https://orcid.org/0000-0001-9568-3323
ABSTRACT
Background
Primary open-angle glaucoma (POAG), the world’s main cause of irreversible blindness, is an asymptomatic and neurodegenerative disease of multifactorial etiology with ethnic and geographic disparities. Multiethnic genome-wide association studies (GWAS) identified single nucleotide variants (SNVs) in ATXN2, FOXC1, and TXNRD2 loci as risk factors for POAG pathophysiology and/or endophenotypes. The aim of this case–control study was to investigate the association of the variants rs7137828 (ATXN2), rs2745572 (FOXC1), and rs35934224 (TXNRD2), as risk factors for POAG development, additionally to rs7137828 association with glaucoma clinical parameters in a Brazilian cohort from the Southeast and South regions.
Methods
This investigation comprised 506 cases and 501 controls. Variants rs2745572 and rs35934224 were genotyped through TaqMan® assays and validated by Sanger sequencing. Variant rs7137828 was genotyped exclusively by Sanger sequencing.
Results
The primary research outcome revealed that the variant rs7137828 (ATXN2) was associated with an increased risk for the development of POAG in the presence of the TT genotype compared to the CC genotype (p = 0.006; Odds Ratio [OR] = 1.717; Confidence Interval [CI] 95% = 1.169–2.535). There was no significant association of rs2745572 and rs35934224 genotypes with POAG. The CT genotype of the rs7137828 was associated with the vertical cup-to-disk ratio (VCDR) (p = .023) but not with the age at diagnosis or the mean deviation.
Conclusion
Our data indicate the rs7137828 associated with increased risk for the development of POAG and VCDR in a Brazilian cohort. If validated in additional populations, these findings may enable the development of relevant strategies for early diagnosis of glaucoma in the future.
Introduction
Glaucoma is the leading cause of irreversible blindness worldwide, affecting nearly 76.5 million individuals in 2020 (Citation1) (10% being bilaterally blind), with an estimated growth prospect of 111.8 million in 2040 (Citation2). Primary Open-Angle Glaucoma (POAG), the most prevalent subtype in all populations (Citation3), is defined as a neurodegenerative disease of multifactorial etiology (Citation4), whose characteristic is the progressive damage to the optic disc, guided by the gradual degeneration of retinal ganglion cells (RGC) and their axons (Citation5,Citation6). Due to RGCs premature apoptosis, a pathogenic increase of the vertical cup/disk ratio (VCDR), and correspondent visual field defects are established (Citation5,Citation6). The POAG phenotype affects about 74% of all cases (Citation3); Latin America has the second-highest global prevalence, second only to Africa (Citation2). In addition, this disease is hardly detected in the initial stages since it is asymptomatic and involves the interaction of systemic, genetic, and environmental factors (Citation4). Therefore, clinical approaches have focused on the management of elevated intraocular pressure (IOP), which is the glaucoma core risk factor and the only treatable parameter (Citation7,Citation8). Other risk factors that underlie glaucoma pathogenesis are ethnicity, age, positive family history, high myopia, and genetics (Citation9–11).
Genetics plays an important role in complex diseases such as glaucoma (Citation12), with 127 single-nucleotide variants (SNVs) related to the disease and/or its endophenotypes, successfully identified through genome-wide association studies (GWAS) (Citation13,Citation14). Despite these findings, the POAG genetic landscape remains uncertain, whereas the variants currently described only elucidate 10% of the cases, reinforcing the role of a polygenic mechanism along with environmental factors on the modulation of the phenotype (Citation15,Citation16).
Among multiple relevant loci, recent publications have highlighted SNVs in Ataxin-2 (ATXN2) (Citation17,Citation18), Forkhead Box C1 (FOXC1) (Citation17,Citation19,Citation20), and Thioredoxin reductase 2 (TXNRD2) (Citation17,Citation21–23) genes as possible risk factors for the development of glaucoma. These genes and their respective variants were identified in a multiethnic GWAS, which comprised 3.853 POAG and 33.480 controls (Citation17).
