Alex W Hewitt

Flinders Medical Centre, Tarndarnya, South Australia, Australia

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Publications (160)889.93 Total impact

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    ABSTRACT: Several individual studies have suggested that autosomal CpG methylation differs by sex both in terms of individual CpG sites and global autosomal CpG methylation. However, these findings have been inconsistent and plagued by spurious associations due to the cross reactivity of CpG probes on commercial microarrays. We collectively analysed 76 published studies (n = 6,795) for sex-associated differences in both autosomal and sex chromosome CpG sites. Overall autosomal methylation profiles varied substantially by study, and we encountered substantial batch effects. We accounted for these by conducting random effects meta-analysis for individual autosomal CpG methylation associations. After excluding non-specific probes, we found 184 autosomal CpG sites differentially methylated by sex after correction for multiple testing. In line with previous studies, average beta differences were small. Many of the most significantly associated CpG probes were new. Of note was differential CpG methylation in the promoters of genes thought to be involved in spermatogenesis and male fertility, such as SLC9A2, SPESP1, CRISP2, and NUPL1. Pathway analysis revealed overrepresentation of genes differentially methylated by sex in several broad Gene Ontology biological processes, including RNA splicing and DNA repair. This study represents a comprehensive analysis of sex-specific methylation patterns. We demonstrate the existence of sex-specific methylation profiles and report a large number of novel DNA methylation differences in autosomal CpG sites between sexes.
    BMC genomics. 11/2014; 15(1):981.
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    ABSTRACT: To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged <25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged <25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E-8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E-07), TOX (rs7823467, P = 3.47E-07) and LINC00340 (rs12212674, P = 1.49E-06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = -0.59, P = 2.10E-04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.
    Hum Genet. 11/2014;
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    ABSTRACT: Previous longitudinal studies suggest that depression and anxiety are associated with risk for cardiovascular disease. The aim of the present study was to test whether an association between depression and anxiety symptoms and retinal vessel caliber, an indicator of subclinical cardiovascular risk, is apparent as early as adolescence and young adulthood.
    Psychosomatic medicine. 11/2014;
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    ABSTRACT: To estimate and project the number of people affected worldwide by giant cell arteritis (GCA) by 2050. Modeling the number of people visually impaired as a result of this disease will help establish the projected morbidity and resource burden.
    The Journal of rheumatology. 11/2014;
  • New England Journal of Medicine 10/2014; 371(17):1652. · 54.42 Impact Factor
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    ABSTRACT: Purpose To investigate the presence of TBK1 copy number variations in a large well characterised Australian cohort of patients with glaucoma comprising both normal-tension glaucoma and high tension glaucoma cases. Design A retrospective cohort study Methods DNA samples from patients with normal-tension glaucoma, high-tension glaucoma and unaffected controls were screened for TBK1 copy number variations using real-time quantitative polymerase chain reaction. Samples with additional copies of the TBK1 gene were further tested using custom comparative genomic hybridization arrays. Results Four out of 334 normal-tension glaucoma cases (1.2%) were found to carry TBK1 copy number variations using quantitative polymerase-chain reaction. One extra dose of the TBK1 gene (duplication), was detected in three normal-tension glaucoma patients, while two extra doses of the gene (triplication), was detected in a fourth normal-tension glaucoma patient. The results were further confirmed by custom comparative genomic hybridization arrays. Further the TBK1 copy number variation segregated with normal-tension glaucoma in the family members of the probands, showing an autosomal dominant pattern of inheritance. No TBK1 copy number variations were detected in 1045 Australian patients with high-tension glaucoma or in 254 unaffected controls. Conclusion We report the presence of TBK1 copy number variations in our Australian normal-tension glaucoma cohort, including the first example of more than one extra copy of this gene in glaucoma patients (gene triplication). These results confirm TBK1 to be an important cause of normal-tension glaucoma, but do not suggest common involvement in high-tension glaucoma.
