Genetic and environmental determinants of risk for cholangiocarcinoma in Thailand

Table 1 Effects of environmental determinants on risks for cholangiocarcinoma

Environmental determinants		Cases	Controls	OR	95%CI		P value	Ref.	Ethnic group
					LL	UL
Anti-OV Ab	ref: < 1/40	101 matched case-control pairs		5.00	2.30	11.00	< 0.001	Parkin et al[2] 1991	Thai
				Adjusted OR
Anti-OV Ab (ELISA)	< 0.200	61	119	1.00	Reference			Honjo et al[5] 2005	Thai
	≥ 0.200	65	8	27.09	6.30	116.57	< 0.01
Alcohol drinking	Never	30	46	1.00	Reference		-
	Occasional	41	54	2.20	0.65	7.45	0.21
	Ex-regular	15	7	6.23	1.23	31.57	0.03
	Regular	41	21	4.31	1.12	16.57	0.03
	Missing	2	-	-	-	-	-
Raw fish	0	30	57	1.00	Reference
	< 2/mo	54	41	2.70	1.28	5.68	< 0.01
	≥ 2/mo	45	31	2.94	1.24	6.96	0.01
Fermented fish or pork	0	28	41	1.00	Reference
	< 2/mo	58	63	2.95	0.98	8.90	0.06
	≥ 2/mo	43	25	4.50	1.30	15.54	0.02
				Adjusted OR
Alcohol drinking	Non-drinker	57	254	1.00	Reference			Songserm et al[6] 2012	Thai
(Units of alcohol per month)	< 14	79	92	5.60	2.85	10.95	< 0.001
	≥ 14	83	92	9.50	4.55	19.79	< 0.001
Total vegetables	< 52	136	214	1.00	Reference
(average times/month)	≥ 52	83	224	0.40	0.23	0.76	0.004
Total fruits	< 35	131	217	1.00	Reference
(average times/month)	≥ 35	88	221	0.60	0.33	0.98	0.04
Family history of cancer	No	85	107	1.00	Reference			Manwong et al[7] 2013	Thai
	Yes	38	16	4.34	1.80	10.43	0.001

OR: Odds ratio; CI: Confidence interval; LL: Lower limit; UL: Upper limit.

Table 2 Effect of modification of alcohol drinking on relationships between smoking, eating fermented fish and risk for cholangiocarcinoma

Variable	Category	Alcohol drinking
		Never drinkers				Ever1 drinkers
		Adjusted2 OR	95%CI		P value	Adjusted2 OR	95% CI		P value
			LL	UL			LL	UL
Smoking	Never	1	Reference			4.25	1.02	17.63	0.05
	Occasional	4.36	0.4	47.49	0.23	1.07	0.06	20.66	0.96
	Ex-regular					9.09	1.27	65.18	0.03
	Regular	3.64	0.19	71.41	0.39	7.99	1.56	40.94	0.01
Pla-ra, Pla-chao	< 3/d	1	Reference			14.07	1.46	135.36	0.02
	≥ 3/d	12.34	1.22	124.75	0.03	20.88	2.27	192.06	< 0.01

¹Including occasional, ex- and currently regular drinkers;

²Adjusted for anti-OV Ab when calculating the OR of smoking, and adjusted for anti-OV Ab and smoking when calculating the OR of eating of fermented fish (pla-ra and/or pla-chao). Nakorn Phanom (Thailand): based on the conditional logistic regression model. CI: Confidence interval; LL: Lower limit; UL: Upper limit; OR: Odds ratio. Adapted from Honjo et al[5] 2005. Allowing for absence of control subject in the category for occasional smoking and absence of case subject in the category for ex-regular smoking among never drinkers, we combined these two categories and confirmed the conclusion in the table is the materially unchanged from that in the table in our previous paper (Honjo et al[5] 2005).

Table 3 Interaction between genetic and environmental determinants on risks for cholangiocarcinoma

Genetic determinants		Environmental determinants		OR	95%CI		P value	Ref.	Ethnic group
					LL	UL
				Adjusted OR
GSTMI	Wild	Anti-OV antibody	Negative	1.00	Reference			Honjo et al[5] 2005	Thai
	Wild		Positive	10.34	1.31	81.63	0.03
	Null		Negative	0.48	0.21	1.11	0.09
	Null		Positive	18.00	3.33	97.40	< 0.01
GSTMI	Wild	Toilet	Inside the house	1.00	Reference
	Wild		Outside or none	0.20	0.04	1.02	0.05
	Null		Inside the house	0.22	0.06	0.88	0.03
	Null		Outside or none	0.25	0.07	0.91	0.04
GSTTI	Wild	Alcohol drinking	Never	1.00	Reference
	Wild		Occasional	3.58	0.71	17.95	0.12
	Wild		Ex-regular	1.28	0.12	14.08	0.84
	Wild		Regular	4.69	0.93	23.51	0.06
	Null		Never	0.75	0.23	2.43	0.63
	Null		Occasional	1.12	0.22	5.80	0.89
	Null		Ex-regular	27.93	1.84	424.60	0.02
	Null		Regular	3.28	0.35	30.91	0.30
				Crude OR
MTHFR 677	CC	Beef sausage	< 1/mo	1.0	Reference			Songserm et al[6] 2012	Thai
	CT		< 1/mo	1.1	0.51	2.37	0.82
	TT		< 1/mo	0.6	0.25	1.53	0.32
	CC		Weekly	0.9	0.45	1.83	0.80
	CT		Weekly	1.2	0.57	2.43	0.65
	TT		Weekly	1.6	0.80	3.31	0.18
	CC		Daily	3.3	1.51	7.07	0.003
	CT		Daily	3.2	1.33	7.62	0.01
	TT		Daily	8.3	2.23	30.82	0.002
MTHFR 1298	AA	Beef sausage	< 1/mo	1.0	Reference
	AC		< 1/mo	1.3	0.63	2.55	0.51
	CC		< 1/mo	0.8	0.28	2.15	0.63
	AA		Weekly	1.3	0.71	2.45	0.39
	AC		Weekly	1.0	0.49	1.79	0.84
	CC		Weekly	3.8	1.48	9.89	0.01
	AA		Daily	3.8	1.71	8.62	0.001
	AC		Daily	3.5	1.56	7.85	0.002
	CC		Daily	18.3	3.68	90.80	< 0.001

