Associations between serum uric acid and hepatobiliary-pancreatic cancer: A cohort study

Table 1 Baseline characteristic

Group	Q1	Q2	Q3	Q4
SUA level (mg/dL)	(1.50, 4.20)	(4.20, 5.09)	(5.09, 6.06)	(6.06, 17.90)
Number	111087	110975	111241	111159
Gender
Male	99225 (89.3%)	73883 (66.6%)	44282 (39.8%)	21466 (19.3%)
Female	11862 (10.7%)	37092 (33.4%)	66959 (60.2%)	89693 (80.7%)
Mean age (SD)	55.30 (8.20)	56.90 (8.00)	57.50 (7.97)	57.70 (8.00)
White European	104975 (94.5%)	104411 (94.1%)	104447 (93.9%)	104475 (94.0%)
Current smokers	11629 (10.5%)	11 95 (10.6%)	12154 (10.9%)	11444 (10.3%)
Alcohol intake
Over four times a week	40852 (36.8%)	45126 (40.7%)	49976 (44.9%)	57439 (51.7%)
Once or twice a week	29330 (26.4%)	29071 (26.2%)	28787 (25.9%)	27396 (24.6%)
One to three times a month	14577 (13.1%)	13324 (12.0%)	1 850 (10.7%)	9681 (8.7%)
Seldom or never	26102 (23.5%)	23203 (20.9%)	20363 (18.3%)	16388 (14.7%)
Fruit and vegetable intake
Yes	47673 (42.9%)	44146 (39.8%)	40049 (36.0%)	35593 (32.0%)
No	63175 (56.9%)	66545 (60.0%)	70869 (63.7%)	75234 (67.7%)
Physical activity
High	36219 (32.6%)	36706 (33.1%)	36948 (33.2%)	36029 (32.4%)
Moderate	37562 (33.8%)	36235 (32.7%)	36318 (32.6%)	36115 (32.5%)
Low	14838 (13.4%)	16003 (14.4%)	17162 (15.4%)	19457 (17.5%)
Annual household income
Less than £18000	20748 (18.7%)	21456 (19.3%)	21341 (19.2%)	21536 (19.4%)
£18000 to £30999	23304 (21.0%)	24243 (21.8%)	24310 (21.9%)	24159 (21.7%)
£31000 to £51999	24672 (22.2%)	24624 (22.2%)	25270 (22.7%)	25168 (22.6%)
£52000 to £100000	19676 (17.7%)	18781 (16.9%)	19544 (17.6%)	20555 (18.5%)
Greater than £100000	5132 (4.6%)	4947 (4.5%)	5211 (4.7%)	5666 (5.1%)
College or University degree	38460 (34.6%)	36499 (32.9%)	35860 (32.2%)	33817 (30.4%)
Family history of cancer	38048 (34.3%)	38942 (35.1%)	39465 (35.5%)	39063 (35.1%)
Mean BMI, kg/m2 (SD)	25.10 (4.01)	26.80 (4.45)	28.10 (4.62)	29.60 (4.82)

SUA: Serum uric acid; SD: Standard deviation; BMI: Body mass index; Q: Quartile.

