Relationships between cell cycle pathway gene polymorphisms and risk of hepatocellular carcinoma

Table 1 Summarized information of selected single nucleotide polymorphisms in cell cycle pathway genes

Genes	SNPs	Chromosome (position)	Allele	MAF (hapmap-HCB)
MCM4	rs2305952	8 (47962049)	C/T	C = 0.18
YWHAB	rs2425675	20 (44906293)	A/G	A = 0.20
CDKN2A	rs3088440	9 (21968160)	A/G	A = 0.08
TGFB3	rs3917148	14 (75980178)	A/C	C = 0.10
RBL2	rs3929	16 (53490396)	C/G	C = 0.20
RAD21	rs6987652	8 (116870042)	A/G	A = 0.12
SMAD3	rs11556090	15 (67194045)	A/G	G = 0.09
	rs8025774	15 (67190938)	C/T	C = 0.45
KAT2B	rs17006625	3 (20119604)	A/G	G = 0.14
	rs4858770	3 (20152931)	C/T	T = 0.47
MCM7	rs2070215	7 (100099174)	A/G	G = 0.29
	rs2261360	7 (100095370)	A/C	A = 0.37
CDKN1A	rs3176320	6 (36679011)	A/G	G = 0.17
CDC25C	rs3734166	5 (138329634)	A/G	G = 0.38
CHEK1	rs515255	11 (125627250)	C/T	T = 0.44

MAF (minor allele frequency) was derived from HCB population in HapMap website (http://hapmap.ncbi.nlm.nih.gov/). SNPs: Single nucleotide polymorphisms.

Table 2 General demographic characteristics and behavioral information among hepatocellular carcinoma patients and controls

Variable	HCC patients	Controls	t/χ2	P value
	n = 1019	n = 1138
Age	48.54 ± 11.44	48.01 ± 11.50	-1.076	0.28
Gender
Male	881	982	0.013	0.91
Female	138	156
Nationality
Han	673	708	3.591	0.17
Zhuang	332	410
Others	14	20
Drinking
Yes	345	145	136.527	< 0.001
No	674	993
Smoking
Yes	355	158	130.222	< 0.001
No	664	980
Chronic HBV infection
Yes	794	109	1031.687	< 0.001
No	225	1029
Family history of HCC
Yes	80	2	86.597	< 0.001
No	939	1136

HCC: Hepatocellular carcinoma.

Table 3 Allele frequencies and genotype distribution of single nucleotide polymorphisms n (%)

SNP	Genotype	HCC patients	Control	χ2	P value of HWE
		n = 1019	n = 1138
rs2305952	TT	801 (78.61)	883 (77.59)
	TC	209 (20.51)	238 (20.91)	0.04	0.83
	CC	9 (0.88)	17 (1.49)
rs2425675	GG	632 (62.02)	724 (63.62)
	AG	348 (34.15)	374 (32.86)	0.96	0.33
	AA	39 (3.83)	40 (3.51)
rs3088440	GG	750 (73.60)	813 (71.44)
	GA	249 (24.44)	300 (26.36)	0.19	0.66
	AA	20 (1.96)	25 (2.20)
rs3917148	AA	773 (75.86)	882 (77.50)
	CA	233 (22.87)	235 (20.65)	1.32	0.25
	CC	13 (1.28)	21 (1.85)
rs3929	GG	619 (60.75)	688 (60.46)
	GC	349 (34.25)	395 (34.71)	0.03	0.86
	CC	51 (5.00)	55 (4.83)
rs6987652	GG	743 (72.91)	843 (74.08)
	AG	251 (24.63)	270 (23.73)	0.38	0.54
	AA	25 (2.45)	25 (2.20)
rs11556090	AA	622 (61.04)	749 (65.82)
	AG	352 (34.54)	346 (30.40)	0.15	0.70
	GG	45 (4.42)	43 (3.78)
rs17006625	AA	526 (51.62)	620 (54.48)
	AG	412 (40.43)	446 (39.19)	0.48	0.49
	GG	81 (7.95)	72 (6.33)
rs2070215	AA	465 (45.63)	554 (48.68)
	AG	424 (41.61)	480 (42.18)	< 0.01	1.00
	GG	130 (12.76)	104 (9.14)
rs2261360	CC	460 (45.14)	484 (42.53)
	CA	433 (42.49)	497 (43.67)	2.61	0.11
	AA	126 (12.37)	157 (13.80)
rs3176320	AA	579 (56.82)	687 (60.37)
	GA	383 (37.59)	377 (33.13)	5.05	0.02
	GG	57 (5.59)	74 (6.50)
rs3734166	AA	421 (41.32)	421 (36.99)
	GA	481 (47.20)	539 (47.36)	0.06	0.8
	GG	117 (11.48)	178 (15.64)
rs4858770	CC	445 (43.67)	465 (40.86)
	CT	461 (45.24)	515 (45.25)	0.65	0.42
	TT	113 (11.09)	158 (13.88)
rs515255	CC	408 (40.04)	411 (36.12)
	TC	469 (46.03)	553 (48.59)	0.29	0.59
	TT	142 (13.94)	174 (15.29)
rs8025774	CC	313 (30.72)	335 (29.44)
	CT	514 (50.44)	547 (48.07)	1.32	0.25
	TT	192 (18.84)	256 (22.50)