Table 4 Effects of genetic determinants on risks for cholangiocarcinoma

Genotype		No. CCA (%)	No. control (%)	OR	95%CI		P value	Ref.	Ethnic group
					LL	UL
				Adjusted OR
CYP1A2, Male	*1F/*1F	85 (57.4)	88 (51.2)	1.0	Reference			Prawan et al[8] 2005	Thai
	*1A/*1F	59 (39.9)	69 (40.1)	0.9	0.55	1.47	0.677
	*1A/*1A	4 (2.7)	15 (8.7)	0.28	0.08	0.94	0.039
NAT2	All, except *6B, *7A and *13	193 (89.4)	162 (69.5)	1.0	Reference
	One or two alleles (All, except *6B, *7A and *13)	23 (10.6)	71 (30.5)	0.26	0.15	0.44	< 0.001
				Crude OR
GST01	A140/A140	13 (43.33)	26 (86.67)	1.0	Reference			Marahatta et al[9] 2006	Thai
	A140/D140 + D140/D140	17 (56.67)	4 (13.33)	0.86	2.07	37.85
		Minor allele frequency
	Alleles	PSC2 with CCA (n = 49)	PSC without CCA (n = 316)	OR			Corrected P
NKG2D1	rs11053781 (Intron 5) G vs A	0.66	0.49	2.08	1.31	3.29	0.011	Melum et al[12] 2008	Norwegian
	rs2617167 (Intron 1) A vs G	0.39	0.22	2.32	1.47	3.66	0.002
		PSC with CCA (n = 49)	Healthy controls (n = 368)
	rs11053781 (Intron 5) G vs A	0.66	0.5	1.95	1.23	3.07	0.021
	rs2617167 (Intron 1) A vs G	0.39	0.23	2.2	1.40	3.44	0.003
		Counts (frequencies) of alleles/genotypes
		2n = 120	2n = 146	Crude OR				Hoeblinger et al[13] 2009	Caucasian
MRP2/ABCC23	ABCC2 c.3972 C (exon 28, synonymous SNP)	73 (0.61)	108 (0.74)
	ABCC2 c.3972 T	47 (0.39)	38 (0.26)	1.83	1.087	3.08	0.022
				OR
MYH rs3219476	T/T	25 (42.4)	26 (26.0)	1.0	Reference			You et al[14] 2013	Han Chinese
	T/G	20 (33.9)	58 (58.0)	0.359	0.17	0.758	0.006
	G/G	14 (23.7)	16 (16.0)	0.91	0.369	2.246	0.838
	T/G + G/G	34 (57.6)	74 (74.0)	0.478	0.241	0.946	0.033
MYH rs3219472	G/G	28 (47.5)	46 (46.0)	1.0	Reference
	G/A	19 (32.2)	47 (47.0)	0.664	0.326	1.351	0.258
	A/A	12 (20.3)	7 (7.0)	2.816	0.992	7.999	0.047
	G/A + A/A	31 (52.5)	54 (54.0)	0.943	0.495	1.797	0.859

¹Natural killer cell receptor G2D;

²Primary sclerosing cholangitis;

³Multidrug resistance-associated protein 2 gene. OR: Odds ratio.

Table 5 Interaction among genetic determinants on risks for cholangiocarcinoma

Genetic determinant		Genetic determinant		OR	95%CI		P value	Ref.	Ethnic group
					LL	UL
MTHFR C677T1	CC	TSER2	2R (-)	1	Reference			Ko et al[17] 2006	South Korean
	CC		2R (+)3	5.38	1.23	23.56	0.026
	CT		2R (-)	1.08	0.68	1.07
	CT		2R (+)3	1.19	0.71	2.01
	TT		2R (-)	1.02	0.7	1.5
	TT		2R (+)3	1.24	0.9	1.71
hOGG1(Codon326)	Ser/Ser	GSTM1	wild	1	Reference			Zeng et al[18] 2013	Thai
	Ser/Ser + Cys/Cys		wild	0.06	0.01	0.54	0.01
	Ser/Ser		null	0.06	0.01	0.53	0.01
	Ser/Ser + Cys/Cys		null	0.14	0.02	1.08	0.06

¹5,10-Methylenetetrahydrofolate reductase;

²Thymidylate synthase enhancer region;

³Including 2R2R and 2R3R.