Circulating levels of vitamin D and colorectal adenoma: A case-control study and a meta-analysis

Table 1 Characteristics of patients according to adenoma case, n (%)

	Adenoma(n = 112)	No adenoma(n = 112)	P value
Age (yr), mean ± SD	60.3 ± 5.3	59.5 ± 5.4	0.37
Men	57 (50.9)	57 (50.9)	Matched
25(OH)D (ng/mL), mean ± SD	15.7 ± 5.8	16.8 ± 5.6	0.16
25(OH)D < 20 ng/mL	91 (81.3)	82 (73.2)	0.12
Education			0.54
Elementary school graduate	16 (14.3)	10 (9.1)
Middle school graduate	25 (22.3)	31 (28.2)
High school graduate	50 (44.6)	46 (41.8)
College graduate or above	21 (18.8)	23 (20.9)
Waist circumference (cm), mean ± SD	87.0 ± 7.8	84.6 ± 6.7	0.02
BMI (kg/m2)			0.10
18.5 < BMI < 23	33 (29.5)	36 (32.1)
23 ≤ BMI < 25	32 (28.6)	45 (40.2)
25 ≤ BMI	47 (41.9)	31 (27.7)
Family history			0.53
Yes	6 (5.4)	4 (3.6)
No	106 (94.6)	108 (96.4)
Smoking status			0.29
Non smoker	56 (50.9)	64 (57.7)
Past smoker	37 (33.6)	31 (27.9)
Current smoker	17 (15.5)	16 (14.4)
Alcohol drinking status			0.002
Never drinker	41 (36.6)	57 (50.9)
Past drinker	6 (5.4)	6 (5.4)
Current drinker	65 (58.0)	49 (43.8)
Physical activity (MET-hr/wk), mean ± SD	29.0 ± 32.0	24.3 ± 25.2	0.22
Supplement use			0.08
Yes	42 (37.5)	56 (50.0)
No	70 (62.5)	56 (50.0)
Red meat intake			0.34
≤ 1/mo	11 (10.1)	10 (8.9)
2-4/mo	77 (70.6)	88 (78.6)
≥ 2/wk	21 (19.3)	14 (12.5)
Energy intake (kcal/d), mean ± SD	1688.8 ± 581.9	1692.4 ± 488.4	0.96

P values were calculated using the Mantel-Haenszel test for categorical variables and the paired t test on loge-transformed variables. BMI: Body mass index.

Table 2 Odds ratios and 95% confidence intervals for adenoma according to quartile of 25-hydroxyvitamin D level

	Quartile of serum 25(OH) D levels				P for trend
	Quartile1	Quartile2	Quartile3	Quartile4
All patients
Median (ng/mL)	10.33	14.25	17.91	24.21
Case/control	37/28	26/28	28/28	21/28
Model 1	1.00	0.71 (0.35-1.45)	0.73 (0.33-1.61)	0.52 (0.23-1.20)	0.15
Model 2	1.00	0.72 (0.31-1.66)	0.73 (0.29-1.82)	0.49 (0.19-1.27)	0.16
Men
Median (ng/mL)	11.08	14.6	17.65	22.66
Case/control	15/14	13/14	17/15	12/14
Model 1	1.00	0.95 (0.35-2.57)	1.10 (0.29-4.18)	0.80 (0.25-2.60)	0.74
Model 2	1.00	1.31 (0.36-4.82)	1.26 (0.23-6.87)	1.80 (0.40-8.12)	0.46
Women
Median (ng/mL)	9.48	13.53	18.4	25.42
Case/control	16/14	22/14	8/14	9/13
Model 1	1.00	1.31 (0.53-3.24)	0.51 (0.18-1.51)	0.65 (0.20-2.14)	0.16
Model 2	1.00	0.89 (0.26-3.10)	0.54 (0.13-2.16)	0.22 (0.04-1.15)	0.05

Model 1 was adjusted for age (continuous). Model 2 was adjusted for the following covariates; men: age (years, continuous), body mass index (BMI) (kg/m², 18.5- < 23, 23- < 25, > 25), alcohol drinking (nondrinker, past drinker, ≤ 1/mo, 2-4/mo, 2-3/wk, ≥ 4/wk), smoking status (never, 0- < 20, 20- < 30, > 30 pack-years of smoking), and folate intake (mcg/d, continuous); women: age (years, continuous), BMI (kg/m², 18.5- < 23, 23- < 25, > 25), alcohol drinking (nondrinker, ever drinker), smoking status (never, ever smoker), folate intake (mcg/d, continuous), and menopausal status and hormone replacement use (premenopausal, postmenopausal without hormone replacement therapy, postmenopausal with hormone replacement therapy, postmenopausal with nonresponse about hormone replacement therapy use).