HCC: Hepatocellular carcinoma; SNP: Single nucleotide polymorphism; HWE: Hardy-Weinberg equilibrium

Table 4 Associations between single nucleotide polymorphisms with the risk of hepatocellular carcinoma

SNP	Genotype	OR (95%CI)1	P value1	OR (95%CI)2	P value2
rs2305952	TT	Reference		Reference
	TC	0.97 (0.79-1.19)	0.76	0.97 (0.72-1.32)	0.85
	CC	0.58 (0.26-1.32)	0.19	0.22 (0.08-0.63)	0.01a
	TC/CC	0.94 (0.77-1.16)	0.57	0.89 (0.66-1.19)	0.43
rs2425675	GG	Reference		Reference
	AG	1.07 (0.89-1.28)	0.49	1.92 (0.71-1.20)	0.54
	AA	1.12 (0.71-1.76)	0.63	0.97 (0.51-1.85)	0.93
	AG/AA	1.07 (0.90-1.28)	0.44	0.93 (0.72-1.20)	0.56
rs3088440	GG	Reference		Reference
	GA	0.90 (0.74-1.09)	0.29	1.02 (0.76-1.35)	0.92
	AA	0.87 (0.48-1.58)	0.64	1.46 (0.62-3.44)	0.38
	GA/AA	0.90 (0.74-1.09)	0.26	1.04 (0.79-1.37)	0.77
rs3917148	AA	Reference		Reference
	CA	1.13 (0.92-1.39)	0.24	1.18 (0.88-1.59)	0.28
	CC	0.71 (0.35-1.42)	0.33	1.05 (0.41-2.68)	0.92
	CA/CC	1.10 (0.90-1.34)	0.37	1.17 (0.88-1.56)	0.29
rs3929	GG	Reference		Reference
	GC	0.98 (0.82-1.18)	0.84	0.97 (0.75-1.26)	0.82
	CC	1.03 (0.69-1.53)	0.88	1.39 (0.80-2.42)	0.25
	GC/CC	0.99 (0.83-1.18)	0.89	1.02 (0.79-1.30)	0.90
rs6987652	GG	Reference		Reference
	AG	1.06 (0.87-1.29)	0.60	0.92 (0.69-1.23)	0.59
	AA	1.14 (0.65-1.99)	0.66	1.26 (0.55-2.88)	0.59
	AG/AA	1.06 (0.88-1.29)	0.54	0.95 (0.72-1.25)	0.71
rs11556090	AA	Reference		Reference
	AG	1.23 (1.02-1.47)	0.03	1.11 (0.85-1.44)	0.44
	GG	1.26 (0.82-1.94)	0.29	1.02 (0.54-1.91)	0.96
	AG/GG	1.23 (1.03-1.47)	0.02	1.10 (0.85-1.42)	0.47
rs17006625	AA	Reference		Reference
	AG	1.09 (0.91-1.30)	0.35	1.07 (0.83-1.38)	0.61
	GG	1.33 (0.95-1.86)	0.10	1.64 (1.01-2.64)	0.04a
