High-resolution MRI vessel wall enhancement in moyamoya disease: risk factors and clinical outcomes.

OBJECTIVES: Intracranial vessel wall enhancement (VWE) on high-resolution magnetic resonance imaging (HRMRI) is associated with the progression and poor prognosis of moyamoya disease (MMD). This study assessed potential risk factors for VWE in MMD. METHODS: We evaluated MMD patients using HRMRI and traditional angiography examinations. The participants were divided into VWE and non-VWE groups based on HRMRI. Logistic regression was performed to compare the risk factors for VWE in MMD. The incidence of cerebrovascular events of the different subgroups according to risk factors was compared using Kaplan-Meier survival and Cox regression. RESULTS: We included 283 MMD patients, 84 of whom had VWE on HRMRI. The VWE group had higher modified Rankin Scale scores at admission (p = 0.014) and a higher incidence of ischaemia and haemorrhage (p = 0.002) than did the non-VWE group. Risk factors for VWE included the ring finger protein 213 (RNF213) p.R4810K variant (odds ratio [OR] 2.01, 95% confidence interval [CI] 1.08-3.76, p = 0.028), hyperhomocysteinaemia (HHcy) (OR 5.08, 95% CI 2.34-11.05, p < 0.001), and smoking history (OR 3.49, 95% CI 1.08-11.31, p = 0.037). During the follow-up of 63.9 ± 13.2 months (median 65 months), 18 recurrent stroke events occurred. Cox regression showed that VWE and the RNF213 p.R4810K variant were risk factors for stroke. CONCLUSION: The RNF213 p.R4810K variant is strongly associated with VWE and poor prognosis in MMD. HHcy and smoking are independent risk factors for VWE. CLINICAL RELEVANCE STATEMENT: Vessel wall enhancement in moyamoya disease is closely associated with poor prognosis, especially related to the ring finger protein 213 p.R4810K variant, hyperhomocysteinaemia, and smoking, providing crucial risk assessment information for the clinic. KEY POINTS: • The baseline presence of vessel wall enhancement is significantly associated with poor prognosis in moyamoya disease. • The ring finger protein 213 p.R4810K variant is strongly associated with vessel wall enhancement and poor prognosis in moyamoya disease. • Hyperhomocysteinaemia and smoking are independent risk factors for vessel wall enhancement in moyamoya disease.

Association of polymorphisms in endothelial dysfunction-related genes with susceptibility to essential hypertension in elderly Han population in Liaoning province, China.

Hypertension is a complex disease which is mainly influenced by genetic factors. Recently, genome-wide association study (GWAS) found three novel endothelial dysfunction-related sites: Vascular endothelial growth factor A (VEGFA) rs9472135, Faciogenital dysplasia 5 (FGD5) rs11128722, Zinc Finger C3HC-type Containing 1 (ZC3HC1) rs11556924. Endothelial dysfunction is one of the early events in pathophysiology of essential hypertension. To investigate the association of endothelial dysfunction-related genes with essential hypertension, we conducted a case-control study of 431 patients with hypertension and 345 controls. The polymorphisms were detected using Taqman Probe. The alleles and genotypes of ZC3HC1 rs11556924 and VEGFA rs9472135 were not statistically different between the two groups, while the allele of FGD5 rs11128722 was different [P = 0.045, OR = 1.265, 95% CI = (1.009-1.586)], especially in the male [P = 0.035, OR = 1.496, 95% CI = (1.037-2.158)]. Analyzing the different of genotype distribution of 3 SNPs in the two groups under different genetic models, the genotypes of FGD5 rs11128722 showed difference in male under dominant model [P = 0.049, OR = 1.610, 95% CI = (1.018-2.544)]. The polymorphism of FGD5 rs11128722 had a significant difference in Body Mass Index (BMI) among different genotypes; In the additive genetic model, BMI of GA genotype was higher than that of GG (P = 0.038); GA + AA was higher than GG in the dominant genetic model (P = 0.011). In our study, we found that the polymorphisms of VEGFA rs9472135 and ZC3HC1 rs11556924 may not significantly associated with the risk of essential hypertension, and FGD5 rs11128722 may increase the risk of it, especially in elderly men.

