01.12.2017 | Research article | Ausgabe 1/2017 Open Access

Effect of genetic variants and traits related to glucose metabolism and their interaction with obesity on breast and colorectal cancer risk among postmenopausal women
- Zeitschrift:
- BMC Cancer > Ausgabe 1/2017
Electronic supplementary material
Background
Methods
Study population
Data collection and outcome variables
Characteristic
|
Non-obese group (BMI < 30.0)
|
Obese group (BMI ≥ 30.0)
|
||
---|---|---|---|---|
(
n = 3675)
|
(
n = 1704)
|
|||
n
|
(%)
|
n
|
(%)
|
|
Age in years, median (range)
|
68
|
(50–79)
|
67
|
(50–71)*
|
Education
|
||||
≤ High school
|
1272
|
(34.6)
|
701
|
(41.1)*
|
> High school
|
2403
|
(65.4)
|
1003
|
(58.9)
|
Family history of diabetes mellitus
|
||||
No
|
2714
|
(73.9)
|
1122
|
(65.8)*
|
Yes
|
961
|
(26.1)
|
582
|
(34.2)
|
Family history of cancer
|
||||
No
|
1327
|
(36.1)
|
567
|
(33.3)
|
Yes
|
2348
|
(63.9)
|
1137
|
(66.7)
|
Family history of breast cancer
|
||||
No
|
3070
|
(83.5)
|
1428
|
(83.8)
|
Yes
|
605
|
(16.5)
|
276
|
(16.2)
|
Family history of colorectal cancer
|
||||
No
|
3106
|
(84.5)
|
1430
|
(83.9)
|
Yes
|
569
|
(15.5)
|
274
|
(16.1)
|
Cardiovascular disease ever
|
||||
No
|
3161
|
(86.0)
|
1430
|
(83.9)
|
Yes
|
514
|
(14.0)
|
274
|
(16.1)
|
Hypertension ever
|
||||
No
|
2702
|
(73.5)
|
1026
|
(60.2)*
|
Yes
|
973
|
(26.5)
|
678
|
(39.8)
|
High cholesterol requiring pills ever
|
||||
No
|
3178
|
(86.5)
|
1460
|
(85.7)
|
Yes
|
497
|
(13.5)
|
244
|
(14.3)
|
Smoking status
|
||||
Never
|
1882
|
(51.2)
|
897
|
(52.6)*
|
Past
|
1498
|
(40.8)
|
705
|
(41.4)
|
Current
|
295
|
(8.0)
|
102
|
(6.0)
|
Lifetime partner
|
||||
Have never had sex
|
56
|
(1.5)
|
38
|
(2.2)
|
Have had sex
|
3619
|
(98.5)
|
1666
|
(97.8)
|
Depressive symptom
a
|
||||
< 0.06
|
3392
|
(92.3)
|
1556
|
(91.3)
|
≥ 0.06
|
283
|
(7.7)
|
148
|
(8.7)
|
METs·hour·week
-1 b
|
||||
< 10
|
1875
|
(51.0)
|
1160
|
(68.1)*
|
≥ 10
|
1800
|
(49.0)
|
544
|
(31.9)
|
Total HEI-2005 score, median (range)
c
|
68.7
|
(25.8–90.8)
|
65.7
|
(27.9–91.2)*
|
Dietary total sugars in g, median (range)
|
91.6
|
(4.6–350.2)
|
94.9
|
(10.8–474.5)*
|
Dietary alcohol per day in g, median (range)
|
1.506
|
(0.0–106.7)
|
0.561
|
(0.0–148.6)*
|
% calories from fat
d
|
||||
< 40%
|
3057
|
(83.2)
|
1268
|
(74.4)*
|
≥ 40%
|
618
|
(16.8)
|
436
|
(25.6)
|
Waist circumference in cm, median (range)
|
81.0
|
(37.5–177.0)
|
100.0
|
(69.0–191.8)*
|
Waist-to-hip ratio, median (range)
|
0.798
|
(0.341–1.893)
|
0.849
|
(0.633–1.696)*
|
Oral contraceptive use
|
||||
Never
|
2448
|