The ATXN2 gene is located on chromosome 12q24.12, and encodes the protein ataxin-2, which is responsible for microsatellite-expansion diseases (Citation18). The FOXC1 gene (6p25.3) is a protein-coding gene member of the forkhead family of transcription factors, whose rare coding-sequence variations are associated with a critical dysfunction in the embryonic brain and eye development including anterior segment dysgenesis (Citation19,Citation20). The TXNRD2 gene (22q11.21) belongs to the thioredoxin (Trx) system, a relevant mitochondrial protein found in mammals. This protein controls redox homeostasis, decreasing the levels of harmful reactive oxygen species (ROS) produced by oxidative phosphorylation, second to other mitochondrial functions (Citation21,Citation23,Citation24). Most studies on the genetic basis of glaucoma were conducted in Caucasian or Asian populations, which exhibit a homogeneous genetic profile. Due to a high incidence of multiple migrations, resulting from more than five centuries of intersection among three main ancestral roots (Amerindians, Europeans, and Africans), the Brazilian population presents a unique ethnic profile that is worth investigating (Citation25,Citation26). These genetic attributes characterize the Brazilian population as a relevant model for potential insights into POAG discovery once our population is under-represented in ophthalmic genetics research worldwide (Citation25).
This study aimed to investigate the association of the variants rs7137828 (ATXN2), rs2745572 (FOXC1), and rs35934224 (TXNRD2) as risk factors for the development of POAG in a Brazilian cohort from the South and Southeast.
Methods
Patients
This association case–control study comprised 506 nonrelated patients with POAG, and a control group composed of 501 individuals without affection, recruited between 2004 and 2019. Brazilian subjects from the South and Southeast were randomly selected from the ophthalmology services at the Clinical Hospital of the University of Campinas (UNICAMP), Campinas, São Paulo, Regional Hospital of Divinolândia, Divinolândia, São Paulo and Ophthalmological Hospital of Londrina (HOFTALON), Londrina, Paraná. The investigation was conducted in agreement with the Faculty of Medical Sciences Ethics Committee and the principles enunciated in the Declaration of Helsinki. All subjects signed an informed consent for participation in this research project.
All participants were submitted to interview, anamnesis, chart review, and complete ophthalmological evaluation by a glaucoma specialist. The POAG cohort comprehended patients aged over 18 years, open-angle at gonioscopy (Citation27), and three of the following criteria: (i) IOP ≥ 21 mmHg (in the absence ocular hypotensive medication); (ii) Typical glaucomatous optic disc, fulfilling at least two of the following clinical characteristics: notching, hemorrhage, cup-to-disk ratio (CDR) > 0.7, CDR asymmetry > 0.2, thinning of the neuroretinal rim; (iii) Ganglion cells complex and/or retinal nerve fiber layer (RNFL) abnormalities detected by optical coherence tomography (OCT) (Spectralis, Heidelberg Engineering Inc, Franklin MA), consistent with glaucomatous damage; (iv) Typical glaucomatous visual field loss, detected with the 30–2 or 24–2 programs of the Humphrey Field Analyzer (Humphrey Instruments, San Leandro, CA) and defined according to Anderson’s criteria (Citation28) and defined as glaucoma hemifield test or pattern standard deviation outside normal limits of 99% and 95%, respectively.
The control cohort consisted of participants aged ≥ 40 years, with no individual or family history of glaucoma and/or blindness, IOP ≤ 16 mmHg in both eyes, CDR ≤ 0.4. POAG patients and non-affected participants with evidence of congenital, secondary, or developmental glaucoma, optic neuropathies of ischemic or inflammatory origin, visual field changes associated with other eye conditions, or high myopia (>−6.00 spherical diopters) were excluded.
Genetic evaluation
Ten milliliters of peripheral whole blood were collected from the antecubital or basilic vein in VACUETTE® tubes with EDTA, followed by genomic DNA extraction through phenol/chloroform method and ethanol precipitation. Quantitative Real-time PCR (qRT-PCR) and Sanger sequencing (Citation29) were used for genotyping. Variants rs2745572 (FOXC1) and rs35934224 (TXNRD2) were analyzed through Taqman® assays (C___2796914_10 and C___2539479_10 probes, respectively; Applied Biosystems Inc., Foster City, CA, USA), followed by validation through Sanger sequencing in 10% of the samples. In contrast, rs7137828 SNV was fully genotyped by direct sequencing. The qRT-PCR reaction was accomplished with 2.5 μL of 2× TaqMan Genotyping Master Mix (Thermo Fisher, Waltham, MA); 1 µL of 50 ŋg/µL genomic DNA; and 1.5 μL of the 5× Taqman® probes (VIC®/FAM™). Products were amplified using the following conditions: 94ºC for 7’; 40 cycles of 94ºC for 1’; 60ºC for 1’; 72ºC for 1’; and 72ºC for 5’ in the StepOne™ Real-Time PCR System (Applied Biosystems Inc., Foster City, CA, USA).