Meta-analysis of genotype and phenotype studies to confirm the predictive role of the RNF213 p.R4810K variant for moyamoya disease.

BACKGROUND AND PURPOSE: The aim of this meta-analysis study was to assess the predictive effects of RNF213 p.R4810K on phenotype in moyamoya disease (MMD). METHODS: Electronic databases (e.g., Pubmed and EMBASE) were searched, and relevant articles published up to August 2020 were retrieved. Review Manager 5.3 and Stata 12.0 were used for all statistical analyses. Pooled odds ratios, with 95% confidence intervals, and three comparison models were evaluated to analyze the association between RNF213 pR4810K variant and clinical characteristics of MMD patients using a fixed-effects model. RESULTS: A total of 2798 patients with MMD were selected and the effects of the heterozygous or homozygous RNF213 p.R4810K variant on 18 clinical features were identified. There were more patients aged <15 years in the GA and AA groups (AA vs GA: p = 0.009; AA vs GG: p = 0.003; GA vs GG: p = 0.001). Among homozygous patients, the majority experienced MMD onset before the age of 4 years (AA vs. GA: p < 0.00001; AA vs GG: p < 0.00001). The frequency of infarctions and transient ischemic attack was significantly higher in homozygotes and heterozygotes，respectively. However, the frequency of intracerebral/intraventricular hemorrhage was lower in patients with the GA than the GG genotype. More MMD patients with AA and GA genotypes had a family history of the disease (p = 0.003, p < 0.00001, respectively). Posterior cerebral artery involvement was more common in patients with the GA genotype (p < 0.00001). CONCLUSION: The homozygous or heterozygous RNF213 variant may be an efficient biomarker with which to classify different clinical phenotypes of MMD.

Clinical and Genetic Risk Factors of Long-Term Outcomes after Encephaloduroarteriosynangiosis in Moyamoya Disease in China.

OBJECTIVES: This retrospective study was conducted to analyze the associations between ring finger protein 213 p.R4810K variant, clinical features and long-term outcomes in patients with moyamoya disease (MMD) after encephaloduroarteriosynangiosis treatment. MATERIALS AND METHODS: A total of 2,545 patients with MMD in China were included in this study (median of follow-up duration: 32.00 months). Multiple Cox regression models were used to assess the associations between p.R4810K variant, clinical features and long-term outcomes. RESULTS: For all patients, in multivariate Cox analysis, no association was observed between p.R4810K and long-term outcomes. Pediatric onset (HR, 0.38; 95%CI, 0.25-0.59) and headache (HR, 0.26; 95%CI, 0.08-0.83) were inversely and hypertension (HR, 1.43 95%CI, 1.06-1.94), diabetes (HR, 1.55; 95%CI, 1.00-2.40), bilateral lesions (HR, 2.73; 95%CI, 1.12-6.65) and posterior cerebral artery involvement (HR, 1.44; 95%CI, 1.08-1.90) were positively associated with follow-up stroke (all P < 0.05). Pediatric onset (HR, 0.46; 95%CI, 0.26-0.82) was inversely and hyperlipidemia (HR, 1.83; 95%CI, 1.23-2.73), smoking (HR, 1.86; 95%CI, 1.13-3.07), high Suzuki angiographic stage (HR, 1.71, 95%CI, 1.09-2.70), poor admission neurologic status (HR, 8.93; 95%CI, 6.49-12.29) and follow-up stroke (HR, 8.31; 95%CI, 6.01-11.49) were positively associated with poor neurologic outcome at the last follow-up visit (all P < 0.05). The factors were not consistent in the different groups of age at onset. CONCLUSIONS: In our study, p.R4810K may play no role in long-term outcomes in Chinese MMD. Clinical features including age at onset, initial symptoms, risk factors of stroke, imaging, poor admission neurologic status were associated with poor outcomes in MMD after EDAS.

Validation and Extension Study Exploring the Role of RNF213 p.R4810K in 2,877 Chinese Moyamoya Disease Patients.

