ε4 allele (APOE4) increase the risk for Alzheimer's disease (AD) and cognitive decline. However, the evidence is sparse. We explored whether APOE4 status modulated the effects of midlife and late-life DM on global cognition of non-demented older adults. Methods: In all, 176 non-demented adults (age 65-90 years) were enrolled. All the participants underwent comprehensive clinical assessments including midlife and late-life DM evaluation and APOE genotyping. The global cognitive performance index was assessed by the total score (TS) of the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery. Results: We found a significant midlife DM × APOE4 interaction effect on the global cognitive performance. Subgroup analyses indicated that an association between midlife DM and decreased global cognitive performance was apparent only in older adults who were APOE4-positive, and not in those with APOE4-negative. Conclusion: Our findings from non-demented older adults suggest that midlife DM increases the risk for AD and cognitive decline, and this risk is modulated by APOE4 status. To prevent AD and cognitive decline, physicians should check for the possible coexistence of midlife DM and APOE4-positive status.

Brain Amyloid Index as a Probable Marker Bridging Between Subjective Memory Complaint and Objective Cognitive Performance.

Background: The association between types of subjective memory complaint (SMC), poor objective cognitive performance, and brain Aß deposition have been poorly understood. We investigated the association between types of SMC and objective global cognitive performance, then assessed whether this association is mediated by the brain amyloid prediction index (API). Methods: In total, 173 non-demented older adults [63 cognitively normal (CN) and 110 mild cognitive impairment (MCI)] underwent comprehensive clinical assessments. Objective global cognitive performance and brain amyloid index were measured using the total score (TS) of the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery and API, respectively. In total, four items of SMC from the subjective memory complaints questionnaire (SMCQ) (SMCQ1: a feeling of memory problem; SMCQ2: the feeling of worse memory than 10 years ago; SMCQ3: the feeling of worse memory than others of similar age; or SMCQ4: the feeling of difficulty in everyday life) in global memory function were assessed. Results: In non-demented and participants with MCI, SMCQ3-positive and SMCQ4-positive groups were associated with decreased TS. In participants with MCI, the SMCQ3-positive group was associated with increased API, and API was associated with decreased TS, but the SMCQ4-positive group did not. In addition, the association between the SMCQ3-positive group and poor TS disappeared when API was controlled as a covariate, indicating that API has a mediation effect. Conclusion: The present findings suggest that SMC, a feeling of worse memory performance than others in a similar age group, in the older adults without dementia is associated with poor objective cognitive performance via increased brain amyloid index.

Association Between Copper and Global Cognition and the Moderating Effect of Iron.

Background: Despite the known association between abnormal serum copper levels and Alzheimer's disease (AD) or cognitive decline, the association between copper, iron, and cognition remains poorly investigated. We examined the association between serum copper levels and global cognition measured using the Mini-Mental State Examination (MMSE) in older adults with normal copper levels. We also explored the moderating effect of iron on this association. Methods: The study enrolled 99 non-demented adults between 65 and 90 years of age. All the participants underwent comprehensive clinical assessments and serum copper measurements. Global cognitive performance was measured by the MMSE. All copper levels were within the normal range and were stratified into three categories: < 87 (low), 87-98 (medium), and > 98 (high: used as a reference category) µg/dL. Results: Serum copper level (as a continuous variable) was significantly associated with MMSE score (B = 0.065, 95% confidence interval = 0.023-0.108, p = 0.003). Low serum copper group showed significantly decreased MMSE score compared to high copper one (B = -2.643, 95% confidence interval = -4.169 to -1.117, p < 0.001), while middle copper category had no difference (B = -1.211, 95% confidence interval = -2.689 to 0.268, p = 0.107). There was a significant low serum copper ×iron interaction effect on the MMSE score (B = 0.065, 95% confidence interval = 0.016-0.114, p = 0.010). Subgroup analyses showed that low serum copper was significantly associated with a low MMSE score in the low-iron (B = -4.174, 95% confidence interval = -6.607 to -1.741, p = 0.001) but not high-iron subgroup (B = -0.721, 95% confidence interval = -2.852 to 1.409, p = 0.495). Conclusion: Our findings from non-demented older adults suggest that a low serum copper level within the normal range was associated with AD or cognitive decline and this is moderated by iron. To prevent AD or cognitive decline, clinicians need to pay attention to avoiding low serum copper and iron levels, even within the clinical normal range.