For validation of rs2745572 and rs35934224 variants and direct sequencing of rs7137828, polymerase chain reaction (PCR) was performed using the following reagents: 0.25 μL of each forward and reverse primers at 20 pmol/μL; 2.5 μL of enzyme buffer (10× Buffer: 20 mM Tris-HCl, pH 8.4, 50 mM KCl, 0.01% gelatin); 1.5 µL of 50 µM MgCl2; 0.5 µL of the 10× nucleotide mixture (dATP, dCTP, dTTP, and dGTP), 0.1 µL of Taq DNA polymerase 10 U/µL (Invitrogen Life Technologies, Gaithersburg, MD, USA) and 1 µL of 50 ŋg/µL genomic DNA. Moreover, for the rs35934224 and rs7137828 SNVs amplification, 1.25 μL of 10% dimethyl sulfoxide (DMSO) was added, and for rs7137828, Taq DNA Polymerase Platinum 10 U/µL (Invitrogen Life Technology, Gaithersburg, MD, EUA) was used. The final volume of 25 µL was completed with ultrapure water. The amplification conditions were as follows: an initial denaturation at 95ºC for 5’; 50 cycles of 95ºC for 1’; annealing for 1’ (temperatures reported in ); and an extension at 72ºC for 1’, an extra extension step of 72ºC for 5’ was added to the last cycle. Both forward and reverse primers for all three variants were designed using as reference the GenBank® - GRCh38.p13 version of the human genome (), synthesized by Sigma-Aldrich® | MERCKTM KGaA (Darmstadt, Germany).
Table 1. Primers used for amplification of the FOXC1 (rs2745572), TXNRD2 (rs35934224), and ATXN2 (rs7137828) variants.
All amplified products were subjected to forward strand sequencing with BigDye Terminator Cycle Sequencing Kit v3.1® (Applied Biosystems Inc., Foster City, CA, USA), in the ABI Prism 3530 DNA Analyzer (Applied Biosystems Inc., Foster City, CA, USA). The FinchTV software v.1.4.0 (Geospiza Inc., Seattle, WA, USA) was utilized to investigate the SNVs’ alterations.
Statistical analysis
All statistical analyses were performed using the R software v.1.4.1717 (Foundation for Statistical Computing, Vienna, Austria). Age and gender between cases and controls were evaluated through logistic regression. To investigate the association of rs7137828, rs2745572, and rs35934224 SNVs with POAG, we used a multivariate logistic regression model (95% confidence interval) adjusted by age and gender. For the ATXN2 rs7137828 variant besides the evaluation of the POAG genetic basis, we investigated its association with age at diagnosis (322 patients), vertical cup/disk ratio (VCDR) (333 patients), and visual field mean deviation (MD) (298 patients) through multiple linear regression; age and genotypes were considered as independent variables. For this analysis, we considered a subset of patients, who were admitted to service from 2014 to 2019. We considered the vertical cup-to-disk ratio measurements and MD values from the right eye in the first evaluation; the left eye was used in the absence of these data. P-values < .05 were considered statistically significant. Deviations from the Hardy-Weinberg equilibrium (HWE) were tested through the chi-square goodness-of-fit test (degrees of freedom = 1). The ClinCalc LLC algorithmic tool (https://clincalc.com/stats/SampleSize.aspx) was used to calculate the necessary sample size to achieve statistical significance for FOXC1 rs2745572, and TXNRD2 rs35934224 variants.
Results
Demographic data
This study comprised a total of 1007 participants. Regarding gender distribution, 50.99% (258/506) were males and 49.01% (248/506) were females clinically diagnosed with POAG, whereas the control group consisted of 43.11% (216/501) males and 56.89% (285/501) females (p = .011). The mean ages in the affected and control groups were 67.44 ± 12.18 and 66,83 ± 10.28 years, respectively (p = .343). Although no statistically significant difference in mean age was observed, the analyses were adjusted for both age and gender.
Association of single nucleotide variants with POAG
The genotype frequencies of the studied SNVs are depicted in . Cases and controls were in Hardy-Weinberg Equilibrium (HWE) (p > .05) for rs2745572 (p = .257 and .283, respectively) and rs35934224 (p = .883 and 0.786, respectively). The rs7137828 variant was in HWE for cases (p = .0978) but not for controls (p = .0363) ().
