Blood DNA methylation signatures are associated with social determinants of health among survivors of childhood cancer

Figures & data

Table 1. Characteristics of study participants.

	African-ancestry		European-ancestry		P^a
	(N = 258)		(N = 1,618)
	n	(%)	n	(%)
General characteristics
Sex					0.05
Female	137	(53.1%)	654	(40.4%)
Male	121	(46.9%)	761	(47.0%)
Body mass index (BMI), kg/m^2					0.84
<18.5	9	(3.5%)	47	(2.9%)
18.5-<25.0	67	(26.0%)	469	(29.0%)
25.0-<30.0	76	(29.5%)	472	(29.2%)
≥30.0	83	(32.2%)	527	(32.6%)
Unknown	23	(8.9%)	103	(6.4%)
Median BMI (IQR)	27.8	(23.3–33.0)	27.2	(23.5–32.3)	0.27
Smoking					<0.0001
Non-smokers	181	(70.2%)	941	(58.2%)
Past smokers	19	(7.4%)	278	(17.2%)
Current smokers	45	(17.4%)	355	(21.9%)
Unknown	13	(5.0%)	44	(2.7%)
Age at primary diagnosis, years
Median (IQR)	9.6	(4.2–14.4)	9.0	(3.8–14.4)	0.85
Age at blood draw, years
Median (IQR)	33.9	(29.4–39.6)	35.3	(30.3–42.1)	0.03
Time from diagnosis to blood draw, years
Median (IQR)	25.2	(19.9–32.1)	27.3	(21.1–33.7)	0.03
Social determinants of health
Educational attainment					<0.0001
Below high school	39	(15.1%)	137	(8.5%)
High school or training after high school	50	(19.4%)	277	(17.1%)
College	84	(32.6%)	401	(24.8%)
College graduate	49	(19.0%)	478	(29.5%)
Post-graduate	12	(4.7%)	179	(11.1%)
Unknown	24	(9.3%)	146	(9.0%)
Personal annual income, US dollars					<0.0001
None	38	(14.7%)	143	(8.8%)
<$20,000	113	(43.8%)	502	(31.0%)
$20,000-<40,000	53	(20.5%)	442	(27.3%)
$40,000-<60,000	19	(7.4%)	256	(15.8%)
≥$60,000	35	(13.6%)	275	(17.0%)
Area deprivation index, national rank^b
Median (IQR)	80.0	(56.0–91.5)	56.0	(36.0–76.0)	<0.0001
Clinical characteristics
Primary cancer diagnosis					<0.0001
Leukaemia	50	(19.4%)	548	(33.9%)
Lymphoma	57	(22.1%)	639	(39.5%)
Central nervous system tumour	27	(10.5%)	136	(8.4%)
Other	124	(48.1%)	295	(18.2%)
Chemotherapy
Alkylating agents	146	(56.6%)	973	(60.1%)	0.28
Anthracyclines	122	(47.3%)	931	(57.5%)	0.002
Corticosteroids	85	(32.9%)	791	(48.9%)	<0.0001
Epipodophyllotoxins	63	(24.4%)	501	(31.0%)	0.03
Platinum	38	(14.7%)	151	(9.3%)	0.008
Vincristine	158	(61.2%)	1,159	(71.6%)	0.0007
Radiation therapy site
Brain	72	(27.9%)	525	(32.4%)	0.15
Chest	81	(31.4%)	513	(31.7%)	0.92
Abdomen/pelvis	76	(29.5%)	391	(24.2%)	0.07
Abbreviations: IQR (interquartile range)

^aChi-square test for categorical variables, Student’s t-test for continuous variables, and Wilcoxon rank sum test for ranked variables.

^bNational rank in percentiles

Table 2. Association of smoking and BMI with SDOH factors among survivors of European ancestry.