    American Journal of Ophthalmology. 10/2014;
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    ABSTRACT: Background The aim was to determine whether latitudinal (Queensland versus Tasmania) variation in reported disease frequency in Australia may be biased by differences in population.MethodsA retrospective analysis was conducted from data of two large Australian twin studies (n = 1,835) having undertaken ophthalmic examination, namely, Twins Eye Study in Tasmania (TEST) and the Brisbane Adolescent Twins Study (BATS). Ordinal logistic regression was used to compute odds ratios and predicted probabilities for each category of eye colour by state.ResultsTasmanian residence was associated with lower odds of darker iris colour (odds ratio 0.77, 95% CI [0.63–0.95]) signifying that participants living in Tasmania (TAS) are less likely to have darker-coloured irides than those residing in Queensland (QLD). For individuals living in Tasmania the predicted probability (TAS versus QLD) of having light blue eyes was greater (16.7 versus 13.3 per cent), approximately the same for green eyes and less for brown/dark brown-coloured eyes (6.2 versus 7.9 per cent).Conclusions We found a general trend of individuals living in the southern states (TAS/VIC) of Australia having lighter-coloured irides compared to those living in the north (QLD). This finding has potential implications for all epidemiological research conducted to explore differences in UV-associated disease frequency in Australia, as population heterogeneity may confound the estimates obtained.
    Clinical and Experimental Optometry 10/2014; · 0.92 Impact Factor
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    ABSTRACT: Background Sun exposure is associated with several ophthalmic diseases, including pterygium which may develop in adolescence. This study reports the prevalence of pterygium and its associations in a large cohort of young Australian adults. Conjunctival ultraviolet autofluorescence, a biomarker of ocular sun exposure, has recently been characterised in some Australian populations.DesignCross-sectional population-based study.Participants1344 subjects aged 18-22 years in the Western Australian Pregnancy Cohort (Raine) Study.Methods Standardised colour and ultraviolet autofluorescence photographs of the nasal and temporal conjunctiva were taken, and assessed for presence of pterygium and area of autofluorescence. Sun exposure and protective factors were assessed by structured questionnaire.Main outcome measuresArea of conjunctival ultraviolet autofluorescence in mm2 and presence of pterygium.ResultsMedian total conjunctival autofluorescence was 44.2mm2 (interquartile range [IQR] 20.2-69.8mm2). Median conjunctival autofluorescence was higher in nasal than in temporal quadrants (23.8mm2 vs 18.9mm2, p<0.001), but did not differ according to age or gender. Higher body mass index was associated with lower levels of autofluorescence. Total autofluorescence increased with increasing time spent outdoors. Prevalence of pterygium was 1.2% (95% CI 0.6-1.8%), and was associated with male gender (odds ratio [OR] 6.71, p=0.012). Participants with pterygium had significantly more conjunctival autofluorescence than those without (median 73.4mm2 vs 44.0mm2, p=0.001).Conclusions Conjunctival ultraviolet autofluorescence is associated with increased time spent outdoors, and increased prevalence of pterygium. The association of this biomarker with other ophthalmohelioses, including cataract, ocular surface squamous neoplasia and eyelid malignancy, has yet to be determined.
    Clinical and Experimental Ophthalmology 10/2014; · 1.96 Impact Factor
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    ABSTRACT: Previous studies have demonstrated a small but significant transient increase in intraocular pressure (IOP) in individuals wearing certain types of swimming goggles. These findings suggested that wearing goggles could represent a significant risk factor for developing and/or worsening of glaucoma in people who swim regularly. The aim of this study was to determine if glaucoma prevalence is increased among adult swimmers.
    British Journal of Ophthalmology 09/2014; · 2.73 Impact Factor
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    ABSTRACT: Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multi-ancestry participants for IOP. We confirm genetic association of known loci for IOP and primary open-angle glaucoma (POAG) and identify four new IOP-associated loci located on chromosome 3q25.31 within the FNDC3B gene (P = 4.19 × 10(-8) for rs6445055), two on chromosome 9 (P = 2.80 × 10(-11) for rs2472493 near ABCA1 and P = 6.39 × 10(-11) for rs8176693 within ABO) and one on chromosome 11p11.2 (best P = 1.04 × 10(-11) for rs747782). Separate meta-analyses of 4 independent POAG cohorts, totaling 4,284 cases and 95,560 controls, showed that 3 of these loci for IOP were also associated with POAG.
    Nature Genetics 08/2014; · 35.21 Impact Factor
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    ABSTRACT: Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness worldwide. We performed a genome-wide association study in an Australian discovery cohort comprising 1,155 cases with advanced POAG and 1,992 controls. We investigated the association of the top SNPs from the discovery stage in two Australian replication cohorts (932 cases and 6,862 controls total) and two US replication cohorts (2,616 cases and 2,634 controls total). Meta-analysis of all cohorts identified three loci newly associated with development of POAG. These loci are located upstream of ABCA1 (rs2472493[G], odds ratio (OR) = 1.31, P = 2.1 × 10(-19)), within AFAP1 (rs4619890[G], OR = 1.20, P = 7.0 × 10(-10)) and within GMDS (rs11969985[G], OR = 1.31, P = 7.7 × 10(-10)). Using RT-PCR and immunolabeling, we show that these genes are expressed within human retina, optic nerve and trabecular meshwork and that ABCA1 and AFAP1 are also expressed in retinal ganglion cells.
