Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry.

Importance:Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders. Objectives:To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma. Design, Settings, and Participants:A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma. Exposures:Genetic variants associated with primary open-angle glaucoma. Main Outcomes and Measures:Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10-8 in the discovery stage and in the meta-analysis of combined discovery and validation data. Results:A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10-13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry. Conclusions and Relevance:In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies

Study of genetics aspects of juvenile open angle glaucoma

Orientador: Mônica Barbosa de MeloTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: O glaucoma é uma doença neurodegenerativa de etiologia multifatorial que inclui várias afecções oculares que tem em comum o dano progressivo no nervo óptico e a perda característica da visão. O glaucoma primário de ângulo aberto (GPAA) é a maior causa de cegueira irreversível no mundo e sua forma juvenil (GPPAJ), uma forma mais precoce e grave do glaucoma. Esta doença raramente é detectada precocemente devido ao fato de ser assintomática em sua fase inicial, quando o tratamento previne perda permanente da visão. Assim, a identificação de fatores genéticos é importante para ajudar no diagnóstico precoce e estabelecer um seguimento clínico mais adequado. Mutações no gene MYOC associadas ao glaucoma são responsáveis por aproximadamente 3 a 5% dos casos de GPAA e 10 a 30% de GPAAJ. O gene CYP1B1 é comumente associado ao glaucoma congênito primário (GCP), mas também tem sido associado ao GPAA e ao GPAAJ em diversos grupos étnicos, mundialmente. O MYOC e o CYP1B1 podem agir por meio de uma via bioquímica onde o CYP1B1 age como modulador do MYOC. Neste estudo, foram avaliadas as variantes na região codificante dos genes MYOC e CYP1B1 em 100 indivíduos com GPAAJ e 200 controles por meio de sequenciamento de Sanger. Além disso, também avaliou-se uma família portadora de GPAAJ por meio de sequenciamento de exoma. Nossos resultados mostram que mutações no gene MYOC têm uma grande importância nesta coorte, correspondendo a 34% dos casos. Mutações no gene CYP1B1, por outro lado, representam apenas 2% dos casos desta coorte, e seus polimorfismos não foram associados com o GPAAJ ou com suas variáveis clínicas. Neste estudo, também foi detectada uma mutação no gene APEX1 segregando com a doença na família analisada. O gene APEX1 nunca foi comprovadamente associado ao GPAAJ, portanto, foram desenvolvidos estudos funcionais com zebrafish para avaliar o possível papel deste gene na etiologia do glaucoma. Morfantes para o gene APEX1 apresentaram um fenótipo interessante, com uma membrana ao redor dos olhos, tamanho do olho reduzido, e desorganização das camadas da retina. Estes dados indicam que o APEX1 pode ser um gene causador do glaucoma ainda não identificadoAbstract: Glaucoma is a neurodegenerative disease of multifactorial etiology that includes several eye disorders whose common features are the progressive damage of the optic nerve with vision loss. It is a major cause of irreversible blindness in the world. Primary open angle glaucoma (POAG) is the most common type of the disease, while Juvenile Open Angle Glaucoma (JOAG) is an earlier onset and more severe form of glaucoma. This disease is rarely detected early, because it is asymptomatic initially, when the treatment prevents permanent loss of visual function. Thus, identification of genetic factors is important to help in early diagnosis and to establish an appropriate clinical outcome. Glaucoma-associated mutations in the MYOC gene are responsible for approximately 3¿5% of POAG and 10¿30% of JOAG. The CYP1B1 gene has been associated with primary congenital glaucoma (PCG) and also has been implicated in juvenile and adult onset forms of glaucoma in several ethnic groups worldwide. CYP1B1 and MYOC might act through a common biochemical pathway with CYP1B1 acting as a modifier for MYOC. In this study, we evaluated the variants in the coding regions of MYOC and CYP1B1 genes in 100 non-related patients with JOAG and 200 controls through Sanger sequencing. In this study, we also studied a JOAG family through exome sequencing. Our results show that MYOC mutations have a great importance in JOAG cases in this cohort, corresponding to 34% of total cases. CYP1B1 mutations, on the other hand were present in only 2 % and its polymorphisms were not associated with JOAG clinical outcomes. In this study, we also detected one damaging mutation in the APEX1 gene segregating in a family harboring JOAG. We performed a functional study using Zebrafish morpholino knockdown for the Apex1 gene to validate this candidate gene that has never been proved to be associated with JOAG. Morphants for the APEX1 gene presented an interesting phenotype, with a "coat" around the eye, diminished eye size and retinal layers disorganization. This data indicates that APEX1 could be a new glaucoma geneDoutoradoGenetica MedicaDoutor em Ciências Médicas2013/17958-2, 2016/04454-4FAPES