Table 2. Descriptive analysis of allele and genotype frequencies between cases and controls.
The results of the multivariate logistic regression analysis between groups according to the presence of the SNVs rs7137828, rs2745572, and rs35934224 are shown in . Our results revealed a statistically significant association of the rs7137828 (ATXN2) TT genotype with the POAG development when compared to the CC genotype (p = .006; Odds Ratio [OR] = 1.717; 95% Confidence Interval [CI] = 1.169–2.535) (). There was no significant association between rs2745572 (FOXC1) and rs35934224 (TXNRD2) genotypes with POAG (). The estimated sample size required to reach statistical significance for the rs2745572 variant is 2200 cases and 2200 controls and for the rs35934224 is 6278 cases and 6278 controls.
Table 3. Association analysis of ATXN2 (rs7137828), FOXC1 (rs2745572) and TXNRD2 (rs35934224) SNVs between cases and controls through multivariate logistic regression, adjusted for age and gender.
Association of single nucleotide variants with vertical cup-to-disc ratio
Since the rs7137828 variant was associated with the risk of POAG, we investigated its association with clinical parameters such as age at diagnosis in 322 patients, endophenotype VCDR in 333 patients, and MD in 298 patients. The CT genotype of the rs7137828 variant demonstrated a significant association with VCDR, compared to the CC genotype (p = .023). No statistical association was observed regarding this SNV and age in diagnosis or visual field MD ().
Table 4. Association analysis of ATXN2 (rs7137828) SNV and clinical variables through linear regression.
Discussion
Primary open-angle glaucoma is a complex disorder originating from the interaction of multiple genes and systemic/environmental factors (Citation4). Since Bailey and colleagues (Citation17) identified ATXN2, FOXC1, and TXNRD2 SNVs associated with POAG and/or its endophenotypes, few independent investigations have evaluated their role in ethnically different cohorts. To elucidate the effect of three previously reported SNVs (rs7137828, rs2745572, and rs35934224) with POAG development in 1007 Brazilian subjects, we conducted a cross-sectional case–control study, whose outcomes indicated association with the ATXN2 locus.
The Brazilian population is highly heterogeneous (Citation25). Genetic composition varies among regions; for autosomal markers, the proportion of European ancestry was estimated to range from 43% to 79%, African ancestry from 14% to 50%, Amerindian ancestry from 7% to 8% (Citation30). When comparing populations from Latin America, Cruz et al. (2022) (Citation31), showed that Brazilians were the most heterogeneous admixed population, reflecting the challenge in performing association studies and extrapolating results from ethnically homogeneous populations.
The ATXN2 gene acts in RNA regulation (Citation32), associated with microsatellite-expansion diseases including optic atrophy, amyotrophic lateral sclerosis, and neurodegenerative disorders (Citation18). Moreover, ATXN2-SH2B3 loci have been recently linked with retinal venular caliber in European ancestry subjects (Citation33). GWAS investigations described rs7137828 SNV associated with both POAG (Citation17,Citation18) development and IOP (Citation34), possibly through neurodegeneration pathways. Bailey and colleagues (2016) (Citation17) also described ATXN2 mRNA expression in the ciliary body, retina, optic nerve, cornea, and trabecular meshwork, structures involved in glaucoma development. Immunolabeling experiments in standard mouse eye sections also evidenced ATXN2 expression in both optic nerve and RGCs, reinforcing a possible pathway for POAG increased risk (Citation17). In this sample of the Brazilian population, our main outcome revealed a possible association between the rs7137828 SNV with increased risk for POAG pathogenesis in the presence of the TT genotype, compared to the CC genotype. This result is consistent with previous research conducted on ethnically different populations. Bailey and co-workers (2016) (Citation17), evaluating 3853 cases and 33,480 controls from a multiethnic GWAS that encompassed eight independent studies involving Australian, European, and Chinese cohorts, reported the first association between ATXN2 rs7137828 [T] as a risk factor for POAG (p = 8.73 × 10−10). Subsequently, Choquet and collaborators (2018) (Citation35) reported similar nominal evidence values for the same association in 4986 cases and 58,426 controls among four race/ethnicity groups including Hispanics/Latinos, East Asians, non-Hispanic whites, and African Americans (p = .0034). The minor allele frequency (MAF) of rs713782 was 31% in cases and 38% in controls, which is similar to Latinos (28% in CLM and 37% in PUR) and European ancestry populations (35% in FIN and 454% in CEU) but different from the range observed for African ancestries (0% in YRI to 11% in ASW) (https://www.ensembl.org/Homo_sapiens/Variation/Population?db=core;r=12:111494496–111495496;v=rs7137828;vdb=variation;vf=730516700). Also, the Brazilian repository ABraOM, composed by 1171 elderly individuals from the same region showed a MAF of 34% for this variant (https://abraom.ib.usp.br).