Olanzapine-induced Concurrent Tardive Dystonia and Tardive Dyskinesia in Schizophrenia with Intellectual Disability: A Case Report.

Tardive dystonia and tardive dyskinesia (TDs) are rare extrapyramidal side effects that develop after long-term use of antipsychotics, but they are different syndromes and rarely occur at the same time. Olanzapine is an atypical antipsychotic drug associated with a low risk of extrapyramidal side effects in schizophrenia, but its associations with tardive movements are not clear. We present a case of a 19-year-old Asian female patient with schizophrenia and intellectual disabilities who developed concurrent TDs after long-term use of olanzapine. At her 10-month follow-up examination, her concurrent TDs had been treated successfully with clozapine. This case demonstrates that although the use of olanzapine to treat psychosis and behavioral disturbances is increasing due to its high efficacy and low rate of extrapyramidal side effects, concurrent TDs should be carefully assessed after long-term use of this antipsychotic, especially in patients with schizophrenia and intellectual disabilities. Clozapine, by preventing or reversing the debilitating consequences of concurrent TDs, may be an effective treatment for these patients.

MMSE Subscale Scores as Useful Predictors of AD Conversion in Mild Cognitive Impairment.

PURPOSE: This study was performed to examine the usefulness of subscores on the Mini-Mental State Examination (MMSE) for predicting the progression of Alzheimer's disease (AD) dementia in individuals with mild cognitive impairment (MCI). PATIENTS AND METHODS: A total of 306 MCI individuals in the Alzheimer's Disease Neuroimaging Initiative database were included in the study. Standardized clinical and neuropsychological tests were performed at baseline and at 2-year follow-up. Logistic regression analysis was conducted to examine the MMSE total and subscale scores to predict progression to AD dementia in MCI individuals. RESULTS: The MMSE total score and the MMSE memory, orientation, and construction subscores were inversely associated with AD progression after controlling for all potential confounders; MMSE attention and language subscores were not correlated with AD progression. The MMSE delayed recall score among the MMSE memory subscores and the MMSE time score among the orientation subscores, especially week and day, were inversely associated with AD progression; the MMSE immediate recall and place scores were not correlated with progression. CONCLUSION: Our findings suggest that the MMSE memory, orientation, and construction subscores, which are simple and readily available clinical measures, could provide useful information to predict AD dementia progression in MCI individuals in practical clinical settings.

Combination of the CAGE and serum gamma-glutamyl transferase: an effective screening tool for alcohol use disorder and alcohol dependence.

Purpose: The CAGE is a convenient test for alcohol-related disorder due to its brevity, but it is not as effective as the alcohol use disorders identification test (AUDIT). Gamma-glutamyl transferase (GGT) is an objective blood biochemical marker of excessive alcohol intake; however, it has low sensitivity. This study tested the performance of the combined use of CAGE and GGT to screen problem drinking (PD), alcohol use disorder (AUD), and alcohol dependence (AD). Methods: A total of 394 subjects composed of 91 normal controls and 303 subjects with PD were enrolled in this study. Of the PD subjects, 147 were diagnosed with AUD (77 alcohol abuse and 70 AD). A series of multiple logistic regression models for PD, AUD, and AD discrimination were used to obtain new combined CAGE and GGT scores after adjusting for age and gender (CAGE+GGT). A receiver operating characteristic curve analysis was conducted to determine how well the CAGE+GGT score discriminated between individuals with PD, AUD, and AD. Results: The discrimination accuracy of the AUDIT for PD was significantly better than that of the CAGE or the CAGE+GGT (z=6.927, p<0.0001; z=5.301, p<0.0001, respectively). The CAGE and the CAGE+GGT were better than the AUDIT at discriminating AUD (z=2.535, p=0.0112; z=2.894, p=0.0038, respectively). The discrimination accuracy of the AUDIT for AD was significantly better than that of the CAGE and GGT (z=3.233, p=0.0012; z=6.529, p<0.0001, respectively), but the CAGE+GGT was comparable with the AUDIT (z=1.652, p=0.0985). Conclusion: Our findings support the combined use of the CAGE questionnaire and serum GGT level as a sensitive and useful tool for AD screening.

