The Impact of BCL11A Polymorphisms on Endometrial Cancer Risk Among Chinese Han Females

Figures & data

Table 1 Basic Information of Endometrial Cancer and Health Controls

Characteristics	Cases (n = 509)	Control (n = 506)	p-value
Age (years, mean ± SD)	54.94 ± 8.85	54.61 ± 9.07	0.553
BMI (kg/m^2)
≥ 24	199 (39.1%)	191 (37.7%)	0.699
< 24	310 (60.9%)	315 (62.3%)
CEA (ng/mL, mean ± SD)	11.20 ± 2.09	2.08 ± 2.22	< 0.001
AFP (ng/mL, mean ± SD)	8.96 ± 5.32	2.86 ± 1.17	< 0.001
CA199 (U/mL, mean ± SD)	17.87± 20.99	12.79 ± 10.45	< 0.001
CA125 (U/mL, mean ± SD)	24.22 ± 39.00	12.97 ± 9.51	< 0.001
Stage
I–II	261 (51.3%)
III–IV	93 (18.3%)
Missing	155 (30.5%)

Notes: p values were calculated using χ² tests or Student’s t-test. Bold indicated that p < 0.05 meant the data was statistically significant.

Abbreviations: SD, standard deviation; BMI, body mass index; CEA, carcinoembryonic antigen; AFP, alpha fetoprotein; CA, carbohydrate antigen.

Table 2 Basic Characteristics and Allele Model About Candidate SNPs in the BCL11A Gene

SNPs ID	Chr:Position	Allele (Minor/Major)	Call Rate	O(HET)	E(HET)	p^a-value for HWE	MAF		Allele Model		Haploreg	Regulome DB
							Case	Control	OR (95% CI)	p^b
rs7581162	2:60,477,349	T/A	99.9%	0.384	0.362	0.219	0.287	0.238	1.29 (1.06–1.57)	0.012	Promoter histone marks, Enhancer histone marks, Motifs changed, GRASP QTLhits	TF binding or DNase peak
rs10189857	2:60,486,100	A/G	99.8%	0.345	0.346	1.000	0.264	0.222	1.26 (1.03–1.54)	0.028	DNAse, Motifs changed, NHGRI/EBI GWAS hits	TF binding or DNase peak
rs1427407	2:60,490,908	T/G	99.8%	0.310	0.321	0.486	0.246	0.200	1.30 (1.05–1.60)	0.015	Enhancer histone marks, Proteins bound, Motifs changed, NHGRI/EBI GWAS hits, GRASP QTL hits	TF binding or DNase peak
rs766432	2:60,492,835	C/A	100%	0.338	0.335	0.895	0.254	0.212	1.27 (1.03–1.56)	0.025	Enhancer histone marks, DNAse, Motifs changed, NHGRI/EBI GWAS hits, GRASP QTL hits	TF binding + any motif + DNase Footprint + DNase peak
rs6729815	2:60,496,537	T/C	100%	0.330	0.335	0.790	0.262	0.212	1.32 (1.07–1.62)	0.008*	Enhancer histone marks, Motifs Changed, NHGRI/EBI GWAS hits	TF binding + DNase peak
rs2556378	2:60,535,367	T/G	100%	0.405	0.352	0.001	/	/	/	/	Promoter histone marks, Enhancer histone marks, DNAse, NHGRI/EBI GWAS hits, GRASP QTL hits	eQTL + TF binding/DNase peak

Notes: p^a-values for the HWE test were calculated using goodness of fit χ² test. p^b were calculated using by Fisher’s exact test. Bold indicated that p < 0.05 meant the data was statistically significant. *p indicate that after Bonferroni correction (p < 0.05/5) means the data is statistically significant.

Abbreviations: SNP, single-nucleotide polymorphism; MAF, minor allele frequency; O(HET), observed heterozygosity; E(HET), expected heterozygosity; HWE, Hardy–Weinberg equilibrium.