OBJECTIVE: To validate, update, and extend the role of RNF213 p.R4810K (G>A) for predicting the phenotype of moyamoya disease (MMD) patients and explore the different effects on pediatric and adult groups. METHODS: A total of 2,877 patients conducted from 2004 to 2018 were included. Review Manage 5.3 and SPSS 20.0 were applied to complete all statistical analyses. Information on age at onset, sex, initial symptom, family history and complications were obtained via retrospective chart review. Angiographic records were evaluated. RESULTS: In China, geographic proximity to Korea or Japan may affect the carrying rate of RNF213 p.R4810K. The proportion of patients with the following characteristics was significantly higher (P <0.017) in the GA than in the GG group: female, age at onset < 18 years, infarct after transient ischemic attack, family history of MMD, and posterior cerebral artery involvement. For pediatric patients, GA showed more cerebral hemorrhage (CH) (odds ratios (ORs) [95% confidence intervals (CIs)] = 3.99 (1.61-9.88), P = 0.003), more patients were in the Suzuki early and intermediate stage (P = 0.001; P = 0.001, respectively), while for the adult group, GA indicated more female (OR [95% CIs] = 1.43 [1.15-1.79], P = 0.001), fewer patients with diabetes (0.58 [0.38-0.86], P = 0.007) and intermediate Suzuki stage (P = 3.70 × 10-4). CONCLUSIONS: The incidence and carrying rates of RNF213 p.R4810K in various regions for Chinese MMD patients were obviously different. RNF213 p.R4810K has different predictive effects on phenotypes of pediatric and adult patients.

Association of Genetic Variants With Moyamoya Disease in 13 000 Individuals: A Meta-Analysis.

Background and Purpose- A growing body of evidence indicates genetic components play critical roles in moyamoya disease (MMD). Firm conclusions from studies of this disease have been stymied by small sample sizes and a lack of replicative results. This meta-analysis was conducted to determine whether these genetic polymorphisms are associated with MMD. Methods- PubMed, Google Scholar, Embase, Wanfang, Web of Science, and China National Knowledge Infrastructure databases were used to identify potentially relevant studies published until January 2020. The Review Manager 5.2 and Stata 15.0 software programs were used to perform the statistical analysis. Heterogeneity was assessed using the Cochran Q test and quantified using the I2 test. Results- Four thousand seven hundred eleven MMD cases and 8704 controls in 24 studies were included, evaluating 7 polymorphisms in 6 genes. The fixed-effect odds ratios (95% CI) in allelic model of MMP-2 rs243865 were 0.60 (0.41-0.88) (P=0.008). In the country-based subgroup analysis, the fixed-effect odds ratios (95% CI) of RNF213 rs112735431 in allelic model were China, 39.74 (26.63-59.31), Japan, 74.65 (42.79-130.24) and Korea, 50.04 (28.83-86.88; all P<0.00001). In the sensitivity analysis, the fixed-effect odds ratios (95% CI) of allelic and dominant models were the RNF213 rs148731719 variant, 2.17 (1.36-3.48; P=0.001), 2.20 (1.35-3.61; P=0.002), the TIMP-2 rs8179090 variant, 0.33 (0.25-0.43; P<0.00001), 0.88 (0.65-1.21; P=0.440) and the MMP-3 rs3025058 variant, 0.61 (0.47-0.79; P=0.0002), 0.55 (0.41-0.75; P=0.0001), respectively. Conclusions- RNF213 rs112735431 and rs148731719 were positively, and TIMP-2 rs8179090, MMP-2 rs243865, and MMP-3 rs3025058 were inversely associated with MMD using multiple pathophysiologic pathways. Studies in larger population should be conducted to clarify whether and how these variants are associated with MMD.

Effects of TNF-α-308G/A Polymorphism on the Risk of Diabetic Nephropathy and Diabetic Retinopathy: An Updated Meta-Analysis.