(66.6)
|
1123
|
(65.9)
|
Ever
|
1227
|
(33.4)
|
581
|
(34.1)
|
History of hysterectomy or oophorectomy
|
||||
No
|
2457
|
(66.9)
|
1006
|
(59.0)*
|
Yes
|
1218
|
(33.1)
|
698
|
(41.0)
|
Age at menarche in years, median (range)
|
13
|
(≤ 9–≥ 17)
|
12
|
(≤ 9–≥ 17)*
|
Age at menopause in years, median (range)
|
50
|
(20–60)
|
50
|
(21–60)
|
Pregnancy history
|
||||
No
|
276
|
(7.5)
|
134
|
(7.9)
|
Yes
|
3399
|
(92.5)
|
1570
|
(92.1)
|
Breastfeeding at least one month
|
||||
No
|
1649
|
(44.9)
|
812
|
(47.7)
|
Yes
|
2026
|
(55.1)
|
892
|
(52.3)
|
Exogenous estrogen use
|
||||
No
|
2224
|
(60.5)
|
1122
|
(65.8)*
|
Yes
|
1451
|
(39.5)
|
582
|
(34.2)
|
Glucose in mg/dl, median (range)
|
92.0
|
(39.0–369.0)
|
97.0
|
(62.0–347.0)*
|
Insulin in μIU/ml, median (range)
|
5.5
|
(0.5–119.4)
|
9.8
|
(0.3–57.0)*
|
HOMA-IR, median (range)
|
1.3
|
(0.1–25.1)
|
2.4
|
(0.1–42.3)*
|
Genotyping and laboratory methods
Statistical analysis
Results
Breast cancer risk associated with glucose metabolism-related SNPs mediated through glucose metabolism traits, stratified by obesity status (BMI, waist, and w/h), level of physical activity, and dietary fat intake
SNP
|
Nearest gene
|
Effect allele/Other allele
|
Favorable Energy Balance Group
|
Unfavorable Energy Balance Group
|
||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Direct effect
|
Indirect effect
|
Total effect
|
Direct effect
|
Indirect effect
|
Total effect
|
|||||||||
Breast cancer risk in relation to SNP through pathways other than
glucose
|
Breast cancer risk in relation to SNP through
glucose
|
Breast cancer risk in relation to SNP
|
Breast cancer risk in relation to SNP through pathways other than
glucose
|
Breast cancer risk in relation to SNP through
glucose
|
Breast cancer risk in relation to SNP
|
|||||||||
HR
a
|
95% CI
|
Effect size
a
|
95% CI
|
HR
a
|
95% CI
|
HR
a
|
95% CI
|
Effect size
a
|
95% CI
|
HR
a
|
95% CI
|
|||
BMI
b
|
||||||||||||||
rs560887
|
G6PC2
|
T/C
|
1.11
|
(0.89–1.39)
|
0.01
|
(−0.04
–0.02)
|
1.12
|
(0.90–1.39)
|
1.34
|
(1.04–1.73)
|
−0.004
|
(−0.01
–0.02)
|
1.35
|
(1.05–1.74)
|
Waist
c
|
||||||||||||||
rs560887
|
G6PC2
|
T/C
|
1.09
|
(0.85–1.39)
|
0.004
|
(−0.02–0.01)
|
1.10
|
(0.86–1.40)
|
1.35
|
(1.07–1.70)
|
−0.01
|
(−0.01–0.02)
|
1.33
|
(1.06–1.66)
|
w/h Ratio
d
|
||||||||||||||
rs560887
|
G6PC2
|
T/C
|
1.07
|
(0.89–1.39)
|
0.01
|
(−0.03–0.01)
|
1.10
|
(0.89–1.36)
|
1.47
|
(1.13–1.92)
|
−0.003
|
(−0.003–0.01)
|
1.42
|
(1.10–1.85)
|
rs780094
|
GCKR
|
C/T
|
1.01
|
(0.82–1.23)
|
−0.01
|
(−0.03–0.01)
|
1.02
|
(0.84–1.24)
|
1.33
|
