DataSheet_1_Potential disease biomarkers for diabetic retinopathy identified through Mendelian randomization analysis.xlsx

BackgroundDiabetic retinopathy (DR), a leading cause of vision loss, has limited options for effective prevention and treatment. This study aims to utilize genomics and proteomics data to identify potential drug targets for DR.MethodsWe utilized plasma protein quantitative trait loci data from the Atherosclerosis Risk in Communities Study and the Icelandic Decoding Genetics Study for discovery and replication, respectively. Genetic associations with DR, including its subtypes, were derived from the FinnGen study. Mendelian Randomization (MR) analysis estimated associations between protein levels and DR risk, complemented by colocalization analysis to examine shared causal variants.ResultsOur MR analysis identified significant associations of specific plasma proteins with DR and proliferative DR (PDR). Elevated genetically predicted levels of WARS (OR = 1.16; 95% CI = 0.095-0.208, FDR = 1.31×10-4) and SIRPG (OR = 1.15; 95% CI = 0.071-0.201, FDR = 1.46×10-2) were associated with higher DR risk, while increased levels of ALDOC (OR = 1.56; 95% CI = 0.246-0.637, FDR = 5.48×10-3) and SIRPG (OR = 1.15; 95% CI = 0.068-0.208, FDR = 4.73×10-2) were associated with higher PDR risk. These findings were corroborated by strong colocalization evidence.ConclusionsOur study highlights WARS, SIRPG, and ALDOC as significant proteins associated with DR and PDR, providing a basis for further exploration in drug development. Additional studies are needed to validate these proteins as disease biomarkers across diverse populations.</p

Supplementary document for Three-dimensional cerebral vasculature topological parameters extraction of transgenic zebrafish embryo with a filling-enhancement deep learning network - 6260471.pdf

Supplemental documen

Characteristics of full-length cDNA sequences of the <i>CYPs</i> overexpressed in AL-R population.

<p>Characteristics of full-length cDNA sequences of the <i>CYPs</i> overexpressed in AL-R population.</p

Overexpression of cytochrome P450s in a lambda-cyhalothrin resistant population of <i>Apolygus lucorum</i> (Meyer-Dür)

<div><p>The mirid bug, <i>Apolygus lucorum</i> Meyer-Dür, has been an important pest of cotton crop in China, and is primarily controlled with insecticides, such as pyrethroids. To elucidate the potential resistant mechanisms of <i>A</i>. <i>lucorum</i> to lambda-cyhalothrin, a series of biological, biochemical, and molecular assays were conducted in the reference (AL-S) and lambda-cyhalothrin-resistant (AL-R) populations. Comparison of the molecular target of pyrethroid insecticides, voltage-gated sodium channel, revealed that there were no mutation sites in the resistant population, indicating target insensitivity is not responsible for increased resistance of AL-R to lambda-cyhalothrin. Furthermore, the synergism assays and the activities of detoxification enzymes were performed to determine detoxification mechanism conferring the lambda-cyhalothrin resistance. In the tested synergists, the piperonyl butoxide had the highest synergism ratio against lambda-cyhalothrin, which was up to five-fold in both populations. In addition, the result also showed that only cytochrome P450 had significantly higher O-deethylase activity with 7-ethoxycoumarin (1.78-fold) in AL-R population compared with AL-S population. Seven cytochrome P450 genes were found to be significantly overexpressed in the resistant AL-R population compared with AL-S population. Taken together, these results demonstrate that multiple over-transcribed cytochrome P450 genes would be involved in the development of lambda-cyhalothrin resistance in AL-R population.</p></div

Comparison of detoxifying enzyme activity between the lambda-cyhalothrin reference and resistant populations (AL-S and AL-R).

<p>Left Y axis (mmol/min/mg protein) represents the unit of CarE and GST activities. Right Y axis (pmol/min/mg protein) represents the unit of ECOD activity.</p

Relative expression levels of <i>A</i>. <i>lucorum</i> CYP genes in AL-S and AL-R adults determined by qPCR.

<p>Relative expression levels of <i>A</i>. <i>lucorum</i> CYP genes in AL-S and AL-R adults determined by qPCR.</p

Relative expression level of the <i>CYP6X2</i> gene in adults of the control (AL-S) and lambda-cyhalothrin-resistant (AL-R) populations of <i>A</i>. <i>lucorum</i> with and without application of lambda-cyhalothrin (9 ng and 70 ng for AL-S and AL-R, respectively).

<p>Error bars indicate standard errors. Different letters indicate significant differences in relative expression level determined by Turkey’s Multiple Comparison test.</p

Neighbor-joining phylogeny of the deduced amino acid sequences of <i>Apolygus lucorum</i> P450s (blue diamond) and selected P450s from other insects.

<p>Neighbor-joining phylogeny of the deduced amino acid sequences of <i>Apolygus lucorum</i> P450s (blue diamond) and selected P450s from other insects.</p

Effects of synergist on the toxicity of lambda-cyhalothrin to the reference (AL-S) and the resistant (AL-R) populations of <i>A</i>. <i>lucorum</i>.

<p>Effects of synergist on the toxicity of lambda-cyhalothrin to the reference (AL-S) and the resistant (AL-R) populations of <i>A</i>. <i>lucorum</i>.</p

Lambda-cyhalothrin toxicity in successive generations of the laboratory selected AL-R population.

<p>Lambda-cyhalothrin toxicity in successive generations of the laboratory selected AL-R population.</p