Diabetic nephropathy (DN) and diabetic retinopathy (DR) are the major factors of morbidity and mortality in the patients with diabetes mellitus (DM). Growing studies have investigated the relationship between the TNF-α-308G/A polymorphism and the susceptibility to DN and DR, without achieving consensus. Thus, we conducted this meta-analysis to reach more comprehensive conclusions for these issues. Eligible studies were retrieved through electronic databases such as PubMed, Embase, Web of Science and China National Knowledge Infrastructure. Summary of odds ratios (OR) and 95% confidence intervals (CIs) were generated to evaluate the intensity of the associations. Statistical analyses were performed by STATA 11.0 and RevMan 5.2. There are fourteen eligible publications involving nineteen studies in this meta-analysis. TNF-α-308G/A polymorphism was significantly related to increasing risk of DN under recessive model (OR=1.37, 95% CI=1.03-1.83) and homozygous model (OR=1.54, 95% CI=1.15-2.06). Moreover, the similar results were also obtained in Asian groups for DN (recessive: OR=1.69, 95% CI=1.18-2.42; homozygous: OR=1.99, 95% CI=1.38-2.86; respectively), and significant association was also detected between TNF-α-308G/A and DN susceptibility in type 2 DM in recessive model (OR=1.39, 95% CI=1.02-1.89). No significant association was observed between TNF-α-308G/A and DR susceptibility in total analyses and subgroup analyses by ethnicity and type of DM. TNF-α-308G/A polymorphism may enhance the susceptibility to diabetic nephropathy, especially in Asian population and in T2DM patients, but not diabetic retinopathy.

Association of MTHFR gene polymorphisms with pancreatic cancer: meta-analysis of 17 case-control studies.

BACKGROUND: Pancreatic cancer (PC) is a seriously malignant tumor with a low 5-year survival rate. The relationship between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and PC has been reported by several studies. However, the results were controversial. Thus, we conducted a meta-analysis to summarize available data on MTHFR gene and PC. METHODS: We searched PubMed, Embase, Web of Science, Wanfang, CNKI databases prior to July 2019. Data were analyzed by RevMan 5.3 and STATA 12.0 software. Odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the strength of the association. Subgroup analysis, sensitivity analysis and assessment of publication bias were performed in this study. RESULTS: Ten articles with 17 reports (10 for C677T, 7 for A1298C) were eligible for inclusion in the meta-analysis (1864 cases and 3165 controls for C677T, and 1488 cases and 1946 controls for A1298C). Our meta-analysis detected that C677T was associated with PC for three genetic models (allele model: OR = 1.24, 95% CI: 1.00-1.53, P = 0.047; recessive model: OR = 1.39, 95% CI: 1.04-1.86, P = 0.027; homozygous model: OR = 1.60, 95% CI: 1.04-2.45, P = 0.034). In the stratified analyses according to ethnicity, source of controls and genotyping method, significant association was observed in genotyping method subgroup. For the A1298C polymorphism, no significant association was observed either in overall analysis or in subgroup analysis under all genetic models. CONCLUSIONS: MTHFR gene C677T rather than A1298C polymorphism may be associated with PC. Larger sample size studies should be performed to find the association between MTHFR gene and PC.

RNF213 p.R4810K Polymorphism and the Risk of Moyamoya Disease, Intracranial Major Artery Stenosis/Occlusion, and Quasi-Moyamoya Disease: A Meta-Analysis.

BACKGROUND: Accumulating studies have reported that there is an association between the Ring finger protein 213 (RNF213) p.R4810K (rs112735431, c.14576G>A) single nucleotide polymorphism and the predisposition of moyamoya disease (MMD), intracranial major artery stenosis/occlusion (ICASO), quasi-moyamoya disease (quasi-MMD), and other vascular diseases. However, to this day, analyses about this association have remained scarce in the literature. We attempted to conduct a meta-analysis to systematically summarize and clarify the issue. METHODS: Electronic databases dated up to January 2018 were searched, retrieved, and used. Revman 5.2 software and STATA version 12.0 were used for statistical analysis. The association between RNF213 p.R4810K and MMD, ICASO, and quasi-MMD were assessed by odds ratios and 95% confidence intervals using fixed effects models. Between-study heterogeneity was evaluated by I-squared (I2) statistics and sensitivity analysis was performed by omitting 1 study at a time. A funnel plot and Begg's test were used to assess the potential publication bias. RESULTS: The outcomes showed a statistically significant association between RNF213 p.R4810K and MMD, ICASO, and quasi-MMD, especially in the dominant model. Apart from the first 2 diseases, no significant association was identified under the recessive, the homozygote, and the heterozygote models in ICASO. CONCLUSIONS: RNF213 p.R4810K was associated with MMD, ICASO, and quasi-MMD in different genetic models. Subgroup analysis indicated highly significantly higher risk in the Japanese patients. However, further well-designed studies with larger sample size and comprehensive data are needed to confirm our findings and provide a profound conclusion.

