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Benjamin T. Whigham

Bio: Benjamin T. Whigham is an academic researcher from Duke University. The author has contributed to research in topics: Population & Allele. The author has an hindex of 6, co-authored 8 publications receiving 337 citations.

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Journal Article
TL;DR: Surprisingly, the G allele of the major susceptibility variant rs3825942 has consistently been shown in multiple populations to increase the risk of XFG and is found with a strong association with the opposite allele in the South African population.
Abstract: 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.

94 citations

Journal ArticleDOI
TL;DR: It is hypothesized that SIX6 risk variants disrupt the development of the neural retina, leading to a reduced number of retinal ganglion cells, thereby increasing the risk of glaucoma-associated vision loss.
Abstract: Glaucoma is a leading cause of blindness worldwide. Primary open-angle glaucoma (POAG) is the most common subtype and is a complex trait with multigenic inheritance. Genome-wide association studies have previously identified a significant association between POAG and the SIX6 locus (rs10483727, odds ratio (OR) = 1.32, p = 3.87×10(-11)). SIX6 plays a role in ocular development and has been associated with the morphology of the optic nerve. We sequenced the SIX6 coding and regulatory regions in 262 POAG cases and 256 controls and identified six nonsynonymous coding variants, including five rare and one common variant, Asn141His (rs33912345), which was associated significantly with POAG (OR = 1.27, p = 4.2×10(-10)) in the NEIGHBOR/GLAUGEN datasets. These variants were tested in an in vivo Danio rerio (zebrafish) complementation assay to evaluate ocular metrics such as eye size and optic nerve structure. Five variants, found primarily in POAG cases, were hypomorphic or null, while the sixth variant, found only in controls, was benign. One variant in the SIX6 enhancer increased expression of SIX6 and disrupted its regulation. Finally, to our knowledge for the first time, we have identified a clinical feature in POAG patients that appears to be dependent upon SIX6 genotype: patients who are homozygous for the SIX6 risk allele (His141) have a statistically thinner retinal nerve fiber layer than patients homozygous for the SIX6 non-risk allele (Asn141). Our results, in combination with previous SIX6 work, lead us to hypothesize that SIX6 risk variants disrupt the development of the neural retina, leading to a reduced number of retinal ganglion cells, thereby increasing the risk of glaucoma-associated vision loss.

90 citations

Journal ArticleDOI
TL;DR: 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.
Abstract: 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.

72 citations

Journal Article
TL;DR: CYP1B1 mutations are the predominant cause of PCG in the Saudi Arabian population with G61E as the dominant disease-associated allele.
Abstract: Purpose: Primary congenital glaucoma (PCG) is a severe form of glaucoma that presents early in life. PCG is a clinical and genetic entity that is distinct from juvenile forms of glaucoma. Inheritance is usually autosomal recessive and therefore the disease might be more common in societies where consanguinity is high. We studied the prevalence of cytochrome P450, family 1, subfamily B, polypeptide 1 (CYP1B1) and latent-transforming growth factor beta-binding protein 2 (LTBP2) mutations in a group of Saudi PCG patients and attempted to correlate the mutation status with the disease severity. Methods: Genomic DNA was collected from 54 unrelated Saudi PCG families (74 patients) who were diagnosed as having PCG by standard ophthalmological examinations and screened for mutations in CYP1B1 and LTBP2 by sequencing. We also examined the effect of mutations on the phenotype of patients with PCG (phenotype-genotype correlation). Results: Mutations in CYP1B1 were identified in 41 (75.9%) of affected patients. No mutation in CYP1B1 was found in 13 (24.1%) affected persons. We detected a total of 13 mutations: 9 missense mutations (G61E, A119S, R390H, P437L, D441G, A443G, G466S, G466D, and R469W), 2 deletions (g.4238_4247del and g.7901_7913del), and 2 nonsense mutations (R355X and R444X). Two mutations, G466S and D441G, were novel. The G61E mutation was by far the most common mutation detected. PCG cases with CYP1B1 mutation(s) presented with a high degree of haze and greater cup/ disc ratio than those with no mutation(s). Also, PCG cases with a mutation had higher post operative indices in terms of post operative haze and the need for anti-glaucoma medications. Additionally, the surgical success rate was higher 13/14 (92.9%) among cases without mutation than those with mutation 42/60 (70%). No mutation(s) were found in LTBP2 in any of the tested patients. Conclusions: CYP1B1 mutations are the predominant cause of PCG in the Saudi Arabian population with G61E as the dominant disease-associated allele. PCG cases with a mutation had higher last postoperative visit indices in terms of postoperative haze and the need for anti-glaucoma medications. This will be a valuable parameter in predicting disease severity earlier on and might help in predicting the surgical outcome.

72 citations

Journal ArticleDOI
TL;DR: It now appears the strong association between LOXL1 and XFS is due to non-coding variants that have not yet been identified, which might alter LO XL1 expression, which is decreased in the late stages of exfoliation syndrome/glaucoma.