SDOH	Smoking
	Total N	Smokers N	(%)	Non-smokers N	(%)	P for trend^a
Educational attainment						<2.2E-16
Below high school	137	93	(67.9)	44	(32.1)
High school or training after high school	277	136	(49.1)	141	(50.9)
College	401	200	(49.9)	201	(50.1)
College graduate	478	138	(28.9)	340	(71.1)
Post-graduate	179	26	(14.5)	153	(85.5)
Personal annual income, US dollars						8.50E-05
None	143	74	(51.7)	69	(48.3)
<$20,000	502	234	(46.6)	268	(53.4)
$20,000-<40,000	442	183	(41.4)	259	(58.6)
$40,000-<60,000	256	78	(30.5)	178	(69.5)
≥$60,000	275	108	(39.3)	167	(60.7)
Area deprivation index, national rank in percentiles						4.70E-09
<40	393	114	(29.0)	279	(71.0)
40–75	611	239	(39.1)	372	(60.9)
>75	332	167	(50.3)	165	(49.7)
SDOH	BMI
	Total N	BMI≥25 N	(%)	BMI<25 N	(%)	P for trend^a
Educational attainment						3.90E-05
Below high school	130	88	(67.7)	42	(32.3)
High school or training after high school	262	190	(72.5)	72	(27.5)
College	379	265	(69.9)	114	(30.1)
College graduate	463	290	(62.6)	173	(37.4)
Post-graduate	175	91	(52.0)	84	(48.0)
Personal annual income, US dollars						1.40E-01
None	135	77	(57.0)	58	(43.0)
<$20,000	470	317	(67.4)	153	(32.6)
$20,000-<40,000	431	275	(63.8)	156	(36.2)
$40,000-<60,000	251	177	(70.5)	74	(29.5)
≥$60,000	229	153	(66.8)	76	(33.2)
Area deprivation index, national rank in percentiles						3.80E-06
<40	386	223	(57.8)	163	(42.2)
40–75	585	394	(67.4)	191	(32.6)
>75	321	238	(74.1)	83	(25.9)
Abbreviations: BMI (body mass index), SDOH (social determinant of health)

^aChi-square test for trend

Table 3. DNA methylation CpG sites that are significantly associated with all three socio-economic factors in survivors of European ancestry.