A Meta-Analysis of the Association between Microrna-196A2 and Risk of Ischemic Stroke and Coronary Artery Disease in Asian Population.

OBJECT: Single nucleotide polymorphisms (SNPs) of small non-coding RNAs (sncRNAs) that affect the sncRNA function and target gene expression to mediate the risk of certain diseases. The association between the miR-196a2 rs11614913 and ischemic stroke (IS) and coronary artery disease (CAD) is still conflicting and inconclusive. This meta-analysis aimed at analysing studies which have been done so far to get a more precise assessment of the association between the mutation and these two diseases. METHODS: Electronic databases dated up to April 2018 were searched, retrieved and used. Revman 5.2 software and STATA version 12.0 were used for statistical analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to identify any potential associations. Heterogeneity, publication bias and sensitivity analysis were conducted to measure the robustness of our findings. RESULTS: The overall meta-analysis results showed that miR-196a2 rs11614913 T > C polymorphism was significantly associated with CAD risk in certain genetic models, as well as in subgroup analysis (CC versus TT, OR = .43, 95%CI = .39-.47, P < .00001). However, no significant association was detected between the miR-196a2 rs11614913 T > C and IS risk in all genetic models. CONCLUSIONS: Our study suggests that miR-196a2 rs11614913 T > C may contribute to CAD susceptibility but further well-designed studies with larger sample size and comprehensive data are needed to confirm our findings and provide a profound conclusion.

Expansion of intronic GGCCTG hexanucleotide repeat in NOP56 causes SCA36, a type of spinocerebellar ataxia accompanied by motor neuron involvement.

Autosomal-dominant spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative disorders. In this study, we performed genetic analysis of a unique form of SCA (SCA36) that is accompanied by motor neuron involvement. Genome-wide linkage analysis and subsequent fine mapping for three unrelated Japanese families in a cohort of SCA cases, in whom molecular diagnosis had never been performed, mapped the disease locus to the region of a 1.8 Mb stretch (LOD score of 4.60) on 20p13 (D20S906-D20S193) harboring 37 genes with definitive open reading frames. We sequenced 33 of these and observed a large expansion of an intronic GGCCTG hexanucleotide repeat in NOP56 and an unregistered missense variant (Phe265Leu) in C20orf194, but we found no mutations in PDYN and TGM6. The expansion showed complete segregation with the SCA phenotype in family studies, whereas Phe265Leu in C20orf194 did not. Screening of the expansions in the SCA cohort cases revealed four additional occurrences, but none were revealed in the cohort of 27 Alzheimer disease cases, 154 amyotrophic lateral sclerosis cases, or 300 controls. In total, nine unrelated cases were found in 251 cohort SCA patients (3.6%). A founder haplotype was confirmed in these cases. RNA foci formation was detected in lymphoblastoid cells from affected subjects by fluorescence in situ hybridization. Double staining and gel-shift assay showed that (GGCCUG)n binds the RNA-binding protein SRSF2 but that (CUG)(6) does not. In addition, transcription of MIR1292, a neighboring miRNA, was significantly decreased in lymphoblastoid cells of SCA patients. Our finding suggests that SCA36 is caused by hexanucleotide repeat expansions through RNA gain of function.

A novel antibacterial strategy for targeting the bacterial methionine biosynthesis pathway.

Bacterial pathogens reprogramme their metabolic networks to support growth and establish infection at specific sites. Bacterial central metabolism has been considered attractive for developing antimicrobial drugs; however, most metabolic enzymes are conserved between humans and bacteria. This study found that blockade of methionine biosynthesis in Citrobacter rodentium and Salmonella enteritidis inhibited bacterial growth and activity of the type III secretion system, resulting in severe defects in colonization and pathogenicity. In addition, α-methyl-methionine was found to inhibit the activity of methionine biosynthetic enzyme MetA, and consequently reduce the virulence and pathogenicity of enteric pathogens. These findings highlight the crucial role of methionine in bacterial virulence, and describe a potential new drug target.