(1.00–1.76)
|
0.002
|
(−0.003–0.01)
|
1.22
|
(0.93–1.60)
|
rs35767
|
IGF1
|
A/G
|
0.91
|
(0.68–1.21)
|
0.002
|
(−0.01–0.004)
|
0.93
|
(0.70–1.23)
|
1.43
|
(1.03–1.98)
|
<0.001
|
(−0.004–0.004)
|
1.48
|
(1.08–2.03)
|
Dietary fat intake
e
|
||||||||||||||
rs560887
|
G6PC2
|
T/C
|
1.14
|
(0.95–1.37)
|
−0.01
|
(−0.003–0.02)
|
1.14
|
(0.95–1.37)
|
1.56
|
(1.07–2.28)
|
0.02
|
(−0.07–0.03)
|
1.59
|
(1.10–2.31)
|
SNP
|
Nearest gene
|
Effect allele/Other allele
|
Favorable Energy Balance Group
|
Unfavorable Energy Balance Group
|
||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Direct effect
|
Indirect effect
|
Total effect
|
Direct effect
|
Indirect effect
|
Total effect
|
|||||||||
Breast cancer risk in relation to SNP through pathways other than
HOMA-IR
|
Breast cancer risk in relation to SNP through
HOMA-IR
|
Breast cancer risk in relation to SNP
|
Breast cancer risk in relation to SNP through pathways other than
HOMA-IR
|
Breast cancer risk in relation to SNP through
HOMA-IR
|
Breast cancer risk in relation to SNP
|
|||||||||
HR
a
|
95% CI
|
Effect size
a
|
95% CI
|
HR
a
|
95% CI
|
HR
a
|
95% CI
|
Effect size
a
|
95% CI
|
HR
a
|
95% CI
|
|||
BMI
b
|
||||||||||||||
rs560887
|
G6PC2
|
T/C
|
1.17
|
(0.93–1.46)
|
<0.001
|
(−0.003
–0.003)
|
1.12
|
(0.90–1.39)
|
1.35
|
(1.04–1.76)
|
<0.001
|
(−0.02
–0.02)
|
1.35
|
(1.05–1.74)
|
Waist
c
|
||||||||||||||
rs560887
|
G6PC2
|
T/C
|
1.11
|
(0.86–1.42)
|
−0.003
|
(−0.01–0.01)
|
1.10
|
(0.86–1.40)
|
1.39
|
(1.10–1.77)
|
−0.002
|
(−0.01–0.01)
|
1.33
|
(1.06–1.66)
|
Waist/hip Ratio
d
|
||||||||||||||
rs560887
|
G6PC2
|
T/C
|
1.11
|
(0.72–1.12)
|
0.001
|
(−0.01–0.004)
|
1.10
|
(0.89–1.36)
|
1.50
|
(1.14–1.97)
|
−0.001
|
(−0.01–0.01)
|
1.42
|
(1.10–1.85)
|
rs35767
|
IGF1
|
A/G
|
0.92
|
(0.69–1.24)
|
0.001
|
(−0.01–0.003)
|
0.93
|
(0.70–1.23)
|
1.42
|
(1.02–1.98)
|
−0.002
|
(−0.01–0.01)
|
1.48
|
(1.08–2.03)
|
Dietary fat intake
e
|
||||||||||||||
rs560887
|
G6PC2
|
T/C
|
1.16
|
(0.96–1.41)
|
0.01
|
(−0.01–0.003)
|
1.14
|
(0.95–1.37)
|
1.59
|
(1.08–2.34)
|
0.003
|
(−0.02–0.02)
|
1.59
|
(1.10–2.31)
|
CRC risk associated with glucose metabolism-related SNPs mediated through glucose metabolism traits, stratified by obesity status (BMI, waist, and w/h), level of physical activity, and dietary fat intake
SNP
|
Nearest gene
|
Favorable Energy Balance Group
|
Unfavorable Energy Balance Group
|
|||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Direct effect
|
Indirect effect
|
Total effect
|
Direct effect
|
Indirect effect
|
Total effect
|
|||||||||
Effect allele/Other allele
