. 2022 Aug 29;130(8):087009. doi: 10.1289/EHP10602

Table 3.

Mediating effects of DNA methylation related to blood metals and ADL disability for participants between 2016 and 2018 in Guangxi, China ( $uppercase italic n equals 212$ ).

Blood metals	Mediators	Gene description	Estimated natural direct effects (NDE, 95% CI)	Estimated natural indirect effect (NIE, 95% CI)^a	Proportion mediated (%)^b	$p$ -Values of mediation^d
Manganese	cg10725542	TM4SF1	0.541 ( $negative 0.156$ , 1.27)	0.041 ( $negative 0.037$ , 0.146)	7.04	0.540
	cg22000984	IRGM	0.385 ( $negative 0.330$ , 1.13)	0.173 (0.037, 0.350)	31.0	0.039
	cg23012519	PKP3	0.395 ( $negative 0.331$ , 1.14)	0.179 (0.039, 0.357)	31.2	0.026
Copper	cg04875128	OTUD7A	0.953 ( $negative 0.650$ , 2.60)	$negative 0.032$ ( $negative 0.398$ , 0.321)	NA^c	—
	cg05825244	EBF4	0.909 ( $negative 0.690$ , 2.55)	0.03 ( $negative 0.203$ , 0.281)	3.19	0.340
	cg06723863	ESRP2	0.733 ( $negative 0.878$ , 2.38)	0.352 (0.033, 0.786)	32.4	0.042
	cg22000984	IRGM	1.695 ( $negative 0.023$ , 3.50)	$negative 0.488$ ( $negative 0.991$ , $negative 0.090$ )	NA^c	—
Arsenic	cg07839457	NLRC5	0.616 ( $negative 0.059$ , 1.32)	0.007 ( $negative 0.086$ , 0.105)	1.12	0.157
	cg09199338	LINC01098	0.697 (0.022, 1.41)	$negative 0.116$ ( $negative 0.258$ , $negative 0.012$ )	NA^c	—
	cg14255237	SARDH	0.862 (0.156, 1.61)	$negative 0.184$ ( $negative 0.371$ , $negative 0.033$ )	NA^c	—
	cg15931375	FAM181B	0.616 ( $negative 0.060$ , 1.32)	0.005 ( $negative 0.088$ , 0.100)	0.810	0.171
	cg23379566	TM4SF1	0.581 ( $negative 0.093$ , 1.29)	0.042 ( $negative 0.031$ , 0.142)	6.74	0.253
	cg24433124	IER3	0.577 ( $negative 0.107$ , 1.29)	0.108 (0.010, 0.243)	15.8	0.038
	cg26682566	IGFBP7-AS1	0.725 (0.043, 1.45)	$negative 0.131$ ( $negative 0.288$ , $negative 0.013$ )	NA^c	—
Cadmium	cg07905190	FREM1	0.193 ( $negative 0.169$ , 0.560)	0.053 (0.003, 0.122)	21.5	0.023
	cg11784243	LRRC16A	0.218 ( $negative 0.136$ , 0.579)	0.033 ( $negative 0.024$ , 0.102)	13.2	0.380
	cg11960359	LINC01300	0.231 ( $negative 0.126$ , 0.596)	0.047 ( $negative 0.002$ , 0.118)	16.9	0.219
	cg17485717	TCP11L1	0.205 ( $negative 0.157$ , 0.573)	0.090 (0.021, 0.180)	30.5	0.010
	cg17951445	PCDH7	0.212 ( $negative 0.144$ , 0.575)	0.032 ( $negative 0.010$ , 0.093)	13.1	0.203
	cg26413501	MIR3668	0.241 ( $negative 0.110$ , 0.599)	$negative 0.004$ ( $negative 0.038$ , 0.027)	NA^c	—

Note: —, no data; ADL, activities of daily living; CI, confidence interval; NDE, natural direct effect; NIE, natural indirect effect.

^{^a}

Mediating (indirect) effect represented effects mediated through DNA methylation and was calculated as a statistical relationship using the “product of coefficients” that multiplies changes in DNA methylation with blood metals and changes in ADL disability with DNA methylation from the “mediation” package.

^{^b}

The proportion of mediation by DNA methylation was calculated as the following formula: Prop. $Mediated = [α_{metal} \times ν_{metal} \div (α_{metal} \times ν_{methylation} + ν_{metal}) \times 100]$ .

^{^c}

NA represents that proportion mediated cannot be calculated when there are opposite signs between the direct effect and the mediated effect.

^{^d}

$p$ -Values of mediation was evaluated by the significance test of “product of coefficients” using “mediation” package in R.