The control cohort of the rs7137828 SNV in the ATXN2 locus was not in the HWE, and we cannot explain the cause of this departure. Waples’s (1998) (Citation36) and Hedrick’s (1999) (Citation37) publications reinforce that, although statistical analysis represents a crucial role in deviations’ divergence, statistically significant HWE departures involving relatively large cohorts are possible, representing a minor degree of biological relevance. According to the authors, since real populations are constantly susceptible to multiple effects capable of modulating allelic/genotypic frequencies throughout generations (migration, selection, genetic drift, mutation, assortative mating, population structure, among others), departures may be rejected once the downstream outcomes are robust to the nature and magnitude of the deviations. Genotyping errors and marker-disease association can be responsible for HWE departures as well (Citation36–38). However, distinguishing between the above-mentioned circumstances is still challenging, as described by Waples in 2015 (Citation38). Wittke-Thompson et al. (2005) analytically demonstrated that under a general disease model, deviation from Hardy-Weinberg—expected and observed genotypic frequencies may occur either in affected or unaffected control samples, and depending on the factors, it can be detected in relatively small samples (Citation39). Our association data are consistent with previous reports and with the MAF observed in Latinos and Europeans. We also discard any potential population substructure in our sample due to our sampling methodology and to the very low IBD levels in urban Brazilian populations (Citation31). We used Sanger sequencing as a genotyping method and obtained high-quality genotyping data. According to Baldin (2006) for population association studies, HWE has been used primarily to check for data quality and usually discard loci that present HWE departure at significance level α = 10−3 or 10−4 (Citation40). Hence, we do not believe that the observed level of HWE deviation invalidates our results.
Regarding the FOXC1 locus, independent studies observed associations of rare variants with broad effects on human pathologies, supporting the development of distinct phenotypes such as Axenfeld-Rieger anomaly and both adult/early-onset glaucoma (Citation19,Citation20). Furthermore, Forkhead box C1 protein plays a relevant role in the regulation of embryonic ocular development of anterior segment structures, including the aqueous humor outflow, important in IOP regulation (Citation19,Citation41). In this sample of the Brazilian population, no statistical association was detected between FOXC1 genotypes and POAG development risk. Our findings diverge from previous research conducted in other populations. Bailey et al. (2016) (Citation17) identified statistically significant association of rs2745572 as risk factor for POAG development (p = 1.76 × 10−10) in a multiethnic cohort. Subsequently, Khawaja and co-workers (2018) also observed through meta-analysis a correlation between the same SNV and increased risk for POAG development (p = 1.8 × 10−28). The current meta-analysis was performed on 139,555 European subjects from three biobanks, namely: UK Biobank, EPIC-Norfolk, and International Glaucoma Genetics Consortium (IGGC) (Citation42). The non-association of the rs2745572 variant [A] with the increased risk of POAG pathogenesis in our population may have been influenced by the limited sample size, which was estimated to be 2200 cases and 2200 controls to reach statistical significance. Another factor that may be taken into account is the small difference in the rs2745572 MAF between cohorts, 32% in cases and 36% in controls, similar to CLM (39%), PUR (37%), as well as in European ancestry populations (31% in GBR, 40% IBS, 36% TSI, 32% in CEU, and 39% in FIN), contrasting with African ancestry populations that varies from 10% in YRI to 18% in GWD) (https://www.ensembl.org/Homo_sapiens/Variation/Population?db=core;r=6:1547634–1548634;v=rs2745572;vdb=variation;vf=168998829).
The TXNRD2 gene encodes the thioredoxin reductase 2, a relevant form of a mitochondrial protein capable of decreasing the levels of damaging reactive oxygen species produced by oxidative phosphorylation involved in the pathophysiology of glaucoma (Citation23,Citation24). Additional research identified TXNRD2 expression in normal human ocular tissue, including optic nerve and retina, supporting ROS reduction as an alternative pathway to avoid RGC apoptosis in POAG caused by cellular oxidative stress (Citation17,Citation21,Citation24). The SNV rs35934224 evaluation revealed no significant correlation with POAG in this Brazilian sample. Our results are inconsistent with the previous Bailey and co-workers (2016) (Citation17) study comprising a different multiethnic cohort, which reports association of the rs35934224 SNV [C] with POAG development (P = 4.05 × 10−11). In addition, the authors reported the role of the TXNRD2 protein as the first mitochondrial protein associated with the risk of POAG pathogenesis (Citation17). In Brazil, Tenorio et al. (2021) (Citation43) evaluated 184 individuals (94 cases and 94 controls) ethnically admixed from the Brazilian Northeast region and reported a possible relationship between the CT genotype and protection against POAG development (p = .022). Nevertheless, despite these data, the authors point out as limitations the restricted sample size and the lack of functional characterization of the TXNRD2 protein in the study, highlighting the requirement of replication in larger cohorts (Citation41). In agreement with the rs2745572 SNV, sample size projection indicated insufficient number of individuals in our cohort; a sample of 6278 cases and 6278 controls would be required to reach statistical significance. The outstanding number projected for association may indicate the small relevance of this SNV with POAG risk in our admixed population. Regarding rs35934224 MAF distribution, we reported 19% in cases and 21% in controls, similar to CLM (22%) and PUR (15%), as well as to some European ancestries (14% in GBR; 17% in IBS, and 19% in CEU/TSI), but discrepant from mostly African ancestry populations (30% in GWD; 31% in MSL; 32% in ASW, and 34% in YRI), (https://www.ensembl.org/Homo_sapiens/Variation/Population?db=core;r=22:19884622–19885622;v=rs35934224;vdb=variation;vf=185866053).
Besides the evaluation of the genetic basis of POAG, some clinical glaucoma phenotypes, including age at diagnosis, VCDR, and visual field MD were evaluated in relation to rs7137828 variant. In this analysis, the CT genotype demonstrated a significant association with larger VCDR compared to the CC genotype. To our knowledge, this is the first analysis suggesting a possible relationship between VCDR among patients with POAG and this variant. However, the lack of association of the TT genotype with VCDR indicates the need for further studies in larger samples to exclude the possibility of spurious findings. No relationship was observed between rs7137828 and age at diagnosis or visual field MD. Although rs7137828 has been included in the polygenic risk score (PRS) associated with earlier age at diagnosis, when independently evaluated rs7137828 did not reach statistical significance (Citation44). Variants in ATXN2 have also been associated with IOP in GWAS, indicating that the age at diagnosis effect could be mediated via raised IOP (Citation42). One possible source of bias is that age at diagnosis might not be properly represented, since many patients are unaware of disease onset.
The present study has limitations in terms of the Brazilian population representativeness, once only the Southeastern and South Brazilian populations were evaluated, requiring further research involving individuals from other Brazilian regions. A larger sample for both cohorts could demonstrate a more robust conclusion regarding unknown associations between rs2745572 and rs35934224 with increased risk for POAG development. Moreover, both rs2745572 and rs35934224 might not be the most informative variants to detect association between POAGs due to different genetic architecture of the Brazilian population (Citation31). The association of the rs7137828 with VCDR also presented limitations. This analysis was not controlled for variables such as disk diameter and insufficient treatment; the latter could influence the severity of the disease and its clinical control.
Nonetheless, notable strengths can be noted in this study. Replication studies in POAG remain rarely developed in South American populations. To our knowledge, this is the first report investigating the association between rs2745572 (FOXC1) and rs7137828 (ATXN2) variants with POAG in a highly admixed and ethnically heterogeneous population such as the Brazilian cohort, which represents roughly 49% of South American inhabitants (United Nations 2020 Demographic Yearbook. 71st Issue. New York, United Nations 2021).
In summary, our data indicate an association between the TT genotype of rs7137828 variant in the ATXN2 gene and the development of POAG as well as between the CT genotype and increased VCDR in this cohort of the Brazilian population. If replicated in studies involving a larger number of patients, these data may contribute to further polygenic risk score investigations, given the valuable resource that the Brazilian population represents for complex trait mapping in humans.
Acknowledgments
We thank the volunteers and patients for their inestimable collaboration for this work.
Disclosure statement
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
Additional information
Funding
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