Homocysteine and Digestive Tract Cancer Risk: A Dose-Response Meta-Analysis

Table 1

Main features of the included studies for the association between homocysteine and digestive tract cancer.

First author,; (year of publication)	Cancer type	Country; study design	Source of control	Case/; Control	Method of measurement; /Type of homocysteine)	Gender	Median or mean age of (y)	Contrast (highest vs. lowest) (µmol/L)	Adjusted OR; (95% CI) (highest vs. lowest)	Adjustment	Quality score
I Kato et al.; (1999) [23]	colorectal cancer	US; Nested case-control	PB	105/; 523	HPLC; /Serum	F	66.2	Quartile; ≥12.21 vs ≤7.9	1.72 (0.83-3.57)	Adjusted for family history of colorectal cancer, beer intake, prior occult blood testing and number of hours spent in sport activities in their early 30s.	8
Pufuete et al. (2003) [24]	colorectal cancer	England; case-control	HB	28/; 76	FPIA; /Plasma	M/F	58	Top third vs bottom third	1.55 (0.21-11.16)	Adjusted for sex, age, body mass index, smoking, alcohol intake, MTHFR, MS, and CBS genotypes.	7
Van Guelpen, Hultdin,; Johansson et al. (2006) [19]	colorectal cancer	Sweden; Nested case-control	PB	226/; 437	FPIA; /Plasma	M/F	59.8	Quintile; Q5 vs Q1	1.12 (0.63-1.99)	Adjusted for body mass index, current smoking, recreational and occupational physical activity, and alcohol intake (alcohol data were available for approximately two thirds of subjects).	8
Stein Emil Vollset et al. (2007) [8]	gastric cancer	EPIC; Nested case-control	PB	245/; 631	GC-MS/; Plasma	M/F	62.2	Q5 vs Q1	0.87 (0.52-1.44)	Adjusted for Hp status, smoking, and energy in conditional logistic model with stratification on matched sets.	8
Lina Wang et al. (2007) [17]	gastric cancer	China; case-control	PB	306/; 615	enzymatic biochemical/; Plasma	M/F	60.6	Quartile; 13.6 vs ≤8.0	1.82 (1.20-2.75)	Adjusted for age, sex, smoking status, and alcohol consumption.	7
Weinstein et al. (2008) [20]	colorectal cancer	Finland; Nested case-control	PB	275/; 275	HPLC; /Serum	M	Colon:59.0 Rectal:58.0	Quintile; Q5 vs Q1; (18.8µmol/L vs 9.2µmol/L)	1.22 (0.68-2.17)	Adjusted for age at randomization, body mass index, occupational and leisure physical activity, and intakes of vitamin D and iron.	8
Marchand et al.; (2009) [25]	colorectal cancer	US; Nested case-control	PB	224/; 411	HPLC; /Plasma	M/F	70.5	Quartile; >11.8 vs ≤7.65	1.00 (0.56-1.79)	Adjusted for sex, ethnicity, study site, age at blood draw, fasting duration and date, time of blood draw, age at blood draw and hours of fasting prior to blood draw, hours of moderate or vigorous physical activity, processed meat, pack-years, BMI, ethanol, family history of colorectal cancer, history of colorectal cancer screening and plasma folate.	8
Miller et al.; (2013) [18]	colorectal cancer	US; Nested; case-control	PB	988/; 988	HPLC; /Plasma	F	67	Quartile; >9.85 vs ≤6.74	1.46 (1.05-2.04)	Adjusted for age, baseline BMI, ever had colonoscopy, smoking, physical activity (min/wk of moderate or strenuous activity), hormone replacement therapy, red blood cell folate, plasma vitamin B-12, and plasma pyridoxal-5#-phosphate.	8
F.-F. Chiang et al.; (2014) [26]	colorectal cancer	China; case-control	HB	168/; 188	HPLC; /Plasma	M/F	60.8	Higher vs lower	1.29 (1.14-1.47)	Adjusted for age, gender, body mass index, systolic blood pressure, creatinine, high sensitivity C-reactive protein, serum total cholesterol, smoking and drinking habits and B-vitamin supplement uses.	7
Gylling et al.; (2014) [27]	colorectal cancer	Sweden; Nested case-control	PB	331/; 662	GC-MS; /Plasma	M/F	59.7	Highest vs lowest	1.01 (0.72-1.43)	Adjusted for BMI, current smoking, recreational and occupational physical activity, and alcohol intake.	8
Fanidi et al.; (2014) [28]	esophagus cancer	EPIC; Nested case-control	PB	74/; 944	HPLC; /Plasma	M/F	62(all cases, including head, neck and esophagus)	Quartile; Q4 vs Q1	1.19 (0.51-2.77)	Adjusting for country, sex, age at recruitment (in 5-year groups), educational attainment (in four groups), smoking status (never/former/current/missing), cotinine (quartiles defined among current smokers) and alcohol intake at recruitment (g/day).	8
Chang et al.; (2015) [29]	gastric Cancer	China; case-control	PB	200/; 409	Chemiluminescent immunoassay/; Plasma	M/F	62.8	Quartile; 13.1 vs ≤6.7	1.12 (0.64-1.96)	Adjusted for age, gender, BMI, education, smoking pack-years, alcohol drinking frequency, H. pylori infection (in stomach cancer analyses), hepatitis B virus surface antigen (in liver cancer analyses), and plasma aflatoxin B1 levels (in liver cancer analyses); further adjusted for the other two plasma micronutrients in quintile distribution. (folate, vitamin B12)	7
Chang et al.; (2015) [29]	esophagus cancer	China; case-control	PB	206/; 409	Chemiluminescent immunoassay/; Plasma	M/F	60.5	Quartile; 13.1 vs ≤6.7	1.54 (0.87-2.72)	Adjusted for age, gender, BMI, education, smoking pack-years, alcohol drinking frequency, H. pylori infection (in stomach cancer analyses), hepatitis B virus surface antigen (in liver cancer analyses), and plasma aflatoxin B1 levels (in liver cancer analyses); further adjusted for the other two plasma micronutrients in quintile distribution. (folate, vitamin B12)	7
Miranti et al.; (2017) [30]	non-cardia gastric adenocarcinoma	Finland; Nested case-control	PB	127/; 326	HPLC; /Serum	M	58	Quartile; 15.6 vs  11.0	1.16 (0.63-2.13)	Adjusted for age, BMI, number of cigarettes smoked, years of cigarette smoking, educational attainment, alcohol consumption, energy intake, fruits and vegetables.	8
Miranti et al.; (2017) [30]	esophagogastric junctional adenocarcinoma	Finland; Nested case-control	PB	46/; 326	HPLC; /Serum	M	59	Quartile; 15.6 vs  11.0	0.85 (0.30-2.44)	Adjusted for age, BMI, number of cigarettes smoked, years of cigarette smoking, educational attainment, alcohol consumption, energy intake, fruits and vegetables.	8
Miranti et al.; (2017) [30]	esophageal squamous cell carcinoma	Finland; Nested case-control	PB	60/; 326	HPLC; /Serum	M	57	Quartile; 15.6 vs  11.0	1.35 (0.56-3.33)	Adjusted for age, BMI, number of cigarettes smoked, years of cigarette smoking, educational attainment, alcohol consumption, energy intake, fruits and vegetables.	8

Abbreviations: EPIC: the European Prospective Investigation into Cancer and Nutrition; vs: versus; M: male; F: female; PB: population-based; HB: hospital-based; HPLC: High Performance Liquid Chromatography; GC-MS: gas chromatography-mass spectrometry; FPIA: fluorescence polarization immunoassay.