    Nature Genetics 08/2014; · 35.21 Impact Factor
  • David A Mackey, Alex W Hewitt
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    ABSTRACT: Much progress in our understanding of the genetic profile of many ophthalmic diseases has been made over the last decade. Identification of novel gene associations allows insight into the mechanisms of disease and potentially enables the identification of individuals at increased risk, as well as facilitating the development of new treatments. We highlight key recent discoveries using the genome-wide association study design.
    Current opinion in ophthalmology. 07/2014;
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    ABSTRACT: Gill, KP, Hewitt, AW, Davidson, KC, Pebay A, Wong RCB. Methods of retinal ganglion cell differentiation from pluripotent stem cells. Tran Vis Sci Tech. 2014; 3(4):2, http://tvstjournal.org/doi/full/ 10.1167/tvst.3.4.2, doi:10.1167/tvst. 3.4.2 Glaucoma, the worldwide leading cause of irreversible blindness, is characterized by progressive degeneration of the optic nerve and loss of retinal ganglion cells. Research into glaucoma pathogenesis has been hampered by difficulties in isolating and culturing retinal ganglion cells in vitro. However, recent improvements in laboratory techniques have enabled the generation of a variety of mature cell types from pluripotent stem cells, including retinal ganglion cells. Indeed, stem cell-based approaches have the potential to revolutionize the field by providing an unlimited source of cells for replacement therapies and by enabling development of in vitro disease models for drug screening and research. Consequently, research aimed at directing pluripotent stem cells to differentiate into retinal ganglion cells has expanded dramatically during the past decade, resulting in significant advances in technique and efficiency. In this paper, we review the methodology for retinal ganglion cell differentiation from pluripotent stem cells of both mouse and human origin and summarize how these techniques have opened up new avenues for modelling glaucoma. Generation of stem cell–derived retinal ganglion cells will have significant translational values, providing an in vitro platform to study the mechanisms responsible for pathogenesis and for drug screening to improve treatment options, as well as for the development of cell therapies for optic neuropathies such as glaucoma.
    Translational vision science & technology. 07/2014; 3(4).
  • Clinical and Experimental Ophthalmology 07/2014; · 1.96 Impact Factor
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    ABSTRACT: Purpose: To investigate the association between serum vitamin D levels and myopia in young adults. Methods: A total of 946 individuals participating in the 20-year follow-up of the Western Australian Pregnancy Cohort (Raine) Study were included in this study. Ethnicity, parental myopia and education status were ascertained by self-reported questionnaire. A comprehensive ophthalmic examination was performed, including post-cycloplegic autorefraction and conjunctival UV autofluorescence photography. Serum 25-hydroxyvitamin D3 (25(OH)D3) concentrations were determined using mass spectrometry. The association between serum 25(OH)D3 concentrations and prevalent myopia was determined using multivariable logistic regression. Myopia was defined as mean spherical equivalent ≤ -0.5 diopters. Results: Of the 946 participants, 221 (23.4%) had myopia (n=725 non-myopic). Myopic subjects had lower serum 25(OH)D3 concentrations compared to non-myopic participants (median 67.6 nmol vs. 72.5 nmol, p=0.003). In univariable analysis, lower serum 25(OH)D3 concentration was associated with higher risk of having myopia (odds ratio [OR] for <50nmol/L vs. ≥50nmol/L: 2.63; 95CI% 1.71 - 4.05; p <0.001). This association persisted after adjustment for potential confounders, including age, sex, ethnicity, parental myopia, education status and ocular sun-exposure biomarker score (Adjusted OR 2.07; 95%CI 1.29-3.32; p=0.002). Conclusions: Myopic participants had significantly lower 25(OH)D3 concentrations. The prevalence of myopia was significantly higher in individuals with vitamin D deficiency compared to the individuals with sufficient levels. Longitudinal studies are warranted to investigate whether higher serum 25(OH)D3 concentration is protective against myopia or whether it is acting as a proxy for some other biologically effective consequence of sun exposure.