Table 2 Baseline characteristic stratified by gender

	Male				Female
Group	Quartile 1	Quartile 2	Quartile 3	Quartile 4	Quartile 1	Quartile 2	Quartile 3	Quartile 4
SUA level (mg/dL)	(1.50, 5.13)	(5.13, 5.87)	(5.87, 6.69)	(6.69, 17.90)	(1.50, 3.77)	(3.77, 4.42)	(4.42, 5.18)	(5.18, 12.90)
Number	51349	51445	51364	51448	59639	59627	59872	59718
Mean age (SD)	56.90 (8.23)	56.90 (8.23)	57.00 (8.17)	57.30 (8.13)	54.60 (8.18)	56.00 (8.05)	57.20 (7.83)	58.90 (7.33)
White European	48082 (93.6%)	48342 (94.0%)	48405 (94.2%)	48480 (94.2%)	56435 (94.6%)	56437 (94.7%)	56340 (94.1%)	55787 (93.4%)
Current smokers	7983 (15.5%)	6579 (12.8%)	5816 (11.3%)	5377 (10.5%)	5759 (9.7%)	5412 (9.1%)	5138 (8.6%)	4958 (8.3%)
Alcohol intake
Over four times a week	23146 (45.1%)	25543 (49.6%)	27432 (53.4%)	29611 (57.5%)	20964 (35.1%)	22423 (37.6%)	22866 (38.2%)	21408 (35.8%)
Once or twice a week	13636 (26.6%)	13770 (26.8%)	13308 (25.9%)	12478 (24.3%)	15822 (26.5%)	15714 (26.4%)	15444 (25.8%)	14412 (24.1%)
One to three times a month	5297 (10.3%)	4919 (9.6%)	4300 (8.4%)	3749 (7.3%)	8141 (13.7%)	7837 (13.1%)	7669 (12.8%)	7520 (12.6%)
Seldom or never	9124 (17.8%)	7098 (13.8%)	6203 (12.0%)	5500 (10.7%)	14598 (24.5%)	13546 (22.7%)	13761 (23.0%)	16226 (27.2%)
Fruit and vegetable intake
Yes	16819 (32.8%)	16373 (31.8%)	15863 (30.9%)	15126 (29.4%)	26202 (43.9%)	26292 (44.1%)	25919 (43.3%)	24867 (41.6%)
No	34326 (66.8%)	34910 (67.9%)	35318 (68.8%)	36183 (70.3%)	33328 (55.9%)	33228 (55.7%)	33826 (56.5%)	34704 (58.1%)
Physical activity
High	19424 (37.8%)	19002 (36.9%)	18382 (35.8%)	17317 (33.7%)	19204 (32.2%)	18936 (31.8%)	18096 (30.2%)	15541 (26.0%)
Low	7605 (14.8%)	7864 (15.3%)	8360 (16.3%)	9204 (17.9%)	7781 (13.0%)	8103 (13.6%)	8586 (14.3%)	9957 (16.7%)
Moderate	16226 (31.6%)	16580 (32.2%)	16858 (32.8%)	16777 (32.6%)	20402 (34.2%)	20063 (33.6%)	19842 (33.1%)	19482 (32.6%)
Annual household income
Less than £18000	10135 (19.7%)	8851 (17.2%)	8622 (16.8%)	9477 (18.4%)	10830 (18.2%)	10982 (18.4%)	11999 (20.0%)	14185 (23.8%)
£18000 to £30999	11380 (22.2%)	11083 (21.5%)	11039 (21.5%)	10931 (21.2%)	12249 (20.5%)	12676 (21.3%)	13038 (21.8%)	13620 (22.8%)
£31000 to £51999	12024 (23.4%)	12537 (24.4%)	12538 (24.4%)	12138 (23.6%)	13368 (22.4%)	13137 (22.0%)	12663 (21.2%)	11329 (19.0%)
£52000 to £100000	9559 (18.6%)	10489 (20.4%)	10708 (20.8%)	10307 (20.0%)	10844 (18.2%)	10200 (17.1%)	9238 (15.4%)	7211 (12.1%)
Greater than £100000	2471 (4.8%)	2874 (5.6%)	3002 (5.8%)	2921 (5.7%)	2839 (4.8%)	2704 (4.5%)	2397 (4.0%)	1748 (2.9%)
College or university degree	18240 (35.5%)	18096 (35.2%)	17459 (34.0%)	15895 (30.9%)	21019 (35.2%)	20036 (33.6%)	18344 (30.6%)	15547 (26.0%)
Family history of cancer	17522 (34.1%)	17651 (34.3%)	17911 (34.9%)	17933 (34.9%)	20375 (34.2%)	20767 (34.8%)	21329 (35.6%)	22030 (36.9%)
Mean BMI, kg/m2 (SD)	26.30 (3.90)	27.30 (3.87)	28.20 (3.99)	29.60 (4.41)	24.60 (3.82)	25.90 (4.29)	27.40 (4.82)	30.30 (5.79)

SUA: Serum uric acid; SD: Standard deviation; BMI: Body mass index.

