Alcohol consumption is associated with glaucoma severity regardless of ALDH2 polymorphism.
ABSTRACT: The present study investigated the effect of aldehyde dehydrogenase2 (ALDH2) rs671 polymorphism and alcohol consumption on the severity of primary open-angle glaucoma (POAG). The questionnaire for alcohol consumption pattern and targeted genotyping for ALDH2 rs671 polymorphism was performed from 445 Korean POAG patients. Retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GCIPL) thicknesses were measured and compared according to alcohol consumption and ALDH2 rs671 genotype. Heavy drinking group eyes had thinner RNFL thickness than did abstinence group eyes (65.0?±?10.9 vs. 70.9?±?11.5 µm, P?=?0.023). Both mild (65.8?±?9.6 µm) and heavy (63.8?±?8.4 µm) drinking group eyes had significantly thinner macular GCIPL thickness than did abstinence group eyes (68.1?±?8.2 µm, P?=?0.003). However, ALDH2 rs671 polymorphism did not show any significant association with RNFL or GCIPL thickness. Alcohol consumption was significantly associated with GCIPL thinning (??=?-0.446, P?=?0.035) after adjustment for multiple confounding factors. As excessive alcohol consumption was significantly associated with thinner GCIPL thickness while ALDH2 polymorphism had no significant effect on RNFL or GCIPL thickness, glaucoma patients should avoid excessive alcohol consumption regardless of ALDH2 polymorphism.
Project description:BACKGROUND:Limited prospective information exists regarding spectral-domain optical coherence tomography (SD-OCT) in secondary progressive multiple sclerosis (SPMS). OBJECTIVE:Document cross-sectional and longitudinal retinal nerve fiber layer (RNFL) and macular ganglion cell plus inner plexiform layer (GCIPL) features of an SPMS clinical trial cohort. METHODS:Prospective, observational study using a 2-year randomized placebo-controlled SPMS trial cohort with yearly SD-OCT testing. Post hoc analysis determined influences of optic neuritis (ON), disease duration, and baseline SD-OCT on annualized atrophy rates and on correlations between OCT and brain atrophy. RESULTS:Mean RNFL and GCIPL values of patients ( n = 47, mean age = 59 years, mean disease duration = 30 years) were significantly lower among eyes with prior ON than those without (no history of ON (NON)). Annualized RNFL (-0.31 µm/year) and GCIPL (-0.29 µm/year) atrophy rates did not differ between ON and NON eyes. Baseline RNFL thickness >75 µm was associated with greater annualized RNFL atrophy (-0.85 µm/year). Neither RNFL nor GCIPL atrophy correlated with whole-brain atrophy. CONCLUSION:This study suggests that eyes with and without ON history may be pooled for atrophy analysis in SPMS clinical trials using SD-OCT. Low baseline RNFL, small retinal atrophy rates, and lack of correlation with whole-brain atrophy in this population are important trial design considerations.
Project description:The associations between genetic polymorphisms in ADH1B (rs1229984) and ALDH2 (rs671), alcohol consumption, the effect of a combination of the two polymorphisms, and breast cancer risk were studied in a population of East-Asian women. In this study, 623 breast cancer cases and 1845 controls, aged 40 or above, were included. The association between ALDH2 polymorphism and breast cancer risk was validated in 2143 breast cancer cases and 3977 controls. Alcohol consumption increased the risk of breast cancer regardless of ADH1B and ALDH2 genotypes. The rs671 polymorphism of ALDH2 was independently associated with increased breast cancer risk (OR?=?1.27, 95% CI?=?1.02-1.58 per increment of A). The ADH1B rs1229984 polymorphism, and combined effects of the rs671 and rs1229984 polymorphisms, did not reveal any significant association with breast cancer. Stratification by menopausal status revealed that rs671 gene polymorphisms were significantly associated with breast cancer only in postmenopausal women (OR?=?1.45, 95% CI?=?1.03-2.05 per increment of A). This is the first study to demonstrate an independent association between ALDH2 gene variants and breast cancer in Asian women. Further studies are warranted to further elucidate the etiology of breast cancer as it relates to alcohol consumption in Asian women.
