Iron homeostasis pathway DNA methylation trajectories reveal a role for STEAP3 metalloreductase in patient outcomes after aneurysmal subarachnoid hemorrhage

Heinsberg, Lacey W.; Weeks, Daniel E.; Alexander, Sheila A.; Minster, Ryan L.; Sherwood, Paula R.; Poloyac, Samuel M.; Deslouches, Sandra; Crago, Elizabeth A.; Conley, Yvette P.

doi:10.1186/s43682-021-00003-5

Epigenetics Communications

Table 2 Discovery results of binary logistic regression and global analysis examining associations of cg25713625 (STEAP3), cg08866780 (APP), and cg08553327 (TNF) unadjusted and CTH-adjusted trajectory groups with patient outcomes while controlling for age, sex, self-identified race, and Fisher grade

From: Iron homeostasis pathway DNA methylation trajectories reveal a role for STEAP3 metalloreductase in patient outcomes after aneurysmal subarachnoid hemorrhage

*Table 2a. cg25713625 (STEAP3***)
Base model, polynomial order 010, Fig. 2a
	Group 2 (intermediate) vs. group 1 (low)			Group 3 (high) vs. group 1 (low)
Outcome	OR	95% CI	p^c	OR	95% CI	p^c	Global p^d
CV	0.662	0.21 to 2.03	0.471	1.126	0.33 to 3.80	0.847	0.351
DCI	1.032	0.45 to 2.41	0.941	1.256	0.49 to 3.20	0.629	0.789
GOS-3	2.982	0.86 to 12.56	0.1	11.743	3.14 to 21.65	0.0006^a	0.00005^a
GOS-12	6.346	1.47 to 31.32	0.029^b	15.595	3.35 to 22.54	0.0018^a	0.0005^a
Death-3	7.147	1.00 to 32.53	0.076	19.081	3.01 to 25.12	0.0093^b	0.0013^a
Death-12	4.859	1.00 to 35.80	0.064	12.762	2.71 to 25.13	0.0041^b	0.0015^a
CTH-adjusted model, polynomial order 000, Fig. 2b
	Group 2 (intermediate) vs. group 1 (low)			Group 3 (high) vs. group 1 (low)
Outcome	OR	95% CI	p^c	OR	95% CI	p^c	Global p^d
CV	0.433	0.14 to 1.26	0.131	0.832	0.25 to 2.70	0.76	0.129
DCI	0.612	0.27 to 1.36	0.231	0.913	0.37 to 2.20	0.84	0.260
GOS-3	2.589	0.80 to 9.35	0.115	4.143	1.25 to 5.01	0.0271^b	0.062
GOS-12	3.960	1.00 to 10.58	0.055	5.972	1.52 to 6.25	0.0182^b	0.0326^b
Death-3	3.768	0.90 to 11.54	0.108	4.847	1.05 to 7.50	0.069	0.122
Death-12	3.120	0.86 to 15.63	0.115	4.249	1.06 to 5.25	0.059	0.123
*Table 2b. cg08866780 (APP***)
Base model, polynomial order 000, Fig. 2d
	Group 2 (intermediate) vs. group 1 (low)			Group 3 (high) vs. group 1 (low)
Outcome	OR	95% CI	p^c	OR	95% CI	p^c	Global p^d
CV	0.443	0.19 to 0.989	0.051	0.366	0.14 to 1.00	0.056	0.069
DCI	0.803	0.44 to 1.48	0.479	1.156	0.56 to 2.41	0.698	0.488
GOS-3	0.349	0.16 to 0.74	0.0060^b	0.760	0.32 to 1.82	0.541	0.0118^b
GOS-12	0.194	0.08 to 0.44	0.0001^a	0.826	0.39 to 1.98	0.672	0.0001^a
Death-3	0.209	0.08 to 0.52	0.0010^a	1.080	0.44 to 2.67	0.868	0.0002^a
Death-12	0.206	0.08 to 0.50	0.0006^a	0.977	0.39 to 2.43	0.96	0.0002^a
CTH-adjusted model, polynomial order 000, Fig. 2e
	Group 2 (intermediate) vs. group 1 (low)			Group 3 (high) vs. group 1 (low)
Outcome	OR	95% CI	p^c	OR	95% CI	p^c	Global p^d
CV	0.813	0.37 to 1.76	0.602	0.654	0.25 to 1.67	0.374	0.672
DCI	1.230	0.68 to 2.24	0.494	1.400	0.67 to 2.97	0.377	0.656
GOS-3	0.332	0.16 to 0.70	0.0040^b	0.683	0.27 to 1.67	0.4072	0.0097^b
GOS-12	0.347	0.15 to 0.77	0.0097^b	1.070	0.43 to 2.68	0.8853	0.0066^b
Death-3	0.359	0.15 to 0.87	0.0237^b	1.284	0.50 to 3.31	0.6028	0.0091^b
Death-12	0.337	0.14 to 0.79	0.0128^b	1.143	0.44 to 2.95	0.7817	0.0072^b
*Table 2c. cg08553327 (TNF***)
Base model, polynomial order 212, Fig. 2g
	Group 2 (intermediate) vs. group 1 (low)			Group 3 (high) vs. group 1 (low)
Outcome	OR	95% CI	p^c	OR	95% CI	p^c	Global p^d
CV	0.850	0.42 to 1.72	0.651	1.223	0.31 to 5.36	0.777	0.844
DCI	0.827	0.47 to 1.46	0.516	3.066	0.98 to 11.64	0.069	0.101
GOS-3	3.686	1.78 to 7.87	0.0005^a	13.134	3.51 to 39.02	0.0003^a	0.00001^a
GOS-12	2.080	0.98 to 4.43	0.0568	4.488	1.24 to 16.50	0.0209^b	0.0244^b
Death-3	2.488	1.11 to 5.57	0.0257^b	5.603	1.47 to 20.44	0.0089^b	0.0094^b
Death-12	2.496	1.12 to 5.56	0.0243^b	7.123	1.89 to 27.94	0.0037^b	0.0038^b

Corresponds to trajectory groups depictured in Fig. 2a (STEAP3), 2b (STEAP3 + CTH), 2d (APP), 2e (APP + CTH), and 2g (TNF). Base model, unadjusted for CTH; OR, odds ratio; CI, confidence interval; p, p-value based on an alpha of 0.05; Global p, p-value computed using partial F test comparing models with and without trajectory group; CTH, cell type heterogeneity; CV, cerebral vasospasm; DCI, delayed cerebral ischemia; GOS-3, Glasgow Outcome Scale at 3 months (unfavorable = 1–3); GOS-12, Glasgow Outcome Scale at 12 months (unfavorable = 1–3); Death-3, death at 3 months; Death-12, death at 12 months. ^aSignificant associations (meeting empirical significance level) have been bolded. ^bSuggestive associations (unadjusted p < 0.05) have been underlined. ^cEmpirical significance threshold = 0.002 (calculated based on the minimum of 12 p-values, including both group 2 vs. group 1 and group 3 vs. group 1 comparisons, in permutation testing). ^dEmpirical significance threshold for global analysis = 0.003 (calculated based on the minimum of 6 p-values in permutation testing)

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