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Desronvil T.,Massachusetts Eye and Ear Infirmary | Logan-Wyatt D.,Massachusetts Eye and Ear Infirmary | Abdrabou W.,Massachusetts Eye and Ear Infirmary | Triana M.,Massachusetts Eye and Ear Infirmary | And 8 more authors.
Molecular Vision | Year: 2010

Purpose: One approach to identify genes that contribute to common complex ocular disorders such as primary open angle glaucoma (POAG) is to study the genetic determinates of endophenotypes that are defined by underlying pre-disposing heritable quantitative traits such as central corneal thickness (CCT). Collagen VIII is a major component of Descemet's membrane and studies in mice have indicated that targeted inactivation of the genes encoding the collagen type 8 alpha1 (Col8a1) and collagen type 8 alpha2 (Col8a2) subunits (COL8A1 and COL8A2) results in thinning of the corneal stroma and of Descemet's membrane. The purpose of this study is to evaluate COL8A1 and COL8A2 as candidate genes for thin CCT in human POAG patients. Methods: 100 Caucasian POAG patients were enrolled in this study. The entire COL8A1 and COL8A2 coding sequence was determined in 8 patients with CCT<513 μm (one standard deviation (36 microns) below the mean (550 microns) and 8 patients with CCT>586 μm (one standard deviation above the mean). Selected COL8A2 exons containing variants of interest were sequenced in the full POAG cohort. Association and quantitative trait analyses were performed. Results: Three patients with CCT less than 513 μm and advanced POAG were found to have missense changes in COL8A2; two patients had a previously identified mutation, R155Q and one had a novel change, P678L (p=0.0035, Fisher's exact test). Missense changes were not found in any of the patients with CCT>513 μm and missense changes in the COL8A1 gene were not found in any patient. One common COL8A2 SNP, rs274754 was also statistically associated with CCT (p=0.018). Conclusions: In this study we have identified COL8A2 missense changes in a group of Caucasian patients with very thin CCT and advanced POAG. These results suggest that DNA sequence variants in the COL8A2 gene may be associated with thin corneas in some glaucoma patients. Further study of COL8A2 variants in other patient populations, especially those with thinner CCT such as African-Americans would provide further support for a role of COL8A2 in corneal thickness and in glaucoma. © 2010 Molecular Vision.

Fan B.J.,Massachusetts Eye and Ear Infirmary | Wang D.Y.,Massachusetts Eye and Ear Infirmary | Pasquale L.R.,Massachusetts Eye and Ear Infirmary | Haines J.L.,Center for Human Genetics Research | Wiggs J.L.,Massachusetts Eye and Ear Infirmary
Investigative Ophthalmology and Visual Science | Year: 2011

PURPOSE. Genetically complex disorders, such as primary open angle glaucoma (POAG), may include highly heritable quantitative traits as part of the overall phenotype, and mapping genes influencing the related quantitative traits may effectively identify genetic risk factors predisposing to the complex disease. Recent studies have identified SNPs associated with optic nerve area and vertical cup-to-disc ratio (VCDR). The purpose of this study was to evaluate the association between these SNPs and POAG in a US Caucasian case-control sample. METHODS. Five SNPs previously associated with optic disc area, or VCDR, were genotyped in 539 POAG cases and 336 controls. Genotype data were analyzed for single SNP associations and SNP interactions with VCDR and POAG. RESULTS. SNPs associated with VCDR rs1063192 (CDKN2B) and rs10483727 (SIX1/SIX6) were also associated with POAG (P = 0.0006 and P = 0.0043 for rs1063192 and rs10483727, respectively). rs1063192, associated with smaller VCDR, had a protective effect (odds ratio [OR] = 0.73; 95% confidence interval [CI], 0.58-0.90), whereas rs10483727, associated with larger VCDR, increased POAG risk (OR = 1.33; 95% CI, 1.08 -1.65). POAG risk associated with increased VCDR was significantly influenced by the C allele of rs1900004 (ATOH7), associated with increased optic nerve area (P-interaction = 0.025; OR = 1.89; 95% CI, 1.22-2.94). CONCLUSIONS. Genetic variants influencing VCDR are associated with POAG in a US Caucasian population. Variants associated with optic nerve area are not independently associated with disease but can influence the effects of VCDR variants suggesting that increased optic disc area can significantly contribute to POAG risk when coupled with risk factors controlling VCDR. © 2011 The Association for Research in Vision and Ophthalmology, Inc.