Table 3 Effect of serum uric acid on hepatobiliary-pancreatic cancer

Cancer	Group	Cases	Incidence1	HR (95%CI)
				Model 1	Model 2	Model 3
Liver	Q1	42	5.76	1.00 (reference)	1.00 (reference)	1.00 (reference)
	Q2	62	8.45	1.08 (0.72-1.60)	1.08 (0.73-1.61)	1.00 (0.67-1.50)
	Q3	62	8.58	0.90 (0.59-1.36)	0.90 (0.59-1.36)	0.79 (0.52-1.21)
	Q4	95	13.12	1.20 (0.80-1.81)	1.18 (0.79-1.78)	0.98 (0.64-1.49)
	Estimated HR (per 1 mg/dL)			1.08 (0.97-1.19)	1.06 (0.96-1.17)	1.01 (0.91-1.13)
Gallbladder	Q1	13	1.78	1.00 (reference)	1.00 (reference)	1.00 (reference)
	Q2	15	2.05	1.02 (0.48-2.19)	1.01 (0.47-2.18)	0.98 (0.45-2.12)
	Q3	10	1.38	0.85 (0.37-1.97)	0.84 (0.36-1.93)	0.79 (0.33-1.86)
	Q4	18	2.49	1.52 (0.68-3.39)	1.45 (0.65-3.24)	1.32 (0.56-3.11)
	Estimated HR (per 1 mg/dL)			1.09 (0.87-1.35)	1.07 (0.86-1.33)	1.04 (0.82-1.31)
Biliary tract	Q1	11	1.51	1.00 (reference)	1.00 (reference)	1.00 (reference)
	Q2	19	2.59	1.36 (0.64-2.89)	1.37 (0.65-2.93)	1.32 (0.61-2.89)
	Q3	27	3.74	1.64 (0.78-3.47)	1.69 (0.80-3.58)	1.48 (0.68-3.22)
	Q4	17	2.35	0.94 (0.41-2.15)	0.99 (0.43-2.27)	0.75 (0.31-1.82)
	Estimated HR (per 1 mg/dL)			0.92 (0.76-1.13)	0.94 (0.77-1.14)	0.85 (0.69-1.05)
Pancreas	Q1	76	10.43	1.00 (reference)	1.00 (reference)	1.00 (reference)
	Q2	115	15.68	1.31 (0.97-1.75)	1.31 (0.98-1.76)	1.29 (0.96-1.73)
	Q3	155	21.45	1.68 (1.26-2.24)	1.69 (1.27-2.26)	1.61 (1.19-2.16)
	Q4	183	25.28	1.91 (1.42-2.58)	1.92 (1.43-2.59)	1.77 (1.29-2.42)
	Estimated HR (per 1 mg/dL)			1.15 (1.07-1.23)	1.15 (1.07-1.23)	1.12 (1.04-1.21)

Model 1 adjusted for gender, age, education, ethnic group and family history of cancer. Model 2 adjusted for gender, age, education, ethnic group, family history of cancer, alcohol intake, smoking status, annual household income, fruit and vegetable intake and physical activity. Model 3 additionally adjusted for body mass index based on model 2.

¹Per 100000 person years. HR: Hazard ratio; CI: Confidence interval.

Table 4 Effect of uric acid on hepatobiliary-pancreatic cancer stratified by gender

