Gene-environment interaction in type 2 diabetes in Korean cohorts: Interaction of a type 2 diabetes polygenic risk score with triglyceride and cholesterol on fasting glucose levels.

Type 2 diabetes (T2D) is caused by genetic and environmental factors as well as gene-environment interactions. However, these interactions have not been systematically investigated. We analyzed these interactions for T2D and fasting glucose levels in three Korean cohorts, HEXA, KARE, and CAVAS, using the baseline data with a multiple regression model. Two polygenic risk scores for T2D (PRST2D ) and fasting glucose (PRSFG ) were calculated using 488 and 82 single nucleotide polymorphisms (SNP) for T2D and fasting glucose, respectively, which were extracted from large-scaled genome-wide association studies with multiethnic data. Both lifestyle risk factors and T2D-related biochemical measurements were assessed. The effect of interactions between PRST2D -triglyceride (TG) and PRST2D -total cholesterol (TC) on fasting glucose levels was observed as follows: ß ± SE = 0.0005 ± 0.0001, p = 1.06 × 10-19 in HEXA, ß ± SE = 0.0008 ± 0.0001, p = 2.08 × 10-8 in KARE for TG; ß ± SE = 0.0006 ± 0.0001, p = 2.00 × 10-6 in HEXA, ß ± SE = 0.0020 ± 0.0004, p = 2.11 × 10-6 in KARE, ß ± SE = 0.0007 ± 0.0004, p = 0.045 in CAVAS for TC. PRST2D -based classification of the participants into four groups showed that the fasting glucose levels in groups with higher PRST2D were more adversely affected by both the TG and TC. In conclusion, blood TG and TC levels may affect the fasting glucose level through interaction with T2D genetic factors, suggesting the importance of consideration of gene-environment interaction in the preventive medicine of T2D.

Associations between exploratory dietary patterns and incident type 2 diabetes: a federated meta-analysis of individual participant data from 25 cohort studies.

PURPOSE: In several studies, exploratory dietary patterns (DP), derived by principal component analysis, were inversely or positively associated with incident type 2 diabetes (T2D). However, findings remained study-specific, inconsistent and rarely replicated. This study aimed to investigate the associations between DPs and T2D in multiple cohorts across the world. METHODS: This federated meta-analysis of individual participant data was based on 25 prospective cohort studies from 5 continents including a total of 390,664 participants with a follow-up for T2D (3.8-25.0 years). After data harmonization across cohorts we evaluated 15 previously identified T2D-related DPs for association with incident T2D estimating pooled incidence rate ratios (IRR) and confidence intervals (CI) by Piecewise Poisson regression and random-effects meta-analysis. RESULTS: 29,386 participants developed T2D during follow-up. Five DPs, characterized by higher intake of red meat, processed meat, French fries and refined grains, were associated with higher incidence of T2D. The strongest association was observed for a DP comprising these food groups besides others (IRRpooled per 1 SD = 1.104, 95% CI 1.059-1.151). Although heterogeneity was present (I2 = 85%), IRR exceeded 1 in 18 of the 20 meta-analyzed studies. Original DPs associated with lower T2D risk were not confirmed. Instead, a healthy DP (HDP1) was associated with higher T2D risk (IRRpooled per 1 SD = 1.057, 95% CI 1.027-1.088). CONCLUSION: Our findings from various cohorts revealed positive associations for several DPs, characterized by higher intake of red meat, processed meat, French fries and refined grains, adding to the evidence-base that links DPs to higher T2D risk. However, no inverse DP-T2D associations were confirmed.

Associations of Total Legume, Pulse, and Soy Consumption with Incident Type 2 Diabetes: Federated Meta-Analysis of 27 Studies from Diverse World Regions.

