Genome-Wide Association Study Identifies Human Genetic Variants Associated with Systemic Chronic Inflammation

Abstract

Chronic low-grade inflammation has been identified as the etiology of disease across the life span; however, the underlying genetic mechanism are poorly understood, and no genetic association study is performed. Here, we quantified chronic low-grade inflammation using the low-grade inflammation score (INFLA-score) and performed a genome-wide association study in a large European cohort of 217,984 individuals, involving 6,134,151 single nucleotide polymorphisms (SNPs). We identified 20,182 SNPs at 194 loci reaching genome-wide significance (p < 5 × 10⁻⁸), with the lead SNP rs429358 in apolipoprotein E (APOE) showing an extremely low p-value of 8.69 × 10⁻¹⁶⁶. Gene analysis found 470 genes with p < 2.70 × 10⁻⁶ (0.05/18,519), among which phosphodiesterase 4B was most significant (p = 1.67 × 10⁻²²). Among those, 15 SNPs were first reported, including GS1-259H13.10, AC068533.7, AL355490.1, and so on. Tissue expression analysis revealed significant links between genetic variants and chronic low-grade inflammation in spleen and whole blood. Our findings identify variants linked to chronic low-grade inflammation and related inflammatory and cellular regulation traits, and suggest a close association between chronic low-grade inflammation and the spleen.