Clinical implications of old and new genes for open-angle glaucoma

Wishal D Ramdas; Leonieke M E van Koolwijk; Angela J Cree; A Cecile J W Janssens; Najaf Amin; Paulus T V M de Jong; Roger C W Wolfs; Jane Gibson; James F Kirwan; Albert Hofman; Fernando Rivadeneira; Ben A Oostra; André G Uitterlinden; Sarah Ennis; Andrew J Lotery; Hans G Lemij; Caroline C W Klaver; Johannes R Vingerling; Nomdo M Jansonius; Cornelia M van Duijn

doi:10.1016/j.ophtha.2011.05.040

Clinical implications of old and new genes for open-angle glaucoma

Wishal D Ramdas, Leonieke M E van Koolwijk, Angela J Cree, A Cecile J W Janssens, Najaf Amin, Paulus T V M de Jong, Roger C W Wolfs, Jane Gibson, James F Kirwan, Albert Hofman, Fernando Rivadeneira, Ben A Oostra, André G Uitterlinden, Sarah Ennis, Andrew J Lotery, Hans G Lemij, Caroline C W Klaver, Johannes R Vingerling, Nomdo M Jansonius, Cornelia M van Duijn

Onderzoeksoutput: Bijdrage aan tijdschrift › Artikel › Onderzoek › peer review

Samenvatting

OBJECTIVE: Genome-wide association studies have revealed new insights into the genetic determinants of open-angle glaucoma (OAG). This study was performed to determine to what extent variants within established genes (MYOC, OPTN, and WDR36) and newly identified common genetic variants (ATOH7, CDKN2B, and SIX1) contribute to the risk of OAG.

DESIGN: Population-based setting, family-based setting, and a case-control study.

PARTICIPANTS: The Rotterdam Study I cohort (N = 5312; mean age±standard deviation [SD], 68.0±8.4 years). Findings were replicated in the Genetic Research in Isolated Populations combined with the Erasmus Rucphen Family study (N = 1750; mean age±SD, 48.3±15.2 years), and a cohort from Southampton (N = 702; mean age±SD, 72.5±10.7 years).

METHODS: After identifying common variants associated with OAG within the established genes, the risk of OAG was analyzed using logistic regression. Discriminative accuracy was assessed by comparing the area under the receiver operator characteristic curve (AUC) for models, including the number of risk alleles, intraocular pressure, age, and gender, with the AUC for the same model but without the risk alleles.

MAIN OUTCOME MEASURES: Odds ratios and AUCs of individual and combined risk alleles.

RESULTS: No consistent significant associations for the established genes (MYOC, OPTN, and WDR36) with OAG were found. However, when comparing the load of risk variants between cases and controls, 2 of 3 studies showed a significant increased risk of OAG for participants carrying more risk alleles of the 3 established genes. When combining all 6 genes, participants carrying a high number of risk alleles (highest tertile) had a 2.29-fold to 3.19-fold increase in risk of OAG compared with those carrying only a few risk alleles. The addition of the newly identified genes to IOP, age, and gender resulted in a higher AUC compared with the AUC without the newly identified genes (P = 0.027).

CONCLUSIONS: A significant contribution to the risk of OAG was found for the new common variants identified by recent genome-wide association studies, but not for variants within the established genes. Participants carrying a high number of risk alleles had an approximately 3-fold increase in the risk of OAG compared with those with a low number of risk alleles.

FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Originele taal-2	Engels
Pagina's (van-tot)	2389-97
Aantal pagina's	9
Tijdschrift	Ophthalmology
Volume	118
Nummer van het tijdschrift	12
DOI's	https://doi.org/10.1016/j.ophtha.2011.05.040
Status	Gepubliceerd - dec. 2011

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10.1016/j.ophtha.2011.05.040

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Ramdas, W. D., van Koolwijk, L. M. E., Cree, A. J., Janssens, A. C. J. W., Amin, N., de Jong, P. T. V. M., Wolfs, R. C. W., Gibson, J., Kirwan, J. F., Hofman, A., Rivadeneira, F., Oostra, B. A., Uitterlinden, A. G., Ennis, S., Lotery, A. J., Lemij, H. G., Klaver, C. C. W., Vingerling, J. R., Jansonius, N. M., & van Duijn, C. M. (2011). Clinical implications of old and new genes for open-angle glaucoma. Ophthalmology, 118(12), 2389-97. https://doi.org/10.1016/j.ophtha.2011.05.040

