Common and Rare Variants Genetic Association Analysis of Circulating Neutrophil Extracellular Traps

Introduction Neutrophils contribute to host defense through different mechanisms, including the formation of neutrophil extracellular traps (NETs). The genetic background and underlying mechanisms contributing to NET formation remain unclear. Materials and Methods We performed a genome-wide association study (GWAS) and exome-sequencing analysis to identify common and rare genetic variants associated with plasma myeloperoxidase (MPO)-DNA complex levels, a biomarker for NETs, in the population-based Rotterdam Study cohort. GWAS was performed using haplotype reference consortium(HRC)-imputed genotypes of common variants in 3,514 individuals from the first and 2,076 individuals from the second cohort of the Rotterdam Study. We additionally performed exome-sequencing analysis in 960 individuals to investigate rare variants in candidate genes. Results The GWAS yielded suggestive associations (p-value < 5.0 x 10(-6)) of SNPs annotated to four genes. In the exome-sequencing analysis, a variant in TMPRSS13 gene was significantly associated with MPO-DNA complex levels (p-value < 3.06x10(-8)). Moreover, gene-based analysis showed ten genes (OR10H1, RP11-461L13.5, RP11-24B19.4, RP11-461L13.3, KHDRBS1, ZNF200, RP11-395I6.1, RP11-696P8.2, RGPD1, AC007036.5) to be associated with MPO-DNA complex levels (p-value between 4.48 x 10(-9) and 1.05 x 10(-6)). Pathway analysis of the identified genes showed their involvement in cellular development, molecular transport, RNA trafficking, cell-to-cell signaling and interaction, cellular growth and proliferation. Cancer was the top disease linked to the NET-associated genes. Conclusion In this first GWAS and exome-sequencing analysis of NETs levels, we found several genes that were associated with NETs. The precise mechanism of how these genes may contribute to neutrophil function or the formation of NETs remains unclear and should be further investigated in experimental studies.

Automated summary

In this study, a genome-wide association study (GWAS) and exome-sequencing analysis were conducted to identify genetic variants associated with plasma myeloperoxidase (MPO)-DNA complex levels, a biomarker for neutrophil extracellular traps (NETs), in a population-based cohort. Several common and rare genetic variants in candidate genes were found to be associated with NETs levels. Pathway analysis revealed involvement in cellular development, molecular transport, RNA trafficking, and cancer association. Further experimental studies are needed to elucidate the precise mechanisms of how these genes contribute to neutrophil function or NET formation.