Publications by authors named "Susan E Williams"

23 Publications

  • Page 1 of 1

Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries.

Nat Commun 2021 02 24;12(1):1258. Epub 2021 Feb 24.

Faculty of Medicine, University of Southampton, Southampton, UK.

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.
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http://dx.doi.org/10.1038/s41467-020-20851-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904932PMC
February 2021

Association of Rare CYP39A1 Variants With Exfoliation Syndrome Involving the Anterior Chamber of the Eye.

JAMA 2021 02;325(8):753-764

Department of Ophthalmology, Asahikawa Medical University, Asahikawa, Japan.

Importance: Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness.

Objective: To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function.

Design, Setting, And Participants: A 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome.

Exposures: Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function.

Main Outcomes And Measures: The primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 × 10-6. The secondary outcomes included biochemical enzymatic assays and gene expression analyses.

Results: The discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 × 10-7). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4% [interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome.

Conclusions And Relevance: In this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings.
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http://dx.doi.org/10.1001/jama.2021.0507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903258PMC
February 2021

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

JAMA 2019 11;322(17):1682-1691

Clayton Eye Care Center Management Inc, Marrow, Georgia.

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.
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http://dx.doi.org/10.1001/jama.2019.16161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865235PMC
November 2019

The protective variant rs7173049 at LOXL1 locus impacts on retinoic acid signaling pathway in pseudoexfoliation syndrome.

Hum Mol Genet 2019 08;28(15):2531-2548

Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

LOXL1 (lysyl oxidase-like 1) has been identified as the major effect locus in pseudoexfoliation (PEX) syndrome, a fibrotic disorder of the extracellular matrix and frequent cause of chronic open-angle glaucoma. However, all known PEX-associated common variants show allele effect reversal in populations of different ancestry, casting doubt on their biological significance. Based on extensive LOXL1 deep sequencing, we report here the identification of a common non-coding sequence variant, rs7173049A>G, located downstream of LOXL1, consistently associated with a decrease in PEX risk (odds ratio, OR = 0.63; P = 6.33 × 10-31) in nine different ethnic populations. We provide experimental evidence for a functional enhancer-like regulatory activity of the genomic region surrounding rs7173049 influencing expression levels of ISLR2 (immunoglobulin superfamily containing leucine-rich repeat protein 2) and STRA6 [stimulated by retinoic acid (RA) receptor 6], apparently mediated by allele-specific binding of the transcription factor thyroid hormone receptor beta. We further show that the protective rs7173049-G allele correlates with increased tissue expression levels of ISLR2 and STRA6 and that both genes are significantly downregulated in tissues of PEX patients together with other key components of the STRA6 receptor-driven RA signaling pathway. siRNA-mediated downregulation of RA signaling induces upregulation of LOXL1 and PEX-associated matrix genes in PEX-relevant cell types. These data indicate that dysregulation of STRA6 and impaired retinoid metabolism are involved in the pathophysiology of PEX syndrome and that the variant rs7173049-G, which represents the first common variant at the broad LOXL1 locus without allele effect reversal, mediates a protective effect through upregulation of STRA6 in ocular tissues.
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http://dx.doi.org/10.1093/hmg/ddz075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6644155PMC
August 2019

Familial congenital cataract, coloboma, and nystagmus phenotype with variable expression caused by mutation in in a South African family.

Mol Vis 2018 9;24:407-413. Epub 2018 Jun 9.

Division of Ophthalmology, Department of Neurosciences, University of Witwatersrand, Johannesburg, South Africa.

Purpose: To report on a clinical and genetic investigation of a large, multigenerational South African family of mixed ancestry with autosomal dominant congenital cataracts, coloboma, and nystagmus.

Methods: Ophthalmic examination was performed in 27 individuals from the same admixed South African family. DNA was sampled from either peripheral blood or buccal swabs in all 27 individuals, and whole genome sequencing was performed in six individuals. Sanger sequencing was used to validate the probable mutation in the remaining family members.

