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1Department of Preventive Medicine, Chonnam National University Medical School, Hwasun, Korea
2Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea
© 2023, Korean Society of Epidemiology
This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
CONFLICT OF INTEREST
The authors have no conflicts of interest to declare for this study.
FUNDING
This study was financially supported by Chonnam National University Hwasun Hospital (HCRI21019).
AUTHOR CONTRIBUTIONS
Conceptualization: Kweon SS. Data curation: Kweon SS, Shin MH. Formal analysis: Choi CK, Yang JH. Funding acquisition: Kweon SS. Methodology: Kweon SS, Choi CK. Writing – original draft: Kweon SS, Choi CK. Writing – review & editing: Kweon SS, Choi CK, Yang JH, Shin MH, Cho SH.
SNP | Chr | Nearby gene | Position1 | EA | RA |
CRP GWAS2 |
CRC GWAS3 |
|||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
EAF | F | Beta | p-value | EAF | Overall mortality HD (/1,000 PY) | p-value | CRC mortality HD (/1,000 PY) | p-value | ||||||
rs2794520 | 1 | CRP | 159678816 | C | T | 0.365 | 961.9 | 0.247 | 7.23×10-200 | 0.366 | -0.230 | 0.887 | 0.018 | 0.989 |
rs12133641 | 1 | IL6R | 154428283 | G | A | 0.433 | 197.0 | -0.116 | 3.52×10-47 | 0.429 | -1.860 | 0.210 | -0.454 | 0.701 |
rs71086917 | 1 | LINC02819 | 159455503 | insA | - | 0.452 | 61.2 | -0.064 | 6.54×10-16 | 0.414 | 0.127 | 0.938 | 0.934 | 0.493 |
rs1260326 | 2 | GCKR | 27730940 | C | T | 0.450 | 133.0 | -0.090 | 1.31×10-29 | 0.452 | 3.017 | 0.050 | 1.535 | 0.201 |
rs7383869 | 7 | IL6 | 22748190 | A | G | 0.362 | 164.1 | 0.105 | 3.53×10-37 | 0.365 | 0.571 | 0.693 | 0.562 | 0.620 |
rs79320731 | 12 | HNF1A | 121422449 | CTGACTGGCACTCAGCA | T | 0.455 | 461.1 | -0.169 | 1.22×10-99 | 0.454 | -0.929 | 0.530 | -1.999 | 0.095 |
rs429358 | 19 | APOE | 45411941 | C | T | 0.096 | 587.6 | -0.321 | 3.53×10-125 | 0.057 | 8.684 | 0.011 | 7.331 | 0.014 |
SNP, single-nucleotide polymorphism; CRP, C-reactive protein; Chr, chromosome; CRC, colorectal cancer; EA, effective allele; EAF, effective allele frequency; GWAS, genome-wide association study; HD, hazard difference; PY, person-year; RA, reference allele.
1 The positions of the SNPs were derived from GRCh37.
2 Age, sex, study centers, survey years, and first 10 principal components were adjusted in all models.
3 Age, sex, genotyping array, tumor, node, metastasis stage, and first 10 principal components were adjusted in all models.