Table 3 The Effect of BCL11A SNPs on the Susceptibility to Endometrial Cancer

SNPs ID	Model	Genotype	Case	Control	Crude Analysis		Adjusted by Age
					OR (95% CI)	p	OR (95% CI)	p
rs7581162	Genotype	AA	261	288	1		1
		AT	204	194	1.16 (0.90–1.50)	0.259	1.16 (0.90–1.50)	0.257
		TT	44	23	2.11 (1.24–3.59)	0.006*	2.16 (1.27–3.69)	0.005*
	Dominant	AA	261	288	1		1
		AT-TT	248	217	1.26 (0.98–1.62)	0.066	1.27 (0.99–1.62)	0.063
	Recessive	AA-AT	465	482	1		1
		TT	44	23	1.98 (1.18–3.34)	0.010	2.03 (1.20–3.42)	0.008*
	Log-additive	—	—	—	1.30 (1.06–1.59)	0.011	1.30 (1.07–1.59)	0.010
rs10189857	Genotype	GG	280	305	1		1
		GA	189	174	1.18 (0.91–1.54)	0.209	1.18 (0.91–1.54)	0.206
		AA	40	25	1.74 (1.03–2.95)	0.038	1.78 (1.05–3.01)	0.033
	Dominant	GG	280	305	1		1
		GA-AA	229	199	1.25 (0.98–1.61)	0.076	1.26 (0.98–1.62)	0.072
	Recessive	GG-GA	469	479	1		1
		AA	40	25	1.63 (0.98–2.74)	0.062	1.66 (0.99–2.79)	0.054
	Log-additive	—	—	—	1.25 (1.02–1.53)	0.030	1.26 (1.03–1.54)	0.027
rs1427407	Genotype	GG	291	325	1		1
		GT	186	156	1.33 (1.02–1.74)	0.034	1.33 (1.02–1.74)	0.033
		TT	32	23	1.55 (0.89–2.72)	0.122	1.59 (0.91–2.78)	0.107
	Dominant	GG	291	325	1		1
		GT-TT	218	179	1.36 (1.06–1.75)	0.017	1.37 (1.06–1.76)	0.016
	Recessive	GG-GT	477	481	1		1
		TT	32	23	1.40 (0.81–2.43)	0.228	1.43 (0.82–2.49)	0.204
	Log-additive	—	—	—	1.29 (1.05–1.59)	0.016	1.30 (1.05–1.60)	0.014
rs766432	Genotype	AA	281	313	1		1
		AC	197	171	1.28 (0.99–1.67)	0.061	1.29 (0.99–1.67)	0.058
		CC	31	22	1.57 (0.89–2.77)	0.121	1.60 (0.90–2.84)	0.107
	Dominant	AA	281	313	1		1
		AC-CC	228	193	1.32 (1.02–1.69)	0.032	1.32 (1.03–1.70)	0.029
	Recessive	AA-AC	478	484	1		1
		CC	31	22	1.43 (0.81–2.50)	0.214	1.45 (0.83–2.55)	0.194
	Log-additive	—	—	—	1.27 (1.03–1.56)	0.025	1.28 (1.04–1.57)	0.022
rs6729815	Genotype	CC	283	315	1		1
		CT	185	167	1.23 (0.95–1.61)	0.120	1.23 (0.95–1.61)	0.119
		TT	41	24	1.90 (1.12–3.23)	0.017	1.94 (1.14–3.29)	0.015
	Dominant	CC	283	315	1		1
		CT-TT	226	191	1.32 (1.03–1.69)	0.031	1.32 (1.03–1.70)	0.030
	Recessive	CC-CT	468	482	1		1
		TT	41	24	1.76 (1.05–2.96)	0.033	1.79 (1.06–3.02)	0.028
	Log-additive	—	—	—	1.30 (1.07–1.60)	0.010	1.31 (1.07–1.61)	0.009*

Notes: p values were calculated by logistic regression analysis without or with adjustments for age. Bold indicated that p < 0.05 meant the data was statistically significant. *p indicate that after Bonferroni correction (p < 0.05/5) means the data is statistically significant.

Abbreviations: SNP, single nucleotide polymorphism; OR, odds ratio; 95% CI, 95% confidence interval.