Ablation of Rnf213 retards progression of diabetes in the Akita mouse.

Moyamoya disease (MMD) and moyamoya syndrome are vasculopathies characterized by progressive stenosis in the circle of Willis and its branches. The RNF213 gene, which encodes a novel class of proteins, characterized by both E3 ligase and AAA+ATPase activities, has been identified as the susceptibility gene for MMD. However, its physiological functions remain unknown. MMD and moyamoya syndrome are often accompanied by diabetes mellitus. In this study, we generated Rnf213 knockout (KO) C57BL/6 mice (Rnf213(-/-); Ins2(+/+)), which were mated with Akita (C57BL/6 Rnf213(+/+); Ins2(+/C96Y)) mice, a strain that develops diabetes spontaneously by 5 weeks of age, to obtain mice lacking Rnf213 and carrying the Akita mutation (KO/Akita, Rnf213(-/-); Ins2(+/C96Y)). Body weight and blood glucose concentration were measured from 6 to 20 weeks. Glucose tolerance, insulin resistance, plasma insulin and leptin concentrations, food consumption, pancreatic insulin content and histopathology were evaluated at 18 weeks of age. We found that glucose tolerance, as indicated by AUC, was 20% lower (p<0.05) and insulin contents in pancreas were 150% higher (p<0.05), in KO/Akita than in Akita mice. The number of CHOP positive ß-cells assayed by histopathological examination was 30% lower and food consumption was 34% lower in KO/Akita than in Akita mice (p<0.05 each). These findings indicated that the disruption of Rnf213 improved glucose tolerance by protecting islet ß cells.

Combined linkage analysis and exome sequencing identifies novel genes for familial goiter.

Familial goiter is a genetic disease showing heterogeneous expression. To identify causative genes, we investigated three multigenerational goiter families with an autosomal dominant inheritance pattern. We performed genome-wide linkage analysis on all the families, combined with whole-exome sequencing in two affected individuals from each family. For linkage analysis, we considered loci with logarithm of odds (LOD) scores >1.5 as candidate regions for identification of rare variants. In one of the families, we found two rare heterozygous missense variants, p.V56M in RGS12 and p.G37D in GRPEL1, which segregate with goiter and are both located within the same haplotype on 4p16. This haplotype was not observed in 150 controls. In the other two families, we identified two additional rare missense variants segregating with goiter, p.A551T in CLIC6 on 21q22.12 and p.V412A in WFS1 on 4p16. In controls, the minor allele frequency (MAF) of p.V412A in WFS1 was 0.017 while p.A551T in CLIC6 was not detected. All identified genes (RGS12, GRPEL1, CLIC6 and WFS1) show expression in the human thyroid gland, suggesting that they may play a role in thyroid gland function. Moreover, these four genes are novel with regard to their involvement in familial goiter, supporting genetic heterogeneity of this disease.

Levels of urinary isoflavones and lignan polyphenols in Japanese women.

OBJECTIVES: High consumption of soybean products has been associated with a reduced risk of hormone-sensitive tumors. Soybean products contain phytoestrogens, such as daidzein, and sesame seeds contain secoisolariciresinol. These compounds are further metabolized to equol, enterodiol, and enterolactone by intestinal bacteria. However, individual differences in the metabolizing potential remain unclear. The aim of this study was to evaluate the urinary daidzein, equol, enterodiol, and enterolactone concentrations in women from several different regions of Japan according to age group. METHODS: Five hundred urine samples collected from Japanese women living in Sapporo, Sendai, Kyoto, Kochi, and Naha were analyzed for daidzein, equol, enterodiol, and enterolactone concentration by gas chromatography-mass spectrometry. RESULTS: The urinary isoflavone and lignan polyphenol levels did not differ significantly among the sampling sites, except for daidzein, which was highest in urine collected at Naha. The prevalence of equol producers was 39 % in the total study cohort. In equol producers, a positive correlation was observed between the urinary daidzein and equol levels (r = 0.399, p < 0.001). However, there was no significant difference between daidzein concentrations in equol producers and non-producers. Moreover, the levels of enterodiol and enterolactone were higher in equol producers than in equol non-producers. In the multivariate logistic analyses, two factors, Sendai dwelling and current smoking, were found to be significant [equol producers to non-producers: odds ratio 2.15 (95 % confidence interval: 1.17-4.02) and odds ratio 0.32 (0.15-0.63), respectively]. CONCLUSIONS: Our data suggest that geographic factors and smoking status should be considered during the evaluation of equol in urine samples and that the same pathway may be responsible for the metabolism of both isoflavones and lignan polyphenols.