@article{2ef5b4a02fd8401e88335d905e0e2c2b,

title = "Clinical implications of old and new genes for open-angle glaucoma",

abstract = "OBJECTIVE: Genome-wide association studies have revealed new insights into the genetic determinants of open-angle glaucoma (OAG). This study was performed to determine to what extent variants within established genes (MYOC, OPTN, and WDR36) and newly identified common genetic variants (ATOH7, CDKN2B, and SIX1) contribute to the risk of OAG.DESIGN: Population-based setting, family-based setting, and a case-control study.PARTICIPANTS: The Rotterdam Study I cohort (N = 5312; mean age±standard deviation [SD], 68.0±8.4 years). Findings were replicated in the Genetic Research in Isolated Populations combined with the Erasmus Rucphen Family study (N = 1750; mean age±SD, 48.3±15.2 years), and a cohort from Southampton (N = 702; mean age±SD, 72.5±10.7 years).METHODS: After identifying common variants associated with OAG within the established genes, the risk of OAG was analyzed using logistic regression. Discriminative accuracy was assessed by comparing the area under the receiver operator characteristic curve (AUC) for models, including the number of risk alleles, intraocular pressure, age, and gender, with the AUC for the same model but without the risk alleles.MAIN OUTCOME MEASURES: Odds ratios and AUCs of individual and combined risk alleles.RESULTS: No consistent significant associations for the established genes (MYOC, OPTN, and WDR36) with OAG were found. However, when comparing the load of risk variants between cases and controls, 2 of 3 studies showed a significant increased risk of OAG for participants carrying more risk alleles of the 3 established genes. When combining all 6 genes, participants carrying a high number of risk alleles (highest tertile) had a 2.29-fold to 3.19-fold increase in risk of OAG compared with those carrying only a few risk alleles. The addition of the newly identified genes to IOP, age, and gender resulted in a higher AUC compared with the AUC without the newly identified genes (P = 0.027).CONCLUSIONS: A significant contribution to the risk of OAG was found for the new common variants identified by recent genome-wide association studies, but not for variants within the established genes. Participants carrying a high number of risk alleles had an approximately 3-fold increase in the risk of OAG compared with those with a low number of risk alleles.FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.",

keywords = "Adolescent, Adult, Aged, Aged, 80 and over, Alleles, Area Under Curve, Basic Helix-Loop-Helix Transcription Factors/genetics, Case-Control Studies, Cell Cycle Proteins, Cyclin-Dependent Kinase Inhibitor p15/genetics, Cytoskeletal Proteins/genetics, Eye Proteins/genetics, Female, Genetic Predisposition to Disease/genetics, Genome-Wide Association Study, Genotype, Genotyping Techniques, Glaucoma, Open-Angle/diagnosis, Glycoproteins/genetics, Homeodomain Proteins/genetics, Humans, Intraocular Pressure/genetics, Male, Membrane Transport Proteins, Middle Aged, Odds Ratio, Polymorphism, Single Nucleotide, Prospective Studies, ROC Curve, Risk Factors, Transcription Factor TFIIIA/genetics, Visual Acuity/physiology",

author = "Ramdas, {Wishal D} and {van Koolwijk}, {Leonieke M E} and Cree, {Angela J} and Janssens, {A Cecile J W} and Najaf Amin and {de Jong}, {Paulus T V M} and Wolfs, {Roger C W} and Jane Gibson and Kirwan, {James F} and Albert Hofman and Fernando Rivadeneira and Oostra, {Ben A} and Uitterlinden, {Andr{\'e} G} and Sarah Ennis and Lotery, {Andrew J} and Lemij, {Hans G} and Klaver, {Caroline C W} and Vingerling, {Johannes R} and Jansonius, {Nomdo M} and {van Duijn}, {Cornelia M}",

year = "2011",

month = dec,

doi = "10.1016/j.ophtha.2011.05.040",

language = "English",

volume = "118",

pages = "2389--97",

number = "12",

}

Ramdas, WD, van Koolwijk, LME, Cree, AJ, Janssens, ACJW, Amin, N, de Jong, PTVM, Wolfs, RCW, Gibson, J, Kirwan, JF, Hofman, A, Rivadeneira, F, Oostra, BA, Uitterlinden, AG, Ennis, S, Lotery, AJ, Lemij, HG, Klaver, CCW, Vingerling, JR, Jansonius, NM & van Duijn, CM 2011, 'Clinical implications of old and new genes for open-angle glaucoma', Ophthalmology, vol. 118, nr. 12, blz. 2389-97. https://doi.org/10.1016/j.ophtha.2011.05.040

