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1.
Outcomes of Japanese patients with non-alcoholic fatty liver disease according to genetic background and lifestyle-related diseases.
Kogiso, T, Sagawa, T, Kodama, K, Taniai, M, Hashimoto, E, Tokushige, K
Annals of hepatology. 2021;:100260
Abstract
INTRODUCTION AND OBJECTIVES Genetic background may be involved in the mechanisms of liver injury and the development of non-alcoholic fatty liver disease (NAFLD). However, its contributions to the long-term outcome of NAFLD have been unclear. METHODS We enrolled 314 Japanese patients with biopsy-confirmed NAFLD from 2000 to 2018 (161 men [51.3%]; median age, 53 [14-84] years; 114 with advanced fibrosis [37.5%]) in the patients without hepatocellular carcinoma at diagnosis. Genomic DNA was extracted from peripheral blood and single nucleotide polymorphisms (SNPs) were analyzed. Associations of mortality with patatin-like phospholipase 3 (PNPLA3) and aldehyde dehydrogenase 2 (ALDH2) were analyzed. Finally, a subgroup analysis according to lifestyle-related disease was performed. RESULTS During the median 7 years of follow-up, 20 patients (6.4%) died (13 liver-related [4.1%] and 7 non-liver-related deaths [2.2%]). Patients with ALDH2 (non-GG genotype) who had reduced alcohol metabolism tended to have a poor prognosis (p = 0.06). Patients carrying both risk SNPs of PNPLA3 (GG) and ALDH2 (non-GG) had a significantly poor prognosis (p = 0.01). In the subgroup analysis, patients with PNPLA3 (GG) who were non-diabetics (p = 0.06) or non-dyslipidemic (p = 0.03), with ALDH2 (non-GG) who were non-dyslipidemic (p = 0.01) or hypertensive (p = 0.03), also had a poor prognosis. The Cox analysis revealed that ALDH2 (non-GG) was associated with a poor prognosis (Hazard ratio: 4.568, 95% Confidence Interval: 1.294-16.131, p = 0.02) similar to the liver function tests. CONCLUSIONS Genetic background may affect NAFLD prognosis and ALDH2 SNP could predict the outcome.
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2.
The Location of Exon 4 Mutations in RP1 Raises Challenges for Genetic Counseling and Gene Therapy.
Nanda, A, McClements, ME, Clouston, P, Shanks, ME, MacLaren, RE
American journal of ophthalmology. 2019;:23-29
Abstract
PURPOSE Mutations in the photoreceptor gene RP1 lead to recessive or dominantly inherited retinitis pigmentosa (RP). Since the dominantly inherited phenotype is generally milder than recessive cases, it raises the possibility that it could arise by haploinsufficiency; however, most mutations are in the terminal exon 4, which would be predicted to generate truncated proteins. We therefore assessed a cohort of RP patients with confirmed mutations in RP1 to examine the genetic basis of the exon 4 mutations. DESIGN Observational case series. METHODS A retrospective review of 15 patients, aged between 36 and 84, with RP1 mutations in exon 4 confirmed by Sanger sequencing. All patients underwent full ophthalmic examination. RESULTS Two patients had homozygous mutations in RP1, p.(Glu1526*) and p.(Ser486fs), and presented with severe early-onset retinal degeneration. Their first-degree relatives were unaffected. Thirteen patients had dominantly inherited RP presenting in adult life with a rod-cone dystrophy phenotype. Four novel mutations were identified. All mutations were predicted to produce truncated RP1 protein of variable lengths, as follows: p.(Arg677*), p.(Gln679*), p.(Leu722*), p.(Ile725Argfs*6), p.(Ser734*)x2, p.(Leu762Tyrfs*17)x2, p.(Leu866Lysfs*7)x2, p.(Arg872Thrfs*2)x2, and p.(Gln917*). CONCLUSION The RP1 protein with a predicted length between 677 and 917 amino acids seems to have a dominant negative effect, whereas proteins shorter (486 amino acids) or longer than this (1526 amino acids) lead to a more severe phenotype, but only in homozygous individuals. Since mutations at various points along exon 4 have divergent consequences, genetic testing alone may be insufficient for counseling, but recessive inheritance should be considered likely in severe early-onset cases.
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Clinical Features, Molecular Genetics, and Long-Term Outcome in Congenital Chloride Diarrhea: A Nationwide Study in Japan.