BACKGROUND: The consumption of legumes is promoted as part of a healthy diet in many countries but associations of total and types of legume consumption with type 2 diabetes (T2D) are not well established. Analyses across diverse populations are lacking despite the availability of unpublished legume consumption data in prospective cohort studies. OBJECTIVE: To examine the prospective associations of total and types of legume intake with the risk of incident T2D. METHODS: Meta-analyses of associations between total legume, pulse, and soy consumption and T2D were conducted using a federated approach without physical data-pooling. Prospective cohorts were included if legume exposure and T2D outcome data were available and the cohort investigators agreed to participate. We estimated incidence rate ratios (IRRs) and CIs of associations using individual participant data including ≤42,473 incident cases among 807,785 adults without diabetes in 27 cohorts across the Americas, Eastern Mediterranean, Europe, and Western Pacific. Random-effects meta-analysis was used to combine effect estimates and estimate heterogeneity. RESULTS: Median total legume intake ranged from 0-140 g/d across cohorts. We observed a weak positive association between total legume consumption and T2D (IRR = 1.02, 95% CI: 1.01 to 1.04) per 20 g/d higher intake, with moderately high heterogeneity (I2 = 74%). Analysis by region showed no evidence of associations in the Americas, Eastern Mediterranean, and Western Pacific. The positive association in Europe (IRR = 1.05, 95% CI: 1.01 to 1.10, I2 = 82%) was mainly driven by studies from Germany, UK, and Sweden. No evidence of associations was observed for the consumption of pulses or soy. CONCLUSIONS: These findings suggest no evidence of an association of legume intakes with T2D in several world regions. The positive association observed in some European studies warrants further investigation relating to overall dietary contexts in which legumes are consumed, including accompanying foods which may be positively associated with T2D.

Gene-environment interactions related to blood pressure traits in two community-based Korean cohorts.

Hypertension is a complex disorder caused by genetic and environmental risk factors. Recently, genome-wide association studies (GWASs) identified more than 100 genetic variants for blood pressure traits and hypertension. However, the interactions between these genetic variants and environmental factors have not been systematically investigated. Therefore, we examined the interaction between genetic and environmental risk factors in blood pressure traits using the genetic risk score (GRS). Two Korean community-based cohorts, Cohort I (KARE; N = 8,840) and Cohort II (CAVAS; N = 9,599), were used for this study, and GRSs were calculated from 42 GWAS single-nucleotide polymorphisms (SNPs) that were validated for their association in these cohorts. We calculated GRSs in both ways by considering the effect sizes of each SNP (weighted GRS) and not considering the effect sizes (unweighted GRS). The unweighted GRS was strongly associated with systolic blood pressure, diastolic blood pressure, and hypertension (p = 9.03 × 10 -47 , p = 9.41 × 10 -48 , and p = 3.22 × 10 -55 by meta-analysis, respectively) and the weighted GRS showed the similar results. The environmental factors of body mass index, waist circumference, and drinking status were significantly associated with blood pressure traits, and the interaction between these factors and GRSs were examined. However, no interactions were found with either the GRS or the individual SNPs considered for the GRS. Our findings show that it is challenging to find GRS-environment interactions regarding blood pressure traits.

Are Genetic Variants Associated with the Location of Cerebral Arterial Lesions in Stroke Patients?

BACKGROUND: Genetic variants may play a role in determining the location of cerebral atherosclerosis. We aimed to investigate the association between RNF213, MMP2, and genetic polymorphisms linked to vascular tortuosity with the location of cerebral arterial atherosclerosis. METHODS: A prospective case-control study was conducted on patients with ischemic stroke and age- and sex-matched stroke-free controls. The stroke patients were categorized into those with intracranial artery atherosclerosis (ICAS), extracranial artery atherosclerosis (ECAS), and small vessel occlusion (SVO). Six single nucleotide polymorphisms (SNPs) including rs2118181 (FBN1), rs2179357 (SLC2A10), rs1036095 (TGFBR2), rs243865 (MMP2), rs1800470 (TGFB1), and rs112735431 (RNF213) were analyzed with the TaqMan Genotyping Assay, and the distribution of genotypes across groups was compared. RESULTS: None of the 6 SNPs were associated with stroke on comparing the 449 stroke patients (71 with ECAS, 169 with ICAS, and 209 with SVO) to the 447 controls. In the subgroup analysis, the adjusted odds ratios (aORs) for age and sex indicated a significant association between rs112735431 and ICAS in the allele comparison analysis and in the additive and dominant model analyses. rs112735431 was associated with anterior circulation involvement and increased burden of cerebral atherosclerosis. rs2179357 was significantly associated with ICAS in the recessive model analysis, and rs1800470 was significantly associated with ECAS in the recessive model analysis when compared to controls. CONCLUSION: rs112735431 was associated with ICAS and increased atherosclerosis burden in Korean stroke patients. Further studies are needed to elucidate the role of rs112735431 and to confirm the association of rs2179357 and rs1800470 with cerebral atherosclerosis.

