Serum 25-Hydroxyvitamin D and Risks of Colon and Rectal Cancer in Finnish Men

Stephanie J. Weinstein; Kai Yu; Ronald L. Horst; Jason Ashby; Jarmo Virtamo; Demetrius Albanes

Am J Epidemiol. 2011;173(5):499-508.

Abstract and Introduction

Abstract

Prospective investigations of circulating vitamin D concentrations suggest inverse associations with colorectal cancer risk, although inconsistencies remain and few studies have examined the impact of season. The authors conducted a prospective case-control study of 239 colon cancer cases and 192 rectal cancer cases (diagnosed in 1993–2005) and 428 controls matched on age and blood collection date within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, a cohort study of Finnish male smokers. Baseline serum 25-hydroxyvitamin D (25(OH)D) concentrations were categorized using a priori defined cutpoints of <25, 25–<37.5, 37.5–<50, 50–<75, and ≥75 nmol/L and by season-specific and season-standardized 25(OH)D quartiles. Conditional logistic regression models yielded multivariate-adjusted odds ratios for the predefined cutpoints of 0.63, 0.91, 0.73, 1.00 (referent), and 1.44 for colon cancer and 0.64, 0.58, 0.84, 1.00, and 0.76 for rectal cancer, respectively (all 95% confidence intervals included 1.00). Colon cancer risks were significantly elevated for the highest season-specific and season-standardized quartiles versus the lowest quartiles (OR = 2.11 (95% CI: 1.20, 3.69) and OR = 1.88 (95% CI: 1.07, 3.28), respectively), while rectal cancer risk estimates were null. These results provide no evidence to support an inverse association between vitamin D status and colon or rectal cancer risk; instead, they suggest a positive association for colon cancer.

Introduction

In 1980, ecologic findings that colorectal cancer mortality rates in the United States were inversely associated with sunlight exposure, with vitamin D as the suggested mechanism,^[1] generated interest in the relation between vitamin D and colorectal cancer. Recent reviews have concluded that low serum vitamin D concentrations are associated with increased risk of colorectal cancer;^[2–4] however, not all reviews interpret the data to be consistent and convincing.^[5]

Most prospective studies have supported the hypothesis of an inverse association;^[6–14] however, differences exist by anatomic subsite, and not all associations are statistically significant. In addition, all but 1^[12] of 9^[6–14] prospective studies matched subjects on the date of blood collection, but only 4^[9–12] used additional techniques to adjust for seasonal variation in vitamin D and its influence on the relation between vitamin D and colorectal cancer.

In addition to dietary and supplemental sources, vitamin D is synthesized from 7-dehydrocholesterol by the skin when exposed to solar radiation^[15] and is then hydroxylated in the liver to form 25-hydroxyvitamin D (25(OH)D), the accepted biomarker of circulating vitamin D.^[16] 25(OH)D is further hydroxylated in the kidney and other organs to its active form, 1,25-dihydroxyvitamin D (1,25(OH)₂D).

As part of a programmatic effort to comprehensively evaluate biomarkers of vitamin D and cancer, we conducted a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, a cohort study of male smokers in Finland. Multiple approaches were used to address the issues related to seasonal variation in 25(OH)D concentrations.

1 2 3 4

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Cite this: Serum 25-Hydroxyvitamin D and Risks of Colon and Rectal Cancer in Finnish Men - Medscape - Mar 01, 2011.