TY - JOUR

T1 - Clinical implications of old and new genes for open-angle glaucoma

AU - Ramdas, Wishal D

AU - van Koolwijk, Leonieke M E

AU - Cree, Angela J

AU - Janssens, A Cecile J W

AU - Amin, Najaf

AU - de Jong, Paulus T V M

AU - Wolfs, Roger C W

AU - Gibson, Jane

AU - Kirwan, James F

AU - Hofman, Albert

AU - Rivadeneira, Fernando

AU - Oostra, Ben A

AU - Uitterlinden, André G

AU - Ennis, Sarah

AU - Lotery, Andrew J

AU - Lemij, Hans G

AU - Klaver, Caroline C W

AU - Vingerling, Johannes R

AU - Jansonius, Nomdo M

AU - van Duijn, Cornelia M

PY - 2011/12

Y1 - 2011/12

N2 - OBJECTIVE: Genome-wide association studies have revealed new insights into the genetic determinants of open-angle glaucoma (OAG). This study was performed to determine to what extent variants within established genes (MYOC, OPTN, and WDR36) and newly identified common genetic variants (ATOH7, CDKN2B, and SIX1) contribute to the risk of OAG.DESIGN: Population-based setting, family-based setting, and a case-control study.PARTICIPANTS: The Rotterdam Study I cohort (N = 5312; mean age±standard deviation [SD], 68.0±8.4 years). Findings were replicated in the Genetic Research in Isolated Populations combined with the Erasmus Rucphen Family study (N = 1750; mean age±SD, 48.3±15.2 years), and a cohort from Southampton (N = 702; mean age±SD, 72.5±10.7 years).METHODS: After identifying common variants associated with OAG within the established genes, the risk of OAG was analyzed using logistic regression. Discriminative accuracy was assessed by comparing the area under the receiver operator characteristic curve (AUC) for models, including the number of risk alleles, intraocular pressure, age, and gender, with the AUC for the same model but without the risk alleles.MAIN OUTCOME MEASURES: Odds ratios and AUCs of individual and combined risk alleles.RESULTS: No consistent significant associations for the established genes (MYOC, OPTN, and WDR36) with OAG were found. However, when comparing the load of risk variants between cases and controls, 2 of 3 studies showed a significant increased risk of OAG for participants carrying more risk alleles of the 3 established genes. When combining all 6 genes, participants carrying a high number of risk alleles (highest tertile) had a 2.29-fold to 3.19-fold increase in risk of OAG compared with those carrying only a few risk alleles. The addition of the newly identified genes to IOP, age, and gender resulted in a higher AUC compared with the AUC without the newly identified genes (P = 0.027).CONCLUSIONS: A significant contribution to the risk of OAG was found for the new common variants identified by recent genome-wide association studies, but not for variants within the established genes. Participants carrying a high number of risk alleles had an approximately 3-fold increase in the risk of OAG compared with those with a low number of risk alleles.FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

AB - OBJECTIVE: Genome-wide association studies have revealed new insights into the genetic determinants of open-angle glaucoma (OAG). This study was performed to determine to what extent variants within established genes (MYOC, OPTN, and WDR36) and newly identified common genetic variants (ATOH7, CDKN2B, and SIX1) contribute to the risk of OAG.DESIGN: Population-based setting, family-based setting, and a case-control study.PARTICIPANTS: The Rotterdam Study I cohort (N = 5312; mean age±standard deviation [SD], 68.0±8.4 years). Findings were replicated in the Genetic Research in Isolated Populations combined with the Erasmus Rucphen Family study (N = 1750; mean age±SD, 48.3±15.2 years), and a cohort from Southampton (N = 702; mean age±SD, 72.5±10.7 years).METHODS: After identifying common variants associated with OAG within the established genes, the risk of OAG was analyzed using logistic regression. Discriminative accuracy was assessed by comparing the area under the receiver operator characteristic curve (AUC) for models, including the number of risk alleles, intraocular pressure, age, and gender, with the AUC for the same model but without the risk alleles.MAIN OUTCOME MEASURES: Odds ratios and AUCs of individual and combined risk alleles.RESULTS: No consistent significant associations for the established genes (MYOC, OPTN, and WDR36) with OAG were found. However, when comparing the load of risk variants between cases and controls, 2 of 3 studies showed a significant increased risk of OAG for participants carrying more risk alleles of the 3 established genes. When combining all 6 genes, participants carrying a high number of risk alleles (highest tertile) had a 2.29-fold to 3.19-fold increase in risk of OAG compared with those carrying only a few risk alleles. The addition of the newly identified genes to IOP, age, and gender resulted in a higher AUC compared with the AUC without the newly identified genes (P = 0.027).CONCLUSIONS: A significant contribution to the risk of OAG was found for the new common variants identified by recent genome-wide association studies, but not for variants within the established genes. Participants carrying a high number of risk alleles had an approximately 3-fold increase in the risk of OAG compared with those with a low number of risk alleles.FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

KW - Adolescent

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Alleles

KW - Area Under Curve

KW - Basic Helix-Loop-Helix Transcription Factors/genetics

KW - Case-Control Studies

KW - Cell Cycle Proteins

KW - Cyclin-Dependent Kinase Inhibitor p15/genetics

KW - Cytoskeletal Proteins/genetics

KW - Eye Proteins/genetics

KW - Female

KW - Genetic Predisposition to Disease/genetics

KW - Genome-Wide Association Study

KW - Genotype

KW - Genotyping Techniques

KW - Glaucoma, Open-Angle/diagnosis

KW - Glycoproteins/genetics

KW - Homeodomain Proteins/genetics

KW - Humans

KW - Intraocular Pressure/genetics

KW - Male

KW - Membrane Transport Proteins

KW - Middle Aged

KW - Odds Ratio

KW - Polymorphism, Single Nucleotide

KW - Prospective Studies

KW - ROC Curve

KW - Risk Factors

KW - Transcription Factor TFIIIA/genetics

KW - Visual Acuity/physiology

U2 - 10.1016/j.ophtha.2011.05.040

DO - 10.1016/j.ophtha.2011.05.040

M3 - Article

C2 - 21872936

SN - 0161-6420

VL - 118

SP - 2389

EP - 2397

JO - Ophthalmology

JF - Ophthalmology

IS - 12

ER -

Clinical implications of old and new genes for open-angle glaucoma

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