Prediction of deep vein thrombosis by ultrasonography and D-dimer in Asian patients with ischemic stroke.

BACKGROUND: Deep vein thrombosis (DVT) is an important complication of ischemic stroke, although the incidence of DVT is regarded as being lower in Asian than in non-Asian patients. Here, we investigated the incidence and factors associated with DVT in Asian patients with ischemic stroke. METHODS: Acute ischemic stroke patients received lower extremity ultrasonography (LEUS) to diagnose the presence of DVT. Clinical characteristics and laboratory results, including D-dimer level, were compared between patients with and without DVT. Independent risk factors for DVT were investigated using multivariable analysis. Similar analysis was performed to identify factors associated with elevated D-dimer level (> 0.5 mg/dl) in acute ischemic stroke patients. RESULTS: During the study period, 289 patients were enrolled, and 38 (13.1%) showed DVT. Female sex (OR = 2.579, 95% CI = 1.224-5.432; p = 0.013) and a high National Institutes of Health Stroke Scale (NIHSS) score (OR = 1.191 95% CI = 1.095-1.294; p = 0.005) were independently associated with the presence of DVT, although D-dimer level was not. Stroke mechanism, especially cardioembolic stroke (OR = 3.777, 95% CI = 1.532-9.313; p = 0.004; reference: large artery atherosclerosis), NIHSS score (OR = 1.087, 95% CI = 1.002-1.179; p = 0.001) and thrombolysis (OR = 12.360, 95% CI 2.456-62.213; p = 0.002) were independently associated with elevated abnormal D-dimer levels. CONCLUSION: The severity of ischemic stroke, but not the D-dimer level, was associated with the presence of DVT in Asian ischemic stroke patients. D-dimer level was influenced by the stroke mechanism. LEUS in patients with severe neurological deficit, rather than screening with D-dimer, may be more beneficial for diagnosing DVT in Asian patients with acute ischemic stroke.

Patterns and Outcomes of the Top of the Basilar Artery Syndrome: The Role of the Posterior Communicating Artery.

BACKGROUND: Clinical syndromes secondary to infarcts in the distal basilar artery (BA) area have been described as "top of the basilar" (TOB) syndrome. However, in the era of advanced imaging technology, it has been realized that the clinical and imaging features are quite diverse in patients with distal BA occlusion. The aim of the present study was to investigate the patterns and clinical outcomes of TOB assessed with modern images and categorize TOBs accordingly. Additionally, we examined the possible influence of the posterior communicating artery (PcoA) on the patterns of TOB. METHODS: Patients with distal BA occlusion on magnetic resonance angiography were categorized as TOB-A, and those with multiple lesions in the distal BA territory on diffusion-weighted magnetic resonance imaging as TOB-L. Patients with angiographically and lesion distribution-defined TOB were classified as having TOB-A&L; those with angiographically defined TOB as having TOB-A without TOB-L; and those with lesion distribution-defined TOB as having TOB-L without TOB-A. The PcoA was categorized as "textbook-type" (good P1) and "fetal-type" (absent P1). Factors associated with unfavorable short-term outcomes (modified Rankin Scale 5-6 at discharge), and 1-year and long-term mortalities, were assessed. RESULTS: Of 1,466 patients with ischemic stroke in the posterior circulation who were admitted to Asan Medical Center within 24 h of symptom onset, 124 (8.5%) had TOB, including 45 with TOB-A&L, 44 with TOB-A, and 35 with TOB-L. NIHSS scores (21 [9.5-26] vs. 6 [3-11.5] vs. 6 [3-9]; p < 0.01) and rates of motor deficit (75.6 vs. 54.5 vs. 34.4%; p < 0.01), concomitant pontine lesions (17.8 vs. 25.0 vs. 2.9%; p < 0.01), PcoA presence (44.4 vs. 68.2 vs. 25.7%; p < 0.01), and unfavorable short-term outcomes (62.2 vs. 25.0 vs. 14.3%; p < 0.01) differed significantly in the 3 patient groups. Multivariate analysis showed that textbook-type PcoA was independently associated with a lower frequency of unfavorable short-term outcomes (OR 0.15, 95% CI 0.03-0.70). Reperfusion therapy (hazard ratio [HR] 0.25, 95% CI 0.07-0.89) and the presence of textbook-type PcoA (HR 0.20, 95% CI 0.05-0.90) were associated with a lower 1-year mortality rate after stroke. CONCLUSION: Patterns and clinical outcomes of TOB vary and are affected by the hemodynamic status of the arterial system, such as BA recanalization and the presence of textbook-type PcoA.

