Genome-Wide Dissection of the Neutrophil-to-Lymphocyte Ratio Uncovers Polygenic Determinants Linked to Inflammatory...

Background: The neutrophil-to-lymphocyte ratio (NLR) is a simple biomarker that reflects the balance between innate immune response and adaptive immunity. Currently, the genetic basis and clinical implications of NLR in relation to inflammatory gastrointestinal diseases have not been extensively explored. Methods: We carried out a genome-wide association study (GWAS) on European individuals from the UK Biobank to detect genetic variants related to NLR, followed by post-GWAS analyses including colocalization analysis, transcriptome-wide association studies (TWAS), and LD score regression. Logistic regression, Cox regression, and gene-environment interaction analysis were used to evaluate the impact of NLR polygenic risk scores (PRS) on inflammatory gastrointestinal disease risks. Results: GWAS of 395,442 Europeans identified 306 genomic regions (731 lead SNPs) associated with NLR, mapping to 1542 genes enriched for immune pathways. Colocalization revealed shared genetic signals with TWAS prioritization of 59, 19, 14, 22 and 28 genes in the whole blood, spleen, terminal ileum, transverse colon and sigmoid colon, respectively. LD-score regression showed significant positive genetic correlations with CD (rg = 0.132), coeliac disease (rg = 0.124), peptic ulcer (rg = 0.138) and duodenal ulcer (rg = 0.220). One-SD increase in NLR PRS predicted higher risk of IBD (OR = 1.05, 95% CI 1.03-1.08), Crohn's disease (OR = 1.06, 1.02-1.10), ulcerative colitis (OR = 1.05, 1.02-1.08) and coeliac disease (OR = 1.07, 1.03-1.11). Restricted cubic splines demonstrated non-linear relationships of NLR PRS for IBD, CD and UC. Gene environment analyses showed smoking and diabetes amplified the risks, while cardioprotective diet, oily fish intake and polyunsaturated fatty acid level attenuated NLR PRS-associated risk in IBD (mainly CD). Conclusions: Our study delineates the polygenic basis of NLR and establishes its genetic correlation with inflammatory gastrointestinal diseases, offering a genetically informed indicator for disease risk stratification with potential utility in population-level prevention strategies.