Associations of BRAP polymorphisms with the risk of alcohol dependence and scores on the Alcohol Use Disorders Identification Test.

BACKGROUND: Alcohol dependence (AD) is a common disorder that is influenced by genetic as well as environmental factors. A previous genome-wide association study (GWAS) of the Korean population performed by our research group identified a number of genes, including BRCA1-associated protein (BRAP) and protein arginine methyltransferase 8 (PRMT8), as novel genetic markers of AD. METHODS: The present investigation was a fine-mapping follow-up study of 459 AD and 455 non-AD subjects of Korean descent to determine the associations between BRAP and PRMT8 polymorphisms and AD. The Alcohol Use Disorders Identification Test (AUDIT) was administered to screen for the degree of AD risk in the subjects and 58 genetic variants, 5 for BRAP and 53 for PRMT8, were genotyped for subsequent association analyses. RESULTS: In the present case-control analysis, BRAP rs3782886 showed the most significant association signal with a risk of AD (P=1.29×10-16, Pcorr =7.74×10-16, OR =0.19). There were also significant differences in the overall and subcategory scores for the BRAP genetic variants, including rs3782886 (P=9.94×10-31, Pcorr =5.96×10-30 at rs3782886 for the overall AUDIT score). However, the genetic effects of PRMT8 polymorphisms observed in our previous GWAS were not replicated in the present study (minimum P=0.0005, Pcorr >0.05, OR =0.30 at rs4766139 in the recessive model). Furthermore, the single-nucleotide polymorphisms of PRMT8 were not associated with the overall and subcategory AUDIT scores. CONCLUSION: The present findings suggest that the genetic variants of BRAP may contribute to a predisposition for an alcohol use disorder.

Gender-Specific Associations between CHGB Genetic Variants and Schizophrenia in a Korean Population.

PURPOSE: Schizophrenia is a devastating mental disorder and is known to be affected by genetic factors. The chromogranin B (CHGB), a member of the chromogranin gene family, has been proposed as a candidate gene associated with the risk of schizophrenia. The secretory pathway for peptide hormones and neuropeptides in the brain is regulated by chromogranin proteins. The aim of this study was to investigate the potential associations between genetic variants of CHGB and schizophrenia susceptibility. MATERIALS AND METHODS: In the current study, 15 single nucleotide polymorphisms of CHGB were genotyped in 310 schizophrenia patients and 604 healthy controls. RESULTS: Statistical analysis revealed that two genetic variants (non-synonymous rs910122; rs2821 in 3'-untranslated region) were associated with schizophrenia [minimum p=0.002; odds ratio (OR)=0.72], even after correction for multiple testing (p(corr)=0.02). Since schizophrenia is known to be differentially expressed between sexes, additional analysis for sex was performed. As a result, these two genetic variants (rs910122 and rs2821) and a haplotype (ht3) showed significant associations with schizophrenia in male subjects (p(corr)=0.02; OR=0.64), whereas the significance disappeared in female subjects (p>0.05). CONCLUSION: Although this study has limitations including a small number of samples and lack of functional study, our results suggest that genetic variants of CHGB may have sex-specific effects on the risk of schizophrenia and provide useful preliminary information for further study.

Prefrontal Cortical Thickness Deficit in Detoxified Alcohol-dependent Patients.

Alcohol dependence is a serious disorder that can be related with a number of potential health-related and social consequences. Cortical thickness measurements would provide important information on the cortical structural alterations in patients with alcohol dependence. Twenty-one patients with alcohol dependence and 22 healthy comparison subjects have been recruited and underwent high-resolution brain magnetic resonance (MR) imaging and clinical assessments. T1-weighted MR images were analyzed using the cortical thickness analysis program. Significantly thinner cortical thickness in patients with alcohol dependence than healthy comparison subjects was noted in the left superior frontal cortical region, correcting for multiple comparisons and adjusting with age and hemispheric average cortical thickness. There was a significant association between thickness in the cluster of the left superior frontal cortex and the duration of alcohol use. The prefrontal cortical region may particularly be vulnerable to chronic alcohol exposure. It is also possible that the pre-existing deficit in this region may have rendered individuals more susceptible to alcohol dependence.

Opioid Analgesics and Depressive Symptoms in Burn Patients: What Is the Real Relationship?