	AG/GG	1.12 (0.95-1.33)	0.18	1.14 (0.89-1.46)	0.29
rs2070215	AA	Reference		Reference
	AG	1.05 (0.88-1.26)	0.58	0.95 (0.73-1.24)	0.71
	GG	1.49 (1.12-1.98)	0.01	1.39 (0.93-2.08)	0.11
	AG/GG	1.13 (0.95-1.34)	0.16	1.03 (0.81-1.32)	0.81
rs2261360	CC	Reference		Reference
	CA	0.92 (0.77-1.10)	0.35	0.84 (0.64-1.09)	0.19
	AA	0.84 (0.65-1.10)	0.21	0.89 (0.60-1.31)	0.55
	CA/AA	0.90 (0.76-1.07)	0.22	0.85 (0.66-1.09)	0.19
rs3734166	AA	Reference		Reference
	GA	0.89 (0.74-1.07)	0.22	0.92 (0.71-1.21)	0.56
	GG	0.66 (0.50-0.86)	0.002	0.86 (0.59-1.25)	0.43
	GA/GG	0.83 (0.70-0.99)	0.04	0.91 (0.71-1.17)	0.45
rs4858770	CC	Reference		Reference
	CT	0.94 (0.78-1.12)	0.47	0.96 (0.74-1.24)	0.74
	TT	0.75 (0.57-0.98)	0.04	0.80 (0.54-1.20)	0.28
	CT/TT	0.89 (0.75-1.06)	0.19	0.92 (0.72-1.18)	0.51
rs515255	CC	Reference		Reference
	TC	0.85 (0.71-1.03)	0.09	0.73 (0.56-0.96)	0.02a
	TT	0.82 (0.63-1.07)	0.14	0.67 (0.46-0.97)	0.04a
	TC/TT	0.85 (0.71-1.01)	0.06	0.72 (0.56-0.92)	0.01a
rs8025774	CC	Reference		Reference
	CT	1.01 (0.83-1.22)	0.95	0.95 (0.72-1.27)	0.74
	TT	0.80 (0.63-1.02)	0.08	0.94 (0.66-1.32)	0.71
	CT/TT	0.94 (0.78-1.13)	0.52	0.95 (0.73-1.24)	0.69

¹OR and 95%CI without adjusting for confounding factors;

²OR and 95%CI after adjusting for age, sex, nationality, smoking, drinking, family history of hepatocellular carcinoma, and HBV infection.

^aP < 0.05 was considered statistically significant. OR: Odds ratio; CI: Confidence interval; SNPs: Single nucleotide polymorphisms.

Table 5 Stratified analysis on the association between single nucleotide polymorphism genotype and hepatocellular carcinoma risk according to hepatitis B virus infection status