Konishi, KI, Mizuochi, T, Yanagi, T, Watanabe, Y, Ohkubo, K, Ohga, S, Maruyama, H, Takeuchi, I, Sekine, Y, Masuda, K, et al
The Journal of pediatrics. 2019;:151-157.e6
Abstract
OBJECTIVE To clarify clinical and genetic features of Japanese children with congenital chloride diarrhea (CCD). STUDY DESIGN This was a multi-institutional, retrospective survey of 616 pediatric centers in Japan with identified patients with CCD between 2014 and 2018. Mutations involving SLC26A3 were detected by Sanger sequencing. RESULTS Thirteen patients met all entry criteria including mutations in SLC26A3, and 14 patients satisfied clinical diagnostic criteria. Homozygous or compound heterozygous mutations in SLC26A3, including 6 novel mutations, were identified in 13 of these 14 patients (93%). The most common (detected in 7 of 13) was c.2063-1g>t. Median age at diagnosis was 1 day. Nine of the patients meeting all criteria were diagnosed as neonates (69%). Median follow-up duration was 10 years. When studied, 8 patients had <5 stools daily (62%), and all had fewer than in infancy. Only 1 patient had nephrocalcinosis, and 3 (23%) had mild chronic kidney disease. Neurodevelopment was generally good; only 1 patient required special education. Five patients (38%) received long-term sodium, potassium, and chloride supplementation. CONCLUSIONS Early fetal ultrasound diagnosis and prompt long-term sodium, potassium, and chloride supplementation were common management features. Genetic analysis of SLC26A3 provided definitive diagnosis of CCD. In contrast with previously reported localities, c.2063-1g>t might be a founder mutation in East Asia.
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Nationwide experience of catecholaminergic polymorphic ventricular tachycardia caused by RyR2 mutations.
Broendberg, AK, Nielsen, JC, Bjerre, J, Pedersen, LN, Kristensen, J, Henriksen, FL, Bundgaard, H, Jensen, HK
Heart (British Cardiac Society). 2017;(12):901-909
Abstract
OBJECTIVE The aim of this study was to characterise disease penetrance, course of disease and use of antiarrhythmic medication and implantable cardioverter-defibrillator (ICD) therapy in a Danish nationwide cohort of patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) due to mutations in the ryanodine receptor-2 (RyR2) gene. METHODS The study population was identified through the national hereditary heart disease database (Progeny). The study population was divided into three groups: probands, symptomatic and asymptomatic relatives. RESULTS We identified 23 symptomatic probands, 18 symptomatic and 10 asymptomatic relatives with a RyR2 mutation. Twenty (87%) probands and 10 (36%) relatives had severe presenting symptoms (sudden cardiac death (SCD), aborted SCD (ASCD) or syncope).As compared with symptomatic relatives, probands had lower age at onset of symptoms (16 years (IQR, 10-33) vs 43 years (IQR, 25-54), p<0.0001) and were more prone to fatal or near-fatal events (ASCD, SCD) (16vs5, p<0.0001). Twenty-eight patients had an ICD implanted, and eight experienced appropriate ICD therapy during follow-up (65 months (IQR, 43-175)). Electrical storm was seen in two of the 28 ICD treated patients (7%). No patients receiving treatment died during follow-up (57 months (IQR, 32-139)). Multifocal atrial tachycardia was the predominant symptom in five patients. CONCLUSIONS In a national cohort of RyR2 mutation-positive CPVT patients, SCD, ASCD and syncope were presenting events in the majority of probands and also occurred in 36% of relatives identified through family screening. Probands were younger at disease onset and more prone to fatal or near-fatal events than relatives.
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Apolipoprotein E4 association with metabolic syndrome depends on body fatness.