Project description:BACKGROUND/AIMS:To investigate the patterns of retinal ganglion cell damage at different stages of glaucoma, using the circumpapillary retinal nerve fiber layer (RNFL) and macula ganglion cell-inner plexiform layer (GCIPL) thicknesses. METHODS:In 296 eyes of 296 glaucoma patients and 55 eyes of 55 healthy controls, the correlations of mean deviation (MD) with the superior and inferior quadrant RNFL/GCIPL thickness (defined as the average of three superior and inferior sectors, resp.) were analyzed. RESULTS:In early to moderate glaucoma, most of the RNFL/GCIPL thicknesses had significant positive correlations with the MD. In advanced glaucoma, the superior GCIPL thickness showed the highest correlation with MD (r = 0.495), followed by the superior RNFL (r = 0.452) (all; P < 0.05). The correlation coefficient of the inferior RNFL thickness with MD (r < 0.471) was significantly stronger in early to moderate glaucoma compared to that in advanced glaucoma (r = 0.192; P < 0.001). In contrast, the correlations of the superior GCIPL thickness with MD (r = 0.452) in advanced glaucoma was significantly stronger compared to that in early to moderate glaucoma (r = 0.159; P < 0.001). CONCLUSIONS:The most preserved region in advanced glaucoma appears to be the superior macular GCIPL, whereas the most vulnerable region for initial glaucoma is the inferior RNFL around the optic disc.
Project description:The aldehyde dehydrogenase 2 (ALDH2) polymorphism rs671 (Glu504Lys) causes ALDH2 inactivation and adverse acetaldehyde exposure among Asians, but little is known of the association between alcohol consumption and rs671 and ovarian cancer (OvCa) in Asians. We conducted a pooled analysis of Asian ancestry participants in the Ovarian Cancer Association Consortium. We included seven case-control studies and one cohort study comprising 460 invasive OvCa cases, 37 borderline mucinous OvCa and 1274 controls of Asian descent with information on recent alcohol consumption. Pooled odds ratios (OR) with 95% confidence intervals (CI) for OvCa risk associated with alcohol consumption, rs671 and their interaction were estimated using logistic regression models adjusted for potential confounders. No significant association was observed for daily alcohol intake with invasive OvCa (OR comparing any consumption to none = 0.83; 95% CI = 0.58-1.18) or with individual histotypes. A significant decreased risk was seen for carriers of one or both Lys alleles of rs671 for invasive mucinous OvCa (OR = 0.44; 95% CI = 0.20-0.97) and for invasive and borderline mucinous tumors combined (OR = 0.48; 95% CI = 0.26-0.89). No significant interaction was observed between alcohol consumption and rs671 genotypes. In conclusion, self-reported alcohol consumption at the quantities estimated was not associated with OvCa risk among Asians. Because the rs671 Lys allele causes ALDH2 inactivation leading to increased acetaldehyde exposure, the observed inverse genetic association with mucinous ovarian cancer is inferred to mean that alcohol intake may be a risk factor for this histotype. This association will require replication in a larger sample.
Project description:This study aimed to develop and validate a deep learning system for diagnosing glaucoma using optical coherence tomography (OCT). A training set of 1822 eyes (332 control, 1490 glaucoma) with 7288 OCT images, an internal validation set of 425 eyes (104 control, 321 glaucoma) with 1700 images, and an external validation set of 355 eyes (108 control, 247 glaucoma) with 1420 images were included. Deviation and thickness maps of retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GCIPL) analyses were used to develop the deep learning system for glaucoma diagnosis based on the visual geometry group deep convolutional neural network (VGG-19) model. The diagnostic abilities of deep learning models using different OCT maps were evaluated, and the best model was compared with the diagnostic results produced by two glaucoma specialists. The glaucoma-diagnostic ability was highest when the deep learning system used the RNFL thickness map alone (area under the receiver operating characteristic curve (AUROC) 0.987), followed by the RNFL deviation map (AUROC 0.974), the GCIPL thickness map (AUROC 0.966), and the GCIPL deviation map (AUROC 0.903). Among combination sets, use of the RNFL and GCIPL deviation map showed the highest diagnostic ability, showing similar results when tested via an external validation dataset. The inclusion of the axial length did not significantly affect the diagnostic performance of the deep learning system. The location of glaucomatous damage showed generally high level of agreement between the heatmap and the diagnosis of glaucoma specialists, with 90.0% agreement when using the RNFL thickness map and 88.0% when using the GCIPL thickness map. In conclusion, our deep learning system showed high glaucoma-diagnostic abilities using OCT thickness and deviation maps. It also showed detection patterns similar to those of glaucoma specialists, showing promising results for future clinical application as an interpretable computer-aided diagnosis.