Results: Twenty-seven family members with 19 affected individuals were included in the study. The predominant phenotype, with highly variable expression, was congenital cataract (14 individuals), posterior segment coloboma (17 individuals), and nystagmus (18 individuals). Other features present included high myopia, microcornea, and strabismus. An R208W mutation in (dbSNP rs757259413; HGMD CM930572; NM_000280.3:c.622G>A; NP_000271.1:p.Arg208Trp) was identified as being the most probable pathogenic mutation. Cosegregation of the mutation with the phenotype was confirmed in all 27 family members.

Conclusions: is a highly conserved gene crucial for normal oculogenesis, and although mutations within the gene may cause an array of ocular developmental abnormalities, most are associated with aniridia and aniridia-related ocular defects. The observation that aniridia phenotypes are largely associated with nonsense mutations and milder non-aniridia phenotypes with missense mutations suggested that there may be specific genotype-phenotype correlations for the gene. The R208W mutation in identified in this family challenges this theory as it has previously been reported in three unrelated families and is associated with aniridia and non-aniridia phenotypes across the four families. with its wide phenotypic associations and highly variable expression should be considered a candidate gene in the diagnostic screen for any ocular developmental abnormality.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5993530PMC
November 2018

Genome-wide association study identifies seven novel susceptibility loci for primary open-angle glaucoma.

Hum Mol Genet 2018 04;27(8):1486-1496

Department of Ophthalmology and Visual Sciences, Hiroshima University, Hiroshima, Japan.

Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide for which 15 disease-associated loci had been discovered. Among them, only 5 loci have been associated with POAG in Asians. We carried out a genome-wide association study and a replication study that included a total of 7378 POAG cases and 36 385 controls from a Japanese population. After combining the genome-wide association study and the two replication sets, we identified 11 POAG-associated loci, including 4 known (CDKN2B-AS1, ABCA1, SIX6 and AFAP1) and 7 novel loci (FNDC3B, ANKRD55-MAP3K1, LMX1B, LHPP, HMGA2, MEIS2 and LOXL1) at a genome-wide significance level (P < 5.0×10-8), bringing the total number of POAG-susceptibility loci to 22. The 7 novel variants were subsequently evaluated in a multiethnic population comprising non-Japanese East Asians (1008 cases, 591 controls), Europeans (5008 cases, 35 472 controls) and Africans (2341 cases, 2037 controls). The candidate genes located within the new loci were related to ocular development (LMX1B, HMGA2 and MAP3K1) and glaucoma-related phenotypes (FNDC3B, LMX1B and LOXL1). Pathway analysis suggested epidermal growth factor receptor signaling might be involved in POAG pathogenesis. Genetic correlation analysis revealed the relationships between POAG and systemic diseases, including type 2 diabetes and cardiovascular diseases. These results improve our understanding of the genetic factors that affect the risk of developing POAG and provide new insight into the genetic architecture of POAG in Asians.
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http://dx.doi.org/10.1093/hmg/ddy053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251544PMC
April 2018

Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci.

Nat Genet 2017 07 29;49(7):993-1004. Epub 2017 May 29.

Department of Ophthalmology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 × 10) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.
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http://dx.doi.org/10.1038/ng.3875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685441PMC
July 2017

Confusion and hypercalcemia in an 80-year-old man.

Cleve Clin J Med 2017 Apr;84(4):281-286

Department of Endocrinology, Diabetes, and Metabolism, Cleveland Clinic, Cleveland, OH, USA.

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http://dx.doi.org/10.3949/ccjm.84a.16017DOI Listing
April 2017

Efficacy of Bimatoprost Plus Timolol Fixed Combination in Open Angle Glaucoma Patients Previously Treated with Dorzolamide Plus Timolol Fixed Combination.

Curr Eye Res 2016 11 26;41(11):1433-1437. Epub 2016 Apr 26.

a University Eye Clinic, San Giuseppe Hospital , University of Milan , Milan, Italy.

Purpose: To evaluate the efficacy and safety of bimatoprost plus timolol fixed combination (BTFC) in patients with primary open angle glaucoma (POAG) previously treated with dorzolamide plus timolol fixed combination (DTFC).

