TY - JOUR
T1 - Mitochondrial Genome Study Identifies Association Between Primary Open-Angle Glaucoma and Variants in MT-CYB, MT-ND4 Genes and Haplogroups
AU - Lifelines Cohort Study
AU - Lo Faro, Valeria
AU - Nolte, Ilja M.
AU - Ten Brink, Jacoline B.
AU - Snieder, Harold
AU - Jansonius, Nomdo M.
AU - Bergen, Arthur A.
N1 - Funding Information:
This project was funded by European Union?s Horizon 2020 research and innovation programme under the Marie Sk?odowska-Curie grant agreement No. 675033 (EGRET plus). Additional funding was provided by the Rotterdamse Stichting Blindenbelangen (Grant ID B20150036). The funding organization had no role in the design, conduct, analysis, or publication of this research. The Lifelines Biobank initiative has been made possible by subsidy from the Dutch Ministry of Health, Welfare and Sport, the Dutch Ministry of Economic Affairs, the University Medical Center Groningen (UMCG the Netherlands), University of Groningen and the Northern Provinces of Netherlands. The Lifelines Biobank initiative has been made possible by funding from the Dutch Ministry of Health,Welfare and Sport, the Dutch Ministry of Economic Affairs, the University Medical Center Groningen(UMCG Netherlands), University of Groningen and the Northern Provinces of the Netherlands. The generation and management of GWAS genotype data for the Lifelines Cohort Study is supported by the UMCG Genetics Lifelines Initiative (UGLI). UGLI is partly supported by a Spinoza Grant from NWO, awarded to Cisca Wijmenga.
Publisher Copyright:
Copyright © 2021 Lo Faro, Nolte, Ten Brink, Snieder, Jansonius, Bergen and Lifelines Cohort Study.
PY - 2021/12/16
Y1 - 2021/12/16
N2 - Background and purpose: Primary open-angle glaucoma (POAG) is an optic neuropathy characterized by death of retinal ganglion cells and atrophy of the optic nerve head. The susceptibility of the optic nerve to damage has been shown to be mediated by mitochondrial dysfunction. In this study, we aimed to determine a possible association between mitochondrial SNPs or haplogroups and POAG.Methods: Mitochondrial DNA single nucleotide polymorphisms (mtSNPs) were genotyped using the Illumina Infinium Global Screening Array-24 (GSA) 700K array set. Genetic analyses were performed in a POAG case-control study involving the cohorts, Groningen Longitudinal Glaucoma Study-Lifelines Cohort Study and Amsterdam Glaucoma Study, including 721 patients and 1951 controls in total. We excluded samples not passing quality control for nuclear genotypes and samples with low call rate for mitochondrial variation. The mitochondrial variants were analyzed both as SNPs and haplogroups. These were determined with the bioinformatics software HaploGrep, and logistic regression analysis was used for the association, as well as for SNPs.Results: Meta-analysis of the results from both cohorts revealed a significant association between POAG and the allele A of rs2853496 [odds ratio (OR) = 0.64; p = 0.006] within the MT-ND4 gene, and for the T allele of rs35788393 (OR = 0.75; p = 0.041) located in the MT-CYB gene. In the mitochondrial haplogroup analysis, the most significant p-value was reached by haplogroup K (p = 1.2 × 10−05), which increases the risk of POAG with an OR of 5.8 (95% CI 2.7–13.1).Conclusion: We identified an association between POAG and polymorphisms in the mitochondrial genes MT-ND4 (rs2853496) and MT-CYB (rs35788393), and with haplogroup K. The present study provides further evidence that mitochondrial genome variations are implicated in POAG. Further genetic and functional studies are required to substantiate the association between mitochondrial gene polymorphisms and POAG and to define the pathophysiological mechanisms of mitochondrial dysfunction in glaucoma.
AB - Background and purpose: Primary open-angle glaucoma (POAG) is an optic neuropathy characterized by death of retinal ganglion cells and atrophy of the optic nerve head. The susceptibility of the optic nerve to damage has been shown to be mediated by mitochondrial dysfunction. In this study, we aimed to determine a possible association between mitochondrial SNPs or haplogroups and POAG.Methods: Mitochondrial DNA single nucleotide polymorphisms (mtSNPs) were genotyped using the Illumina Infinium Global Screening Array-24 (GSA) 700K array set. Genetic analyses were performed in a POAG case-control study involving the cohorts, Groningen Longitudinal Glaucoma Study-Lifelines Cohort Study and Amsterdam Glaucoma Study, including 721 patients and 1951 controls in total. We excluded samples not passing quality control for nuclear genotypes and samples with low call rate for mitochondrial variation. The mitochondrial variants were analyzed both as SNPs and haplogroups. These were determined with the bioinformatics software HaploGrep, and logistic regression analysis was used for the association, as well as for SNPs.Results: Meta-analysis of the results from both cohorts revealed a significant association between POAG and the allele A of rs2853496 [odds ratio (OR) = 0.64; p = 0.006] within the MT-ND4 gene, and for the T allele of rs35788393 (OR = 0.75; p = 0.041) located in the MT-CYB gene. In the mitochondrial haplogroup analysis, the most significant p-value was reached by haplogroup K (p = 1.2 × 10−05), which increases the risk of POAG with an OR of 5.8 (95% CI 2.7–13.1).Conclusion: We identified an association between POAG and polymorphisms in the mitochondrial genes MT-ND4 (rs2853496) and MT-CYB (rs35788393), and with haplogroup K. The present study provides further evidence that mitochondrial genome variations are implicated in POAG. Further genetic and functional studies are required to substantiate the association between mitochondrial gene polymorphisms and POAG and to define the pathophysiological mechanisms of mitochondrial dysfunction in glaucoma.
KW - genetic association study
KW - haplogroup K
KW - mitochondrial haplogroup
KW - mitochondrial polymorphism
KW - MT-CYB
KW - MT-ND4
KW - primary open-angle glaucoma (POAG)
U2 - 10.3389/fgene.2021.781189
DO - 10.3389/fgene.2021.781189
M3 - Article
AN - SCOPUS:85122207219
VL - 12
JO - Frontiers in Genetics
JF - Frontiers in Genetics
SN - 1664-8021
M1 - 781189
ER -