Table 1. Selected Baseline Characteristics of Cases and Controls, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, Finland, 1985–2005
Characteristic	Colon							Rectum
	Cases (n = 239)			Controls (n = 239)			P Value^a	Cases (n = 192)			Controls (n = 192)			P Value^a
	Median	IQR	%	Median	IQR	%	P Value^a	Median	IQR	%	Median	IQR	%	P Value^a
Age, years^b	58	54–61		58	54–61			57	53–62		57	53–62
Height, cm	174	170–178		174	170–177		0.43	174	170–178		174	169–178		0.77
Weight, kg	81.2	71.3–89.6		77.1	70.7–86.1		0.02	77.9	69.1–86.1		77.1	70.0–84.9		0.77
Body mass index^c	26.6	24.1–29.8		26.0	23.7–28.4		0.04	25.7	23.3–28.5		25.6	23.7–27.7		0.81
Physical activity (heavy)
Leisure			4.2			8.8	0.08			7.3			7.3	0.98
Occupational			6.3			6.7	0.85			7.8			11.5	0.23
Family history of colorectal cancer^d			4.8			1.5	0.06			1.5			0.6	0.47
Smoking amount, cigarettes/day	20	12–25		20	12–20		0.29	20	15–25		20	15–22		0.97
Smoking duration, years	38	30–42		37	31–42		0.70	36	32–42		36	30–42		0.42
Blood collected in darker months (November–April)^b			69.5			66.5				61.5			62.0
Supplement use
Calcium (yes)			8.8			9.2	0.28			13.0			13.0	0.58
Vitamin D (yes)			6.7			5.9	0.16			8.9			10.9	0.68
Daily dietary intake^e
Energy, kcal	2,531	2,086–3,102		2,648	2,214–3,160		0.31	2,622	2,149–3,138		2,549	2,136–3,061		0.57
Milk, g	0	0–340		0	0–340		0.83	0	0–340		13.3	0–460		0.23
Fish, g	31.0	21.5–46.8		34.9	20.6–56.3		0.36	34.0	20.7–54.0		32.7	20.3–47.9		0.22
Vitamin D, μg	4.7	3.3–6.8		5.0	3.2–7.1		0.69	4.9	3.1–7.0		4.6	3.3–6.2		0.29
Calcium, mg	1,316	966–1,728		1,354	1,007–1,775		0.37	1,303	966–1,578		1,378	1,016–1,708		0.17
Serum biomarkers
25(OH)D, nmol/L	32.4	22.5–49.3		29.6	20.5–45.7		0.14	34.6	21.3–50.9		31.2	22.1–45.6		0.63
α-tocopherol, mg/L	11.7	9.9–13.4		11.7	10.4–14.0		0.14	11.5	9.4–13.7		11.2	9.8–13.5		0.98
β-carotene, μg/L	159	104–256		193	127–299		0.001	167	105–263		184	131–280		0.08
Total cholesterol, mmol/L	6.14	5.47–6.93		6.28	5.54–7.20		0.28	6.13	5.33–6.89		6.17	5.57–6.93		0.35
Retinol, μg/L	602	520–683		572	505–662		0.06	580	500–655		572	494–670		0.90

Abbreviations: 25(OH)D, 25-hydroxyvitamin D; IQR, interquartile range.
^a Based on the chi-squared test (for categorical variables) or the Wilcoxon rank-sum test (for continuous variables). All P values were 2-sided.
^b Matching factor.
^c Weight (kg)/height (m)².
^d Family history of colon or rectal cancer, respectively; data were available for 82% of the colon cancer set and 78% of the rectal cancer set.
^e Dietary data were available on 95% of subjects.

Table 2. Odds Ratios for the Association Between Serum 25-Hydroxyvitamin D and Risks of Colon and Rectal Cancer Obtained Using A Priori Defined Cutpoints, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, Finland, 1985–2005
	25-Hydroxyvitamin D Concentration, nmol/L										P _trend ^a
	<25.0		25.0–<37.5		37.5–<50.0		50.0–<75.0		≥75.0
	OR	95% CI	OR	95% CI	OR	95% CI	OR	95% CI	OR	95% CI
Colorectal Cancer
Total
No. of cases/no. of controls	143/155		105/105		73/77		85/72		22/19
Crude OR	0.77	0.51, 1.14	0.85	0.56, 1.27	0.79	0.50, 1.25	1.00	Reference	1.01	0.51, 2.02	0.22
Multivariate-adjusted OR^b	0.68	0.45, 1.03	0.78	0.51, 1.20	0.78	0.49, 1.25	1.00	Reference	1.00	0.49, 2.03	0.07
Darker months^c
No. of cases/no. of controls	115/126		71/66		48/48		40/37		7/7
Crude OR	0.78	0.47, 1.30	0.93	0.53, 1.61	0.86	0.47, 1.57	1.00	Reference	0.88	0.27, 2.87	0.40
Multivariate-adjusted OR	0.75	0.45, 1.27	0.94	0.53, 1.67	0.90	0.48, 1.68	1.00	Reference	0.91	0.27, 3.08	0.27
Sunnier months^d
No. of cases/no. of controls	28/29		34/39		25/29		45/38		15/12
Crude OR	0.81	0.40, 1.65	0.75	0.40, 1.38	0.72	0.36, 1.46	1.00	Reference	1.07	0.45, 2.52	0.35
Multivariate-adjusted OR	0.58	0.26, 1.27	0.56	0.28, 1.12	0.61	0.29, 1.27	1.00	Reference	0.98	0.39, 2.43	0.10
Colon Cancer
Total
No. of cases/no. of controls	77/87		63/60		40/44		47/40		12/8
Crude OR	0.73	0.42, 1.25	0.89	0.53, 1.50	0.76	0.42, 1.38	1.00	Reference	1.32	0.48, 3.60	0.22
Multivariate-adjusted OR	0.63	0.36, 1.12	0.91	0.52, 1.59	0.73	0.39, 1.36	1.00	Reference	1.44	0.49, 4.26	0.11
Darker months
No. of cases/no. of controls	62/70		46/43		28/28		25/21		5/4
Crude OR	0.73	0.38, 1.44	0.90	0.46, 1.75	0.83	0.38, 1.79	1.00	Reference	1.10	0.23, 5.27	0.36
Multivariate-adjusted OR	0.65	0.32, 1.31	0.90	0.44, 1.84	0.78	0.35, 1.75	1.00	Reference	1.00	0.19, 5.18	0.24
Sunnier months
No. of cases/no. of controls	15/17		17/17		12/16		22/19		7/4
Crude OR	0.74	0.28, 1.96	0.88	0.37, 2.10	0.67	0.26, 1.73	1.00	Reference	1.44	0.38, 5.47	0.40
Multivariate-adjusted OR	0.48	0.15, 1.54	0.66	0.23, 1.90	0.49	0.16, 1.48	1.00	Reference	2.14	0.44, 10.35	0.12
Rectal Cancer
Total
No. of cases/no. of controls	68/70		42/46		33/33		39/32		10/11
Crude OR	0.79	0.44, 1.44	0.74	0.39, 1.41	0.82	0.41, 1.68	1.00	Reference	0.77	0.29, 2.02	0.58
Multivariate-adjusted OR	0.64	0.34, 1.22	0.58	0.29, 1.17	0.84	0.40, 1.75	1.00	Reference	0.76	0.28, 2.07	0.21
Darker months
No. of cases/no. of controls	55/58		25/24		20/20		16/13		2/3
Crude OR	0.80	0.36, 1.75	0.85	0.32, 2.23	0.83	0.31, 2.21	1.00	Reference	0.58	0.09, 3.87	0.74
Multivariate-adjusted OR	0.68	0.29, 1.59	0.70	0.24, 2.02	0.99	0.35, 2.84	1.00	Reference	0.74	0.10, 5.47	0.34
Sunnier months
No. of cases/no. of controls	13/12		17/22		13/13		23/19		8/8
Crude OR	0.91	0.31, 2.61	0.64	0.27, 1.55	0.85	0.29, 2.45	1.00	Reference	0.87	0.28, 2.72	0.64
Multivariate-adjusted OR	0.81	0.24, 2.66	0.61	0.23, 1.65	0.94	0.30, 2.90	1.00	Reference	0.85	0.25, 2.93	0.58