Materials And Methods: Retrospective, medical records review study. Medical records of patients with POAG previously treated with DTFC and then switched to BTFC for poor intraocular pressure (IOP) control or ocular discomfort were included in the analysis. One baseline IOP diurnal curve, and one diurnal curve under each treatment were required to be eligible for this study. The primary outcome was to compare the mean diurnal IOP between DTFC and BTFC. Secondary outcomes were to compare the IOP diurnal fluctuation, and the percentage of patients achieving a target IOP <14, <16, and <18 mmHg between the two treatments.

Results: Medical records of 96 patients were analyzed (mean age 65.8 years ± 7.2, range 39-89 years). The mean diurnal IOP was 23.7 ± 3.8 mmHg at baseline, 16.9 ± 3.4 mmHg with DTFC and 15.1 ± 2.9 mmHg after therapy was switched to BTFC (p < 0.0001 each treatment vs baseline; p < 0.0001 DTFC vs BTFC). The proportion of patients achieving a mean diurnal IOP <18, <16, and <14 mmHg was 76%, 35.4%, and 12.5% with DTFC and 81.2%, 68.8%, and 37.5% with BTFC (p = 0.20, p < 0.01, and p < 0.0001 between the two treatments, respectively). IOP fluctuation did not differ significantly between the treatments.

Conclusion: BTFC can provide additional lowering in the mean diurnal IOP in patients previously treated with DTFC with no significant differences in the safety and tolerability profile.
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http://dx.doi.org/10.3109/02713683.2015.1125507DOI Listing
November 2016

The Ocular Surface in Medically Controlled Glaucoma: An In Vivo Confocal Study.

Invest Ophthalmol Vis Sci 2016 Mar;57(3):1003-10

Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy 2Eye Clinic San Giuseppe Hospital, Milan, Italy.

Purpose: To study clinical and in vivo laser scanning confocal microscopy (LSCM) ocular surface findings in stable, medically controlled primary open-angle glaucoma (MCPOAG) patients.

Methods: We recruited 100 consecutive patients with MCPOAG and 50 healthy controls. Patients had to have been treated with the same medical regimen without variation for the 18 months before enrollment and were excluded if there was a history of dry eye prior to glaucoma diagnosis. Each participant underwent ocular surface clinical and LSCM examination.

Results: In MCPOAG patients, subbasal nerve length and tortuosity and dendritic cell density were increased compared to controls (P < 0.01), but there were no clinical abnormalities. Patients treated with preserved drugs (n = 80) had reduced tear film breakup time (P < 0.05, ANOVA), and those preserved with benzalkonium chloride (n = 72) had reduced Schirmer test values (P < 0.001). Patients (n = 50) treated with two or more drugs had increased lissamine green conjunctival staining (P < 0.001, LSD post hoc test). Patients (n = 29) treated with three or more eye drops daily had decreased Schirmer test values. Laser scanning confocal microscopy showed subbasal changes related to preservatives, type and number of drugs, and number of eye drops.

Conclusions: In stable MCPOAG patients without dry eye history, the ocular surface changes due to antiglaucoma medications are mostly subclinical. Active ingredients, preservatives, number of concomitant drugs, and number of eye drops instilled per day are all elements that can induce ocular surface changes. The clinical relevance of these changes remains to be determined.
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http://dx.doi.org/10.1167/iovs.15-17455DOI Listing
March 2016

Genetic variants and cellular stressors associated with exfoliation syndrome modulate promoter activity of a lncRNA within the LOXL1 locus.

Hum Mol Genet 2015 Nov 25;24(22):6552-63. Epub 2015 Aug 25.

Division of Ophthalmology, Department of Neurosciences, University of the Witwatersrand, Johannesburg, South Africa and.