Gender	Cancer	Group	Cases	Incidence1	HR (95%CI)
					Model 1	Model 2	Model 3
Male	Liver	Quartile 1	44	13.12	1.00 (reference)	1.00 (reference)	1.00 (reference)
		Quartile 2	39	11.71	0.89 (0.58-1.37)	0.92 (0.60-1.42)	0.87 (0.57-1.34)
		Quartile 3	29	8.67	0.65 (0.41-1.05)	0.68 (0.42-1.08)	0.61 (0.38-0.98)
		Quartile 4	53	15.78	1.16 (0.78-1.73)	1.17 (0.78-1.75)	0.96 (0.63-1.46)
		Estimated HR (per 1 mg/dL)			1.07 (0.95-1.21)	1.07 (0.95-1.21)	1.01 (0.89-1.15)
	Gallbladder	Quartile 1	2	0.60	1.00 (reference)	1.00 (reference)	1.00 (reference)
		Quartile 2	5	1.50	2.48 (0.48-12.80)	2.54 (0.93-6.94)	2.45 (0.90-6.70)
		Quartile 3	6	1.79	2.91 (0.59-14.41)	2.93 (1.14-7.56)	2.71 (1.05-6.98)
		Quartile 4	8	2.38	3.67 (0.78-17.30)	3.56 (1.47-8.58)	3.09 (1.28-7.46)
		Estimated HR (per 1 mg/dL)			1.20 (0.86-1.67)	1.17 (0.85-1.60)	1.11 (0.81-1.53)
	Biliary tract	Quartile 1	13	3.88	1.00 (reference)	1.00 (reference)	1.00 (reference)
		Quartile 2	10	3.00	0.77 (0.34-1.76)	0.80 (0.35-1.84)	0.81 (0.35-1.88)
		Quartile 3	9	2.69	0.69 (0.30-1.62)	0.74 (0.32-1.75)	0.69 (0.29-1.67)
		Quartile 4	11	3.27	0.82 (0.37-1.83)	0.89 (0.39-2.00)	0.75 (0.32-1.75)
		Estimated HR (per 1 mg/dL)			0.82 (0.64-1.07)	0.85 (0.65-1.10)	0.80 (0.61-1.04)
	Pancreas	Quartile 1	68	20.28	1.00 (reference)	1.00 (reference)	1.00 (reference)
		Quartile 2	62	18.61	0.91 (0.65-1.29)	0.93 (0.66-1.32)	0.93 (0.66-1.32)
		Quartile 3	80	23.92	1.18 (0.85-1.62)	1.20 (0.87-1.66)	1.15 (0.83-1.60)
		Quartile 4	76	22.62	1.06 (0.77-1.48)	1.08 (0.77-1.50)	1.04 (0.74-1.47)
		Estimated HR (per 1 mg/dL)			1.02 (0.93-1.12)	1.02 (0.93-1.12)	1.01 (0.91-1.12)
Female	Liver	Quartile 1	20	5.06	1.00 (reference)	1.00 (reference)	1.00 (reference)
		Quartile 2	21	5.35	0.87 (0.47-1.64)	0.87 (0.47-1.64)	0.86 (0.46-1.62)
		Quartile 3	23	5.86	1.06 (0.59-1.91)	1.05 (0.58-1.90)	1.02 (0.56-1.87)
		Quartile 4	32	8.21	1.22 (0.69-2.15)	1.16 (0.65-2.05)	1.09 (0.59-2.02)
		Estimated HR (per 1 mg/dL)			1.10 (0.93-1.31)	1.08 (0.91-1.28)	1.06 (0.88-1.28)
	Gallbladder	Quartile 1	6	1.52	1.00 (reference)	1.00 (reference)	1.00 (reference)
		Quartile 2	10	2.55	1.47 (0.53-4.06)	1.49 (0.72-3.10)	1.47 (0.71-3.06)
		Quartile 3	10	2.55	1.31 (0.47-3.61)	1.30 (0.63-2.72)	1.27 (0.61-2.65)
		Quartile 4	9	2.31	1.02 (0.36-2.88)	0.99 (0.46-2.10)	0.94 (0.44-2.00)
		Estimated HR (per 1 mg/dL)			1.20 (0.86-1.67)	1.17 (0.85-1.60)	1.01 (0.75-1.35)
	Biliary tract	Quartile 1	4	1.01	1.00 (reference)	1.00 (reference)	1.00 (reference)
		Quartile 2	8	2.04	1.77 (0.53-5.88)	1.78 (0.80-3.97)	1.66 (0.74-3.71)
		Quartile 3	6	1.53	1.19 (0.33-4.22)	1.17 (0.48-2.85)	0.98 (0.40-2.39)
		Quartile 4	13	3.34	2.24 (0.72-6.94)	2.33 (1.14-4.76)	1.65 (0.81-3.36)
		Estimated HR (per 1 mg/dL)			0.82 (0.64-1.07)	0.85 (0.65-1.1)	1.09 (0.81-1.48)
	Pancreas	Quartile 1	35	8.86	1.00 (reference)	1.00 (reference)	1.00 (reference)
		Quartile 2	36	9.17	0.93 (0.58-1.48)	0.93 (0.58-1.47)	0.91 (0.57-1.44)
		Quartile 3	64	16.29	1.51 (1.00-2.28)	1.50 (0.99-2.27)	1.43 (0.94-2.18)
		Quartile 4	108	27.71	2.27 (1.54-3.34)	2.25 (1.53-3.31)	2.04 (1.35-3.08)
		Estimated HR (per 1 mg/dL)			1.02 (0.93-1.12)	1.02 (0.93-1.12)	1.33 (1.21-1.47)