Variables |
Main analysis (7 serum CRP level-related SNPs) |
Sensitivity analysis (excluding rs429358) |
|||||||
---|---|---|---|---|---|---|---|---|---|
Overall mortality | p-value | CRC-specific | p-value | Overall mortality | p-value | CRC-specific mortality | p-value | ||
Using summary statistics1 | |||||||||
IVW | -2.92 (-14.05, 8.21) | 0.607 | -0.76 (-9.61, 8.08) | 0.866 | 1.11 (-8.18, 10.40) | 0.815 | 2.40 (-4.51, 9.31) | 0.497 | |
Simple median | -0.93 (-13.67, 11.81) | 0.886 | 0.07 (-10.64, 10.78) | 0.989 | 2.25 (-9.74, 14.24) | 0.713 | 2.00 (-7.80, 11.80) | 0.689 | |
Weighted median | 1.43 (-8.96, 11.81) | 0.788 | 1.70 (-7.00, 10.41) | 0.701 | 3.39 (-7.00, 13.78) | 0.523 | 2.71 (-5.97, 11.39) | 0.540 | |
MR-Egger intercept | 0.92 (-3.29, 5.12) | 0.669 | 0.27 (-3.11, 3.65) | 0.876 | -0.57 (-4.21, 3.08) | 0.760 | -1.02 (-3.52, 1.49) | 0.426 | |
Using individual GRS2 | |||||||||
GRS per 1 SD increment | -3.18 (-5.77, -0.59) | 0.016 | -2.09 (-4.26, 0.08) | 0.056 | 0.17 (-1.82, 2.16) | 0.870 | 0.11 (-1.49, 1.70) | 0.897 | |
GRS quintile | |||||||||
1st | 8.53 (1.12, 15.94) | 0.024 | 5.51 (-0.71, 11.73) | 0.082 | 1.94 (-4.47, 8.34) | 0.554 | 2.39 (-2.17, 6.95) | 0.349 | |
2nd | 1.86 (-5.16, 8.88) | 0.603 | 1.04 (-4.85, 6.93) | 0.730 | -2.15 (-8.56, 4.27) | 0.512 | -1.41 (-5.96, 3.14) | 0.598 | |
3rd | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | |||||
4th | -2.64 (-9.13, 3.85) | 0.425 | -1.54 (-6.68, 3.60) | 0.557 | -0.52 (-6.74, 5.70) | 0.870 | -2.06 (-6.53, 2.40) | 0.417 | |
5th | 1.14 (-5.17, 7.45) | 0.723 | 0.99 (-4.12, 6.09) | 0.705 | 2.00 (-4.45, 8.45) | 0.554 | 3.16 (-1.45, 7.77) | 0.229 |
Values are presented as hazard difference per 1,000 person-year (95% confidence interval).
CRC, colorectal cancer; CRP, C-reactive protein; GRS, genetic risk score; IVW, inverse-variance weighted method; SD, standard deviation; SNP, single-nucleotide polymorphism.
1 Results are expressed per 2-fold increase in serum CRP levels.
2 Age, sex, genotyping array, and tumor, node, metastasis stage were adjusted.
Variables |
Non-metastatic CRC |
Metastatic CRC |
|||||||
---|---|---|---|---|---|---|---|---|---|
Overall mortality | p-value | CRC-specific mortality | p-value | Overall mortality | p-value | CRC-specific mortality | p-value | ||
Using summary statistics1 | |||||||||
IVW | 1.73 (-6.95, 10.41) | 0.697 | 3.37 (-3.41, 10.15) | 0.330 | -27.69 (-95.81, 40.43) | 0.426 | -28.19 (-91.79, 35.42) | 0.385 | |
Simple median | 3.57 (-6.96, 14.09) | 0.506 | 2.96 (-5.93, 11.85) | 0.514 | -24.08 (-121.25, 73.10) | 0.627 | 8.90 (-85.99, 103.79) | 0.854 | |
Weighted median | 4.73 (-3.69, 13.16) | 0.271 | 5.11 (-1.29, 11.51) | 0.117 | -42.26 (-125.36, 40.83) | 0.319 | -30.04 (-108.51, 48.43) | 0.453 | |
MR-Egger intercept | 0.04 (-3.37, 3.44) | 0.984 | -0.68 (-3.24, 1.89) | 0.605 | 12.62 (-10.94, 36.18) | 0.294 | 12.53 (-9.56, 34.62) | 0.266 | |
Using individual GRS2 | |||||||||
GRS per 1 SD increment | -1.74 (-3.95, 0.46) | 0.121 | -0.45 (-2.20, 1.30) | 0.613 | -18.65 (-42.48, 5.17) | 0.125 | -22.65 (-45.57, 0.27) | 0.053 | |
GRS quintile | |||||||||
1st | 3.00 (-3.48, 9.49) | 0.364 | 0.37 (-4.51, 5.26) | 0.881 | 61.88 (-5.52, 129.29) | 0.072 | 60.52 (-4.77, 125.81) | 0.069 | |
2nd | -2.96 (-8.76, 2.84) | 0.317 | -3.08 (-7.39, 1.22) | 0.160 | 45.84 (-14.95, 106.64) | 0.139 | 37.64 (-21.03, 96.31) | 0.209 | |
3rd | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | |||||
4th | -0.76 (-6.00, 4.49) | 0.778 | 0.61 (-3.21, 4.43) | 0.755 | -31.00 (-80.02, 18.02) | 0.215 | -30.44 (-72.34,11.46) | 0.155 | |
5th | -0.87 (-6.38, 4.65) | 0.758 | -0.07 (-3.94, 3.80) | 0.972 | 17.10 (-35.25, 69.44) | 0.522 | 2.43 (-43.66, 48.53) | 0.918 |
Values are presented as hazard difference per 1,000 person-year (95% confidence interval).