Exfoliation syndrome (XFS) is a common, age-related, systemic fibrillinopathy. It greatly increases risk of exfoliation glaucoma (XFG), a major worldwide cause of irreversible blindness. Coding variants in the lysyl oxidase-like 1 (LOXL1) gene are strongly associated with XFS in all studied populations, but a functional role for these variants has not been established. To identify additional candidate functional variants, we sequenced the entire LOXL1 genomic locus (∼40 kb) in 50 indigenous, black South African XFS cases and 50 matched controls. The variants with the strongest evidence of association were located in a well-defined 7-kb region bounded by the 3'-end of exon 1 and the adjacent region of intron 1 of LOXL1. We replicated this finding in US Caucasian (91 cases/1031 controls), German (771 cases/1365 controls) and Japanese (1484 cases/1188 controls) populations. The region of peak association lies upstream of LOXL1-AS1, a long non-coding RNA (lncRNA) encoded on the opposite strand of LOXL1. We show that this region contains a promoter and, importantly, that the strongly associated XFS risk alleles in the South African population are functional variants that significantly modulate the activity of this promoter. LOXL1-AS1 expression is also significantly altered in response to oxidative stress in human lens epithelial cells and in response to cyclic mechanical stress in human Schlemm's canal endothelial cells. Taken together, these findings support a functional role for the LOXL1-AS1 lncRNA in cellular stress response and suggest that dysregulation of its expression by genetic risk variants plays a key role in XFS pathogenesis.
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http://dx.doi.org/10.1093/hmg/ddv347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4614704PMC
November 2015

Acute Kidney Dysfunction in Patients with Chronic Hepatitis C Virus Infection: Analysis of Viral and Non-viral Factors.

J Clin Exp Hepatol 2014 Mar 20;4(1):8-13. Epub 2014 Feb 20.

Division of Gastroenterology, New York Medical College, Metropolitan Hospital Center, 1901 First Avenue, New York 10029, NY, USA.

Background: Multiple studies have shown a relationship between chronic hepatitis C infection and chronic kidney disease. The prevalence, severity, underlying etiologies and predictors of acute kidney dysfunction (AKD) events in patients with hepatitis C has not been studied.

Methods: We investigated viral and non-viral factors in the development renal dysfunction in 468 HCV patients retrospectively over a period of observation ranging from 3 months to 6 yrs.

Results: A total of 124 AKD events occurred in 63 patients. On regression analysis; gender, race, alcohol abuse, HIV (Human immune deficiency virus) status, body mass index, baseline viral load (HCV-PCR), and genotype did not predict an event of AKD. Decompensated liver disease, history of IVDU, diabetes mellitus and baseline creatinine were independent predictors of AKD.

Conclusion: Development of AKD in patient with hepatitis C virus infection is independent of the genotype and viral load at baseline and is mostly predisposed by known prevalent factors in patients with hepatitis C such as diabetes, hypertension and intravenous drug use. Decompensated liver disease is the single most viral-related factor that predisposes for AKD.
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http://dx.doi.org/10.1016/j.jceh.2014.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017169PMC
March 2014

The genetics of POAG in black South Africans: a candidate gene association study.

Sci Rep 2015 Feb 11;5:8378. Epub 2015 Feb 11.

1] Division of Human Genetics, National Health Laboratory Service, School of Pathology, University of the Witwatersrand, Johannesburg, South Africa [2] Sydney Brenner Institute of Molecular Bioscience, University of the Witwatersrand, Johannesburg, South Africa.

Multiple loci have been associated with either primary open angle glaucoma (POAG) or heritable ocular quantitative traits associated with this condition. This study examined the association of these loci with POAG, with central corneal thickness (CCT), vertical cup-to-disc ratio (VCDR) and with diabetes mellitus in a group of black South Africans (215 POAG cases and 214 controls). The population was homogeneous and distinct from other African and European populations. Single SNPs in the MYOC, COL8A2, COL1A1 and ZNF469 gene regions showed marginal associations with POAG. No association with POAG was identified with tagging SNPs in TMCO1, CAV1/CAV2, CYP1B1, COL1A2, COL5A1, CDKN2B/CDKN2BAS-1, SIX1/SIX6 or the chromosome 2p16 regions and there were no associations with CCT or VCDR. However, SNP rs12522383 in WDR36 was associated with diabetes mellitus (p = 0.00008). This first POAG genetic association study in black South Africans has therefore identified associations that require additional investigation in this and other populations to determine their significance. This highlights the need for larger studies in this population if we are to achieve the goal of facilitating early POAG detection and ultimately preventing irreversible blindness from this condition.
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http://dx.doi.org/10.1038/srep08378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323640PMC
February 2015

Lack of association between lysyl oxidase-like 1 polymorphisms and primary open angle glaucoma: a meta-analysis.

Int J Ophthalmol 2014 18;7(3):550-6. Epub 2014 Jun 18.