CpG label	Chr	Position	HGNC gene and functional annotation	CpG Island region	Educational Attainment					Personal Income					Area deprivation index
					Effect size 1	(SE)	P	Effect size 2^a	(% Effect remaining)	Effect size 1	(SE)	P	Effect size 2^a	(% Effect remaining)	Effect size 1	SE	P	Effect size 2^a	(% Effect remaining)
cg01731783	chr14	73,745,084	ELMSAN1 (5ʹUTR; 3ʹUTR)		0.018	(0.002)	1.9E-13	0.006	(30.8%)	0.0133	(0.002)	2.2E-09	0.007	(52.3%)	−0.0007	(0.0001)	3.1E-08	−0.0003	(44.9%)
cg08840017	chr2	230,944,894	GPR55 (5ʹUTR)		0.034	(0.005)	2.9E-12	0.015	(43.9%)	0.0258	(0.004)	7.2E-09	0.014	(55.9%)	−0.0013	(0.0002)	4.0E-08	−0.0008	(58.7%)
cg00385142	chr3	98,517,073	CLDND1 (3ʹUTR; 1st exon)		0.039	(0.004)	1.8E-20	0.019	(48.8%)	0.0246	(0.004)	1.0E-10	0.014	(58.8%)	−0.0015	(0.0002)	7.1E-14	−0.0009	(61.5%)
cg18754985	chr3	98,518,905	CLDND1 (3ʹUTR)	N-Shelf	0.054	(0.005)	7.9E-23	0.017	(32.4%)	0.0373	(0.005)	4.6E-14	0.019	(50.8%)	−0.0017	(0.0003)	5.2E-10	−0.0007	(39.1%)
cg08064403	chr3	98,521,413	CLDND1 (3ʹUTR; TSS200; 5ʹUTR); CPOX (3ʹUTR); RP11-227H4.5 (TSS1500)	N-Shore	0.103	(0.009)	3.4E-28	0.033	(32.2%)	0.0695	(0.008)	2.6E-16	0.034	(49.3%)	−0.0033	(0.0005)	1.3E-12	−0.0014	(41.4%)
cg05659611	chr3	98,521,779	CLDND1 (3ʹUTR; TSS1500; 1st exon; 5ʹUTR); CPOX (3ʹUTR); RP11-227H4.5 (TSS1500)	N-Shore	0.065	(0.005)	5.0E-31	0.026	(40.6%)	0.0375	(0.005)	1.9E-13	0.019	(50.1%)	−0.0024	(0.0003)	1.3E-17	−0.0012	(51.6%)
cg19859270	chr3	98,532,449	CPOX (3ʹUTR); GPR15 (1st exon)		0.109	(0.008)	4.5E-37	0.037	(34.1%)	0.0671	(0.008)	8.7E-18	0.029	(43.3%)	−0.0032	(0.0004)	4.4E-14	−0.0011	(35.1%)
cg04180924	chr3	98,553,219	CPOX (3ʹUTR)		0.100	(0.008)	1.9E-35	0.039	(39.0%)	0.0689	(0.007)	3.8E-21	0.037	(53.3%)	−0.0028	(0.0004)	4.4E-12	−0.0011	(38.3%)
cg00010201	chr3	98,568,261	CPOX		0.081	(0.008)	1.4E-25	0.029	(36.1%)	0.0488	(0.007)	2.1E-12	0.022	(44.4%)	−0.0023	(0.0004)	1.3E-09	−0.0007	(31.4%)
cg02978227	chr3	98,573,182	CPOX		0.080	(0.007)	3.5E-32	0.025	(30.8%)	0.0481	(0.006)	8.1E-15	0.020	(40.7%)	−0.0023	(0.0003)	1.8E-12	−0.0008	(35.9%)
cg02657160	chr3	98,592,218	CPOX (3ʹUTR)	N-Shore	0.055	(0.005)	8.9E-29	0.020	(36.4%)	0.0366	(0.004)	2.0E-16	0.018	(48.3%)	−0.0019	(0.0002)	7.9E-15	−0.0009	(48.9%)
cg05575921	chr5	373,262	AHRR (5ʹUTR)	N-Shore	0.136	(0.010)	8.1E-37	0.040	(29.4%)	0.0868	(0.010)	1.3E-18	0.036	(42.0%)	−0.0038	(0.0005)	2.5E-13	−0.0014	(35.9%)
cg26768182	chr9	131,397,291	PRRC2B (5ʹUTR)	S-Shelf	0.061	(0.006)	4.6E-26	0.027	(44.0%)	0.0286	(0.005)	8.0E-08	0.011	(38.5%)	−0.0015	(0.0003)	5.1E-08	−0.0006	(40.0%)
Combined									(36.8%)					(48.3%)					(43.3%)

Abbreviations: BMI (body mass index), Chr (chromosome), CpG (5’-cytosine-phosphate-guanine-3’), HGNC (The HUGO genome nomenclature committee), SE (standard error)

^aSmoking/BMI contribution % was calculated by the effect size and additionally adjusted for smoking and BMI divided by the original effect size.

Figure 1. Circos plot for epigenome-wide association studies of SDOH factors among survivors of European ancestry.

Outer circle (red): EWAS for educational attainment; middle circle (green): EWAS for personal annual income; inner circle (blue): EWAS for area deprivation index. Each dot depicts -log₁₀ p-value for each DNAm CpG site mapped to a chromosome location along the genome. The black lines indicate the epigenome-wide significance level (P = 9 × 10⁻⁸).Abbreviations: Epigenome-wide association studies (EWAS), social determinants of health (SDOH)

Figure 2. Regional association plots for DNAm CpG sites at chromosome 3 associated with SDOH factors.

Significant epigenome-wide CpGs (n = 9) are labelled in red text.Abbreviation: 5’-cytosine-phosphate-guanine-3’ (CpG), Social determinants of health (SDOH)