P.R4810K, a polymorphism of RNF213, the susceptibility gene for moyamoya disease, is associated with blood pressure.

BACKGROUND: Moyamoya disease-an idiopathic vascular disorder of intracranial arteries-is often accompanied by hypertension. RNF213 has been identified as a susceptibility gene for moyamoya disease. In the present study, the association of p.R4810K (G>A) with blood pressure (BP) was investigated in a Japanese population. METHODOLOGY/PRINCIPAL FINDINGS: Three independent study populations, the Nyukawa (n = 984), Noshiro (n = 2,443) and Field (n = 881) studies, joined this study. BP, body weight and height were measured. Past and present symptoms and disease and medication histories were assessed by interview. Associations of p.R4810K (rs112735431, ss179362673) of RNF213 with BP were investigated. Two linkage disequilibrium blocks were constructed for moyamoya patients with p.R4810K (n = 140) and the general population (n = 384) using 39 single nucleotide polymorphisms (SNPs) spanning 390 kb around RNF213. A total of 60 carriers (3 for AA genotype and 57 for GA genotype) were found in these samples, and the minor allele frequencies were 1.4 % in the Nyukawa and Field studies and 0.2 % in the Noshiro study. Regression analyses adjusted for age, sex and body mass index based on an additive model demonstrated significant associations with systolic BP (mmHg/allele): ß (standard error) was 8.2 (2.9) in the Nyukawa study (P = 4.7 × 10(-3)), 18.7 (5.4) in the Noshiro study (P = 4.6 × 10(-4)) and 8.9 (2.0) (P = 1.0 × 10(-5)) in the three populations. In contrast, diastolic BP showed significant associations only in the Noshiro study. Linkage disequilibrium blocks contained none of the BP-associated proxy SNPs reported by previous studies. CONCLUSIONS/SIGNIFICANCE: Our study suggests that p.R4810K of RNF213 is associated strongly with systolic BP.

Moyamoya disease: diagnosis and interventions.

Moyamoya disease is a rare cause of stroke, radiologically characterised by progressive stenosis of the terminal portion of the internal carotid arteries and compensatory capillary collaterals. The discovery that RNF213, which encodes an unconventional E3 ubiquitin ligase, is the major susceptibility gene for moyamoya disease in people from east Asia has opened new avenues for investigation into the mechanisms of disease and potential treatment targets. The Arg4810Lys variant of the gene is most strongly associated with moyamoya disease, but the penetrance is lower than 1%, suggesting a synergistic relationship with additional environmental and genetic risk factors. White people carry less common non-Arg4810Lys variants of RNF213, which partly explains the lower prevalence of moyamoya disease in European countries and in the USA than in east Asian countries. Several monogenic moyamoya syndromes possess the radiological characteristics of moyamoya disease and have been associated with multiple genes and pathways involved in moyamoya angiopathy pathogenesis. Further clarification of the genetic and environmental factors that contribute to the emergence of moyamoya angiopathy could enable development of new treatment strategies for moyamoya disease.

Predictive role of modifiable factors in stroke: an umbrella review.