Swim training and the genetic expression of adipokines in monosodium glutamate-treated obese rats

Objective The aim of this study was to evaluate the genetic expression of adipokines in the adipocytes of monosodium glutamate (MSG)-treated obese rats submitted to physical activity.Materials and methods Obesity was induced by neonatal MSG administration. Exercised rats (MSG and control) were subjected to swim training for 30 min for 10 weeks, whereas their respective controls remained sedentary. Total RNA was obtained from sections of the mesenteric adipose tissue of the rats. mRNA levels of adiponectin (Adipoq), tumor necrosis factor alpha (Tnf), peroxisome proliferator-activated receptor alpha (Ppara), and peroxisome proliferator-activated receptor gamma (Pparg) adipokines were quantified by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR).Results In the exercise-trained control group, the expression of Adipoq increased compared to the sedentary control, which was not observed in the MSG-obese rats. Increased levels of Tnf in MSG-obese rats were not reversed by the swim training. The expression of Ppara was higher in sedentary MSG-obese rats compared to the sedentary control. Swimming increased this adipokine expression in the exercise-trained control rats compared to the sedentary ones. mRNA levels of Pparg were higher in the sedentary MSG-rats compared to the sedentary control; however, the exercise did not influenced its expression in the groups analyzed.Conclusions In conclusion, regular physical activity was not capable to correct the expression of proinflammatory adipokines in MSG-obese rat adipocytes

Swim training and the genetic expression of adipokines in monosodium glutamate- treated obese rats

ABSTRACT Objective: The aim of this study was to evaluate the genetic expression of adipokines in the adipocytes of monosodium glutamate (MSG)-treated obese rats submitted to physical activity. Materials and methods: Obesity was induced by neonatal MSG administration. Exercised rats (MSG and control) were subjected to swim training for 30 min for 10 weeks, whereas their respective controls remained sedentary. Total RNA was obtained from sections of the mesenteric adipose tissue of the rats. mRNA levels of adiponectin (Adipoq), tumor necrosis factor alpha (Tnf), peroxisome proliferatoractivated receptor alpha (Ppara), and peroxisome proliferator-activated receptor gamma (Pparg) adipokines were quantified by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). Results: In the exercise-trained control group, the expression of Adipoq increased compared to the sedentary control, which was not observed in the MSG-obese rats. Increased levels of Tnf in MSG-obese rats were not reversed by the swim training. The expression of Ppara was higher in sedentary MSGobese rats compared to the sedentary control. Swimming increased this adipokine expression in the exercise-trained control rats compared to the sedentary ones. mRNA levels of Pparg were higher in the sedentary MSG-rats compared to the sedentary control; however, the exercise did not influenced its expression in the groups analyzed. Conclusions: In conclusion, regular physical activity was not capable to correct the expression of proinflammatory adipokines in MSG-obese rat adipocytes. Arch Endocrinol Metab. 2015;59(3):210-

Association of genetic variants with primary open-angle glaucoma among individuals with african ancestry

Are there differences in genetic risk factors for primary open-angle glaucoma based on ancestry? FindingsIn this multistage, case-control, genome-wide association study that included 26295 participants, the amyloid-beta A4 precursor protein-binding family B member 2 (APBB2) locus was significantly associated with primary open-angle glaucoma among individuals of African ancestry (odds ratio, 1.19 per copy of the risk allele for single-nucleotide polymorphism rs59892895T>C), but not of European or Asian ancestry. MeaningThis study identified a single-nucleotide polymorphism that demonstrated differential association with primary open-angle glaucoma by ancestry. ImportancePrimary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders. ObjectivesTo perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma. Design, Settings, and ParticipantsA 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma. ExposuresGenetic variants associated with primary open-angle glaucoma. Main Outcomes and MeasuresPresence of primary open-angle glaucoma. Genome-wide significance was defined as PC) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P=2x10(-8)). The association was validated in an analysis of an additional 6937 affected individuals and 14917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P<.001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P=4x10(-13)). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry. Conclusions and RelevanceIn this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies. This genome-wide association study (GWAS) investigates genetic loci associated with primary open-angle glaucoma in individuals in Africa and in the United States with African ancestry.3221716821691FAPESP – Fundação de Amparo à Pesquisa Do Estado De São Paulo10/18353-9; 02/11575-

Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry.

ImportancePrimary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders.ObjectivesTo perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma.Design, settings, and participantsA 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma.ExposuresGenetic variants associated with primary open-angle glaucoma.Main outcomes and measuresPresence of primary open-angle glaucoma. Genome-wide significance was defined as P &lt; 5 × 10-8 in the discovery stage and in the meta-analysis of combined discovery and validation data.ResultsA total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T&gt;C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P &lt; .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10-13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry.Conclusions and relevanceIn this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies