Genomics

Genomics Publications

Martinez Sanchez M, Chan W-M, MacKinnon SE, Barry B, Hunter DG, Engle EC, Whitman MC. Presence of Copy Number Variants Associated With Esotropia in Patients With Exotropia. JAMA Ophthalmol 2024;Abstract
IMPORTANCE: Strabismus is a common ocular disorder of childhood. There is a clear genetic component to strabismus, but it is not known if esotropia and exotropia share genetic risk factors. OBJECTIVE: To determine whether genetic duplications associated with esotropia are also associated with exotropia. DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study conducted from November 2005 to December 2023. Individuals with constant or intermittent exotropia of any magnitude or a history of surgery for exotropia were recruited from pediatric ophthalmic practices. Data were analyzed from March to December 2023. EXPOSURE: Genetic duplication. MAIN OUTCOMES AND MEASURES: Presence of genetic duplications at 2p11.2, 4p15.2, and 10q11.22 assessed by digital droplet polymerase chain reaction. Orthoptic measurements and history of strabismus surgery were performed. RESULTS: A total of 234 individuals (mean [SD] age, 19.5 [19.0] years; 127 female [54.3%]) were included in this study. The chromosome 2 duplication was present in 1.7% of patients with exotropia (4 of 234; P = .40), a similar proportion to the 1.4% of patients with esotropia (23 of 1614) in whom it was previously reported and higher than the 0.1% of controls (4 of 3922) previously reported (difference, 1.6%; 95% CI, 0%-3.3%; P < .001). The chromosome 4 duplication was present in 3.0% of patients with exotropia (7 of 234; P = .10), a similar proportion to the 1.7% of patients with esotropia (27 of 1614) and higher than the 0.2% of controls (6 of 3922) in whom it was previously reported (difference, 2.8%; 95% CI, 0.6%-5.0%; P < .001). The chromosome 10 duplication was present in 6.0% of patients with exotropia (14 of 234; P = .08), a similar proportion to the 4% of patients with esotropia (64 of 1614) and higher than the 0.4% of controls (18 of 3922) in whom it was previously reported (difference, 5.6%; 95% CI, 2.5%-8.6%; P < .001). Individuals with a duplication had higher mean (SD) magnitude of deviation (31 [13] vs 22 [14] prism diopters [PD]; difference, 9 PD; 95% CI, 1-16 PD; P = .03), were more likely to have constant (vs intermittent) exotropia (70% vs 29%; difference, 41%; 95% CI, 20.8%-61.2%; P < .001), and had a higher rate of exotropia surgery than those without a duplication (58% vs 34%; difference, 24%; 95% CI, 3%-44%; P = .02). CONCLUSIONS AND RELEVANCE: In this cross-sectional study, results suggest that the genetic duplications on chromosomes 2, 4, and 10 were risk factors for exotropia as well as esotropia. These findings support the possibility that esotropia and exotropia have shared genetic risk factors. Whether esotropia or exotropia develops in the presence of these duplications may be influenced by other shared or independent genetic variants or by environmental factors.
Hong F, Kishi JY, Delgado RN, Jeong J, Saka SK, Su H, Cepko CL, Yin P. Thermal-plex: fluidic-free, rapid sequential multiplexed imaging with DNA-encoded thermal channels. Nat Methods 2024;21(2):331-341.Abstract
Multiplexed fluorescence imaging is typically limited to three- to five-plex on standard setups. Sequential imaging methods based on iterative labeling and imaging enable practical higher multiplexing, but generally require a complex fluidic setup with several rounds of slow buffer exchange (tens of minutes to an hour for each exchange step). We report the thermal-plex method, which removes complex and slow buffer exchange steps and provides fluidic-free, rapid sequential imaging. Thermal-plex uses simple DNA probes that are engineered to fluoresce sequentially when, and only when, activated with transient exposure to heating spikes at designated temperatures (thermal channels). Channel switching is fast (<30 s) and is achieved with a commercially available and affordable on-scope heating device. We demonstrate 15-plex RNA imaging (five thermal × three fluorescence channels) in fixed cells and retina tissues in less than 4 min, without using buffer exchange or fluidics. Thermal-plex introduces a new labeling method for efficient sequential multiplexed imaging.
Zhang H, Daheron L, Cerna-Chavez R, Place EM, Huckfeldt RM, Pierce EA, Garita-Hernandez M. Generation of a human induced pluripotent stem cell line (OGIi001) from peripheral blood mononuclear cells of a healthy male donor. Stem Cell Res 2024;74:103280.Abstract
We have successfully derived a novel human induced pluripotent stem cell (hiPSC) line using non-integrative Sendai virus. This hiPSC line was generated from a healthy male adult donor, aged 55, and subjected to thorough characterization and extensive quality control. The analysis confirmed the expression of undifferentiated stem cell markers, demonstrated the ability to differentiate into the three germ layers, and revealed the absence of any chromosomal abnormalities.
Kounatidou NE, Kondylis G, Klavdianou O, Venkateswaran N, Fryssira E, Palioura S. Progressive Keratoconus in a Patient With Severe Pectus Excavatum and a Cartilage Oligomeric Matrix Protein Gene Mutation: A Case Report. Eye Contact Lens 2024;50(1):48-51.Abstract
INTRODUCTION: Keratoconus is a progressive ocular disorder associated with numerous systemic diseases, many of which affect the musculoskeletal system. Although the etiology and pathophysiology of the disorder remain elusive, recent studies suggest a significant role of genetic predisposition in the pathogenesis of keratoconus. This case report aims to elucidate a potential genetic association in a patient presenting with keratoconus, severe pectus excavatum, generalized muscular weakness, and skeletal deformities. CASE DESCRIPTION: A 31-year-old Iranian man presented with progressively diminishing vision in both eyes over the years, eventually diagnosed with keratoconus. The patient's history and further examination indicated generalized muscular weakness, skeletal deformities, and severe pectus excavatum with cardiac and large vessel displacement. Whole-exome sequencing identified two heterozygous gene variants: one in the Cartilage Oligomeric Matrix Protein (COMP) gene and another in the Regulating Synaptic Membrane Exocytosis 1 gene. The patient's systemic and ocular symptoms, combined with the gene variants identified, suggested a connective tissue systemic disorder, potentially within the clinical spectrum of COMPopathies. CONCLUSION: This is the first documented case of bilateral progressive keratoconus associated with severe pectus excavatum, generalized musculoskeletal dystrophy, and a COMP gene mutation. It highlights the necessity of continued search into the pathogenic genes of keratoconus, particularly in cases with coexisting systemic manifestations, to further our understanding of the etiology and pathogenesis of this complex disease.
Romano F, Lamanna F, Boon CJF, Siligato A, Kalra G, Agarwal A, Medori C, Bertelli M, Pellegrini M, Invernizzi A, Staurenghi G, Salvetti AP. Clinical, Genotypic and Imaging Characterization of the spectrum of ABCA4 Retinopathies. Ophthalmol Retina 2023;Abstract
PURPOSE: To investigate the clinical and genotypic differences in the spectrum of ABCA4-associated retinopathies (ABCA4R). DESIGN: Observational, cross-sectional case series. PARTICIPANTS: Sixty-six patients (132 eyes) carrying biallelic ABCA4 variants. METHODS: Patients underwent visual acuity measurement and multimodal imaging. Clinical records were reviewed for age at onset, presenting symptoms, genetic variants, and electroretinogram (ERG). Each eye was assigned to a phenotype based on age at onset, imaging and ERG: cone dystrophy-bull's eye maculopathy (CD-BEM, 40 eyes), cone-rod dystrophy (CRD, 12 eyes), Stargardt disease (SD, 28 eyes), late-onset SD (LO-SD, 38 eyes), fundus flavimaculatus (FFM, 14 eyes). Images were analyzed for: peripapillary sparing, retinal pigment epithelium (RPE) atrophy (definitely decreased autofluorescence, DDAF), flecks patterns using autofluorescence; type of atrophy according to CAM reports, macular and choroidal thickness on optical coherence tomography (OCT); choriocapillaris flow deficits on OCT angiography. MAIN OUTCOME MEASURES: Primary outcome was to report the demographic, genotypic and imaging characteristics of the different ABCA4R phenotypes. Secondary objectives included the assessment of imaging biomarkers as outcome measures for clinical trials. RESULTS: Age at onset was lower in CRD (12±8 years) and higher in LO-SD patients (59±9 years) (all p<0.01). Central vision loss was a common presenting symptom in CD-BEM and SD, whereas LO-SD patients primarily complained of difficult dark adaptation. Missense variants were more frequent in CD-BEM, and splice site in CRD and LO-SD (p<0.05). Peripapillary sparing was absent in three eyes with LO-SD (8%). CD-BEM eyes typically had cORA alterations (98%), while CRD and SD eyes showed both cORA and cRORA (71-100%). LO-SD patients had larger areas of DDAF (100% cRORA) and of choriocapillaris flow deficits (all p<0.01). Repeatability of DDAF measurements was low for some phenotypes (CD-BEM and CRD) and atrophic areas <7.5 mm2. Resorbed flecks were significantly associated with CRD and LO-SD (p<0.01). CONCLUSIONS: This research provides a thorough evaluation of the spectrum of ABCA4R. Our findings suggest that certain phenotypes show preferential photoreceptor degeneration (e.g., CD-BEM), while others have substantial RPE and choriocapillaris alterations (e.g., LO-SD). We recommend that clinical trial endpoints take into consideration these imaging features to improve the interpretation of their results.
Gharahkhani P, He W, Han X, Ong JS, Rentería ME, Wiggs JL, Khawaja AP, Trzaskowski M, Mackey DA, Craig JE, Hewitt AW, Hewitt AW, Macgregor S, Wu Y. Genome-wide risk prediction of primary open-angle glaucoma across multiple ancestries. medRxiv 2023;Abstract
BACKGROUND: Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. The disease is often only diagnosed after retinal ganglion cell damage has occurred, with current treatments unable to restore lost vision. Developing risk identification tools for POAG will help enable timely diagnosis and prevent irreparable damage from occurring, especially for ancestry groups (such as African (AFR)) where the disease prevalence is high. Given the heritable nature of POAG, we aim to develop a polygenic score (PGS), which could facilitate earlier POAG risk detection for timely prevention and diagnosis. METHODS: We applied a multi-ancestry multi-trait approach to build powerful PGS for POAG. We first integrated the new and existing genetics data on POAG and two key endophenotypes, intraocular pressure (IOP) and vertical cup-to-disc ratio (VCDR). We then leveraged the shared POAG genetic information across European (EUR), AFR and Asian ancestries and between POAG and each of IOP and VCDR to develop PGS for POAG risk prediction. We systematically assessed the PGS prediction power and risk stratification ability in POAG cohorts of different ancestries. RESULTS: Our newly developed PGS showed improved accuracy compared to previous PGS for POAG risk prediction in EUR ancestry. We showed the transferability of PGS based on EUR ancestry in the prediction of POAG status in AFR and Asian ancestries. Utilizing the shared genetic information across ancestries further improved PGS prediction power for POAG in AFR and East Asian (EAS). For individuals with South Asian ancestry, those in the top PGS decile were diagnosed ~18 years earlier than those in the bottom decile. For AFR ancestry, individuals in the top percentile had an odds ratio of 4.08 (95% CI: 2.33-7.45) compared with the remainder of the population using the newly developed AFR-specific PGS. CONCLUSIONS: In the current study, we developed PGS for POAG risk prediction in EUR, Asian and AFR populations. These PGS, to our best knowledge, are the most powerful PGS currently for POAG risk screening and stratification. We believe that our study will lead to improved POAG detection across diverse populations in the future by enabling targeting clinical screening of people at high levels of genetic risk.
Nelson MR, Liu P, Agrawal A, Yip O, Blumenfeld J, Traglia M, Kim MJ, Koutsodendris N, Rao A, Grone B, Hao Y, Yoon SY, Xu Q, De Leon S, Choenyi T, Thomas R, Lopera F, Quiroz YT, Arboleda-Velasquez JF, Reiman EM, Mahley RW, Huang Y. The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation. Nat Neurosci 2023;26(12):2104-2121.Abstract
Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD), leading to earlier age of clinical onset and exacerbating pathologies. There is a critical need to identify protective targets. Recently, a rare APOE variant, APOE3-R136S (Christchurch), was found to protect against early-onset AD in a PSEN1-E280A carrier. In this study, we sought to determine if the R136S mutation also protects against APOE4-driven effects in LOAD. We generated tauopathy mouse and human iPSC-derived neuron models carrying human APOE4 with the homozygous or heterozygous R136S mutation. We found that the homozygous R136S mutation rescued APOE4-driven Tau pathology, neurodegeneration and neuroinflammation. The heterozygous R136S mutation partially protected against APOE4-driven neurodegeneration and neuroinflammation but not Tau pathology. Single-nucleus RNA sequencing revealed that the APOE4-R136S mutation increased disease-protective and diminished disease-associated cell populations in a gene dose-dependent manner. Thus, the APOE-R136S mutation protects against APOE4-driven AD pathologies, providing a target for therapeutic development against AD.
Robinette ML, Weeks LD, Kramer RJ, Agrawal M, Gibson CJ, Yu Z, Sekar A, Mehta A, Niroula A, Brown JT, McDermott GC, Reshef ER, Lu JE, Liou VD, Chiou CA, Natarajan P, Freitag SK, Rao DA, Ebert BL. Somatic TET2 Mutations are Associated with Giant Cell Arteritis. Arthritis Rheumatol 2023;Abstract
OBJECTIVE: Giant cell arteritis (GCA) is an age-related vasculitis. Prior studies have identified an association between GCA and hematologic malignancies (HM). How the presence of somatic mutations which drive development of HM, or clonal hematopoiesis (CH), may influence clinical outcomes in GCA is not well understood. METHODS: To examine an association between CH and GCA, we analyzed sequenced exomes of 470960 UK Biobank participants for the presence of CH and used multivariable Cox regression. To examine the clinical phenotype of GCA in patients with and without somatic mutations across the spectrum of CH to HM, we performed targeted sequencing of blood samples and electronic health record review on 114 patients with GCA seen at our institution. We then examined associations between specific clonal mutations and GCA disease manifestations. RESULTS: UKB participants with CH had a 1.48-fold increased risk of incident GCA compared to UKB participants without CH. GCA risk was highest among individuals with cytopenia (HR 2.98, p = 0.00178) and with TET2 mutation (HR 2.02, p = 0.00116). Mutations were detected in 27.2% of our institutional GCA cohort, 3 of whom had HM at GCA diagnosis. TET2 mutations were associated with vision loss in patients with GCA (OR 4.33, p = 0.047). CONCLUSIONS: CH increases risk for development of GCA in a genotype-specific fashion, with greatest risk being conferred by the presence of mutations in TET2. Somatic TET2 mutations likewise increase the risk of GCA-associated vision loss. Integration of somatic genetic testing in GCA diagnostics may be warranted in the future. This article is protected by copyright. All rights reserved.
de Guimaraes TAC, Georgiou M, Robson AG, Fujinami K, Vincent A, Nasser F, Khateb S, Mahroo OA, Pontikos N, Vargas ME, Thiadens AAHJ, de Carvalho ER, Nguyen X-T-A, Arno G, Fujinami-Yokokawa Y, Liu X, Tsunoda K, Hayashi T, Jiménez-Rolando B, Martin-Merida MI, Avila-Fernandez A, Salas EC, Garcia-Sandoval B, Ayuso C, Sharon D, Kohl S, Huckfeldt RM, Banin E, Pennesi ME, Khan AO, Wissinger B, Webster AR, Heon E, Boon CJF, Zrenner E, Michaelides M. KCNV2-associated retinopathy: genotype-phenotype correlations - KCNV2 study group report 3. Br J Ophthalmol 2023;Abstract
BACKGROUND/AIMS: To investigate genotype-phenotype associations in patients with KCNV2 retinopathy. METHODS: Review of clinical notes, best-corrected visual acuity (BCVA), molecular variants, electroretinography (ERG) and retinal imaging. Subjects were grouped according to the combination of KCNV2 variants-two loss-of-function (TLOF), two missense (TM) or one of each (MLOF)-and parameters were compared. RESULTS: Ninety-two patients were included. The mean age of onset (mean±SD) in TLOF (n=55), TM (n=23) and MLOF (n=14) groups was 3.51±0.58, 4.07±2.76 and 5.54±3.38 years, respectively. The mean LogMAR BCVA (±SD) at baseline in TLOF, TM and MLOF groups was 0.89±0.25, 0.67±0.38 and 0.81±0.35 for right, and 0.88±0.26, 0.69±0.33 and 0.78±0.33 for left eyes, respectively. The difference in BCVA between groups at baseline was significant in right (p=0.03) and left eyes (p=0.035). Mean outer nuclear layer thickness (±SD) at baseline in TLOF, MLOF and TM groups was 37.07±15.20 µm, 40.67±12.53 and 40.38±18.67, respectively, which was not significantly different (p=0.85). The mean ellipsoid zone width (EZW) loss (±SD) was 2051 µm (±1318) for patients in the TLOF, and 1314 µm (±965) for MLOF. Only one patient in the TM group had EZW loss at presentation. There was considerable overlap in ERG findings, although the largest DA 10 ERG b-waves were associated with TLOF and the smallest with TM variants. CONCLUSIONS: Patients with missense alterations had better BCVA and greater structural integrity. This is important for patient prognostication and counselling, as well as stratification for future gene therapy trials.
Yin Z, Rosenzweig N, Kleemann KL, Zhang X, Brandão W, Margeta MA, Schroeder C, Sivanathan KN, Silveira S, Gauthier C, Mallah D, Pitts KM, Durao A, Herron S, Shorey H, Cheng Y, Barry J-L, Krishnan RK, Wakelin S, Rhee J, Yung A, Aronchik M, Wang C, Jain N, Bao X, Gerrits E, Brouwer N, Deik A, Tenen DG, Ikezu T, Santander NG, McKinsey GL, Baufeld C, Sheppard D, Krasemann S, Nowarski R, Eggen BJL, Clish C, Tanzi RE, Madore C, Arnold TD, Holtzman DM, Butovsky O. APOE4 impairs the microglial response in Alzheimer's disease by inducing TGFβ-mediated checkpoints. Nat Immunol 2023;24(11):1839-1853.Abstract
The APOE4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). The contribution of microglial APOE4 to AD pathogenesis is unknown, although APOE has the most enriched gene expression in neurodegenerative microglia (MGnD). Here, we show in mice and humans a negative role of microglial APOE4 in the induction of the MGnD response to neurodegeneration. Deletion of microglial APOE4 restores the MGnD phenotype associated with neuroprotection in P301S tau transgenic mice and decreases pathology in APP/PS1 mice. MGnD-astrocyte cross-talk associated with β-amyloid (Aβ) plaque encapsulation and clearance are mediated via LGALS3 signaling following microglial APOE4 deletion. In the brains of AD donors carrying the APOE4 allele, we found a sex-dependent reciprocal induction of AD risk factors associated with suppression of MGnD genes in females, including LGALS3, compared to individuals homozygous for the APOE3 allele. Mechanistically, APOE4-mediated induction of ITGB8-transforming growth factor-β (TGFβ) signaling impairs the MGnD response via upregulation of microglial homeostatic checkpoints, including Inpp5d, in mice. Deletion of Inpp5d in microglia restores MGnD-astrocyte cross-talk and facilitates plaque clearance in APP/PS1 mice. We identify the microglial APOE4-ITGB8-TGFβ pathway as a negative regulator of microglial response to AD pathology, and restoring the MGnD phenotype via blocking ITGB8-TGFβ signaling provides a promising therapeutic intervention for AD.
Goto S, Zhang Y, Vyas SA, Zhu Q, Wildsoet CF. Changes in Expression in BMP2 and Two Closely Related Genes in Guinea Pig Retinal Pigment Epithelium during Induction and Recovery from Myopia. Biomolecules 2023;13(9)Abstract
PURPOSE: We previously reported differential gene expression of the bone morphogenetic protein 2 (Bmp2) in guinea pig retinal pigment epithelium (RPE) after 1 day of hyperopic defocus, imposed with a negative contact lens (CLs). The study reported here sought to obtain insights into the temporal profiles of gene expression changes in Bmp2, as well as those of two closely related genes, the inhibitor of DNA binding 3 (Id3) and Noggin (Nog), both during myopia induction and when the CL treatment was terminated to allow recovery from induced myopia. METHODS: To induce myopia, 2-week-old pigmented guinea pigs (New Zealand strain, n = 8) wore monocular -10 diopter (D) rigid gas-permeable (RGP) CLs for one week, while the other eye served as a control. Ocular measurements were made at baseline, 3 days, and 7 days after the initiation of CL wear, with treatment then being terminated and additional measurements being made after a further 3 days, 1 week, and 2 weeks. Spherical equivalent refractive errors (SERs), axial length (AL), choroidal thickness (ChT), and scleral thickness (ScT) data were collected using retinoscopy, optical biometry (Lenstar), and spectral domain optical coherence tomography (SD-OCT), respectively. RPE samples were collected from both eyes of the guinea pigs after either 1 day or 1 week of CL wear or 1 day or 2 weeks after its termination, and RNA was subsequently isolated and subjected to quantitative real-time PCR (qRT-PCR) analyses, targeting the Bmp2, Id3, and Nog genes. RESULTS: Mean interocular differences (treated-control) in AL and SER were significantly different from baseline after 3 and 7 days of CL wear, consistent with induced myopia (p < 0.001 for all cases). Termination of CL wear resulted in the normalization (i.e., recovery) of the ALs and SERs of the treated eyes within 7 days, and the earlier significant ChT thinning with CL wear (p = 0004, day 7) was replaced by rapid thickening, which remained significant on day 7 (p = 0.009) but had normalized by day 14. The ChT changes were much smaller in magnitude than the AL changes in both phases. Interocular differences in the ScT showed no significant changes. The Bmp2 and Id3 genes were both significantly downregulated with CL wear, after 1 day (p = 0.012 and 0.016) and 7 days (p = 0.002 and 0.005), while Bmp2 gene expression increased and Nog gene expression decreased after the termination of CL wear, albeit transiently, which was significant on 1 day (p = 0.004 and 0.04) but not 2 weeks later. No change in Id3 gene expression was observed over the latter period. Conclusions: The above patterns of myopia induction and recovery validate this negative RGP-CL model as an alternative to traditional spectacle lens models for guinea pigs. The defocus-driven, sign-dependent changes in the expression of the Bmp2 gene in guinea pig RPE are consistent with observations in chicks and demonstrate the important role of BMP2 in eye growth regulation.
Yang M, Delcroix V, Lennikov A, Wang N, Makarenkova HP, Dartt DA. Genomic DNA activates the AIM2 inflammasome and STING pathways to induce inflammation in lacrimal gland myoepithelial cells. Ocul Surf 2023;Abstract
PURPOSE: Primary Sjögren's syndrome (pSS) is an autoimmune disease that mainly attacks the lacrimal glands causing severe aqueous-deficient dry eye. Clinical evidence indicates the DNA sensing mechanism in the pathogenesis of pSS. The purpose of the present study is to determine the pro-inflammatory effect of self-genomic DNA (gDNA) on myoepithelial cells (MECs), which along with acinar and ductal cells is a major cell type of the lacrimal gland. METHOD: MECs primary culture was acquired from female C57BL6J mice. Genomic DNA was extracted from the spleen of the same animal. The MECs were challenged with self-gDNA. The cytokine secretion was detected using supernatant by enzyme-linked immunosorbent assay (ELISA). The activation of inflammasomes was determined using FAM-FLICA. Cryosections of NOD.B10.H2b mouse model of pSS were obtained for immunofluorescence microscopy (IF), with Balb/C as control. RESULT: Treatment with gDNA activated AIM2 inflammasome assembly and function, leading to secretion of interleukin (IL)-1β and IL-18 in MECs. The stimulation of IL-1β secretion by gDNA appeared to be solely at the post-translational level, whereas IL-18 secretion was a combination of increased protein synthesis and post-translational modification. Genomic DNA also induced the activation of STimulators of INterferon Genes (STING), which correlated to the activation of STING in the lacrimal gland from the NOD.B10.H2b mouse. STING activation led to the secretion of IFN-β via Nuclear Factor-κB (NF-κB). The IFN-β further enhances the secretion of IL-1β. The contractility of MECs was disabled by treatment with gDNA or poly AnT, independent of the level of intracellular [Ca2+]. CONCLUSION: Self-gDNA induces a proinflammatory response in lacrimal gland MECs by activating both the AIM2 inflammasome and STING and thus may contribute to the pathogenesis of pSS.
Ferreira Neto LC, Alves MS, Prichula J, Agnes G, de Oliveira TF, Trentin D, Merib J. An affordable and semiautomated approach as a novel strategy for the extraction of DNA using magnetic ionic liquids followed by real time-polymerase chain reaction. Anal Methods 2023;15(30):3752-3757.Abstract
This technical note describes a novel and straightforward experimental strategy for the extraction/capture of DNA using magnetic ionic liquid (MIL) followed by real time-polymerase chain reaction (qPCR) analysis. An affordable and low-cost magneto-based multiwell platform was first examined for capturing DNA allowing for simultaneous extractions that increased the analysis throughput of the experimental workflow. This configuration was composed of a series of neodymium rod magnets attached to a multiwell device in which a magneto-active extraction phase (MIL) was suspended for a single drop microextraction (SDME) approach. In this configuration, up to 32 extractions were able to be performed simultaneously, and DNA was successfully extracted from aqueous samples. Furthermore, as a proof-of-concept, this affordable and simple experimental strategy proved to be efficient for the extraction/capture of DNA from challenging samples such as whole blood without any pretreatment. This fact also consists of important feature compared to previous methodologies that required additional steps of sample preparation.
Stuart KV, Pasquale LR, Kang JH, Foster PJ, Khawaja AP. Towards modifying the genetic predisposition for glaucoma: An overview of the contribution and interaction of genetic and environmental factors. Mol Aspects Med 2023;93:101203.Abstract
Glaucoma, the leading cause of irreversible blindness worldwide, is a complex human disease, with both genetic and environmental determinants. The availability of large-scale, population-based cohorts and biobanks, combining genotyping and detailed phenotyping, has greatly accelerated research into the aetiology of glaucoma in recent years. Hypothesis-free genome-wide association studies have furthered our understanding of the complex genetic architecture underpinning the disease, while epidemiological studies have provided advances in the identification and characterisation of environmental risk factors. It is increasingly recognised that the combined effects of genetic and environmental factors may confer a disease risk that reflects a departure from the simple additive effect of the two. These gene-environment interactions have been implicated in a host of complex human diseases, including glaucoma, and have several important diagnostic and therapeutic implications for future clinical practice. Importantly, the ability to modify the risk associated with a particular genetic makeup promises to lead to personalised recommendations for glaucoma prevention, as well as novel treatment approaches in years to come. Here we provide an overview of genetic and environmental risk factors for glaucoma, as well as reviewing the evidence and discussing the implications of gene-environment interactions for the disease.
Han X, Lains I, Li J, Li J, Chen Y, Yu B, Qi Q, Boerwinkle E, Kaplan R, Thyagarajan B, Daviglus M, Joslin CE, Cai J, Guasch-Ferré M, Tobias DK, Rimm E, Ascherio A, Costenbader K, Karlson E, Mucci L, Eliassen HA, Zeleznik O, Miller J, Vavvas DG, Kim IK, Silva R, Miller J, Hu F, Willett W, Lasky-Su J, Kraft P, Richards BJ, Macgregor S, Husain D, Liang L. Integrating genetics and metabolomics from multi-ethnic and multi-fluid data reveals putative mechanisms for age-related macular degeneration. Cell Rep Med 2023;4(7):101085.Abstract
Age-related macular degeneration (AMD) is a leading cause of blindness in older adults. Investigating shared genetic components between metabolites and AMD can enhance our understanding of its pathogenesis. We conduct metabolite genome-wide association studies (mGWASs) using multi-ethnic genetic and metabolomic data from up to 28,000 participants. With bidirectional Mendelian randomization analysis involving 16,144 advanced AMD cases and 17,832 controls, we identify 108 putatively causal relationships between plasma metabolites and advanced AMD. These metabolites are enriched in glycerophospholipid metabolism, lysophospholipid, triradylcglycerol, and long chain polyunsaturated fatty acid pathways. Bayesian genetic colocalization analysis and a customized metabolome-wide association approach prioritize putative causal AMD-associated metabolites. We find limited evidence linking urine metabolites to AMD risk. Our study emphasizes the contribution of plasma metabolites, particularly lipid-related pathways and genes, to AMD risk and uncovers numerous putative causal associations between metabolites and AMD risk.

Pages