Background: Neutrophil to lymphocyte Ratio (NLR) is a biomarker of inflammation and was associated with diabetic retinopathy (DR) in earlier studies. Objective: To investigate the genetic loci influencing NLR and to estimate the heritability and causality of DR with the NLR polygenic risk score (PRS). Design: Genome-wide association study, conditional analysis, Fine and Gray model (FGR), Mendelian Randomization (MR) Setting: Scottish and South Indian populations drawn from population cohorts and electronic medical records. Participants: 29,317 individuals, with a considerable proportion diagnosed with diabetes. Measurements: Effect estimates from GWAS to compute PRS and causal association with DR. Results: Heritability estimates for the Scottish and Indian cohorts were 35.3% and 8.7% respectively. The top Single Nucleotide Polymorphisms (SNPs) in the multi-ancestry analysis (n=29,317) were intergenic: rs1825819 (Chr4:T/C) (Beta=-0.05, p=2.00x10-9), rs2980871 (Chr8:A/G) (Beta=0.04, p=4.64x10-8), rs2227322 (Chr17:C/G) (Beta=0.07, p=4.12x10-20) and rs4808047 (Chr19:T/C) (Beta= -0.07, p=5.93x10-12). For the construction of best-fit PRS, we used 74,377 of 55,333,12 variants. There was a dose-response relationship between the PRS and NLR. The subhazard ratio (sHR) for NLR PRS association with DR was not statistically significant sHR=1.01 (95% CI: 0.97, 1.06, p=0.48). Null associations were observed in both cross-sectional and time-based MR analyses for PRS with DR. Limitations: A substantial proportion of the dataset was used for training the PRS algorithm. Due to trans-ancestry differences, PRS and subsequent analysis were conducted only in the Scottish cohorts. Conclusions: Multiple novel intergenic SNP associations were discovered, complementing those previously identified. Of these, some SNPs were also associated with genes known to regulate white blood cells, but not specifically NLR. More studies are required to confirm the causality between systemic inflammation and DR.

The authors have declared no competing interest.

National Institute for Health Research, Pioneer and Leading Goose R&D Program of Zhejiang 2023, and the Ningbo International Collaboration Program 2023.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Tayside, Scotland UK: Ethical approval for the study was provided by the Tayside Medical Ethics Committee (REF:053/04) and the study has been carried out in accordance with the Declaration of Helsinki. SHARE, Scotland UK: Ethical approval of the study was provided by the ethics committee SHARE East of Scotland (REF: NHS REC 13/ES/0020). DMDSC: NIHR Global Health Research Unit on Global Diabetes Outcomes Research, Institutional Ethics Committee of Madras Diabetes Research Foundation, Chennai, India. IRB number IRB00002640. Granted 24th August 2017.

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