NIH scientists target genes associated with AMD

Scientists at the National Eye Institute conducted a collaborative, targeted study of the genes badociated with age-related macular degeneration (AMD), a leading cause of vision loss and blindness in people 65 years and older . These results provide a more detailed and detailed picture of the genetic contributions to AMD, as well as new pathways for treatment development. The study was published on February 11 in Nature Genetics.

"If we conducted a criminal investigation, previous research would have located different crime syndicates in 52 streets out of 34 codes.These latest discoveries identify real suspects – direct targets on which we can investigate more closely," said the report. Lead investigator of the study, Anand Swaroop, Ph.D., head of the neurobiology-neurodegeneration and repair laboratory at NEI, part of the National Institutes of Health.

Previously, Swaroop and colleagues compared populations of people with and without AMD and identified 34 small genomic regions – called loci – and 52 genetic variants within these loci significantly badociated with AMD. "However, as with other common and complex diseases, most variants have been shown not to be present in the regions of the genome encoding proteins, which leaves us wondering how they have a biological effect on AMD, "said Swaroop.

The researchers examined whether variants could regulate AMD-related genes, possibly at the level of promoters, which are sequences in DNA-activating genes, or enhancers, that increase the activity of promoters. If variants actually regulated gene expression, there remained one key question: what genes did the variants regulate?

The Swaroop team studied 453 retinas, the ocular tissue affected by AMD, from deceased human donors with and without AMD. The badysis consisted in sequencing the ribonucleic acid (RNA) of each retina, the messenger molecule containing the instructions of the DNA for the manufacture of proteins. A total of 13,662 RNA sequences encoding proteins and 1,462 non-coding for proteins were identified.

To look for genetic variants regulating the expression of genes in the retina, they used a quantitative trait locus expression (eQTL) badysis. Computer-based methods allowed researchers to detect patterns between genes expressed in the retina and a pool of over 9 million previously identified genetic variants. Specifically, they searched for variants with a high probability of being responsible for variations in gene expression in people with and without AMD. The badysis highlighted target genes for the disease in six of the 34 AMD loci identified during the previous search.

In addition, the integration of these data with previous studies on AMD has identified three additional AMD target genes, which have never been previously demonstrated to play a role in AMD. a role in AMD. This badysis also suggested the presence of 20 additional candidate genes providing information on the genes and pathways involved in the pathobiology of AMD.

"Until now, most AMD studies have focused on the badysis of genetic variants of DNA." This study relies for the first time on transcription data. (RNA) to develop the genetic architecture of AMD, "said Rinki Ratnapriya, Ph.D. on studying as an NEI researcher and is currently at Baylor College of Medicine in Houston.

The most plausible target genes are B3GLCT and BLOC1S1, which could affect AMD-related cellular functions such as signaling; decomposition and elimination of unwanted proteins; and the stability of the extracellular matrix, the cell infrastructure for distribution.

"It's important to note that the ability to define the impact of genetic variation on gene expression opens up new perspectives for examining the biology of the eye," Swaroop said.

Swaroop has developed a database on retinal gene expression. The database, EyeGEx, is a resource for vision researchers, not only for studies on AMD, but also for research into the genetic causes of other diseases such as diabetic retinopathy and glaucoma.

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

Future studies will focus on explaining the function of AMD target genes, determining their link to the pathobiology of AMD, and finding targets for new treatment strategies.