The Role of Genetic Variants in the Association between Dietary Acrylamide and Advanced Prostate Cancer in the Netherlands Cohort Study on Diet and Cancer

Figures & data

Figure 1. Flow diagram of subcohort members and advanced prostate cancer cases for 20.3 years of follow-up; Netherlands Cohort Study on diet and cancer (1986–2006). (a) Analysis on the association between selected genetic variants and advanced prostate cancer risk including 1,720 subcohort members and 1,000 advanced prostate cancer cases. (b) Analysis on the interaction between selected genetic variants and acrylamide intake on advanced prostate cancer risk including 1,608 subcohort members and 948 advanced prostate cancer cases.

Table 1. Baseline characteristics of subcohort members and advanced prostate cancer cases in the Netherlands Cohort Study on diet and cancer (1986–2006)¹.

Variable	Subcohort (n = 1,608)	Cases (n = 948)
Acrylamide (μg/day)	22.4 (11.9)	22.9 (12.2)
Age (years)	61.2 (4.2)	61.7 (4.1)
BMI (kg/m^2)	24.9 (2.6)	25.0 (2.4)
Non-occupational physical activity (min/day)^1	63 (37–103)	64 (41–103)
Level of education (%)
Primary school	23.9	24.3
Lower vocational	20.8	18.0
High school	35.2	35.7
Higher vocational/university	20.1	22.0
Cigarette smoking status (%)
Never smoker	13.8	14.7
Former smoker	54.2	57.2
Current smoker	32.0	28.2
Former smokers >10 years cessation
Frequency of cigarette smoking (n/day)	16.4 (11.8)	15.5 (10.4)
Duration of cigarette smoking (years)	22.4 (8.5)	22.7 (8.3)
Time since cessation (years)	20.8 (7.0)	20.6 (7.0)
Positive history of diabetes (%)	3.1	2.2
Family history of prostate cancer (%)	2.5	3.5
Dietary intake
Total energy intake (kcal/day)	2,155 (498)	2,166 (486)
Fruit (g/day)^2	137 (78–209)	142 (79–215)
Vegetables (g/day)	193 (84)	198 (82)
Dairy products (g/day)^2	266 (165–399)	291 (181–419)
Lycopene (µg/day)^2	751 (363–1,237)	802 (389–1,366)
Calcium (mg/day)	944 (341)	971 (339)
Vitamin E (mg/day)	14.7 (6.6)	15.2 (6.6)

¹ Values are means + SEMs or percentages unless otherwise indicated.

² Values are medians; ranges in parentheses.

Table 2. Association between dietary acrylamide intake and advanced prostate cancer risk after 13.3 and 20.3 years of follow-up; Netherlands Cohort Study on diet and cancer (1986).

		Acrylamide, continuous		Acrylamide, quintiles of intake
			10 µg/day	Q1		Q2		Q3		Q4		Q5
Study population	Follow-up	n cases total	HR (95% CI)^1	n cases	HR (95% CI)^1	n cases	HR (95% CI)^1	n cases	HR (95% CI)^1	n cases	HR (95% CI)^1	n cases	HR (95% CI)^1	P trend
Total	20.3y	1,290	1.02 (0.96–1.08)	267	1.00 (ref)	264	1.05 (0.83–1.32)	242	0.95 (0.75–1.20)	245	0.99 (0.78–1.25)	272	1.03 (0.82–1.29)	0.89
	13.3y	813	1.01 (0.94–1.08)	169	1.00 (ref)	183	1.17 (0.90–1.51)	144	0.95 (0.72–1.25)	150	1.02 (0.78–1.34)	167	1.04 (0.80–1.36)	0.97
Never-smokers	20.3y	190	1.00 (0.85–1.17)	47	1.00 (ref)	41	0.96 (0.54–1.71)	30	0.94 (0.50–1.77)	31	0.85 (0.47–1.55)	41	0.90 (0.51–1.60)	0.68
	13.3y	121	0.90 (0.74–1.09)	33	1.00 (ref)	30	1.04 (0.55–1.98)	18	0.89 (0.43–1.84)^2	18	0.81 (0.40–1.65)	22	0.68 (0.34–1.36)	0.19
Non-smokers^3	20.3y	670	1.00 (0.92–1.08)	161	1.00 (ref)	119	0.83 (0.60–1.15)	128	1.01 (0.73–1.41)^2	114	0.86 (0.62–1.20)	148	0.93 (0.68–1.26)	0.78
	13.3y	409	0.99 (0.90–1.09)	98	1.00 (ref)	81	0.97 (0.67–1.41)	73	1.05 (0.71–1.55)	73	1.01 (0.68–1.48)	84	0.93 (0.64–1.34)	0.71

Abbreviations: CI, confidence interval; HR, hazard ratio.

¹ Hazard ratios adjusted for age, family history of prostate cancer, cigarette smoking status (never/former/current), frequency of smoking (number of cigarettes per day; centered), and duration of smoking (number of years; centered).

² Possible violation of the proportional hazards assumption but no statistically significant interaction with time (P value ≥ 0.05).

³ Never smokers combined with former smokers who had quit smoking more than 10 years before baseline.

Table 3. SNPs showing nominally statistically significant association (P trend < 0.05) with advanced prostate cancer risk after 20.3 years of follow-up; Netherlands Cohort Study on diet and cancer (1986–2006).