Torres-Perez, E, Ledesma, M, Garcia-Sobreviela, MP, Leon-Latre, M, Arbones-Mainar, JM
Atherosclerosis. 2016;:35-42
Abstract
BACKGROUND AND AIMS The human Apolipoprotein E (APOE) gene is polymorphic. The APOE*4 allele is a risk factor for cardiovascular disease and could contribute to the development of the metabolic syndrome (MetS) as it may affect all MetS components. We hypothesize that the common APOE4 polymorphism differentially regulates MetS risk and that this association might be modulated by body fatness. METHODS & RESULTS We used body mass index (BMI) as surrogate of fatness and cross-sectionally studied the prevalence of MetS in 4408 middle-aged men of the Aragon Workers Health Study (AWHS). Our analysis revealed i) a gene dose-dependent association between APOE*4 allele and increased risk for MetS, ii) this association primarily derived from the overweight subjects. For these individuals, the MetS risk was higher in APOE*4 carriers than in non-carriers (Odds Ratio = 1.31; 95% CI, 1.03-1.67). Additionally, we examined 3908 healthy young individuals from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort, followed-up for 25 years. Compared with APOE*4 non-carriers, APOE*4 presence significantly increased the risk of developing MetS (Hazard Ratio, 1.12; 95% CI, 1.00-1.26). Again, an interplay between APOE*4 and the longitudinal development of fatness towards the onset of MetS occurred throughout the study. For individuals with BMI gain below the median, the cumulative onset rate of MetS was significantly higher in APOE*4 carriers than in the non-carriers (HR, 1.29; 95% CI, 1.07-1.55). CONCLUSIONS Carrying APOE*4 alleles increases MetS in a dose-dependent manner, characterizing individual's APOE genotype might help identify at-risk subjects for preventive intervention.
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Association of Apolipoprotein E Polymorphism with Intravitreal Ranibizumab Treatment Outcomes in Age-Related Macular Degeneration.
Bakbak, B, Ozturk, BT, Zamani, AG, Gonul, S, Iyit, N, Gedik, S, Yıldırım, MS
Current eye research. 2016;(6):862-6
Abstract
PURPOSE Genetic factors are known to influence the response to anti-vascular endothelial growth factor (VEGF) treatment in exudative age-related macular degeneration (AMD). The current study was conducted to investigate the association of Apolipoprotein E (ApoE) polymorphism with the treatment response to ranibizumab for exudative AMD. METHODS One hundred nine eyes (109 patients, 59.6% male, mean age 63.84 ± 7.22 years) treated with intravitreal ranibizumab injections were included in the analysis. Smoking status and lesion type were recorded. Patients were categorized into three groups according to visual acuity (VA) change at 6 months after the first injection: VA loss >5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (Group 1); VA change between five ETDRS letters gain and loss (Group 2); VA improvement >5 ETDRS letters (Group 3). The association of ApoE gene polymorphisms with the three groups was evaluated. RESULTS Both smoking status and lesion type showed no significant association with VA change (p = 0.12 and p = 0.64, respectively). A lower frequency of ɛ2 and a higher frequency of ɛ4 were observed in Group 3 (2.9 and 25.7%, respectively). VA improvement with more than five ETDRS letters was significantly associated with the presence of the ɛ4 genotype (p = 0.01). CONCLUSIONS This study demonstrated that carriers of the ApoE ɛ4 polymorphism genotype show demonstrable improvement in VA after treatment with ranibizumab in exudative AMD. ApoE polymorphism identification may be used as a genetic screening to tailor individualized therapeutic approach for optimal treatment in neovascular AMD.
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The biophysical characterization of the first SCN5A mutation R1512W identified in Chinese sudden unexplained nocturnal death syndrome.
Zheng, J, Zhou, F, Su, T, Huang, L, Wu, Y, Yin, K, Wu, Q, Tang, S, Makielski, JC, Cheng, J
Medicine. 2016;(23):e3836
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Abstract
Increasing evidence observed in clinical phenotypes show that abrupt breathing disorders during sleep may play an important role in the pathogenesis of sudden unexplained nocturnal death syndrome (SUNDS). The reported Brugada syndrome causing mutation R1512W in cardiac sodium channel α subunit encoded gene SCN5A, without obvious loss of function of cardiac sodium channel in previous in vitro study, was identified as the first genetic cause of Chinese SUNDS by us. The R1512W carrier was a 38-year-old male SUNDS victim who died suddenly after tachypnea in nocturnal sleep without any structural heart disease. To test our hypothesis that slight acidosis conditions may contribute to the significant loss of function of mutant cardiac sodium channels underlying SUNDS, the biophysical characterization of SCN5A mutation R1512W was performed under both extracellular and intracellular slight acidosis at pH 7.0. The cDNA of R1512W was created using site-directed mutagenesis methods in the pcDNA3 plasmid vector. The wild type (WT) or mutant cardiac sodium channel R1512W was transiently transfected into HEK293 cells. Macroscopic voltage-gated sodium current (INa) was measured 24 hours after transfection with the whole-cell patch clamp method at room temperature in the HEK293 cells. Under the baseline conditions at pH 7.4, R1512W (-175 ± 15 pA/pF) showed about 30% of reduction in peak INa compared to WT (-254 ± 23 pA/pF, P < 0.05). Under the acidosis condition at pH 7.0, R1512W (-130 ± 17 pA/pF) significantly decreased the peak INa by nearly 50% compared to WT (-243 ± 23 pA/pF, P < 0.005). Compared to baseline condition at pH 7.4, the acidosis at pH 7.0 did not affect the peak INa in WT (P > 0.05) but decreased peak INa in R1512W (P < 0.05). This initial functional study for SCN5A mutation in the Chinese SUNDS victim revealed that the acidosis aggravated the loss of function of mutant channel R1512W and suggested that nocturnal sleep disorders-associated slight acidosis may trigger the lethal arrhythmia underlying the sudden death of SUNDS cases in the setting of genetic defect.