Intracranial Pressure Soon After Hemicraniectomy in Malignant Middle Cerebral Artery Infarction.

BACKGROUND: Decompressive hemicraniectomy reduces secondary brain injury related to brain edema and increased intracranial pressure (ICP) in patients with malignant middle cerebral artery infarction (MMI). However, a substantial proportion of patients still die despite hemicraniectomy due to refractory brain swelling. OBJECTIVE: We aim to investigate whether ICP measured immediately after hemicraniectomy may indicate decompression effects and predict survival in patients with MMI. METHODS: We included 25 patients with MMI who underwent ICP monitoring and brain computed tomography within the first hour of hemicraniectomy. Midline shifts were measured as radiological surrogates of decompression. The Glasgow Coma Scale and pupillary enlargements during the first day after hemicraniectomy were assessed as clinical surrogates of decompression. Long-term survival status at 6 months was used as the final outcome. We analyzed the relationships between early ICP and findings of midline shift, Glasgow Coma Scale, pupillary enlargement, and survival. RESULTS: Initial ICP was correlated with mean ICP ( P < .001) and maximal ICP ( P < .001) during the first postoperative day. Intracranial pressure was associated with midline shifts ( P = .009), lower Glasgow Coma Scale scores ( P = .025), and the pupillary enlargement ( P = .015). Sixteen (64.0%) patients survived at 6 months. In a Cox proportional hazard model, elevated ICP was associated with mortality at 6 months (hazard ratio: 1.13; 95% confidence interval: 1.03-1.24; P = .008). CONCLUSION: Increase in ICP soon after hemicraniectomy was associated with midline shift, poor neurological status, and mortality in patients with MMI. Measurements of ICP soon after hemicraniectomy may permit earlier interventions as well as more refined clinical assessments.

On the association analysis of CNV data: a fast and robust family-based association method.

BACKGROUND: Copy number variation (CNV) is known to play an important role in the genetics of complex diseases and several methods have been proposed to detect association of CNV with phenotypes of interest. Statistical methods for CNV association analysis can be categorized into two different strategies. First, the copy number is estimated by maximum likelihood and association of the expected copy number with the phenotype is tested. Second, the observed probe intensity measurements can be directly used to detect association of CNV with the phenotypes of interest. RESULTS: For each strategy we provide a statistic that can be applied to extended families. The computational efficiency of the proposed methods enables genome-wide association analysis and we show with simulation studies that the proposed methods outperform other existing approaches. In particular, we found that the first strategy is always more efficient than the second strategy no matter whether copy numbers for each individual are well identified or not. With the proposed methods, we performed genome-wide CNV association analyses of hematological trait, hematocrit, on 521 Korean family samples. CONCLUSIONS: We found that statistical analysis with the expected copy number is more powerful than the statistic with the probe intensity measurements regardless of the accuracy of the estimation of copy numbers.

Fluid-Attenuated Inversion Recovery Hyperintensity Is Associated with Hemorrhagic Transformation following Reperfusion Therapy.

