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NIH researchers focus on genes related to age-related macular degeneration

Press release

Monday, February 11, 2019

The findings point to possible treatment strategies.

Scientists at the National Eye Institute led a collaborative study and focused on genes associated with age-related macular degeneration (AMD), one of the leading causes of vision loss and blindness among people 65 and older. . These findings provide a broader and deeper picture of the genetic contributions to AMD, and present new avenues for the development of treatment. The study was published on February 11 in Nature Genetics.

"If we were conducting a criminal investigation, a previous investigation would have located different criminal syndicates in 52 streets within 34 zip codes. These latest findings identify real suspects, direct targets that we can investigate more closely, "said the study's principal investigator, Anand Swaroop, Ph.D., head of the Neurobiology-Neurodegeneration and Repair Laboratory at NEI, part of the Institutes. National Health

Previously, Swaroop and his colleagues compared populations of people with and without AMD and identified 34 small genomic regions, called loci, and 52 genetic variants within these loci that were significantly associated with AMD. "However, as with other common and complex diseases, most of the variants turned out not to be present in the protein coding regions of the genome, which makes us wonder how they had a biological effect on AMD," said Swaroop.

The researchers explored whether the variants could regulate the relevant AMD genes, possibly in the promoters, which are sequences within the DNA that activate the genes, or enhancers, that increase the activity of the promoters. If the variants did regulate the expression of the genes, there remained a key question: what were the genes that regulated the variants?

Swaroop's team studied 453 retinas, ocular tissue affected by AMD, from deceased human donors with and without AMD. The analysis involved the sequencing of ribonucleic acid (RNA) from each retina, the messenger molecule that carries instructions from DNA to produce proteins. A total of 13,662 protein-encoding RNA sequences and 1,462 non-protein encodings were identified.

To search for the genetic variants that regulate gene expression in the retina, they used quantitative trait expression loci (eQTL) analysis. The computational methods allowed the researchers to detect patterns between the genes expressed in the retina and a set of more than 9 million previously identified genetic variants. Specifically, they searched for variants with a high probability of being responsible for variations in gene expression between people with and without AMD. The analysis targeted the genes of the target disease in six of the 34 AMD loci identified in the previous investigation.

In addition, the integration of these data with previous studies of AMD identified three additional target AMD genes, which had never before been shown to play a role in AMD. This analysis also suggested up to 20 additional candidate genes that provide information on the genes and pathways involved in the pathobiology of AMD.

"Until now, most studies in AMD have focused on the analysis of genetic variants in DNA. "For the first time, this study takes advantage of transcription (RNA) data to expand the genetic architecture of AMD," said Rinki Ratnapriya, Ph.D., who worked on the study as a NEI researcher and is currently at Baylor College. of Medicine in Houston

Among the most plausible target genes were B3GLCT Y BLOC1S1, which could affect cellular functions related to AMD, such as signaling; the degradation and elimination of unwanted proteins; and the stability of the extracellular matrix, the infrastructure of the cell for distribution.

"It is important to note that the ability to define how genetic variation affects gene expression opens completely new directions to observe the biology of the eye," said Swaroop.

Crucial to the study was the development of Swaroop from a database of gene expression of the retina. Called EyeGEx, the database provides a resource for vision researchers, not only for AMD studies, but also for the investigation of the genetic causes of other diseases such as diabetic retinopathy and glaucoma.

AMD is a complex disease influenced by a combination still to be understood from genetic and behavioral factors. Smoking, for example, increases the risk of developing the disease, while eating leafy green vegetables and fish reduces it. More research is needed to understand how these environmental factors interact with genes to contribute to the development of the disease and its severity.

Future studies will try to explain the function of target AMD genes to determine how they relate to the pathobiology of the disease and to search for targets for new treatment strategies.

The study was a collaboration between the NEI researchers; University of Minnesota, Minneapolis; University of Michigan, Ann Arbor; and Johns Hopkins University, Baltimore. It was funded by the NEI Intramural Research Program, the Lindsay Family Foundation, an anonymous benefactor for AMD research, the Minnesota Lions Vision Foundation and the Distinguished Endowment of the Johns Hopkins Bloomberg Chair.

NEI leads the federal government's research on the visual system and eye diseases. NEI supports basic science and clinical programs to develop treatments that allow vision and meet the special needs of people with vision loss. For more information, visit https://www.nei.nih.gov.

About the National Institutes of Health (NIH):
NIH, the nation's medical research agency, includes 27 institutes and centers and is a component of the US Department of Health and Human Services. UU NIH is the leading federal agency that conducts and supports basic, clinical and translational medical research, and is investigating the causes, treatments and cures for common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

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Ratnapriya R, Sosina OA, Starostik MR, Kwicklis M, Kapphahn RJ, Fritsche LG, Walton A, Arvanitis M, Gieser L, Pietraszkiewicz A, Montezuma SR, Chew EY, Battle A, Abecasis GR, Ferrington DA, Chatterjee N, Swaroop A Retinal transcriptome and eQTL analyzes identify genes associated with age-related macular degeneration. Genetics of nature. February 11, 2019. DOI 10.1038 / s41588-019-0351-9


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