OBJECTIVE: Major burn injuries are strongly associated with both psychological trauma and severe pain, and opioids are the mainstay analgesics for the treatment of severe burn pain. The objectives of this study are to find the complex relationship between opioid dose, depression, and post-traumatic stress disorder (PTSD) symptoms during the acute management of pain in burn patients. METHODS: The symptoms of depression and PTSD were assessed in 43 burn patients immediately following wound stabilization and 2 weeks after the initial evaluation. RESULTS: Total opioid doses and Hamilton Depression Scale (HAMD) scores obtained during the second evaluation were positively but weakly correlated after controlling for age and total burn surface area (R=0.33, p=0.03). Moreover, pain management with opioids was significantly more common in burn patients with low Clinician Administered PTSD Scale scores (evaluation 1) and high HAMD scores (evaluation 2) (F=6.66, p=0.001). CONCLUSION: High opioid dose following acute burn trauma might have correlation with depressive symptoms. Monitoring of depressive symptoms may be important following acute burn trauma and consequent opioids pain management, particularly when PTSD symptoms appear minimal during the early stabilization of patients.

Genome-wide association study with the risk of schizophrenia in a Korean population.

Schizophrenia is regarded as a multifactorial and polygenic brain disorder that is attributed to different combinations of genetic and environmental risk factors. Recently, several genome-wide association studies (GWASs) of schizophrenia have identified numerous risk factors, but the replication results remain controversial and ambiguous. To identify schizophrenia susceptibility loci in the Korean population, we performed a GWAS using the Illumina HumanOmni1-Quad V1.0 Microarray. We genotyped 1,140,419 single nucleotide polymorphisms (SNPs) in 350 Korea schizophrenia patients and 700 control subjects, and approximately 620,001 autosomal SNPs were passed our quality control. In the case-control analysis, the rs9607195 A>G on intergenic area 250 kb away from the ISX gene and the rs12738007 A>G on the intron of the MECR gene were the most strongly associated SNPs with the risk of schizophrenia (P = 6.2 × 10(-8) , OR = 0.50 and P = 3.7 × 10(-7) , OR = 2.39, respectively). In subsequent fine-mapping analysis, 6 SNPs of MECR were genotyped with 310 schizophrenia patients and 604 control subjects. The association of the MECR rs12738007, a top ranked-SNP in GWAS, was replicated (P = 1.5 × 10(-2) , OR = 1.53 in fine mapping analysis, P = 1.5 × 10(-6) , OR = 1.90 in combined analysis). The identification of putative schizophrenia susceptibility loci could provide new insights into genetic factors related with schizophrenia and clues for the development of diagnosis strategies.

Reduction of Nfia gene expression and subsequent target genes by binge alcohol in the fetal brain.

The objective of the present study was to investigate the changes in gene expression in the fetal brain (forebrain and hippocampus) caused by maternal binge alcohol consumption. Pregnant C57BL/6J mice were treated intragastrically with distilled phosphate-buffered saline (PBS) or ethanol (2.9 g/kg) from embryonic day (ED) 8-12. Microarray analysis revealed that a significant number of genes were altered at ED 18 in the developing brain. Specifically, in hippocampus, nuclear factor one alpha (Nfia) and three N-methyl-D-aspartate (Nmda) receptors (Nmdar1, Nmdar2b, and Nmdar2d) were down-regulated. The transcription factor Nfia controls gliogenesis, cell proliferation and Nmda-induced neuronal survival by regulating the expression of target genes. Some of the Nfia-target gene (Aldh1a, Folh1, Gjb6, Fgf1, Neurod1, Sept4, and Ntsr2) expressions were also altered as expected. These results suggest that the altered expression of Nfia and Nmda receptors may be associated with the etiology of fetal alcohol syndrome (FAS). The data presented in this report will contribute to the understanding of the molecular mechanisms associated with the effects of alcohol in FASD individuals.

Association between HTR7 genetic polymorphisms and alcohol dependence, using the alcohol use disorders identification test (AUDIT).