BACKGROUND: It is still controversial whether early fluid-attenuated inversion recovery (FLAIR) hyperintensity within acute ischemic lesions carries the risk of hemorrhagic transformation (HT) after reperfusion therapy. Furthermore, the association between the location of FLAIR hyperintensity and HT has not been investigated. METHODS: We retrospectively reviewed patients who underwent reperfusion therapy within 6 hours of stroke onset and magnetic resonance imaging including a FLAIR sequence before completing reperfusion therapy. FLAIR hyperintensity within the diffusion-weighted imaging (DWI) lesion was rated qualitatively, and HT was assessed on follow-up gradient echo imaging. The location of the FLAIR change and HT was classified as subcortical, cortical, or cortico-subcortical. RESULTS: Of 134 patients with acute ischemic stroke included in this study, early FLAIR changes within DWI lesions were identified in 56 (41.8%) patients, and HT was noted in 51 (38.1%) patients. FLAIR change was independently associated with HT (odds ratio: 4.37, 95% confidence interval: 1.72-11.12). Geographically, 48.2% of the patients with a FLAIR change developed a matched HT (restricted to the region with the FLAIR change), and the risk of HT was further increased in patients with a FLAIR change in the cortico-subcortical region (68.8%). CONCLUSIONS: In patients in the acute stage of stroke, an early FLAIR change is associated with the risk of HT following reperfusion therapy with a highly matched geographic relationship and common risk factors. Thus, identification of FLAIR change may be a useful surrogate marker to assess the likelihood of subsequent HT in patients treated with reperfusion therapy.

Nonatheroscleotic Isolated Middle Cerebral Artery Disease May Be Early Manifestation of Moyamoya Disease.

BACKGROUND AND PURPOSE: Middle cerebral artery steno-occlusive disease (MCAD) is not an uncommon cause of ischemic stroke in young Asians. Aside from atherosclerosis, the pathogenesis of MCAD include various nonatherosclerotic vasculopathies, most of which are yet to be defined. This study investigated the pathogenesis of symptomatic isolated MCAD in young Asian patients using high-resolution magnetic resonance imaging (HR-MRI) and mutation analysis of RNF213. METHODS: Patients aged <60 years with stroke or transient ischemic attack caused by MCAD were prospectively enrolled. Patients with a confirmed diagnosis of moyamoya disease, dissection, and vasculitis; with significant steno-occlusion in cerebral arteries other than the MCA; or with high-risk cardioembolic source were excluded. Using high-resolution MRI, patients were classified into an atherosclerosis group and a nonatherosclerosis group. RESULTS: Eighty-one patients were enrolled, 45 (56.6%) in the atherosclerosis and 36 (44.4%) in the nonatherosclerosis group. The nonatherosclerosis group was significantly younger (P=0.013), had a smaller number of vascular risk factors (P=0.001), showed a lower homocysteine level (P<0.001), thinner intima-media thickness (P=0.006), and had more frequent heterozygotes at RNF213 (P=0.045) than the atherosclerosis group. Diffusion-weighted image lesion pattern showed no significant differences in assumed stroke mechanisms between the 2 groups. CONCLUSIONS: Nonatherosclerotic pathogenesis are common in young Asians with symptomatic isolated MCAD. Clinical findings, high-resolution MRI features, and results of RNF213 mutation analysis suggest that moyamoya disease is responsible etiologically for a significant portion of nonatherosclerotic lesions. Symptomatic isolated MCAD may be an early manifestation of moyamoya disease in young Asian adults.

Genome-wide association study of electrocardiographic parameters identifies a new association for PR interval and confirms previously reported associations.