|
CRC risk in relation to SNP through pathways other than
glucose
|
CRC risk in relation to SNP through
glucose
|
CRC risk in relation to SNP
|
CRC risk in relation to SNP through pathways other than
glucose
|
CRC risk in relation to SNP through
glucose
|
CRC risk in relation to SNP
|
||||||||
HR
a
|
95% CI
|
Effect size
a
|
95% CI
|
HR
a
|
95% CI
|
HR
a
|
95% CI
|
Effect size
a
|
95% CI
|
HR
a
|
95% CI
|
|||
BMI
b
|
||||||||||||||
rs4607517
|
GCK
|
G/A
|
0.79
|
(0.60–1.02)
|
0.02
|
(0.002–0.04)
|
0.80
|
(0.64–1.00)
|
1.00
|
(0.65–1.55)
|
0.001
|
(−0.01
–0.01)
|
1.06
|
(0.75–1.51)
|
rs174550
|
FADS1
|
T/C
|
1.15
|
(0.92–1.43)
|
−0.002
|
(−0.01
–0.01)
|
1.05
|
(0.87–1.27)
|
1.40
|
(0.97–2.03)
|
<0.001
|
(−0.01
–0.01)
|
1.37
|
(1.02–1.83)
|
rs11605924
|
CRY2
|
C/A
|
0.89
|
(0.73–1.09)
|
−0.004
|
(−0.01
–0.02)
|
0.82
|
(0.69–0.98)
|
1.32
|
(0.94–1.85)
|
<0.001
|
(−0.004
–0.004)
|
1.07
|
(0.82–1.39)
|
Waist
c
|
||||||||||||||
rs560887
|
G6PC2
|
T/C
|
0.75
|
(0.58–
0.99)
|
0.01
|
(−0.03
–0.004)
|
0.88
|
(0.70
–1.11)
|
1.00
|
(0.75
–1.34)
|
0.01
|
(−0.04
–0.02)
|
1.01
|
(0.80
–1.27)
|
rs174550
|
FADS1
|
T/C
|
1.17
|
(0.91–1.51)
|
−0.01
|
(−0.02–0.01)
|
1.03
|
(0.83–1.28)
|
1.23
|
(0.93–1.63)
|
0.01
|
(−0.01–0.02)
|
1.25
|
(1.00–1.57)
|
rs11605924
|
CRY2
|
C/A
|
0.84
|
(0.67–1.06)
|
−0.01
|
(−0.01–0.02)
|
0.81
|
(0.66–0.99)
|
1.20
|
(0.92–1.56)
|
0.004
|
(−0.02–0.01)
|
0.97
|
(0.79–1.20)
|
w/h Ratio
d
|
||||||||||||||
rs10885122
|
ADRA2A
|
G/T
|
0.80
|
(0.59–1.07)
|
−0.002
|
(−0.01–0.01)
|
0.84
|
(0.64–1.08)
|
1.36
|
(0.81–2.30)
|
<0.001
|
(−0.003–0.003)
|
1.58
|
(1.01–2.48)
|
Physical activity level
e
|
||||||||||||||
rs4607517
|
GCK
|
G/A
|
0.73
|
(0.52–1.00)
|
0.01
|
(−0.01–0.04)
|
0.72
|
(0.55–0.95)
|
0.95
|
(0.70–1.31)
|
0.01
|
(−0.01–0.02)
|
0.99
|
(0.76–1.28)
|
Dietary fat intake
f
|
||||||||||||||
rs4607517
|
GCK
|
G/A
|
0.91
|
(0.71–1.17)
|
0.01
|
(−0.004–0.03)
|
0.94
|
(0.76–1.17)
|
0.57
|
(0.33–1.01)
|
−0.003
|
(−0.01–0.01)
|
0.66
|
(0.43–1.00)
|
rs11558471
|
SLC30A8
|
A/G
|
1.07
|
(0.87–1.31)
|
−0.02
|
(−0.04–0.004)
|
0.95
|
(0.80–1.12)
|
1.60
|
(0.93–2.75)
|
−0.002
|
(−0.01–0.01)
|
1.60
|
(1.07–2.40)
|
SNP
|
Nearest gene
|
Effect allele/ Other allele
|
Favorable Energy Balance Group
|
Unfavorable Energy Balance Group
|
||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Direct effect
|
Indirect effect
|
Total effect
|
Direct effect
|
Indirect effect
|
Total effect
|
|||||||||
CRC risk in relation to SNP through pathways other than
HOMA-IR
|
CRC risk in relation to SNP through
HOMA-IR
|