CRC, colorectal cancer; CRP, C-reactive protein; GRS, genetic risk score; IVW, inverse-variance weighted method; SD, standard deviation.
1 Results are expressed per 2-fold increase in serum CRP levels.
2 Age, sex, and genotyping array were adjusted.
SNP | Chr | Nearby gene | Position |
EA | RA | CRP GWAS |
CRC GWAS |
|||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
EAF | F | Beta | p-value | EAF | Overall mortality HD (/1,000 PY) | p-value | CRC mortality HD (/1,000 PY) | p-value | ||||||
rs2794520 | 1 | CRP | 159678816 | C | T | 0.365 | 961.9 | 0.247 | 7.23×10-200 | 0.366 | -0.230 | 0.887 | 0.018 | 0.989 |
rs12133641 | 1 | IL6R | 154428283 | G | A | 0.433 | 197.0 | -0.116 | 3.52×10-47 | 0.429 | -1.860 | 0.210 | -0.454 | 0.701 |
rs71086917 | 1 | LINC02819 | 159455503 | insA | - | 0.452 | 61.2 | -0.064 | 6.54×10-16 | 0.414 | 0.127 | 0.938 | 0.934 | 0.493 |
rs1260326 | 2 | GCKR | 27730940 | C | T | 0.450 | 133.0 | -0.090 | 1.31×10-29 | 0.452 | 3.017 | 0.050 | 1.535 | 0.201 |
rs7383869 | 7 | IL6 | 22748190 | A | G | 0.362 | 164.1 | 0.105 | 3.53×10-37 | 0.365 | 0.571 | 0.693 | 0.562 | 0.620 |
rs79320731 | 12 | HNF1A | 121422449 | CTGACTGGCACTCAGCA | T | 0.455 | 461.1 | -0.169 | 1.22×10-99 | 0.454 | -0.929 | 0.530 | -1.999 | 0.095 |
rs429358 | 19 | APOE | 45411941 | C | T | 0.096 | 587.6 | -0.321 | 3.53×10-125 | 0.057 | 8.684 | 0.011 | 7.331 | 0.014 |
Variables | Main analysis (7 serum CRP level-related SNPs) |
Sensitivity analysis (excluding rs429358) |
|||||||
---|---|---|---|---|---|---|---|---|---|
Overall mortality | p-value | CRC-specific | p-value | Overall mortality | p-value | CRC-specific mortality | p-value | ||
Using summary statistics |
|||||||||
IVW | -2.92 (-14.05, 8.21) | 0.607 | -0.76 (-9.61, 8.08) | 0.866 | 1.11 (-8.18, 10.40) | 0.815 | 2.40 (-4.51, 9.31) | 0.497 | |
Simple median | -0.93 (-13.67, 11.81) | 0.886 | 0.07 (-10.64, 10.78) | 0.989 | 2.25 (-9.74, 14.24) | 0.713 | 2.00 (-7.80, 11.80) | 0.689 | |
Weighted median | 1.43 (-8.96, 11.81) | 0.788 | 1.70 (-7.00, 10.41) | 0.701 | 3.39 (-7.00, 13.78) | 0.523 | 2.71 (-5.97, 11.39) | 0.540 | |