Previous reports have described several associations of PR, QRS, QT and heart rate with genomic variations by genome-wide association studies (GWASs). In the present study, we examined the association of ∼2.5 million SNPs from 2994 Japanese healthy volunteers obtained from the JPDSC database with electrocardiographic parameters. We confirmed associations of PR interval, QRS duration and QT interval in individuals of Japanese ancestry with 11 of the 45 SNPs (6 of 20 for QT, 5 of 19 for PR and 0 of 6 for QRS) observed among individuals of European, African and Asian (Indian and Korean) ancestries. Those results indicate that many of the electrocardiographic associations with genes are shared by different ethnic groups including Japanese. Possible novel associations found in this study were validated by Korean data. As a result, we identified a novel association of SNP rs4952632[G] (maps near SLC8A1, sodium-calcium exchanger) (P = 7.595 × 10(-6)) with PR interval in Japanese individuals, and replication testing among Koreans confirmed the association of the same SNP with prolonged PR interval. Meta-analysis of the Japanese and Korean datasets demonstrated highly significant associations of SNP rs4952632[G] with a 2.325-ms (95% CI, 1.693-2.957 ms) longer PR interval per minor allele copy (P = 5.598 × 10(-13)). Cell-type-specific SLC8A1 knockout mice have demonstrated a regulatory role of sodium-calcium exchanger in automaticity and conduction in sinoatrial node, atrium and atrioventricular node. Our findings support a functional role of sodium-calcium exchanger in human atrial and atrioventricular nodal conduction as suggested by genetically modified mouse models.

Identification of three novel genetic variations associated with electrocardiographic traits (QRS duration and PR interval) in East Asians.

The electrocardiogram has several advantages in detecting cardiac arrhythmia-it is readily available, noninvasive and cost-efficient. Recent genome-wide association studies have identified single-nucleotide polymorphisms that are associated with electrocardiogram measures. We performed a genome-wide association study using Korea Association Resource data for the discovery phase (Phase 1, n = 6805) and two consecutive replication studies in Japanese populations (Phase 2, n = 2285; Phase 3, n = 5010) for QRS duration and PR interval. Three novel loci were identified: rs2483280 (PRDM16 locus) and rs335206 (PRDM6 locus) were associated with QRS duration, and rs17026156 (SLC8A1 locus) correlated with PR interval. PRDM16 was recently identified as a causative gene of left ventricular non-compaction and dilated cardiomyopathy in 1p36 deletion syndrome, which is characterized by heart failure, arrhythmia and sudden cardiac death. Thus, our finding that a PRDM16 SNP is linked to QRS duration strongly implicates PRDM16 in cardiac function. In addition, C allele of rs17026156 increases PR interval (beta ± SE, 2.39 ± 0.40 ms) and exists far more frequently in East Asians (0.46) than in Europeans and Africans (0.05 and 0.08, respectively).

Combinatorial approach to estimate copy number genotype using whole-exome sequencing data.

Copy number variations (CNVs) are known risk factors in complex diseases. Array-based approaches have been widely used to detect CNVs, but limitations of array-based CNV detection methods, such as noisy signal and low resolution, have hindered detection of small CNVs. Recently, the development of next-generation sequencing techniques has increased rapidly owing to declines in cost. Particularly, whole-exome sequencing has proved useful for finding causal genes and variants in complex diseases. Because gene copy number may affect expression, CNV genotyping can be very valuable in disease association studies. However, almost all current CNV detection tools consider only two types of CNV genotypes. In this study, we propose a CNV genotype estimation approach using a combination of existing methods. Our approach was comprehensively compared with the customized Agilent array-comparative genomic hybridization. We found that our genotyping approach proved to be accurate, and reproducible, suggesting that it can complement existing CNV genotyping methods.

Isolated MCA disease in patients without significant atherosclerotic risk factors: a high-resolution magnetic resonance imaging study.