Table 4 Stratification Analysis by Age and BMI for the Effect of BCL11A SNPs on the Susceptibility to Endometrial Cancer

SNPs ID	Model	Genotype	Case	Control	OR (95% CI)	p	Case	Control	OR (95% CI)	p
Age			> 55 years				≤ 55 years
rs7581162	Allele	A	333	326	1		393	444	1
		T	113	96	1.15 (0.84–1.57)	0.373	179	144	1.40 (1.09–1.82)	0.010
	Genotype	AA	117	123	1		144	165	1
		AT	99	80	1.30 (0.88–1.92)	0.185	105	114	1.06 (0.75–1.50)	0.746
		TT	7	8	0.92 (0.32–2.61)	0.872	37	15	2.84 (1.50–5.40)	0.001*
	Dominant	AA	117	123	1		144	165	1
		AT-TT	106	88	1.27 (0.87–1.85)	0.224	142	129	1.27 (0.91–1.76)	0.158
	Recessive	AA-AT	216	203	1		249	279	1
		TT	7	8	0.82 (0.29–2.30)	0.707	37	15	2.78 (1.49–5.18)	0.001*
	Log-additive	—	—	—	1.18 (0.84–1.64)	0.343	—	—	1.38 (1.08–1.78)	0.012
rs10189857	Allele	G	344	331	1		405	453	1
		A	102	89	1.10 (0.80–1.52)	0.551	167	135	1.38 (1.06–1.80)	0.016
	Genotype	GG	128	131	1		152	174	1
		GA	88	69	1.31 (0.88–1.94)	0.190	101	105	1.10 (0.78–1.56)	0.588
		AA	7	10	0.72 (0.26–1.94)	0.512	33	15	2.53 (1.33–4.85)	0.005*
	Dominant	GG	128	131	1		152	174	1
		GA-AA	95	79	1.23 (0.84–1.81)	0.291	134	120	1.28 (0.92–1.78)	0.142
	Recessive	GG-GA	216	200	1		253	279	1
		AA	7	10	0.65 (0.24–1.74)	0.389	33	15	2.44 (1.29–4.60)	0.006*
	Log-additive	—	—	—	1.11 (0.80–1.55)	0.540	—	—	1.36 (1.05–1.75)	0.020
rs1427407	Allele	G	353	342	1		415	464	1
		T	93	80	1.13 (0.81–1.57)	0.485	157	122	1.44 (1.10–1.89)	0.008*
	Genotype	GG	134	140	1		157	185	1
		GT	85	62	1.43 (0.96–2.15)	0.081	101	94	1.27 (0.89–1.80)	0.187
		TT	4	9	0.46 (0.14–1.54)	0.209	28	14	2.37 (1.21–4.67)	0.012
	Dominant	GG	134	140	1		157	185	1
		GT-TT	89	71	1.31 (0.89–1.94)	0.177	129	108	1.41 (1.01–1.97)	0.043
	Recessive	GG-GT	219	202	1		258	279	1
		TT	4	9	0.41 (0.12–1.35)	0.142	28	14	2.18 (1.12–4.23)	0.022
	Log-additive	—	—	—	1.14 (0.80–1.60)	0.472	—	—	1.41 (1.08–1.83)	0.011
rs766432	Allele	A	350	338	1		409	459	1
		C	96	86	1.08 (0.78–1.50)	0.653	163	129	1.42 (1.09–1.85)	0.010
	Genotype	AA	130	135	1		151	178	1
		AC	90	68	1.37 (0.92–2.04)	0.118	107	103	1.23 (0.87–1.74)	0.248
		CC	3	9	0.34 (0.09–1.30)	0.114	28	13	2.55 (1.27–5.09)	0.008*
	Dominant	AA	130	135	1		151	178	1
		AC-CC	93	77	1.25 (0.85–1.84)	0.254	135	116	1.37 (0.99–1.91)	0.059
	Recessive	AA-AC	220	203	1		258	281	1
		CC	3	9	0.30 (0.08–1.14)	0.078	28	13	2.35 (1.19–4.64)	0.014
	Log-additive	—	—	—	1.09 (0.77–1.53)	0.644	—	—	1.40 (1.08–1.83)	0.012
rs6729815	Allele	C	347	338	1		404	459	1
		T	99	86	1.12 (0.81–1.55)	0.490	168	129	1.48 (1.14–1.93)	0.004*
	Genotype	CC	131	135	1		152	180	1
		CT	85	68	1.29 (0.87–1.92)	0.212	100	99	1.20 (0.84–1.70)	0.316
		TT	7	9	0.80 (0.29–2.21)	0.668	34	15	2.70 (1.42–5.14)	0.003*
	Dominant	CC	131	135	1		152	180	1
		CT-TT	92	77	1.23 (0.84–1.81)	0.289	134	114	1.39 (1.00–1.94)	0.050
	Recessive	CC-CT	216	203	1		252	279	1
		TT	7	9	0.73 (0.27–2.00)	0.540	34	15	2.52 (1.34–4.74)	0.004*