Department of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang Province, China.

Aim: To study the associations between lysyl oxidase-like 1 (LOXL1) polymorphisms and primary open angle glaucoma (POAG) remain inconsistent. In this study, we have performed a meta-analysis to investigate the association of LOXL1 polymorphisms with POAG risk.

Methods: Published literature from PubMed and other databases were retrieved. All studies evaluating the association between LOXL1 polymorphisms (rs2165241, rs1048661, rs3825942) and POAG risk were included. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using random- or fixed-effects model.

Results: Twelve studies were identified as eligible articles, with thirteen (2098 cases and 16 473 controls), thirteen (1795 cases and 2916 controls) and sixteen population cohorts (2456 cases and 2846 controls) for the association of rs2165241, rs1048661 and rs3825942 with POAG risk respectively. Overall analyses showed no association between each LOXL1 polymorphism and POAG risk, and the negative associations were remained when the subjects were stratified as Caucasian and Asian. The heterozygote of rs2165241 was associated with reduced POAG risk in hospital-based populations (TC vs CC: OR, 0.79, 95%CI: 0.63-0.99), and rs1048661 was associated with increased POAG risk in hospital-based populations in a dominant model (TT vs CC+CT: OR, 1.23, 95%CI: 1.01-1.50); however, these associations were not found in population-based subjects.

Conclusion: This meta-analysis suggests that LOXL1 polymorphisms are not associated with POAG risk. Given the limited sample size, the associations of LOXL1 polymorphisms with POAG risk in hospital-based populations await further investigation.
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http://dx.doi.org/10.3980/j.issn.2222-3959.2014.03.29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067675PMC
June 2014

Introduction from the guest editors.

J Clin Densitom 2013 Oct-Dec;16(4):387-8

Division of Clinical Immunology and Rheumatology, Department of Medicine, UAB Osteoporosis Prevention and Treatment Clinic, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jocd.2013.10.001DOI Listing
January 2014

Calcium primer: current controversies and common clinical questions.

J Clin Densitom 2013 Oct-Dec;16(4):389-93. Epub 2013 Sep 22.

Cleveland Clinic Center for Human Nutrition, Cleveland, OH, USA.

The use of calcium supplements has recently come under fire because of studies purportedly showing a relationship to cardiovascular events. Although the conclusions made sensational headlines in the popular press, numerous editorials and convincing scientific evidence to the contrary went unnoticed. This controversy and others, such as the relationship of proton-pump inhibitors and osteoporosis, caffeine consumption and the risk of calciuria, and the effects of loop diuretics on fracture risk, are common clinical queries of both primary care physicians and subspecialists. The purpose of this article, therefore, is to provide a concise review of select literature pertinent to current clinical practice and to provide no-nonsense recommendations for common clinical dilemmas regarding calcium supplementation.
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http://dx.doi.org/10.1016/j.jocd.2013.08.009DOI Listing
January 2014

Bone mineral density testing: is a T score enough to determine the screening interval?

Cleve Clin J Med 2013 Apr;80(4):234-9

Department of Endocrinology, Diabetes, and Metabolism, F20, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.

To find the rational intervals for bone mineral density screening, Gourlay et al (N Engl J Med 2012; 366:225-233) used T scores to calculate the time required for women age 67 and older with normal bone mineral density or osteopenia to progress to osteoporosis. They estimated that the screening interval for women with normal bone mineral density or mild osteopenia (T score -1.49 or higher) could be as long as 15 years. However, the investigators focused mainly on T scores and when these scores reached -2.5. In our opinion, the testing interval should be guided by an assessment of clinical risk factors and not just baseline T scores.
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http://dx.doi.org/10.3949/ccjm.80a.12069DOI Listing
April 2013

The role of lysyl oxidase-like 1 DNA copy number variants in exfoliation glaucoma.

Mol Vis 2012 14;18:2976-81. Epub 2012 Dec 14.

Center for Human Genetics, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.

Purpose: To investigate whether DNA copy number variants (CNVs) in the lysyl oxidase-like 1 (LOXL1) gene are associated with exfoliation glaucoma (XFG) in black South Africans.