    Investigative ophthalmology & visual science. 06/2014;
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    ABSTRACT: IMPORTANCE Nanophthalmos is a congenital disorder characterized by small eyes, with the main complications being severe hyperopia and angle-closure glaucoma. OBJECTIVE To perform a clinical and genetic investigation of a large white family with autosomal dominant nanophthalmos. DESIGN, SETTING, AND PARTICIPANTS Detailed clinical evaluation and a genome-wide linkage scan was conducted in the family NNO-SA1. Linkage was evaluated with a 10K single-nucleotide polymorphism array, followed by whole exome sequencing, to identify novel segregating coding variants within the linked region. The candidate gene was screened for mutations in additional independent families by direct sequencing of the coding exons and intron/exon boundaries. The expression pattern of the candidate gene in ocular tissues was analyzed by reverse transcriptase-polymerase chain reaction. Participants were recruited through ophthalmology clinics at Flinders Medical Centre, Adelaide, South Australia, Australia. Nanophthalmos was defined as an axial length less than 20.0 mm and/or refractive error greater than +7.00. Of the 35 available individuals from family NNO-SA1, 16 participants (46%) had a diagnosis of nanophthalmos, with mean refraction of +11.8 D and mean axial length of 17.6 mm. Unaffected unrelated individuals serving as controls were screened for the identified mutation. Additional independent families with clinically diagnosed nanophthalmos were also recruited. MAIN OUTCOMES AND MEASURES Nanophthalmos status. RESULTS Significant linkage was detected on chromosome 17 between single-nucleotide polymorphism markers rs2323659 and rs967293, with a maximum location score of 4.1. Exome sequencing identified a single novel segregating missense variant within the linkage region located in exon 8 of the transmembrane-98 (TMEM98) gene c.577G>C (p.Ala193Pro), which was absent in the Exome Variant Server database and among 285 local white individuals serving as controls. The TMEM98 gene was expressed in all ocular tissues tested including sclera and optic nerve head. CONCLUSIONS AND RELEVANCE A novel gene associated with nanophthalmos, TMEM98 most likely represents the cause of the disease in this family. To our knowledge, this represents the first gene identified causing autosomal dominant nanophthalmos.
    Jama Ophthalmology 05/2014; · 3.83 Impact Factor
  • The Medical journal of Australia 05/2014; 200(9):521-2. · 2.85 Impact Factor
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    ABSTRACT: Objectives Through comprehensive ophthalmic examination of adult offspring we sought to determine the impact of multiple prenatal ultrasound scans on ocular development.Methods2743 pregnant women recruited to the Western Australian Pregnancy (Raine) Cohort study during 1989–1991 were randomised to receive either multiple prenatal ultrasounds and Doppler flow studies (intensive group) or single ultrasound at 18 weeks’ gestation at King Edward Memorial Hospital, Western Australia. Neonatal birth weight of offspring and other physical measurements were collected prospectively. At age 20 years, participants underwent a comprehensive ophthalmic examination including measures of ocular biometry and visual acuity.ResultsComplete data were available for 1134 adult offspring participants. The mothers of 563 of these had been randomised to receive multiple prenatal ultrasounds. The mean age of participants at follow-up was 20.0 years. There was no statistically significant difference between the two groups with regard to ocular biometric or visual outcomes, except for slightly higher intraocular pressures identified in individuals exposed to multiple ultrasounds. Although infants in the intensive-ultrasound arm were more likely to have birth weights in the lower quartiles, this was not reflected in adult eye development. Axial length, lens thickness, corneal curvature and thickness and optic-disc-to-cup ratio were not significantly influenced by the more frequent ultrasound protocol.Conclusions Prior to this study, there was a paucity of ultrasound safety data for eye development. We found that frequent in utero ultrasound, including B-mode imaging and use of spectral Doppler mode, from 18 weeks’ gestation had no significant impact on visual outcomes or ocular biometry.