BACKGROUND: A recent genome-wide association study has identified 5-hydroxytrytamine (serotonin) receptor 7, adenylate cyclase-coupled (HTR7) as a risk gene for alcohol dependence. In addition, the serotonergic system has been considered as a modulator that plays an important role in alcohol use disorders. Functional, pharmacological, and genetic studies of serotonin neurotransmission have revealed that serotonin receptors are potential targets for the treatment of alcohol use disorders. The aim of this study is to investigate whether associations between HTR7 genetic polymorphisms and alcohol dependence could be replicated. METHODS: This study genotyped a total of 22 common single nucleotide polymorphisms (SNPs) in 459 alcoholic patients and 444 nonalcoholic controls. RESULTS: Logistic regression analysis of the case-control study, controlling for age and sex as covariates, showed nominal associations of 7 SNPs (p = 0.02 to 0.04; odds ratio = 0.60 to 1.35). In further linear regression analysis based on the Alcohol Use Disorders Identification Test score for alcohol dependence, 8 SNPs and 3 haplotypes showed relatively significant associations with alcohol dependence (minimum p = 0.001; p(corr) = 0.02). CONCLUSIONS: Although further replications and functional evaluations are needed, our findings suggest that genetic variations of HTR7 may contribute to the predisposition for alcohol dependence.

Association study of DKK2 polymorphisms with alcohol dependence and alcohol-related harm.

BACKGROUND: Alcohol dependence (AD) is a common disorder with both environmental and genetic factors. Previous studies have shown that the genomic region from chromosome 4q22-q32 is closely associated with AD. Furthermore, a study with Irish subjects revealed that the polymorphisms of Dickkopf WNT signaling pathway inhibitor (DKK2), located at 4q25, showed a significant association with AD. METHODS: We conducted a replication study of the association between DKK2 polymorphisms and AD with 459 alcoholics and 444 normal controls, all of Korean descendent. To rank the AD of the subjects, Alcohol Use Disorders Identification Test (AUDIT) was utilized. Using the TaqMan assay, 21 single-nucleotide polymorphisms (SNPs) of DKK2 were genotyped. RESULTS: Our analysis showed that rs17037102 (Q146R) was significantly associated with overall AUDIT score (p = 0.003, p(corr)  = 0.05 in dominant model). Further analysis showed that the SNP was significantly associated with alcohol-related harm (p = 0.001, p(corr)  = 0.02 in co-dominant model). Several other SNPs, including the 3 SNPs which were associated with AD in European population, showed marginal associations that were erased when corrections for multiple testing was applied. Furthermore, rs17037102 was in linkage disequilibrium with the nonexonic DKK2 SNPs which showed associations with AD in the previous study with Irish population, which suggests that rs17037102 may be the causal SNP. CONCLUSIONS: We found 1 DKK2 SNP to be significantly associated with alcohol-related harm in alcoholic subjects. The SNP might be the causal SNP which led its linked SNPs to show associations in previous studies.

Association between Alcoholism Family History and Alcohol Screening Scores among Alcohol-dependent Patients.

OBJECTIVE: Several tests can be used to screen for alcohol dependence (AD), a prevalent disease with a heterogeneous etiology. As some patients with AD have a strong familial tendency in this regard, a family history of alcohol use disorders can affect the outcomes of screening tests and diagnostic evaluations for AD. In this study, we evaluated associations between a family history of alcohol use disorders and evaluations using the Cut down, Annoyed, Guilty, Eye-opener (CAGE) test, Alcohol Use Disorder Identification Test (AUDIT), and Diagnostic and Statistical Manual of Mental Disorders-fourth edition (DSM-IV) diagnostic criteria among patients with AD. METHODS: We recruited 487 male patients with AD from eight hospitals in Korea. Patients were evaluated using the CAGE, AUDIT, and DSM-IV diagnostic criteria. Patients with and without family histories were compared in terms of these assessment tools. RESULTS: Drinking initiation, uncontrollable drinking, and problem drinking occurred earlier and CAGE "annoyed" scores were higher in patients with a family history. Alcohol problems before the age of 25 years, frequency of spontaneous or compulsive alcohol-seeking behavior, and frequencies of psychological dependence and guilt related to alcohol use were also higher. CONCLUSION: Earlier drinking problems, higher scores on specific items of the CAGE, and AUDIT, and meeting more diagnostic criteria indicate more dependent, harmful drinking by patients with AD who have a family history of this condition. Clinicians should consider patients' family history of alcohol use disorders when screening for AD to identify the correct diagnosis and develop appropriate treatment plans for these patients.