Model 1 adjusted for age, education, ethnic group and family history of cancer. Model 2 adjusted for age, education, ethnic group, family history of cancer, alcohol intake, smoking status, annual household income, fruit and vegetable intake and physical activity. Model 3 additionally adjusted for body mass index based on model 2.

¹Per 100000 person years. HR: Hazard ratio; CI: Confidence interval.

Table 5 Sensitivity analysis

Cancer	Group	HR (95%CI)
		Model 1	Model 2	Model 3
Liver	Quartile 1	1.00 (reference)	1.00 (reference)	1.00 (reference)
	Quartile 2	1.00 (0.64-1.55)	1.01 (0.65-1.57)	0.92 (0.59-1.43)
	Quartile 3	0.78 (0.49-1.24)	0.79 (0.50-1.25)	0.68 (0.42-1.08)
	Quartile 4	1.04 (0.66-1.63)	1.04 (0.66-1.63)	0.82 (0.51-1.31)
Gallbladder	Quartile 1	1.00 (reference)	1.00 (reference)	1.00 (reference)
	Quartile 2	1.68 (0.66-4.28)	1.71 (0.67-4.36)	1.63 (0.63-4.21)
	Quartile 3	1.41 (0.51-3.89)	1.42 (0.52-3.93)	1.31 (0.46-3.72)
	Quartile 4	2.71 (1.02-7.21)	2.72 (1.03-7.23)	2.40 (0.85-6.80)
Biliary tract	Quartile 1	1.00 (reference)	1.00 (reference)	1.00 (reference)
	Quartile 2	1.09 (0.48-2.47)	1.10 (0.49-2.51)	1.12 (0.48-2.61)
	Quartile 3	1.10 (0.48-2.50)	1.14 (0.50-2.60)	1.08 (0.46-2.55)
	Quartile 4	0.75 (0.31-1.82)	0.79 (0.32-1.93)	0.68 (0.26-1.75)
Pancreas	Quartile 1	1.00 (reference)	1.00 (reference)	1.00 (reference)
	Quartile 2	1.26 (0.90-1.76)	1.26 (0.90-1.77)	1.25 (0.89-1.76)
	Quartile 3	1.76 (1.27-2.44)	1.77 (1.28-2.46)	1.71 (1.22-2.40)
	Quartile 4	2.09 (1.49-2.92)	2.11 (1.51-2.95)	1.96 (1.38-2.80)

Model 1 adjusted for genders, age, education, ethnic group and family history of cancer. Model 2 adjusted for genders, age, education, ethnic group, family history of cancer, alcohol intake, smoking status, annual household income, fruit and vegetable intake and physical activity. Model 3 additionally adjusted for body mass index based on model 2. Participants with less than 2 yrs of follow-up were excluded. HR: Hazard ratio; CI: Confidence interval.