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Estimated glomerular filtration rate (eGFR), 25(OH) D3, chronic kidney disease (CKD), the MYH9 (myosin heavy chain 9) gene in old and very elderly people.
Otero Gonzalez, A, Prol, MP, Caride, MJ, Nores, JS, Novoa, E, Melon, CP, Macia, P, Alves, MT, Cid, M, Osorio, E, et al
International urology and nephrology. 2015;(8):1403-8
Abstract
It is known that the common physiological denominator of the ageing process is an attenuation of functional performance with respect to the situation of young people and adults. However, since the first cohort-based longitudinal studies, it has not been possible to establish a "linear" relationship between age and glomerular filtration in all cases. This does not mean that there is no physiological ageing process at all; in addition to those already elucidated, its mechanisms include cell senescence, podocyte dysfunction, a vitamin D deficiency, and homozygotic forms of the MYH9 gene. The aim of the present work was to analyse the prevalence of chronic kidney disease (CKD) and, where possible, the correlation between CKD, defined by an eGFR < 60 ml/min/1.73 m(2), plasma 25(OH)D3 levels and the MYH9 gene in a population of elderly and very elderly persons. These parameters have not been evaluated previously in populations of elderly and very elderly patients. It is concluded that a moderate decrease in the eGFR occurs with age. This does not imply the presence of CKD in elderly people, since in most individuals the reduced eGFR is not accompanied by anaemia, and no individuals show hypocalcaemia, hyperphosphataemia or a high Alb/Cr ratio. Here we observed a lower Hb level and an elevated Alb/Cr ratio in subjects heterozygotic for the MYH9 gene. This could be interpreted in the sense that the gene could exert some protective effect on renal function, whereas the heterozygotic form (allele A) of the MYH9 gene could be considered a very early marker, a new risk factor for the appearance of CKD, or a sign of renal frailty in elderly people.
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Polymorphism of SLC25A32, the folate transporter gene, is associated with plasma folate levels and bone fractures in Japanese postmenopausal women.
Urano, T, Shiraki, M, Saito, M, Sasaki, N, Ouchi, Y, Inoue, S
Geriatrics & gerontology international. 2014;(4):942-6
Abstract
AIM: Elevation of homocysteine is associated with an increased risk for bone fractures. We previously reported that the methylenetetrahydrofolate reductase (MTHFR) gene polymorphism is associated with homocysteine levels and fracture. The association between the fracture and folate levels or their related gene polymorphisms is not completely clear. We speculated that the SLC25A32 gene, the mitochondrial inner membrane folate transporter, also could be implicated in the regulation of folate metabolism and fracture. METHODS A total of 851 Japanese postmenopausal women participated in the association study between the single nucleotide polymorphism genotype and plasma homocysteine or folate. We also tested the association between the candidate single nucleotide polymorphism and 663 postmenopausal women. RESULTS The AA genotype of rs2241777 single nucleotide polymorphism at the 3'UTR region in the SLC25A32 gene was associated with lower plasma folate concentration compared with the other genotypes in 851 postmenopausal women. A total of 674 postmenopausal ambulatory Japanese women were followed up for 5.5 ± 0.1 years (mean ± SE). The AA genotype groups also showed an apparently higher rate and earlier onset of incident fractures than the other genotypes. A total of 407 participants had >70% young-adult mean bone mineral density at the start of the observation. CONCLUSIONS These results show that the SLC25A32 gene polymorphism could be a risk factor for lower folate concentration and future fracture.