SNP	HBsAg-positive				HBsAg-negative
	Case	Control	OR (95%CI)1	P value1	Case	Control	OR (95%CI)1	P value1
rs2305952
TT	624	80	Reference		177	803	Reference
TC	161	24	0.86 (0.53-1.42)	0.56	48	214	1.05 (0.72-1.52)	0.80
CC	9	5	0.25 (0.08-0.80)	0.02a	0	12	-	1.00
TC/CC	170	29	0.76 (0.48-1.21)	0.25	48	226	0.99 (0.68-1.43)	0.95
rs17006625
AA	411	60	Reference		115	560	Reference
AG	323	42	1.15 (0.75-1.76)	0.54	89	404	1.07 (0.77-1.48)	0.68
GG	60	7	1.36 (0.59-3.17)	0.47	21	65	1.79 (1.02-3.12)	0.04a
AG/GG	383	49	1.18 (0.78-1.77)	0.44	110	469	1.17 (0.86-1.59)	0.32
rs515255
CC	301	39	Reference		107	372	Reference
TC	377	52	0.93 (0.59-1.46)	0.75	92	501	0.64 (0.46-0.89)	0.01a
TT	116	18	0.81 (0.44-1.50)	0.51	26	156	0.69 (0.36-0.96)	0.03a
TC/TT	493	70	0.90 (0.59-1.37)	0.62	118	657	0.63 (0.46-0.86)	0.003a

¹OR and 95%CI after adjusting for age, sex, nationality, smoking, drinking and family history of hepatocellular carcinoma.

^aP < 0.05 was considered statistically significant. OR: Odds ratio; CI: Confidence interval; SNPs: Single nucleotide polymorphisms.

Table 6 Stratified analysis on the association between single nucleotide polymorphism genotype and hepatocellular carcinoma risk according to drinking status

SNP	Drinking				Non-drinking
	Case	Control	OR (95%CI)1	P value1	Case	Control	OR (95%CI)1	P value1
rs2305952
TT	273	111	Reference		528	772	Reference
TC	69	33	0.82 (0.44-1.52)	0.53	140	205	1.02 (0.72-1.44)	0.93
CC	3	1	0.51 (0.03-9.74)	0.66	6	16	0.19 (0.06-0.60)	0.004a
TC/CC	72	34	0.81 (0.44-1.49)	0.49	146	221	0.91 (0.65-1.27)	0.57
rs515255
CC	145	56	Reference		263	355	Reference
TC	154	71	0.69 (0.40-1.19)	0.18	315	482	0.73 (0.54-0.99)	0.05a
TT	46	18	1.10 (0.50-2.43)	0.82	96	156	0.56 (0.36-0.86)	0.01a
TC/TT	200	89	0.77 (0.46-1.29)	0.31	411	638	0.69 (0.52-0.92)	0.01a

¹OR and 95%CI after adjusting for age, sex, nationality, smoking, family history of hepatocellular carcinoma, and hepatitis B virus infection.

^aP < 0.05 was considered statistically significant. OR: Odds ratio; CI: Confidence interval; SNPs: Single nucleotide polymorphisms.

Table 7 Stratified analysis on the association between single nucleotide polymorphism genotype and hepatocellular carcinoma risk according to smoking status

SNP	Smoking				Non-smoking
	Case	Control	OR (95%CI)1	P value1	Case	Control	OR (95%CI)1	P value1
rs2305952
TT	274	124	Reference		527	759	Reference
TC	77	32	1.05 (0.58-1.91)	0.87	132	206	0.94 (0.66-1.34)	0.75
CC	4	2	0.54 (0.06-4.97)	0.59	5	15	0.17 (0.05-0.56)	0.004a
TC/CC	81	34	1.01 (0.57-1.82)	0.96	137	221	0.84 (0.60-1.19)	0.33
rs515255
CC	145	53	Reference		263	358	Reference
TC	155	84	0.54 (0.32-0.93)	0.03a	314	469	0.81 (0.59-1.10)	0.17
TT	55	21	0.87 (0.41-1.85)	0.72	87	153	0.60 (0.39-0.94)	0.03a
TC/TT	210	105	0.61 (0.67-1.02)	0.06	401	622	0.75 (0.56-1.01)	0.06

¹OR and 95%CI after adjusting for age, sex, nationality, drinking, family history of hepatocellular carcinoma, and HBV infection.

^aP < 0.05 was considered statistically significant. OR: Odds ratio; CI: Confidence interval; SNPs: Single nucleotide polymorphisms.