				Advanced prostate cancer
Gene	SNP^1	Genotype	Person-years	n cases	HR (95% CI)^2	P trend	FDR-adjusted P value^3
AKR1C2	rs11252887	CC	13 828	464	1.00 (ref)
		CT	11 065	422	1.14 (0.96–1.35)
		TT	2191	101	1.38 (1.03–1.85)
		Per minor allele	27 084	987	1.16 (1.03–1.32)	0.02	0.26
CAT	rs511895	GG	9882	308	1.00 (ref)
		AG	12 786	495	1.25 (1.04–1.50)
		AA	4691	197	1.36 (1.07–1.71)
		Per minor allele	27 359	1000	1.17 (1.05–1.31)	0.01	0.15
HSD3B1/B2	rs10923823	TT	9270	314	1.00 (ref)
		CT	13 032	467	1.06 (0.88–1.27)
		CC	5021	218	1.31 (1.04–1.64)
		Per minor allele	27 323	999	1.14 (1.01–1.27)	0.03	0.29
HSD3B1/B2	rs7546652	TT	9279	313	1.00 (ref)
		CT	13 080	469	1.06 (0.88–1.28)
		CC	5001	218	1.32 (1.05–1.65)
		Per minor allele	27 359	1,000	1.14 (1.02–1.28)	0.03	0.29
PTGS2	rs5275	TT	12 500	493	1.00 (ref)
		TC	11 310	402	0.88 (0.74–1.04)
		CC	3358	99	0.71 (0.54–0.93)
		Per minor allele	27 169	994	0.85 (0.76–0.96)	0.01	0.19
XPC	rs2228001	AA	9514	392	1.00 (ref)
		CA	13 049	477	0.89 (0.75–1.06)^4
		CC	4796	130	0.67 (0.52–0.85)^4
		Per minor allele	27 359	999	0.83 (0.74–0.94)	0.002	0.11

Abbreviations: AKR1C2, aldo-keto reductase family 1 member C2; CAT, catalase; CI, confidence interval; FDR, false discovery rate; HR, hazard ratio; HSD3B1/B2, 3beta-hydroxysteroid dehydrogenase; PTGS2, prostaglandin-endoperoxide synthase 2; SNP, single nucleotide polymorphism; XPC, xeroderma pigmentosum, complementation group C.

¹ Catalase (CAT) rs1001179 showed a positive association with advanced prostate cancer in the Netherlands Cohort Study on diet and cancer as previously reported by our group (ref. 34) and is therefore not presented here.

² Hazard ratios adjusted for age.

³ P values adjusted for multiple testing comparisons using the false discovery rate (FDR) approach of Benjamini-Hochberg (1995); the FDR threshold was set at 0.20.

⁴ Possible violation of the proportional hazards assumption but no statistically significant interaction with time (P value ≥ 0.05).

Table 4. SNPs showing nominally statistically significant interaction (P for interaction < 0.05) with dietary acrylamide on advanced prostate cancer risk after 20.3 years of follow-up; Netherlands Cohort Study on diet and cancer (1986–2006).

				Acrylamide, continuous		Acrylamide, quartiles of intake
					10 µg/day	Q1		Q2		Q3		Q4
Gene	SNP	Study population	Genotype	n cases total	HR (95% CI)^1	n cases	HR (95% CI)^1	n cases	HR (95% CI)^1	n cases	HR (95% CI)^1	n cases	HR (95% CI)^1	P trend	P for interaction	FDR-adjusted P value^2
NQO1	rs1800566	Total	CC	645	1.09 (1.00–1.19)	157	1.00 (ref)	159	1.02 (0.77–1.35)	151	1.03 (0.78–1.38)	178	1.17 (0.89–1.55)	0.22	0.03	0.96
			CT+TT	302	0.93 (0.82–1.06)	82	1.00 (ref)	79	0.87 (0.57–1.33)	73	0.74 (0.48–1.12)	68	0.70 (0.46–1.07)	0.14
TXN	rs2301241	Total	TT	377	0.94 (0.83–1.05)	100	1.00 (ref)	94	0.90 (0.61–1.33)	89	0.79 (0.54–1.15)	94	0.76 (0.52–1.11)	0.16	0.04	0.96
			CT+CC	569	1.09 (1.01–1.19)	138	1.00 (ref)	144	1.02 (0.76–1.38)	134	1.04 (0.76–1.41)	153	1.20 (0.89–1.62)	0.19

Abbreviations: CI, confidence interval; FDR, false discovery rate; HR, hazard ratio; NQO1, NAD(P)H quinone dehydrogenase 1; SNP, single nucleotide polymorphism; TXN, thioredoxin.

¹ Hazard ratios adjusted for age, family history of prostate cancer, cigarette smoking status (never/former/current), frequency of smoking (number of cigarettes per day; centered), and duration of smoking (number of years; centered).

² P values adjusted for multiple testing comparisons using the false discovery rate (FDR) approach of Benjamini–Hochberg (1995); the FDR threshold was set at 0.20.

Geybels MS, van den Brandt PA, van Schooten FJ, and Verhage BA: Oxidative stress-related genetic variants, pro- and antioxidant intake and status, and advanced prostate cancer risk. Cancer Epidemiol Biomarkers Prev 24(1), 178–186, 2015. doi:10.1158/1055-9965.epi-14-0968.

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