CRC risk in relation to SNP
|
CRC risk in relation to SNP through pathways other than
HOMA-IR
|
CRC risk in relation to SNP through
HOMA-IR
|
CRC risk in relation to SNP
|
|||||||||
HR
a
|
95% CI
|
Effect size
a
|
95% CI
|
HR
a
|
95% CI
|
HR
a
|
95% CI
|
Effect size
a
|
95% CI
|
HR
a
|
95% CI
|
|||
BMI
b
|
||||||||||||||
rs2191349
|
DGKB/TMEM195
|
G/T
|
1.04
|
(0.84–1.28)
|
<0.001
|
(−0.004
–0.004)
|
1.07
|
(0.90–1.28)
|
1.45
|
(1.03–2.03)
|
<0.001
|
(−0.003
–0.003)
|
1.17
|
(0.90–1.52)
|
rs4607517
|
GCK
|
G/A
|
0.79
|
(0.61–1.03)
|
<0.001
|
(−0.01–0.01)
|
0.80
|
(0.64–1.00)
|
1.04
|
(0.66–1.62)
|
<0.001
|
(−0.004
–0.003)
|
1.06
|
(0.75–1.51)
|
rs174550
|
FADS1
|
T/C
|
1.16
|
(0.93–1.45)
|
<0.001
|
(−0.001
–0.001)
|
1.05
|
(0.87–1.27)
|
1.40
|
(0.96–2.04)
|
−0.01
|
(−0.02
–0.01)
|
1.37
|
(1.02–1.83)
|
rs11605924
|
CRY2
|
C/A
|
0.87
|
(0.71–1.07)
|
<0.001
|
(−0.01–0.01)
|
0.82
|
(0.69–0.98)
|
1.32
|
(0.93–1.87)
|
<0.001
|
(−0.003
–0.003)
|
1.07
|
(0.82–1.39)
|
Waist
c
|
||||||||||||||
rs2191349
|
DGKB/TMEM195
|
G/T
|
0.97
|
(0.76–1.23)
|
0.002
|
(−0.01–0.01)
|
1.00
|
(0.81–1.23)
|
1.37
|
(1.05–1.79)
|
−0.002
|
(−0.004–0.01)
|
1.20
|
(0.97–1.48)
|
rs174550
|
FADS1
|
T/C
|
1.22
|
(0.94–1.58)
|
−0.002
|
(−0.01–0.01)
|
1.03
|
(0.83–1.28)
|
1.24
|
(0.93–1.65)
|
−0.01
|
(−0.02–0.002)
|
1.25
|
(1.00–1.57)
|
rs11605924
|
CRY2
|
C/A
|
0.84
|
(0.67–1.06)
|
<0.001
|
(−0.01–0.01)
|
0.81
|
(0.66–0.99)
|
1.17
|
(0.90–1.54)
|
<0.001
|
(−0.01–0.01)
|
0.97
|
(0.79–1.20)
|
Waist/hip Ratio
d
|
||||||||||||||
rs2191349
|
DGKB/TMEM195
|
G/T
|
1.04
|
(0.84–1.29)
|
0.003
|
(−0.01–0.004)
|
1.03
|
(0.86–1.23)
|
1.38
|
(1.00–1.89)
|
<0.001
|
(−0.01–0.01)
|
1.24
|
(0.97–1.59)
|
rs10885122
|
ADRA2A
|
G/T
|
0.78
|
(0.58–1.05)
|
<0.001
|
(−0.01–0.01)
|
0.84
|
(0.64–1.08)
|
1.31
|
(0.77–2.20)
|
<0.001
|
(−0.01–0.01)
|
1.58
|
(1.01–2.48)
|
rs174550
|
FADS1
|
T/C
|
1.15
|
(0.92–1.45)
|
0.002
|
(−0.004–0.01)
|
1.08
|
(0.89–1.30)
|
1.43
|
(1.01–2.03)
|
−0.008
|
(−0.02–0.004)
|
1.27
|
(0.97–1.66)
|
Physical activity level
e
|
||||||||||||||
rs4607517
|
GCK
|
G/A
|
0.73
|
(0.52–1.01)
|
<0.001
|
(−0.003–0.003)
|
0.72
|
(0.55–0.95)
|
0.95
|
(0.69–1.31)
|
−0.001
|
(−0.01–0.004)
|
0.99
|
(0.76–1.28)
|
Dietary fat intake
f
|
||||||||||||||
rs4607517
|
GCK
|
G/A
|
0.92
|
(0.72–1.18)
|
<0.001
|
(−0.01–0.004)
|
0.94
|
(0.76–1.17)
|
0.58
|
(0.33–1.03)
|
−0.001
|
(−0.01–0.001)
|
0.66
|
(0.43–1.00)
|
rs11558471
|
SLC30A8
|
A/G
|
1.08
|
(0.88–1.33)
|
<0.001
|
(−0.01–0.01)
|
0.95
|
(0.80–1.12)
|
1.64
|
(0.94–2.85)
|
−0.003
|
(−0.01–0.01)
|
1.60
|
(1.07–2.40)
|