Methods: Black South African subjects with XFG and age-matched unaffected controls were recruited from the St. John Eye Hospital in Soweto (Johannesburg, South Africa) and East London Hospital Complex (Eastern Cape, South Africa) using standard clinical examination techniques. A customized array comparative genomic hybridization (aCGH) from Roche NimbleGen was designed to cover a 1.5 million base genomic region centered on the LOXL1 gene on chromosome 15. Twenty selected XFG cases were examined using this custom aCGH to identify common CNVs in the LOXL1 gene. The potential DNA copy number variants identified from aCGH were further validated using TaqMan probe-based CNV real-time PCR in a data set containing 91 XFG cases and 52 controls. The frequencies of CNVs in the LOXL1 region were compared between the XFG cases and the controls using Fisher's exact test.

Results: Several DNA CNV variants were identified in the LOXL1 genomic region using aCGH in the selected XFG cases. However, we were unable to validate these candidate CNVs using real-time PCR-based TaqMan CNV assays. There was no significant difference in the frequency of the DNA copy number variants in the LOXL1 region between the XFG cases and the controls.

Conclusions: This represents the first DNA CNV study of LOXL1 in the black South African population with XFG. Our study did not identify any significant DNA copy number alterations in the genomic region containing the LOXL1 gene. This suggests that other as yet unknown causal variants of LOXL1 or variants in other genes in linkage disequilibrium with the LOXL1 locus contribute to the genetic risk of XFG in black South Africans.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3534139PMC
May 2013

Myocilin mutations in black South Africans with POAG.

Mol Vis 2011 Apr 27;17:1064-9. Epub 2011 Apr 27.

Center for Human Genetics, Duke University Medical Center, Durham, NC, USA.

Purpose: Myocilin (MYOC) mutations are associated with primary open-angle glaucoma (POAG) in multiple populations. Here we examined the role of MYOC mutations in a black South African population with primary open-angle glaucoma (POAG).

Methods: Unrelated black South African subjects with POAG and unaffected controls were recruited from the St. John Eye Hospital (Soweto, Johannesburg, South Africa) and East London Hospital Complex (Eastern Cape, South Africa). A complete eye examination including visual field assessment was performed in all subjects. Blood samples were obtained for DNA extraction. The complete coding region of MYOC was sequenced using the PCR-based Sanger method. Identified mutations were compared to known MYOC mutations.

Results: One hundred-thirteen POAG cases and 131 controls were recruited for analysis. A total of 19 variants were observed. Probable glaucoma-causing mutations were observed in 4.4% of POAG cases. A previously reported glaucoma-causing mutation, Tyr453MetfsX11, was observed in three cases and one control. Two other sequence variants, Gly374Val and Lys500Arg, occurred only in cases. Other sequence variants, including 6 novel variants, occurred in at least one control.

Conclusions: A small minority of black South Africans with POAG carry MYOC mutations. The Gly374Val mutation might represent a novel glaucoma-causing mutation. The Tyr453MetFSX11 mutation appears to be a glaucoma-causing mutation with incomplete penetrance.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086605PMC
April 2011

Metabolic bone disease in the bariatric surgery patient.

Authors:
Susan E Williams

J Obes 2011 28;2011:634614. Epub 2010 Dec 28.

Department of Internal Medicine, Cleveland Clinic, 9500 Euclid Avenue / G-10, Cleveland, OH 44195-0001, USA.

Bariatric surgery has proven to be a life-saving measure for some, but for others it has precipitated a plethora of metabolic complications ranging from mild to life-threatening, sometimes to the point of requiring surgical revision. Obesity was previously thought to be bone protective, but this is indeed not the case. Morbidly obese individuals are at risk for metabolic bone disease (MBD) due to chronic vitamin D deficiency, inadequate calcium intake, sedentary lifestyle, chronic dieting, underlying chronic diseases, and the use of certain medications used to treat those diseases. After bariatric surgery, the risk for bone-related problems is even greater, owing to severely restricted intake, malabsorption, poor compliance with prescribed supplements, and dramatic weight loss. Patients presenting for bariatric surgery should be evaluated for MBD and receive appropriate presurgical interventions. Furthermore, every patient who has undergone bariatric surgery should receive meticulous lifetime monitoring, as the risk for developing MBD remains ever present.
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http://dx.doi.org/10.1155/2011/634614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3022191PMC
July 2011

Major LOXL1 risk allele is reversed in exfoliation glaucoma in a black South African population.