BACKGROUND AND PURPOSE: Diagnosis of intracranial artery atherosclerosis remains often uncertain. The high-resolution magnetic resonance imaging (HR-MRI) enables vessel wall assessment for more precise diagnoses. The aim of the present study was to investigate the etiologies of middle cerebral artery steno-occlusive disease in young adult patients with few atherosclerotic risk factors using HR-MRI. METHODS: We prospectively studied patients who visited a tertiary hospital in Seoul, Korea, and had (1) unilateral middle cerebral artery disease (≥50% stenosis or occlusion), (2) were ≤55 years old and had no or minimal (≤1) atherosclerotic risk factors. We excluded patients with a confirmed diagnosis of Moyamoya disease, vasculitis, or dissection and those having emboligenic sources. A presumptive diagnosis was made based on HR-MRI findings, and patients were categorized as HR-athero (atherosclerotic disease), HR-MMD (Moyamoya disease), HR-dissection, or HR-vasculitis. RESULTS: Among 95 patients analyzed, 26 (27.4%) had HR-athero who were more often male (P=0.004), smokers (P=0.018), and had focal stenosis (P=0.003) than others.As compared with the HR-athero patients, 29 HR-MMD patients were more often female (P<0.001) and more often had occlusive lesions (P=0.001) and nonfocal stenosis (P<0.001). The 22 HR-dissection patients tended to have hypertension less often, and the 13 HR-vasculitis patients were younger (P=0.004) and tended to have nonfocal stenosis. [corrected]. CONCLUSIONS: In our cohort of young patients with minimal risk factors, atherosclerosis seems to be an uncommon pathology of middle cerebral artery stenosis. HR-MRI aids us to make a more reliable diagnosis.

Vaccinia-based influenza vaccine overcomes previously induced immunodominance hierarchy for heterosubtypic protection.

Growing concerns about unpredictable influenza pandemics require a broadly protective vaccine against diverse influenza strains. One of the promising approaches was a T cell-based vaccine, but the narrow breadth of T-cell immunity due to the immunodominance hierarchy established by previous influenza infection and efficacy against only mild challenge condition are important hurdles to overcome. To model T-cell immunodominance hierarchy in humans in an experimental setting, influenza-primed C57BL/6 mice were chosen and boosted with a mixture of vaccinia recombinants, individually expressing consensus sequences from avian, swine, and human isolates of influenza internal proteins. As determined by IFN-γ ELISPOT and polyfunctional cytokine secretion, the vaccinia recombinants of influenza expanded the breadth of T-cell responses to include subdominant and even minor epitopes. Vaccine groups were successfully protected against 100 LD50 challenges with PR/8/34 and highly pathogenic avian influenza H5N1, which contained the identical dominant NP366 epitope. Interestingly, in challenge with pandemic A/Cal/04/2009 containing mutations in the dominant epitope, only the group vaccinated with rVV-NP + PA showed improved protection. Taken together, a vaccinia-based influenza vaccine expressing conserved internal proteins improved the breadth of influenza-specific T-cell immunity and provided heterosubtypic protection against immunologically close as well as distant influenza strains.

A nonsynonymous SNP in BANK1 is associated with serum LDL cholesterol levels in three Korean populations.

Serum levels of lipids, such as cholesterol and triglycerides, are heritable risk factors for cardiovascular disease and targets for therapeutic intervention. Because previous genome-wide association studies (GWASs) did not target functional genetic variants, we employed an alternate approach using nonsynonymous single-nucleotide polymorphisms (SNPs) to identify functional genetic variants associated with the regulation of serum lipid levels. We selected 3667 healthy individuals from a rural community-based cohort (CAVAS; Cardio Vascular disease Association Study) of the Korean Genome and Epidemiology Study project. We analyzed demographic and lifestyle information, lipid measurements and genotypes using the Illumina-1M SNP chip. For genotyping, we isolated 11 558 nonsynonymous SNPs and conducted a linear regression analysis with four lipid traits (total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterols and triglycerides). Significantly associated SNPs were validated in two independent Korean populations, Korean Association Resource (KARE) (n=4116) and Health Examinee (HEXA) (n=2178). Of the 11 558 SNPs, one SNP (rs3733197) from the CAVAS was significantly associated with serum LDL cholesterols (beta±s.e.=4.67±0.94, P-value=1.0 × 10(-6 and) Bonferroni corrected P-value=0.012). The replication results of HEXA and KARE were beta±s.e.=2.88±1.12, P-value=0.016 and beta±s.e.=1.26±0.97, P-value=0.196, respectively. An overall meta-analysis of the three data sets revealed beta=2.98±0.57, P-value=6.19 × 10(-7). The rs3733197 is located in the coding region of BANK1 (B-cell scaffold protein with ankyrin repeats 1), and the minor allele (A) resulted in the replacement of the Alanine at position 383 with Threonine.

