Circulating Folate, Vitamin B12, Homocysteine, Vitamin B12 Transport Proteins, and Risk of Prostate Cancer: a Case-Control Study, Systematic Review, and Meta-analysis

Simon M. Collin; Chris Metcalfe; Helga Refsum; Sarah J. Lewis; Luisa Zuccolo; George Davey Smith; Lina Chen; Ross Harris; Michael Davis; Gemma Marsden; Carole Johnston; J. Athene Lane; Marta Ebbing; Kaare Harald Bønaa; Ottar Nygård; Per Magne Ueland; Maria V. Grau; John A. Baron; Jenny L. Donovan; David E. Neal; Freddie C. Hamdy; A. David Smith; Richard M. Martin

doi:10.1158/1055-9965.EPI-10-0180

DOI: 10.1158/1055-9965.EPI-10-0180 Published June 2010

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Figure 1.
Meta-analyses of associations of circulating folate, vitamin B₁₂, and tHcy concentrations with prostate cancer risk.
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Figure 2.
Meta-analyses of associations of circulating folate, vitamin B₁₂, and tHcy concentrations with prostate cancer risk in prospective cohort studies.

Table 1.

Baseline characteristics of participants stratified by case-control status

Characteristic	Measure	Cases (n = 1,461)	Controls (n = 1,507)	P^*
Age	Mean (SD)	62.5 (5.1)	62.3 (5.1)	0.2
Ethnicity (white)		98.5%	98.7%	0.3
BMI (kg/m²)^†	Mean (SD)	27.9 (3.7)	28.2 (4.1)	0.1
Tobacco use^†	Current smoker	20.2%	17.3%	0.1
Tobacco use^†	Ever smoked	63.3%	65.5%	0.3
Alcohol consumption in the past 12 mo^†	Almost daily or more often	38.5%	37.8%	0.5
	Once or twice per week	41.2%	42.4%
	Once or twice per month	8.5%	6.9%
	Special occasions or never	11.9%	12.9%
Vitamin supplement use in past 12 mo (yes/no)^†		7.8%	7.9%	0.9

Circulating vitamin and metabolite concentrations	Median (5th-95th percentile) Cases	Median (5th-95th percentile) Controls	P^*
Folate (nmol/L)	15.9 (6.1-51.4)	15.8 (6.2-52.3)	0.6
Vitamin B₁₂ (pmol/L)	307 (156-542)	299 (158-521)	0.1
Holo-haptocorrin (pmol/L)	247 (119-439)	240 (120-425)	0.04
Holo-transcobalamin (pmol/L)	57 (23-117)	56 (24-119)	0.9
Total transcobalamin (pmol/L)	860 (612-1,269)	874 (602-1,270)	0.1
tHcy (μmol/L)	11.1 (7.8-17.6)	11.1 (7.7-17.7)	0.9

↵*χ² test (proportions), Student's t test (means), or two-sample Wilcoxon rank-sum (Mann-Whitney) test (medians).
↵^†Numbers of cases and controls for whom these data were available: BMI (1,183 cases and 1,105 controls), current smoker (846 cases and 808 controls), ever smoked (1,208 cases and 1,117 controls), alcohol consumption (1,204 cases and 1,116 controls), and vitamin supplementation (875 cases and 831 controls).

Table 2.

ORs for prostate cancer by categorical (quartiles) and continuous (log_e-transformed) measures of plasma vitamin and metabolite concentrations