20 citations


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22 Sep 2016
TL;DR: Primary open-angle glaucoma (POAG) is the most common type and management of POAG includes topical drug therapies and surgery to reduce IOP, although new therapies targeting neuroprotection of RGCs and axonal regeneration are under development.
Abstract: Glaucoma is an optic neuropathy that is characterized by the progressive degeneration of the optic nerve, leading to visual impairment. Glaucoma is the main cause of irreversible blindness worldwide, but typically remains asymptomatic until very severe. Open-angle glaucoma comprises the majority of cases in the United States and western Europe, of which, primary open-angle glaucoma (POAG) is the most common type. By contrast, in China and other Asian countries, angle-closure glaucoma is highly prevalent. These two types of glaucoma are characterized based on the anatomic configuration of the aqueous humour outflow pathway. The pathophysiology of POAG is not well understood, but it is an optic neuropathy that is thought to be associated with intraocular pressure (IOP)-related damage to the optic nerve head and resultant loss of retinal ganglion cells (RGCs). POAG is generally diagnosed during routine eye examination, which includes fundoscopic evaluation and visual field assessment (using perimetry). An increase in IOP, measured by tonometry, is not essential for diagnosis. Management of POAG includes topical drug therapies and surgery to reduce IOP, although new therapies targeting neuroprotection of RGCs and axonal regeneration are under development.

955 citations

Journal ArticleDOI
TL;DR: The roles of members of the lysyl oxidase (LOX) family in the remodelling of the tumour microenvironment and their paradoxical roles in tumorigenesis and metastasis are discussed.
Abstract: The therapeutic targeting of extracellular proteins is becoming hugely attractive in light of evidence implicating the tumour microenvironment as pivotal in all aspects of tumour initiation and progression. Members of the lysyl oxidase (LOX) family of proteins are secreted by tumours and are the subject of much effort to understand their roles in cancer. In this Review we discuss the roles of members of this family in the remodelling of the tumour microenvironment and their paradoxical roles in tumorigenesis and metastasis. We also discuss how targeting this family of proteins might lead to a new avenue of cancer therapeutics.

453 citations

Journal ArticleDOI
TL;DR: Aggregate analysis of mutation data revealed a significantly increased number of rare variants across 58 neuropathy-associated genes in subjects versus controls, suggesting that mutation burden potentially contributes to phenotypic variability.

208 citations

Journal ArticleDOI
Jessica N. Cooke Bailey1, Stephanie Loomis2, Jae H. Kang2, R. Rand Allingham3, Puya Gharahkhani4, Chiea Chuen Khor5, Chiea Chuen Khor6, Kathryn P. Burdon7, Kathryn P. Burdon8, Hugues Aschard2, Daniel I. Chasman2, Robert P. Igo1, Pirro G. Hysi9, Craig A. Glastonbury9, Allison E. Ashley-Koch3, Murray H. Brilliant10, Andrew A. Brown11, Donald L. Budenz12, Alfonso Buil11, Ching-Yu Cheng13, Ching-Yu Cheng5, Hyon K. Choi14, William G. Christen2, Gary C. Curhan2, Immaculata De Vivo2, John H. Fingert15, Paul J. Foster16, Paul J. Foster17, Charles S. Fuchs2, Douglas E. Gaasterland, Terry Gaasterland18, Alex W. Hewitt19, Frank B. Hu2, David J. Hunter2, Anthony P Khawaja20, Richard K. Lee21, Zheng Li6, Paul R. Lichter22, David A. Mackey23, David A. Mackey24, Peter McGuffin9, Paul Mitchell25, Sayoko E. Moroi22, Shamira A. Perera5, Shamira A. Perera13, Keating W. Pepper, Qibin Qi26, Tony Realini27, Julia E. Richards22, Paul M. Ridker2, Eric B. Rimm2, Robert Ritch28, Marylyn D. Ritchie29, Joel S. Schuman30, William K. Scott21, Kuldev Singh31, Arthur J. Sit32, Yeunjoo E. Song1, Rulla M. Tamimi2, Fotis Topouzis33, Ananth C. Viswanathan16, Shefali S. Verma29, Douglas Vollrath31, Jie Jin Wang25, Nicole Weisschuh34, Bernd Wissinger34, Gadi Wollstein30, Tien Yin Wong13, Tien Yin Wong5, Brian L. Yaspan35, Donald J. Zack36, Kang Zhang18, Robert N. Weinreb18, Margaret A. Pericak-Vance21, Kerrin S. Small9, Christopher J Hammond9, Tin Aung13, Tin Aung5, Yutao Liu37, Eranga N. Vithana5, Eranga N. Vithana13, Stuart MacGregor4, Jamie E Craig7, Peter Kraft2, Gareth R. Howell, Michael A. Hauser3, Louis R. Pasquale2, Jonathan L. Haines1, Janey L. Wiggs2 
TL;DR: New pathways underlying POAG susceptibility are identified and new targets for preventative therapies are suggested, including TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head.
Abstract: Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10(-11)) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10(-10)); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10(-10)). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.

205 citations

01 Jan 1996
TL;DR: In this article, an extracellular matrix digestion technique was used for the isolation of microvascular endothelial cells to isolate human trabecular meshwork cells, which was shown to be efficient and rapid for isolating large numbers of trabellular meshworks.
Abstract: Like corneal endothelial cells, human trabecular meshwork cells are believed to be of neural crest origin, but demonstrate physiological properties and an antithrombogenic surface similar to vascular endothelial cells. One current method for isolating trabecular meshwork cells utilizes the motile nature of these cells to migrate away from a trabecular meshwork explant in culture to more distal regions of the culture dish. This 'outgrowth' technique is limited in practice by the relatively small number of cells that migrate per explant per unit time, thus hindering the ability to gather sufficient numbers of cells for comprehensive experimentation. For this reason, we have modified an extracellular matrix digestion technique in current use for the isolation of microvascular endothelial cells to isolate human trabecular meshwork cells. This procedure is both efficient and rapid for isolating large numbers of trabecular meshwork cells and results in the availability of trabecular meshwork cells in sufficient quantities for subsequent experimentation.

160 citations