Xanthine oxidoreductase gene polymorphisms are associated with high risk of sepsis and organ failure

Gao, Li; Rafaels, Nicholas; Dudenkov, Tanda M.; Damarla, Mahendra; Damico, Rachel; Maloney, James P.; Moss, Marc; Martin, Greg S.; Sevransky, Jonathan; Shanholtz, Carl; Herr, Dan L.; Garcia, Joe G.N.; Hernandez-Beeftink, Tamara; Villar, Jesús; Flores, Carlos; Beaty, Terri H.; Brower, Roy; Hassoun, Paul M.; Barnes, Kathleen C.

doi:10.1186/s12931-023-02481-8

Respiratory Research

Table 5 Functional annotation of 28 XDH variants and their relevance for sepsis according to findings in this study

From: Xanthine oxidoreductase gene polymorphisms are associated with high risk of sepsis and organ failure

SNPs	RegulomedB rank (score)	eQTLs (GTEx) Tissue-specific p ≤ 0.05	SiNoPsis*	CADD (scaled)	Relevance for sepsis
rs206816	Other (7, 0.18412)	9 tissues (in cultured fibroblasts: p = 3.8e-7)		2.26	Associated with XOR activity among sepsis patients with ARDS
rs7575607	Other (7, 0.51392)	11 tissues (in cultured fibroblasts: p = 7.2e-6)		0.783
rs206811	eQTL + TF binding/DNase peak (1f, 0.55436)	8 tissues (in cultured fibroblasts: p = 3.5e-6)		1.22
rs206805	Other (7, 0.51392)	5 tissues		1.81	Associated with risk of sepsis
rs1366814	eQTL + TF binding/DNase peak (1f, 0.08217)	2 tissues		0.446
rs513311	eQTL + TF binding/DNase peak (1f, 0.66703)			1.58	Associated with risk of sepsis & replicated in the GEN-SEP cohort
rs6714794	eQTL + TF binding/DNase peak (1f, 0.55436)	1 tissue		5.17
rs206859	eQTL + TF binding/DNase peak (1f, 0.19549)	9 tissues (in cultured fibroblasts: p = 3.3e-6)		4.12
rs206849	eQTL + TF binding/DNase peak (1f, 0.66703)	5 tissues	creSNP	0.841	Associated with XOR activity among sepsis patients with ARDS
rs13418515	Other (7, 0.51392)	2 tissues		4.05
rs185925	eQTL + TF binding/DNase peak (1f, 0.55436)	7 tissues (in cultured fibroblasts: p = 1.3e-5)		6.84	Associated with risk of sepsis and XOR activity
rs561525	TF binding or DNase peak (5, 0.13454)			0.0560	Associated with risk of sepsis & replicated in the GEN-SEP cohort
rs17011403	TF binding + DNase peak (4, 0.60906)			0.192
rs1864280	eQTL + TF binding + any motif + DNase footprint + DNase peak (1b, 0.98786)	3 tissues	creSNP	6.25
rs2163059	eQTL + TF binding + any motif + DNase footprint + DNase peak (1b, 0.99571)	1 tissue		0.339	Associated with risk of sepsis & replicated in the GEN-SEP cohort
rs2281547	eQTL + TF binding/DNase peak (1f, 0.22271)	3 tissues		6.05
rs1366817	Other (7, 0.51392)	3 tissues		5.68
rs17011368	TF binding or DNase peak (5, 0.13454)			22.4	Associated with mortality among sepsis patients with ARDS
rs2281550	eQTL + TF binding/DNase peak (1f, 0.22271)	2 tissues		0.975
rs13387204	eQTL + TF binding/DNase peak (1f, 0.08)	2 tissues		6.54	Associated with risk of sepsis
rs12621192	eQTL + TF binding/DNase peak (1f, 0.22271)	3 tissues		0.429
rs1884725	eQTL + TF binding/DNase peak (1f, 0.02)	1 tissue		11.5	Associated with renal dysfunction among sepsis patients
rs4952085	eQTL + TF binding/DNase peak (1f, 0.55436)	1 tissue	creSNP	0.307	Associated with renal dysfunction among sepsis patients
rs207432	eQTL + TF binding/DNase peak (1f, 0.55436)	2 tissues		0.844
rs207431	TF binding or DNase peak (5, 0.64)			0.0120
rs932559	Motif hit (6, 0.0575)	1 tissue		2.52
rs12478111	eQTL + TF binding/DNase peak (1f, 0.22271)	1 tissue		0.839
rs6756897	eQTL + TF binding/DNase peak (1f, 0.55324)	2 tissues		1.19

*Cis-regulatory elements (CREs) are the regions of non-coding DNA, which play a critical role in gene expression regulation. creSNPs are defined as variants that could potentially be modifying CRE regions/functions, according to the SNP classification scheme in SiNoPsis

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