Recurrent steroid-responsive cerebral vasogenic edema in status migrainosus and persistent aura.

BACKGROUND: Status migrainosus (SM) and persistent aura (PA) without infarction are complications of migraine. Although several patients have been reported to have reversible brain lesions associated with complications of migraine, their nature and pathophysiology remain unclear. CASE: We report on a 38-year-old male who presented with nine episodes of SM and PA over eight years. Serial neuroimaging studies including brain magnetic resonance imaging (MRI), blood flow single photon emission tomography (SPECT),(18) F-fluorodeoxyglucose positron emission tomography (FDG-PET) and(11) C-flumazenil PET (FMZ-PET) demonstrated cerebral vasogenic edema (CVE) with hypoperfusion and hypometabolism in the area, anatomically corresponding to the area with PA. SM and PA were effectively controlled by corticosteroid therapy. Follow-up MRI revealed complete reversibility of the CVE, which was supported by normal FMZ-PET and FDG-PET findings. CONCLUSION: We have described a patient with transient brain lesions associated with complications of migraine who was diagnosed with fully reversible and steroid responsive CVE.

A genome-wide association study of copy-number variation identifies putative loci associated with osteoarthritis in Koreans.

BACKGROUND: OA is a complex disease caused by environmental and genetic risk factors. The purpose of this study is to identify candidate copy number variations (CNVs) associated with OA. METHODS: We performed a genome-wide association study of CNV to identify potential loci that confer susceptibility to or protection from OA. CNV genotyping was conducted using NimbleGen HD2 3 × 720K comparative hybridization array and included samples from 371 OA patients and 467 healthy controls. The putative CNV regions identified were confirmed with a TaqMan assay. RESULTS: We identified six genomic regions associated with OA encompassing CNV loci. None of six loci had previously been reported in genome-wide association studies with OA, although a genetic analysis suggested that they have functional effects. The protein product of a candidate risk gene for obesity, TNKS, targets Wnt inhibition, and this gene was significantly associated with hand and knee OA. Copy number deletion on TNKS was associated with a 1.37-fold decreased risk for OA. In addition, CA10, which shows a strong association with osteoporosis, was also significant in our study. Copy number deletion on this gene was associated with a 1.69-fold decreased risk for OA. CONCLUSION: We identified several CNV loci that may contribute to OA susceptibility in Koreans. Further functional investigations of these genes are warranted to fully characterize their putative association.

Color-coded fluid-attenuated inversion recovery images improve inter-rater reliability of fluid-attenuated inversion recovery signal changes within acute diffusion-weighted image lesions.

BACKGROUND AND PURPOSE: Diffusion-weighted image fluid-attenuated inversion recovery (FLAIR) mismatch has been considered to represent ischemic lesion age. However, the inter-rater agreement of diffusion-weighted image FLAIR mismatch is low. We hypothesized that color-coded images would increase its inter-rater agreement. METHODS: Patients with ischemic stroke <24 hours of a clear onset were retrospectively studied. FLAIR signal change was rated as negative, subtle, or obvious on conventional and color-coded FLAIR images based on visual inspection. Inter-rater agreement was evaluated using κ and percent agreement. The predictive value of diffusion-weighted image FLAIR mismatch for identification of patients <4.5 hours of symptom onset was evaluated. RESULTS: One hundred and thirteen patients were enrolled. The inter-rater agreement of FLAIR signal change improved from 69.9% (k=0.538) with conventional images to 85.8% (k=0.754) with color-coded images (P=0.004). Discrepantly rated patients on conventional, but not on color-coded images, had a higher prevalence of cardioembolic stroke (P=0.02) and cortical infarction (P=0.04). The positive predictive value for patients <4.5 hours of onset was 85.3% and 71.9% with conventional and 95.7% and 82.1% with color-coded images, by each rater. CONCLUSIONS: Color-coded FLAIR images increased the inter-rater agreement of diffusion-weighted image FLAIR recovery mismatch and may ultimately help identify unknown-onset stroke patients appropriate for thrombolysis.