Project description:Alcohol consumption is a serious health issue in Korea in terms of the amount consumed and the behavior related to its consumption. Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme in alcohol metabolism that degrades acetaldehyde to nontoxic acetic acid. The enzyme is coded by the ALDH2 gene, which is commonly polymorphic in East Asian populations. A point mutation in the ALDH2 gene (the rs671 allele) yields an inactive form of ALDH2 that causes acetaldehyde accumulation in the body after alcohol consumption, thereby inhibiting normal alcohol metabolism. Individuals who are homozygous for polymorphism in ALDH2 tend to refrain from drinking alcohol, decreasing their chances of developing alcoholism and exposure to the associated risks. Mendelian randomization (MR) studies have demonstrated that alcohol consumption predicted by ALDH2 genotype is causally related to cardiovascular risks. Moreover, recent MR studies suggest that the ALDH2 variant has mechanistic effects on some disease outcomes or mortality through increased blood levels of acetaldehyde, showing differences therein between heterozygotes (ALDH2*2*2) and homozygotes (ALDH2*1*2) in those who consume alcohol. Accordingly, consideration of ALDH2 genotype in alcohol prevention programs is warranted. In conclusion, strategies that incorporate genetic information and provide an evidential basis from which to help people make informed decisions on alcohol consumption are urgently required.
Project description:The purpose of this study was to examine whether application of optical coherence tomography (OCT) measurements can provide a useful biomarker for distinguishing central nervous system (CNS) involvement in autoimmune connective tissue diseases (CTD) from multiple sclerosis (MS). An observational study included non-optic neuritis eyes of 121 individuals: 59 patients with MS, 30 patients with CNS involvement in CTD, and 32 healthy controls. OCT examination was performed in all subjects to measure retinal nerve fiber layer (RNFL) thickness, ganglion cell complex (GCC) thickness, ganglion cell layer-inner plexiform layer (GCIPL) thickness, and volume of the macula. There was a significant group effect with regard to superior optic disc RNFL, macular RNFL, GCC, and GCIPL thickness, and macular volume. Post-hoc analysis revealed that MS patients have significantly smaller macular volume and thinner superior optic disc RNFL, macular RNFL, GCC, and GCIPL compared to healthy controls. CTD patients have significantly smaller superior optic disc RNFL, GCIPL, and GCC thickness compared to healthy controls. However, no significant group differences were observed between the patient groups (MS vs. CTD) on any outcome. Although a prominent retinal thinning may be a useful biomarker in MS patients, in a general population of individuals with a confirmed CNS involvement the use of OCT is not specific enough to discriminate between MS and autoimmune CTD.
Project description:To evaluate the changes of retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), and ganglion cell-inner plexiform layer (GCIPL) thicknesses and compare structure-function relationships of 4 retinal layers using spectral-domain optical coherence tomography (SD-OCT) in macular region of glaucoma patients.In cross-sectional study, a total of 85 eyes with pre-perimetric to advanced glaucoma and 26 normal controls were enrolled. The glaucomatous eyes were subdivided into three groups according to the severity of visual field defect: a preperimetric glaucoma group, an early glaucoma group, and a moderate to advanced glaucoma group. RNFL, GCL, IPL, and GCIPL thicknesses were measured at the level of the macula by the Spectralis (Heidelberg Engineering, Heidelberg, Germany) SD-OCT with automated segmentation software. For functional evaluation, corresponding mean sensitivity (MS) values were measured using 24-2 standard automated perimetry (SAP).RNFL, GCL, IPL, and GCIPL thicknesses were significantly different among 4 groups (P < .001). Macular structure losses were positively correlated with the MS values of the 24-2 SAP for RNFL, GCL, IPL, and GCIPL (R = 0.553, 0.636, 0.648 and 0.646, respectively, P < .001). In regression analysis, IPL and GCIPL thicknesses showed stronger association with the corresponding MS values of 24-2 SAP compared with RNFL and GCL thicknesses (R2 = 0.420, P < .001 for IPL; R2 = 0.417, P< .001 for GCIPL thickness).Segmented IPL thickness was significantly associated with the degree of glaucoma. Segmental analysis of the inner retinal layer including the IPL in macular region may provide valuable information for evaluating glaucoma.