    Ultrasound in Obstetrics and Gynecology 04/2014; · 3.56 Impact Factor
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    ABSTRACT: PurposeTo investigate the age range for which cycloplegia provides additional information compared with non-cycloplegic refraction in teenagers and young adults.Methods Data for 1295 subjects (704 female; 591 male) from the Twins Eye Study in Tasmania (TEST) and the Brisbane Adolescent Twin Study (mean age: 19.65 ± 3.56, range: 13–26 years) were included. For all participants, cycloplegia was induced by instillation of either one drop of 1% cyclopentolate (13–14 years) or one drop of 1% tropicamide (15–26 years). Pre- and postcycloplegic refractive errors for both eyes were measured using a Humphrey-598 automated refractor and spherical equivalents of refractive error were calculated. Generalized Estimating Equations (GEE) were used to model the spherical equivalent refraction (SER) for each eye against age (by year) and axial length (in the given eye).ResultsThe mean group difference between pre- and postcycloplegic SER (post minus pre) was 0.17 ± 0.52 D and 0.12 ± 0.51 D for the right and left eyes, respectively, indicating that postcycloplegic refraction was generally more hyperopic/less myopic. The mean difference between pre- and postcycloplegic SER decreased from 0.36 ± 0.41 D in the 13-year-olds to 0.06 ± 0.50 D in people aged 25 years. After adjusting for family-relatedness, the difference between pre- and postcycloplegia SER was significant in all age groups up until the age of 20 years.Conclusions Non-cycloplegic autorefraction can result in group mean SER differences of greater myopia than cycloplegic autorefraction and occurs in teenagers (13–19 years of age), but not in adults 20–26 years. These data suggest that cycloplegia is not required in population estimates of refractive error for young adults once they reach approximately 20 years of age.
    Acta ophthalmologica 03/2014; · 2.44 Impact Factor
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    ABSTRACT: Recent genome-wide association studies for diabetic retinopathy (DR) have identified novel single nucleotide polymorphisms associated with this potentially blinding disease. These markers could prove useful in risk profiling, if the association are validated by replication. To date, these associations have not been well assessed in independent cohorts. The objective of this study was to ascertain any association of these polymorphisms with advanced stages of DR. A total of 463 patients who had either type 1 (n=46) or 2 (n=417) diabetes were genotyped for 24 single nucleotide polymorphisms previously implicated in DR. Cases (n=163) were defined as people with severe non-proliferative DR or proliferative DR. Control participants (n=300) with a confirmed duration of diabetes of at least five years had either no evidence of DR or only mild DR. Two SNPs (rs1073203 and rs4838605) were found to be significantly associated with DR in patients with diabetes after adjusting for co-variants; rs1073203-G (p=0.012, odds ratio (OR)=0.317, 95% CI:0.129-0.778), rs1073203 in a dominant model (p=0.005, OR=0.251, 95% CI:0.096-0.655), rs4838605 in an additive model (p=0.047, OR=1.650, 95% CI:1.007-2.703), In a dominant model rs1073203 (p=0.027, OR=1.400, 95% CI:0.101-0.857), was significantly associated with diabetic retinopathy in type 2 diabetes after adjustment for co-variants. This study was sufficiently powered to replicate previous findings. CONCLUSIONS. This study has confirmed two variants (rs1073203 and rs4838605) are associated with advanced stages of DR in our cohort. The underlying genes in these candidate regions provide interesting future gene association targets for understanding the pathogenesis of DR.
    Investigative ophthalmology & visual science 02/2014; · 3.43 Impact Factor

Publication Stats

2k Citations
889.93 Total Impact Points

Institutions

  • 2014
    • Flinders Medical Centre
      Tarndarnya, South Australia, Australia
  • 2013–2014
    • Victoria University Melbourne
      Melbourne, Victoria, Australia
  • 2008–2014
    • University of Melbourne
      • • Centre for Eye Research Australia
      • • Department of Ophthalmology
      Melbourne, Victoria, Australia
  • 2006–2014
    • Royal Victorian Eye and Ear Hospital
      Melbourne, Victoria, Australia
  • 2005–2014
    • University of Tasmania
      • Menzies Research Institute
      Hobart Town, Tasmania, Australia
  • 2010–2013
    • Erasmus MC
      • Department of Epidemiology
      Rotterdam, South Holland, Netherlands
    • King's College London
      • Department of Twin Research and Genetic Epidemiology
      London, ENG, United Kingdom
  • 2009–2013
    • University of Western Australia
      • Lions Eye Institute
      Perth City, Western Australia, Australia
  • 2008–2013
    • Queensland Institute of Medical Research
      Brisbane, Queensland, Australia
  • 2006–2012
    • Flinders University
      • Department of Ophthalmology
      Adelaide, South Australia, Australia
  • 2005–2006
    • The Royal Hobart Hospital
      Hobart Town, Tasmania, Australia