	Log-additive	—	—	—	1.13 (0.81–1.58)	0.477	—	—	1.43 (1.11–1.85)	0.006*
BMI			≥ 24 kg/m^2				< 24 kg/m^2
rs7581162	Allele	A	293	287	1		433	483	1
		T	105	93	1.11 (0.80–1.53)	0.541	187	147	1.42 (1.10–1.83)	0.006*
	Genotype	AA	109	105	1		152	183	1
		AT	75	77	0.94 (0.62–1.42)	0.756	129	117	1.33 (0.95–1.85)	0.092
		TT	15	8	1.77 (0.71–4.37)	0.218	29	15	2.41 (1.24–4.68)	0.009*
	Dominant	AA	109	105	1		152	183	1
		AT-TT	90	85	1.01 (0.68–1.51)	0.948	158	132	1.45 (1.06–1.99)	0.022
	Recessive	AA-AT	184	182	1		281	300	1
		TT	15	8	1.82 (0.75–4.41)	0.188	29	15	2.14 (1.12–4.08)	0.022
	Log-additive	—	—	—	1.10 (0.79–1.53)	0.569	—	—	1.44 (1.11–1.86)	0.005*
rs10189857	Allele	G	296	289	1		453	495	1
		A	102	91	1.09 (0.79–1.52)	0.587	167	133	1.37 (1.06–1.78)	0.017
	Genotype	GG	114	108	1		166	197	1
		GA	68	73	0.88 (0.58–1.35)	0.564	121	101	1.43 (1.02–2.00)	0.037
		AA	17	9	1.76 (0.75–4.14)	0.196	23	16	1.75 (0.89–3.42)	0.104
	Dominant	GG	114	108	1		166	197	1
		GA-AA	85	82	0.98 (0.65–1.46)	0.917	144	117	1.47 (1.07–2.03)	0.018
	Recessive	GG-GA	182	181	1		287	298	1
		AA	17	9	1.85 (0.80–4.28)	0.153	23	16	1.52 (0.79–2.95)	0.212
	Log-additive	—	—	—	1.09 (0.79–1.50)	0.620	—	—	1.38 (1.06–1.78)	0.016
rs1427407	Allele	G	304	299	1		464	507	1
		T	94	81	1.14 (0.81–1.60)	0.442	156	121	1.41 (1.08–1.84)	0.012
	Genotype	GG	118	117	1		173	208	1
		GT	68	65	1.04 (0.68–1.59)	0.867	118	91	1.57 (1.12–2.21)	0.009*
		TT	13	8	1.56 (0.62–3.95)	0.344	19	15	1.57 (0.77–3.18)	0.214
	Dominant	GG	118	117	1		173	208	1
		GT-TT	81	73	1.09 (0.73–1.64)	0.664	137	106	1.57 (1.13–2.17)	0.007*
	Recessive	GG-GT	186	182	1		291	299	1
		TT	13	8	1.54 (0.62–3.85)	0.352	19	15	1.33 (0.66–2.68)	0.419
	Log-additive	—	—	—	1.13 (0.81–1.58)	0.478	—	—	1.41 (1.08–1.84)	0.012
rs766432	Allele	A	303	298	1		156	499	1
		C	95	84	1.11 (0.80–1.55)	0.533	164	131	1.37 (1.05–1.78)	0.019
	Genotype	AA	71	70	1		165	199	1
		AC	12	7	1.00 (0.65–1.52)	0.985	126	101	1.52 (1.09–2.12)	0.014
		CC	116	114	1.64 (0.62–4.34)	0.321	19	15	1.58 (0.78–3.21)	0.208
	Dominant	AA	83	77	1		165	199	1
		AC-CC	187	184	1.05 (0.70–1.58)	0.799	145	116	1.53 (1.11–2.10)	0.010
	Recessive	AA-AC	12	7	1		291	300	1
		CC	—	—	1.64 (0.63–4.29)	0.313	19	15	1.34 (0.67–2.69)	0.411
	Log-additive	—	71	70	1.11 (0.79–1.55)	0.559	—	—	1.39 (1.07–1.82)	0.015
rs6729815	Allele	C	300	193	1		451	504	1
		T	98	89	1.08 (0.77–1.49)	0.665	169	126	1.50 (1.15–1.95)	0.003*
	Genotype	CC	117	110	1		166	205	1
		CT	66	73	0.85 (0.56–1.30)	0.456	119	94	1.57 (1.12–2.21)	0.009*
		TT	16	8	1.84 (0.76–4.50)	0.179	25	16	1.99 (1.03–3.87)	0.042
	Dominant	CC	117	110	1		166	205	1
		CT-TT	82	81	0.95 (0.63–1.42)	0.802	144	110	1.63 (1.18–2.26)	0.003*
	Recessive	CC-CT	183	183	1		285	299	1
		TT	16	8	1.96 (0.81–4.72)	0.134	25	16	1.68 (0.88–3.23)	0.116
	Log-additive	—	—	—	1.07 (0.77–1.48)	0.694	—	—	1.49 (1.15–1.93)	0.003*

