Integration of genomics and transcriptomics predicts diabetic retinopathy susceptibility genes.
Adult
Case-Control Studies
Cell Line, Transformed
Diabetes Mellitus, Type 1
/ complications
Diabetic Retinopathy
/ diagnosis
Female
Gene Expression Profiling
Genetic Predisposition to Disease
Genome-Wide Association Study
Glucose
/ toxicity
Humans
Lymphocytes
/ drug effects
Male
Mendelian Randomization Analysis
Polymorphism, Single Nucleotide
Proto-Oncogene Proteins
/ genetics
Quantitative Trait Loci
Transcriptome
Tumor Suppressor Proteins
/ genetics
Young Adult
LCLs
diabetic retinopathy
eQTL
folliculin
gene expression
genetics
genomics
human
mendelian randomization
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
09 11 2020
09 11 2020
Historique:
received:
13
06
2020
accepted:
06
11
2020
pubmed:
10
11
2020
medline:
17
3
2021
entrez:
9
11
2020
Statut:
epublish
Résumé
We determined differential gene expression in response to high glucose in lymphoblastoid cell lines derived from matched individuals with type 1 diabetes with and without retinopathy. Those genes exhibiting the largest difference in glucose response were assessed for association with diabetic retinopathy in a genome-wide association study meta-analysis. Expression quantitative trait loci (eQTLs) of the glucose response genes were tested for association with diabetic retinopathy. We detected an enrichment of the eQTLs from the glucose response genes among small association p-values and identified folliculin ( One of the side effects of diabetes is loss of vision from diabetic retinopathy, which is caused by injury to the light sensing tissue in the eye, the retina. Almost all individuals with diabetes develop diabetic retinopathy to some extent, and it is the leading cause of irreversible vision loss in working-age adults in the United States. How long a person has been living with diabetes, the extent of increased blood sugars and genetics all contribute to the risk and severity of diabetic retinopathy. Unfortunately, virtually no genes associated with diabetic retinopathy have yet been identified. When a gene is activated, it produces messenger molecules known as mRNA that are used by cells as instructions to produce proteins. The analysis of mRNA molecules, as well as genes themselves, can reveal the role of certain genes in disease. The studies of all genes and their associated mRNAs are respectively called genomics and transcriptomics. Genomics reveals what genes are present, while transcriptomics shows how active genes are in different cells. Skol et al. developed methods to study genomics and transcriptomics together to help discover genes that cause diabetic retinopathy. Genes involved in how cells respond to high blood sugar were first identified using cells grown in the lab. By comparing the activity of these genes in people with and without retinopathy the study identified genes associated with an increased risk of retinopathy in diabetes. In people with retinopathy, the activity of the folliculin gene (FLCN) increased more in response to high blood sugar. This was further verified with independent groups of people and using computer models to estimate the effect of different versions of the folliculin gene. The methods used here could be applied to understand complex genetics in other diseases. The results provide new understanding of the effects of diabetes. They may also help in the development of new treatments for diabetic retinopathy, which are likely to improve on the current approach of using laser surgery or injections into the eye.
Autres résumés
Type: plain-language-summary
(eng)
One of the side effects of diabetes is loss of vision from diabetic retinopathy, which is caused by injury to the light sensing tissue in the eye, the retina. Almost all individuals with diabetes develop diabetic retinopathy to some extent, and it is the leading cause of irreversible vision loss in working-age adults in the United States. How long a person has been living with diabetes, the extent of increased blood sugars and genetics all contribute to the risk and severity of diabetic retinopathy. Unfortunately, virtually no genes associated with diabetic retinopathy have yet been identified. When a gene is activated, it produces messenger molecules known as mRNA that are used by cells as instructions to produce proteins. The analysis of mRNA molecules, as well as genes themselves, can reveal the role of certain genes in disease. The studies of all genes and their associated mRNAs are respectively called genomics and transcriptomics. Genomics reveals what genes are present, while transcriptomics shows how active genes are in different cells. Skol et al. developed methods to study genomics and transcriptomics together to help discover genes that cause diabetic retinopathy. Genes involved in how cells respond to high blood sugar were first identified using cells grown in the lab. By comparing the activity of these genes in people with and without retinopathy the study identified genes associated with an increased risk of retinopathy in diabetes. In people with retinopathy, the activity of the folliculin gene (FLCN) increased more in response to high blood sugar. This was further verified with independent groups of people and using computer models to estimate the effect of different versions of the folliculin gene. The methods used here could be applied to understand complex genetics in other diseases. The results provide new understanding of the effects of diabetes. They may also help in the development of new treatments for diabetic retinopathy, which are likely to improve on the current approach of using laser surgery or injections into the eye.
Identifiants
pubmed: 33164750
doi: 10.7554/eLife.59980
pii: 59980
pmc: PMC7728435
doi:
pii:
Substances chimiques
FLCN protein, human
0
Proto-Oncogene Proteins
0
Tumor Suppressor Proteins
0
Glucose
IY9XDZ35W2
Banques de données
Dryad
['10.5061/dryad.zkh18938j']
GEO
['GSE146615']
Types de publication
Journal Article
Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NEI NIH HHS
ID : P30 EY001792
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY023644
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA EY000546
Pays : United States
Informations de copyright
© 2020, Skol et al.
Déclaration de conflit d'intérêts
AS, SJ, AS, SC, SF, OS, PB, AL, MS, DC, AS, IB, BS, MG No competing interests declared
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