BACKGROUND: A growing number of meta-analyses reviewed the existing associations between modifiable factors and stroke. However, the methodological quality of them and quality of evidence remain to be assessed by validated tools. Thus, this umbrella review was conducted to consolidate evidence from systematic reviews and meta-analyses of cohort studies investigating the association between modifiable factors and incidence of stroke. METHODS: PubMed, Web of Science, Embase, Wanfang and China National Knowledge Infrastructure databases for systematic reviews and meta-analyses of cohort studies from inception until March 2021. Assess the methodological quality of systematic reviews 2 was used to evaluate the methodological quality of each included published meta-analysis. Excess significance test was used to investigate whether the observed number of studies (O) with nominally significant results ('positive' studies, p<0.05) was larger than the expected number of significant results (E). Statistically significant (p<0.05) associations were rated into five levels (strong, highly suggestive, suggestive, weak and no) using specific criteria. Sensitivity analyses were performed. RESULTS: 2478 records were identified through database searching. At last, 49 meta-analyses including 70 modifiable factors and approximately 856 801 stroke cases were included in the present review. The methodological quality of three meta-analyses was low, while others were critically low. Evidence of walking pace was strong. High suggestive evidence mainly included total meat, processes meat, chocolate, sodium, obesity, pulse pressure, systolic blood pressure, diastolic blood pressure, sleep duration and smoking. Suggestive evidence mainly included dietary approaches to stop hypertension (DASH) diet, vitamin C, magnesium, depression and particulate matter 2.5. After sensitivity analyses, evidence of DASH diet, magnesium and depression turned to weak. No publication bias existed, except only one study which could be explained by reporting bias. DISCUSSION: Diet with rich macronutrients and micronutrients, healthy dietary patterns and favourable physical, emotional health and environmental management should be promoted to decrease the burden of stroke. PROSPERO REGISTRATION NUMBER: CRD42021249921.

Confirmation of an association of single-nucleotide polymorphism rs1333040 on 9p21 with familial and sporadic intracranial aneurysms in Japanese patients.

BACKGROUND AND PURPOSE: Genetic factors are important determinants of intracranial aneurysm (IA). Recently, a multinational, genome-wide association study identified 3 loci associated with IA, located on 2q (rs700651), 8q (rs10958409), and 9p (rs1333040 and rs10757278). The aim of this study was to evaluate these associations. METHODS: Familial and sporadic cases were investigated. Familial cases, consisting of 96 subjects with IA, and 46 subjects of unknown status from 31 pedigrees were analyzed with the transmission disequilibrium test and linkage analysis. Associations of single-nucleotide polymorphisms (SNPs) with IA were tested in 419 sporadic IA cases and in 408 control subjects. Sequencing of CDKN2A, CDKN2B, and CDKN2BAS revealed additional SNPs, and their associations with IA were also tested. RESULTS: The transmission disequilibrium test revealed associations of 2 SNPs, rs700651 (P=0.036) and rs1333040 (P=0.002), with familial IA. Analysis of SNPs in sporadic cases revealed an allelic association of rs1333040 with IA (odds ratio=1.28; 95% CI, 1.04-1.57; P=0.02) but failed to show associations of rs10757278 and rs496892 with IA. We sequenced 3 candidate genes; CDKN2A, CDKN2B, and CDKN2BAS. All 6 index cases from IA families had the rs1333040-T allele and SNPs (rs10965215, rs10120688, and rs7341791) in CDKN2BAS. None of these SNPs had linkage disequilibrium with rs1333040 and was associated with IA. CONCLUSIONS: A region between introns 7 and 15 of CDKN2BAS carrying the rs1333040-T allele may confer risk for IA.

Developmental iodine deficiency and hypothyroidism impair neural development in rat hippocampus: involvement of doublecortin and NCAM-180.

BACKGROUND: Developmental iodine deficiency results in inadequate thyroid hormone (TH), which damages the hippocampus. Here, we explored the roles of hippocampal doublecortin and neural cell adhesion molecule (NCAM)-180 in developmental iodine deficiency and hypothyroidism. METHODS: Two developmental rat models were established with either an iodine-deficient diet, or propylthiouracil (PTU)-adulterated water (5 ppm or 15 ppm) to impair thyroid function, in pregnant rats from gestational day 6 until postnatal day (PN) 28. Silver-stained neurons and protein levels of doublecortin and NCAM-180 in several hippocampal subregions were assessed on PN14, PN21, PN28, and PN42. RESULTS: The results show that nerve fibers in iodine-deficient and 15 ppm PTU-treated rats were injured on PN28 and PN42. Downregulation of doublecortin and upregulation of NCAM-180 were observed in iodine-deficient and 15 ppm PTU-treated rats from PN14 on. These alterations were irreversible by the restoration of serum TH concentrations on PN42. CONCLUSION: Developmental iodine deficiency and hypothyroidism impair the expression of doublecortin and NCAM-180, leading to nerve fiber malfunction and thus impairments in hippocampal development.