Abbreviations: CI, confidence interval; OR, odds ratio.
^a All P values were 2-sided.
^b Conditional logistic regression models with adjustment for years of smoking and serum α-tocopherol, β-carotene, and retinol concentrations.
^c November–April.
^d May–October.

Table 3. Odds Ratios for the Association Between Serum 25-Hydroxyvitamin D and Risks of Colon and Rectal Cancer Obtained Using Season-Specific and Season-Standardized (Residuals) Quartiles, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, Finland, 1985–2005
	Quartile of 25-Hydroxyvitamin D Concentration								P _trend ^a
	1		2		3		4
	OR	95% CI	OR	95% CI	OR	95% CI	OR	95% CI
Colon cancer
Season-specific model^b
No. of cases/no. of controls	49/72		57/50		65/58		68/59
Multivariate-adjusted OR^c	1.00	Reference	1.97	1.13, 3.45	1.96	1.14, 3.36	2.11	1.20, 3.69	0.01
Season-standardized model^d
No. of cases/no. of controls	54/71		61/51		54/55		70/62
Multivariate-adjusted OR	1.00	Reference	1.77	1.01, 3.08	1.39	0.81, 2.40	1.88	1.07, 3.28	0.06
Rectal cancer
Season-specific model
No. of cases/no. of controls	48/37		39/58		48/50		57/47
Multivariate-adjusted OR	1.00	Reference	0.46	0.24, 0.88	0.78	0.41, 1.51	1.18	0.62, 2.26	0.31
Season-standardized model
No. of cases/no. of controls	51/37		35/57		49/53		57/45
Multivariate-adjusted OR	1.00	Reference	0.41	0.21, 0.77	0.69	0.37, 1.28	1.13	0.61, 2.07	0.57

Abbreviations: CI, confidence interval; OR, odds ratio; Q, quartile.
^a All P values were 2-sided.
^b Cutpoints for season-specific quartiles: darker months (November–April)—Q1, ≤18.3; Q2, >18.3 and ≤26.9; Q3, >26.9 and ≤42.0; Q4, >42.0 nmol/L; sunnier months (May–October)—Q1, ≤27.0; Q2, >27.0 and ≤38.7; Q3, >38.7 and ≤53.4; Q4, >53.4 nmol/L.
^c Conditional logistic regression models with adjustment for years of smoking and serum α-tocopherol, β-carotene, and retinol concentrations.
^d Cutpoints for season-standardized quartiles: Q1, ≤3.10; Q2, >3.10 and ≤3.47; Q3, >3.47 and ≤3.85; Q4, >3.85. Season-standardized quartiles were created by calculating residuals from the regression line of log-transformed 25-hydroxyvitamin D concentration against calendar week of blood collection.

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