Table 3 Included studies of circulating levels of 25-hydroxyvitamin D and colorectal adenoma

First author, year	Country (sex)	Study design	study dates	Endpoint	Type of endoscopy	25(OH)D, mean or median	No. of cases/controls	25(OH)D levels in the highest vs lowest categories	OR (95%Cl)
Platz, 2000	United States (W)	Prospective study	1989-1996	First adenoma	Sigmoidoscopy or colonoscopy	26.4 in cases and 26.8 ng/mL in controls, mean	326/326	38.0 ng/mL vs 16.3 ng/mL, median	1.00 (ref), 0.64, 0.58, 1.04 (0.66-1.66)
Levine, 2001	United States (M, W)	Case-control study	1991-1993	First adenoma	Sigmoidoscopy	25.6 in cases and 26.9 ng/mL in controls, mean	473/506	34.3-115 ng/mL vs 1-15.2 ng/mL, range	1.00 (ref), 0.99, 0.86, 0.74 (0.51-1.09)
Peters, 2001	United States (M, W)	Case-control study	1994-1996	First (61%) or recurrent adenoma	Colonoscopy (86.2%) or sigmoidoscopy	24.7 in cases and 26.5 ng/mL in controls, median	236/218	33.7-67.2 ng/mL vs 5.3-19.4 ng/mL, range	1.0(ref), 0.40, 0.67, 0.47, 0.43(0.23-0.81)
Grau, 2003	United States (M, W)	Prospective study	1992-1996	Recurrent adenoma	Colonoscopy	29.1 ng/mL, median	376/422	-	0.99 (0.91-1.07) OR for serum vitD levels per 12 (1SD) units increase
Peters, 2004	United States (M, W)	Prospective study	1993-1999	First advanced adenoma	Sigmoidoscopy	27.0 in cases and 28.3 ng/mL in controls, mean	394/397	-	0.87 (0.75-1.01) OR for serum vitD levels per 10 units increase.
Miller, 2007	United States (M, W)	Cross-sectional study	1998-2000	First adenoma	Colonoscopy	27.5 in cases and 31.4 ng/mL in controls, mean	111/238	> 33.8 ng/mL vs < 20.8 ng/mL, range	1.00 (ref), 0.74, 0.51 (0.27-0.98)
Takahashi, 2010	Japan (M)	Case-control study	1997-2004	First adenoma	Colonoscopy	26.2 in cases and 26.1 ng/mL in controls, mean	656/648	≥ 30 ng/mL vs < 22 ng/ml, range	1.00 (ref), 1.21, 1.21, 1.25 (0.85-1.84)
Fedirko, 2010	United States (M, W)	Pooled case-control study	1991-2002	First adenoma	Colonoscopy	24.5 in cases and 25.5 ng/mL in controls, mean	616/770		1.00 (ref), 0.77, 0.85, 0.59 (0.41-0.84)
Adams, 2011	United States (M, W)	Cross-sectional study	1998- 2003	Fitst or recurrent adenoma	Colonoscopy	23.1 in cases and 24.9 ng/mL in controls, mean	149/ 225	> 28.9 ng/mL vs ≤ 20.5 ng/ml, range	1.00 (ref), 0.97, 0.71 (0.38-1.30)
Ashktorab, 2011	United States (M, W)	Case-control study			Colonoscopy	41.2 in cases and 41.4 ng/mL in controls, mean	93/187	> 57.7 ng/mL vs < 29.5 ng/mL, range	1.00 (ref), 1.4, 1.9, 0.6 (0.3-1.4)
Hong, 2012	Korea (M, W)	Case-control study	2009-2010	First adenoma	Colonoscopy	20.0 in cases and 25.0 ng/mL in controls, mean	143/ 143	≥ 23.9 ng/mL vs < 14.3 ng/mL, range	1.00 (ref), 0.87, 0.40, 0.38 (0.18-0.80)
Yamaji, 2012	Japan (M,W)	Cross-sectional study	2004-2005	First adenoma	Colonoscopy		737/ 703	32 ng/mL vs 16 ng/mL, median	1.00 (ref), 0.86, 0.91, 1.03, 0.64 (0.45-0.92)
Jacobs, 2013	United States (M, W)	Prospective study	1990-1999	Recurrent adenoma	Colonoscopy		942/ 1132	> 30 ng/mL vs < 20 ng/mL, range	1.00 (ref), 0.91, 0.95 (0.73-1.24)
Aigner, 2014	Austria (W)	Cross-sectional study	2010-2013	First adenoma	Colonoscopy	22.8 ng/mL in women	90/629		0.976 (0.954-0.999) for 1 ng/mL increment
Choi, 2015 (our study)	Korea (M, W)	Case-control study	2011-2012	First or recurrent(5%) adenoma	Colonoscopy	15.7 ng/mL in cases and 16.6 in controls	112/112	23.4 ng/mL vs 10.0 ng/mL, mean	1.00 (ref), 0.72, 0.73, 0.49 (0.19-1.27)

Table 4 Combined relative risk (RR)s and 95% confidence intervals of colorectal adenoma for the associations by sex, calcium intake, study region, and adenoma site

	Studies, n	Ref.	Combined RR (95%CI) comparing the highest vs the lowest categories	P for difference
Sex				0.30
Men	6	[13-15,20,27] and our study	0.78 (0.51-1.06)
Women	7	[14,15,20,23,27,37] and our study	0.58 (0.33-0.83)
Calcium intake				0.48
Low	7	[14,19,24-26,28] and our study	0.73 (0.46-1.01)
High	7	[14,19,24-26,28] and our study	0.61 (0.40-0.82)
Study region				0.88
United States	10	[19,21,23-30]	0.70 (0.52-0.88)
Asia	4	[13-15] and our study	0.66 (0.35-0.98)
Site				0.50
Distal adenoma	10	[13-15,21,23-25,27,28] and our study	0.67 (0.53-0.81)
Proximal adenoma	8	[13-15,21,25,28,37] and our study	0.61 (0.44-0.79)