Notes: p values were calculated by Fisher’s exact test or logistic regression analysis with adjustments for age. Bold indicated that p < 0.05 meant the data was statistically significant. *p indicate that after Bonferroni correction (p < 0.05/5) means the data is statistically significant.

Abbreviations: SNP, single nucleotide polymorphism; BMI, body mass index; OR, odds ratio; 95% CI, 95% confidence interval.

Figure 1 LD plots of six SNPs in the BCL11A gene. The number in the diamond indicates the D’ value of pairwise LD between SNPs.

Table 5. SNP–SNP Interaction Models of the BCL11A Gene the Predisposition of Endometrial Cancer

Model	Training Bal. Acc.	Testing Bal. Acc.	CVC	OR (95% CI)	p
rs1427407	0.5356	0.5356	10/10	1.35 (1.05–1.74)	0.0277
rs7581162, rs766432	0.5412	0.5336	5/10	1.42 (1.08–1.86)	0.0106
rs7581162, rs10189857, rs766432	0.5447	0.5287	4/10	1.44 (1.12–1.86)	0.0047
rs7581162, rs10189857, rs1427407, rs766432	0.5470	0.5208	4/10	1.47 (1.14–1.90)	0.0029
rs7581162, rs10189857, rs1427407, rs766432, rs6729815	0.5479	0.5178	10/10	1.46 (1.14–1.88)	0.0029

Notes: p values were calculated using χ² tests. Bold indicated that p < 0.05 meant the data was statistically significant.

Abbreviations: MDR, multifactor dimensionality reduction; Bal. Acc., balanced accuracy; CVC, cross-validation consistency; OR, odds ratio; CI, confidence interval.

Figure 2 The dendrogram (A) and Fruchterman Reingold (B) of BCL11A SNP-SNP interaction for EC risk. (A) Short connections among nodes represent stronger redundant interactions. Green and blue color indicated weak interactions. (B) This graphical model describes the percent entropy explained by each SNP. Values in nodes represent the information gains of individual attribute (main effects). Values between nodes are information gains of each pair of attributes (interaction effects). Positive percent entropy indicates synergy whereas the negative percent entropy indicates redundancy.