Project description:Existing evidence remains inconclusive as to how the association between inactive ALDH2 and esophageal cancer (EC) depends on alcohol consumption. The study is based on the China Kadoorie Biobank cohort, with 10 years follow-up of 0.5 million adults aged 30-79 years. ALDH2 activity was assessed by both self-reported flushing response and Glu504Lys (rs671 G?>?A) polymorphism. Among both male and female participants who consumed alcohol less than weekly (n?=?69,519; 211 EC cases), low active or inactive ALDH2 was not associated with increased EC risk [HRs (95% CIs): GA vs. GG 0.75 (0.54, 1.04); AA vs. GG 1.01 (0.46, 2.20)]. Among male weekly alcohol consumers, both flushing response [n?=?59,380; 501 EC cases; HRs (95% CIs): "soon after drinking" vs. "no" flushing response 1.45 (1.05, 2.01)] and rs671 [n?=?10,692; 94 EC cases; GA vs. GG 3.31 (1.94, 5.67)] were associated with EC risk. The increased EC risk associated with "soon" response or rs671 GA was apparent in men consuming alcohol ?30g/d. Among male daily consumers, the HRs (95% CIs) for EC associated with 15g/d of alcohol were 1.28 (1.15, 1.44) for "soon" response [vs. other responses: 1.12 (1.09, 1.15); pinteraction ?=?0.047; n?=?36,401, 425 EC cases] and 1.41 (1.08, 1.82) for rs671 GA [vs. GG: 1.16 (1.06, 1.27); pinteraction ?=?0.493; n?=?6,607, 80 EC cases]. Self-reported flushing response had low sensitivity (56.8%) and high specificity (88.4%) in identifying rs671 A allele among male weekly alcohol consumers. In conclusion, low-activity ALDH2 was associated with increased EC risk among male heavy alcohol consumers. More accurate measurement of alcohol-related EC risk allows better achievement of precision prevention.
Project description:Acetaldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme detoxifying acetaldehyde and endogenous lipid aldehydes; previous studies suggest a protective role of ALDH2 against cardiovascular disease (CVD). Around 40% of East Asians carrying the single nucleotide polymorphism (SNP) ALDH2 rs671 have an increased incidence of CVD. However, the role of ALDH2 in CVD beyond alcohol consumption remains poorly defined. Here we report that ALDH2/LDLR double knockout (DKO) mice have decreased atherosclerosis compared with LDLR-KO mice, whereas ALDH2/APOE-DKO mice have increased atherosclerosis, suggesting an unexpected interaction of ALDH2 with LDLR. Further studies demonstrate that in the absence of LDLR, AMPK phosphorylates ALDH2 at threonine 356 and enables its nuclear translocation. Nuclear ALDH2 interacts with HDAC3 and represses transcription of a lysosomal proton pump protein ATP6V0E2, critical for maintaining lysosomal function, autophagy, and degradation of oxidized low-density lipid protein. Interestingly, an interaction of cytosolic LDLR C-terminus with AMPK blocks ALDH2 phosphorylation and subsequent nuclear translocation, whereas ALDH2 rs671 mutant in human macrophages attenuates this interaction, which releases ALDH2 to the nucleus to suppress ATP6V0E2 expression, resulting in increased foam cells due to impaired lysosomal function. Our studies reveal a novel role of ALDH2 and LDLR in atherosclerosis and provide a molecular mechanism by which ALDH2 rs671 SNP increases CVD.