Fan B.J.,Massachusetts Eye and Ear Infirmary | Pasquale L.R.,Massachusetts Eye and Ear Infirmary | Rhee D.,Massachusetts Eye and Ear Infirmary | Li T.,U.S. National Institutes of Health | And 2 more authors.
Investigative Ophthalmology and Visual Science | Year: 2011

PURPOSE. LOXL1 is a major genetic risk factor for exfoliation syndrome (ES) and exfoliation glaucoma (EG). Recent evidence documenting reversal of risk alleles for the diseaseassociated missense variants R141L and G153D suggests that these variants are not causative and that they may be proxies for other unknown functional LOXL1 variants. The purpose of this study was to investigate the disease association of LOXL1 variants spanning the gene region, including the 5 ́ and 3 ́ regulatory regions, in a U.S. Caucasian case- control sample. METHODS. Twenty-five LOXL1 single-nucleotide polymorphisms (SNPs), distributed throughout the gene, were genotyped in 196 Caucasian patients with ES/EG and 201 matched controls. Genotype data were analyzed for single SNP associations, SNP interactions, and haplotype associations. RESULTS. Promoter region haplotypes that included the risk alleles for rs12914489, a SNP located in the distal promoter region and independently associated with ES, and rs16958477, a SNP previously shown to affect gene transcription, were associated with increased disease risk (P = 0.0008; odds ratio [OR], 2.34; 95% confidence interval [CI], 1.42-3.85) and with protective effects (P = 2.3 × 10-6; OR, 0.38; 95% CI, 0.25- 0.57). Haplotypes containing rs12914489 and rs16958477 risk and protective alleles also significantly influenced the disease risk associated with missense alleles R141L and G153D. CONCLUSIONS. LOXL1 promoter haplotypes were identified that are significantly associated with ES/EG in a U.S. Caucasian population. These results suggest that promoter region SNPs can influence LOXL1 gene expression, potentially causing a reduction of enzyme activity that may predispose to disease. © 2011 The Association for Research in Vision and Ophthalmology, Inc.

Van Driest S.L.,Vanderbilt University | Van Driest S.L.,Monroe Hospital | McGregor T.L.,Vanderbilt University | McGregor T.L.,Monroe Hospital | McGregor T.L.,Center for Human Genetics Research
Personalized Medicine | Year: 2013

The use of genetic information to guide medication decisions holds great promise to improve therapeutic outcomes through increased efficacy and reduced adverse events. As in many areas of medicine, pediatric research and clinical implementation in pharmacogenetics lag behind corresponding adult discovery and clinical applications. In adults, genotype-guided clinical decision support for medications such as clopidogrel, warfarin and simvastatin are in use in some medical centers. However, research conducted in pediatric populations demonstrates that the models and practices developed in adults may be inaccurate in children, and some applications lack any pediatric research to guide clinical decisions. To account for additional factors introduced by developmental considerations in pediatric populations and provide pediatric patients with maximal benefit from genotype-guided therapy, the field will need to develop and employ creative solutions. In this article, we detail some concerns about research and clinical implementation of pharmacogenetics in pediatrics, and present potential mechanisms for addressing them. © 2013 Future Medicine Ltd.

Pare G.,Population Health Research Institute | Pare G.,McMaster University | Kubo M.,RIKEN | Byrd J.B.,University of Michigan | And 8 more authors.
Pharmacogenetics and Genomics | Year: 2013

Objective: The objective of this study was to identify genetic variants associated with angiotensin-converting enzyme (ACE) inhibitor-associated angioedema. Participants and Methods: We carried out a genome-wide association study in 175 individuals with ACE inhibitor-associated angioedema and 489 ACE inhibitor-exposed controls from Nashville (Tennessee) and Marshfield (Wisconsin). We tested for replication in 19 cases and 57 controls who participated in Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET). Results: There were no genome-wide significant associations of any single-nucleotide polymorphism (SNP) with angioedema. Sixteen SNPs in African Americans and 41 SNPs in European Americans were associated moderately with angioedema (P<10) and evaluated for association in ONTARGET. The T allele of rs500766 in PRKCQ was associated with a reduced risk, whereas the G allele of rs2724635 in ETV6 was associated with an increased risk of ACE inhibitor-associated angioedema in the Nashville/Marshfield sample and ONTARGET. In a candidate gene analysis, rs989692 in the gene encoding neprilysin (MME), an enzyme that degrades bradykinin and substance P, was significantly associated with angioedema in ONTARGET and Nashville/Marshfield African Americans. Conclusion: Unlike other serious adverse drug effects, ACE inhibitor-associated angioedema is not associated with a variant with a large effect size. Variants in MME and genes involved in immune regulation may be associated with ACE inhibitor-associated angioedema. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

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