Table 6 Sensitivity analysis stratified by gender

Gender	Cancer	Group	HR (95%CI)
			Model 1	Model 2	Model 3
Male	Liver	Quartile 1	1.00 (reference)	1.00 (reference)	1.00 (reference)
		Quartile 2	0.88 (0.55-1.40)	0.92 (0.57-1.46)	0.86 (0.54-1.38)
		Quartile 3	0.60 (0.36-1.01)	0.62 (0.37-1.05)	0.56 (0.33-0.94)
		Quartile 4	0.99 (0.63-1.55)	0.99 (0.63-1.56)	0.81 (0.51-1.29)
	Gallbladder	Quartile 1	1.00 (reference)	1.00 (reference)	1.00 (reference)
		Quartile 2	3.04 (0.32-29.21)	3.20 (0.90-11.35)	3.01 (0.85-10.67)
		Quartile 3	4.92 (0.57-42.13)	5.22 (1.78-15.28)	4.58 (1.57-13.41)
		Quartile 4	5.52 (0.66-45.96)	5.85 (2.08-16.43)	4.64 (1.65-13.03)
	Biliary tract	Quartile 1	1.00 (reference)	1.00 (reference)	1.00 (reference)
		Quartile 2	0.83 (0.34-1.99)	0.87 (0.36-2.10)	0.88 (0.36-2.17)
		Quartile 3	0.82 (0.34-1.97)	0.88 (0.36-2.15)	0.83 (0.33-2.06)
		Quartile 4	0.70 (0.28-1.73)	0.77 (0.30-1.93)	0.64 (0.24-1.68)
	Pancreas	Quartile 1	1.00 (reference)	1.00 (reference)	1.00 (reference)
		Quartile 2	1.04 (0.70-1.55)	1.07 (0.72-1.59)	1.06 (0.71-1.59)
		Quartile 3	1.37 (0.95-1.99)	1.41 (0.97-2.04)	1.33 (0.91-1.95)
		Quartile 4	1.15 (0.78-1.69)	1.17 (0.79-1.73)	1.11 (0.74-1.66)
Female	Liver	Quartile 1	1.00 (reference)	1.00 (reference)	1.00 (reference)
		Quartile 2	0.91 (0.45-1.81)	0.92 (0.46-1.85)	0.89 (0.44-1.78)
		Quartile 3	0.98 (0.50-1.92)	1.00 (0.51-1.95)	0.92 (0.47-1.83)
		Quartile 4	1.05 (0.55-2.00)	1.02 (0.53-1.96)	0.88 (0.43-1.76)
	Gallbladder	Quartile 1	1.00 (reference)	1.00 (reference)	1.00 (reference)
		Quartile 2	2.06 (0.53-7.98)	2.13 (0.55-8.24)	2.11 (0.54-8.20)
		Quartile 3	2.38 (0.64-8.81)	2.47 (0.66-9.15)	2.42 (0.64-9.15)
		Quartile 4	2.08 (0.56-7.74)	2.10 (0.56-7.85)	2.02 (0.51-8.08)
	Biliary tract	Quartile 1	1.00 (reference)	1.00 (reference)	1.00 (reference)
		Quartile 2	1.56 (0.46-5.33)	1.56 (0.45-5.33)	1.48 (0.43-5.09)
		Quartile 3	0.80 (0.20-3.22)	0.80 (0.20-3.23)	0.72 (0.18-2.97)
		Quartile 4	1.23 (0.36-4.26)	1.29 (0.37-4.47)	1.04 (0.27-3.96)
	Pancreas	Quartile 1	1.00 (reference)	1.00 (reference)	1.00 (reference)
		Quartile 2	0.78 (0.47-1.32)	0.78 (0.46-1.31)	0.77 (0.46-1.29)
		Quartile 3	1.21 (0.77-1.92)	1.20 (0.76-1.90)	1.16 (0.73-1.85)
		Quartile 4	2.07 (1.37-3.13)	2.05 (1.35-3.10)	1.93 (1.24-3.01)

Model 1 adjusted for age, education, ethnic group and family history of cancer. Model 2 adjusted for age, education, ethnic group, family history of cancer, alcohol intake, smoking status, annual household income, fruit and vegetable intake and physical activity. Model 3 additionally adjusted for body mass index based on model 2. Participants with less than 2 yrs of follow-up were excluded. HR: Hazard ratio; CI: Confidence interval.