Metabolite	Quartiles in controls (n = 1,507)	All cases (n = 1,461) vs controls	Localized cases (n = 1,298) vs controls	Advanced cases (n = 163) vs controls
Metabolite	Quartiles in controls (n = 1,507)	OR^* (95% CI)	OR^* (95% CI)	OR^* (95% CI)
Folate (nmol/L)	<10.8	1.00 (Reference)	1.00 (Reference)	1.00 (Reference)
	10.8-15.8	1.12 (0.91-1.37)	1.18 (0.96-1.46)	0.67 (0.39-1.18)
	15.9-26.2	1.18 (0.96-1.44)	1.17 (0.94-1.44)	1.47 (0.89-2.45)
	>26.2	1.01 (0.82-1.24)	1.07 (0.86-1.34)	0.71 (0.42-1.22)
	P_trend^†	0.7	1.0	0.4
	Per log_e	0.94 (0.84-1.06)	0.96 (0.86-1.08)	0.90 (0.67-1.21)
			P_{heterogeneity}^‡ = 0.5
Vitamin B₁₂ (pmol/L)	<239	1.00 (Reference)	1.00 (Reference)	1.00 (Reference)
	239-299	0.91 (0.74-1.12)	0.95 (0.77-1.18)	0.70 (0.40-1.22)
	300-376	0.99 (0.80-1.22)	0.99 (0.80-1.24)	0.93 (0.55-1.57)
	>376	1.17 (0.95-1.43)	1.20 (0.97-1.48)	1.00 (0.61-1.65)
	P_trend^†	0.06	0.05	0.7
	Per log_e	1.19 (0.98-1.43)	1.21 (0.99-1.48)	1.04 (0.64-1.68)
			P_{heterogeneity}^‡ = 0.4
Holo-haptocorrin (pmol/L)	<187	1.00 (Reference)	1.00 (Reference)	1.00 (Reference)
	187-240	0.94 (0.76-1.16)	0.95 (0.76-1.19)	0.85 (0.50-1.44)
	241-304	0.99 (0.80-1.22)	1.04 (0.84-1.29)	0.68 (0.39-1.19)
	>304	1.27 (1.04-1.56)	1.27 (1.02-1.57)	1.24 (0.75-2.04)
	P_trend^†	0.01	0.01	0.3
	Per log_e	1.21 (1.01-1.44)	1.23 (1.02-1.48)	1.05 (0.67-1.64)
			P_{heterogeneity}^‡ = 0.3
Holo-transcobalamin (pmol/L)	<42	1.00 (Reference)	1.00 (Reference)	1.00 (Reference)
	42-56	1.08 (0.88-1.33)	1.11 (0.89-1.37)	1.02 (0.60-1.75)
	57-78	1.09 (0.89-1.34)	1.12 (0.90-1.38)	1.00 (0.61-1.65)
	>78	1.04 (0.84-1.28)	1.09 (0.87-1.35)	0.85 (0.50-1.44)
	P_trend^†	0.9	0.6	0.5
	Per log_e	0.99 (0.86-1.14)	1.01 (0.87-1.18)	0.93 (0.66-1.32)
			P_{heterogeneity}^‡ = 0.7
Total transcobalamin (pmol/L)	<749	1.00 (Reference)	1.00 (Reference)	1.00 (Reference)
	749-874	1.05 (0.86-1.29)	1.00 (0.81-1.23)	1.63 (0.94-2.83)
	875-1,024	1.02 (0.83-1.25)	1.00 (0.80-1.24)	1.36 (0.78-2.37)
	>1,024	0.84 (0.68-1.05)	0.80 (0.64-1.00)	1.36 (0.77-2.40)
	P_trend^†	0.09	0.04	0.6
	Per log_e	0.76 (0.55-1.05)	0.71 (0.50-0.99)	1.45 (0.65-3.25)
			P_{heterogeneity}^‡ = 0.06
tHcy(μmol/L)	<9.52	1.00 (Reference)	1.00 (Reference)	1.00 (Reference)
	9.52-11.13	1.10 (0.90-1.35)	1.11 (0.89-1.37)	0.93 (0.54-1.59)
	11.14-13.21	1.03 (0.84-1.27)	1.01 (0.81-1.26)	1.16 (0.68-1.95)
	>13.21	1.04 (0.84-1.28)	1.01 (0.81-1.26)	1.05 (0.61-1.79)
	P_trend^†	1.0	0.8	0.8
	Per log_e	0.90 (0.69-1.19)	0.88 (0.66-1.17)	0.94 (0.47-1.91)
			P_{heterogeneity}^‡ = 0.3

↵*From conditional logistic regression matching on 5-y age group and recruiting center, further adjusted for exact age (continuous).
↵^†From conditional logistic regression matching on 5-y age group and recruiting center, further adjusted for exact age (continuous), using quartile means as a linear variable.
↵^‡From multinomial logistic regression, adjusted for age (continuous) and study center, using log-transformed concentration.