Mol Vis 2010 Apr 21;16:705-12. Epub 2010 Apr 21.

Division of Ophthalmology, Department of Neurosciences, University of the Witwatersrand, Johannesburg, South Africa.

Purpose: To investigate whether variants in the lysyl oxidase-like 1 (LOXL1) gene are associated with exfoliation glaucoma (XFG) and primary open-angle glaucoma (POAG) in an ancestral population from South Africa.

Methods: Black South African subjects with XFG, POAG, and age matched unaffected controls were recruited from the St. John Eye Hospital in Soweto, Johannesburg, South Africa, using standard clinical examination techniques. Fifty individuals were collected for each of the three groups: XFG, POAG, and normal controls. The complete coding region of LOXL1 was sequenced using the PCR-based Sanger method. The allele frequencies of the identified sequence variants were compared between XFG or POAG and controls using Fisher's exact test.

Results: A large number of coding variants were identified, including rs1048661 (R141L), rs3825942 (G153D), S159A, S161L, rs41435250 (A320A), rs13329473 (F489F), and T567A. The allele frequencies of both rs3825942 and rs1048661 differed significantly between the XFG and control subjects from South Africa (p=5.2 x 10(-13) and 1.7 x 10(-5), respectively). The G allele for rs1048661 (encoding arginine) was the risk allele which is similar to other populations. The A allele of rs3825942 (encoding aspartic acid) was the risk allele, in sharp contrast to the G allele (encoding glycine) reported in multiple other populations. There was no significant difference in the allele frequencies of coding variants in LOXL1 between POAG and control subjects.

Conclusions: This represents the first genetic association study of LOXL1 in an ancestral African population with XFG. We have confirmed the association between variants of LOXL1 and XFG. To date, the G allele of the major susceptibility variant rs3825942 has consistently been shown in multiple populations to increase the risk of XFG. Surprisingly, we have found a strong association with the opposite allele in the South African population. This suggests that other as yet unknown causal variants of LOXL1 contribute to the genetic risk of XFG.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2861124PMC
April 2010

Perioperative management of bariatric surgery patients: focus on metabolic bone disease.

Cleve Clin J Med 2008 May;75(5):333-4, 336, 338 passim

Center for Nutrition and Metabolic Medicine, Greene Memorial Hospital Advanced Medical Group, Xenia, OH 45385, USA.

Chronic vitamin D deficiency, inadequate calcium intake, and secondary hyperparathyroidism are common in obese individuals, placing them at risk for low bone mass and metabolic bone disease. After bariatric surgery, they are at even higher risk, owing to malabsorption and decreased oral intake. Meticulous preoperative screening, judicious use of vitamin and mineral supplements, addressing modifiable risk factors, and monitoring the absorption of key nutrients postoperatively are essential in preventing metabolic bone disease in bariatric surgery patients.
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http://dx.doi.org/10.3949/ccjm.75.5.333DOI Listing
May 2008

Metabolic bone disease in gastrointestinal illness.

Gastroenterol Clin North Am 2007 Mar;36(1):161-90, viii

Department of Gastroenterology and Hepatology, Cleveland Clinic Foundation, 9500 Euclid Avenue, A 30, Cleveland, OH 44195, USA.

Metabolic bone disease is often silent, often undiagnosed, and occurs frequently in patients with chronic gastrointestinal illnesses. Potentially modifiable risk factors, such as malnutrition, malabsorption, prolonged use of glucocorticoids, and a sedentary lifestyle, can lead to low bone mass, an increased rate of bone loss, and debilitating bone disease. This article explores common gastrointestinal illnesses that place patients at risk for developing metabolic bone disease. Concepts are presented to assist the practitioner in identifying patients at risk; clinical evaluation and diagnostic test selection are discussed, and therapeutic options for the prevention and treatment of metabolic bone disease in gastrointestinal illness are presented.
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http://dx.doi.org/10.1016/j.gtc.2007.01.005DOI Listing
March 2007
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