MR-Egger intercept | 0.92 (-3.29, 5.12) | 0.669 | 0.27 (-3.11, 3.65) | 0.876 | -0.57 (-4.21, 3.08) | 0.760 | -1.02 (-3.52, 1.49) | 0.426 | |
Using individual GRS |
|||||||||
GRS per 1 SD increment | -3.18 (-5.77, -0.59) | 0.016 | -2.09 (-4.26, 0.08) | 0.056 | 0.17 (-1.82, 2.16) | 0.870 | 0.11 (-1.49, 1.70) | 0.897 | |
GRS quintile | |||||||||
1st | 8.53 (1.12, 15.94) | 0.024 | 5.51 (-0.71, 11.73) | 0.082 | 1.94 (-4.47, 8.34) | 0.554 | 2.39 (-2.17, 6.95) | 0.349 | |
2nd | 1.86 (-5.16, 8.88) | 0.603 | 1.04 (-4.85, 6.93) | 0.730 | -2.15 (-8.56, 4.27) | 0.512 | -1.41 (-5.96, 3.14) | 0.598 | |
3rd | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | |||||
4th | -2.64 (-9.13, 3.85) | 0.425 | -1.54 (-6.68, 3.60) | 0.557 | -0.52 (-6.74, 5.70) | 0.870 | -2.06 (-6.53, 2.40) | 0.417 | |
5th | 1.14 (-5.17, 7.45) | 0.723 | 0.99 (-4.12, 6.09) | 0.705 | 2.00 (-4.45, 8.45) | 0.554 | 3.16 (-1.45, 7.77) | 0.229 |
Variables | Non-metastatic CRC |
Metastatic CRC |
|||||||
---|---|---|---|---|---|---|---|---|---|
Overall mortality | p-value | CRC-specific mortality | p-value | Overall mortality | p-value | CRC-specific mortality | p-value | ||
Using summary statistics |
|||||||||
IVW | 1.73 (-6.95, 10.41) | 0.697 | 3.37 (-3.41, 10.15) | 0.330 | -27.69 (-95.81, 40.43) | 0.426 | -28.19 (-91.79, 35.42) | 0.385 | |
Simple median | 3.57 (-6.96, 14.09) | 0.506 | 2.96 (-5.93, 11.85) | 0.514 | -24.08 (-121.25, 73.10) | 0.627 | 8.90 (-85.99, 103.79) | 0.854 | |
Weighted median | 4.73 (-3.69, 13.16) | 0.271 | 5.11 (-1.29, 11.51) | 0.117 | -42.26 (-125.36, 40.83) | 0.319 | -30.04 (-108.51, 48.43) | 0.453 | |
MR-Egger intercept | 0.04 (-3.37, 3.44) | 0.984 | -0.68 (-3.24, 1.89) | 0.605 | 12.62 (-10.94, 36.18) | 0.294 | 12.53 (-9.56, 34.62) | 0.266 | |
Using individual GRS |
|||||||||
GRS per 1 SD increment | -1.74 (-3.95, 0.46) | 0.121 | -0.45 (-2.20, 1.30) | 0.613 | -18.65 (-42.48, 5.17) | 0.125 | -22.65 (-45.57, 0.27) | 0.053 | |
GRS quintile | |||||||||
1st | 3.00 (-3.48, 9.49) | 0.364 | 0.37 (-4.51, 5.26) | 0.881 | 61.88 (-5.52, 129.29) | 0.072 | 60.52 (-4.77, 125.81) | 0.069 | |
2nd | -2.96 (-8.76, 2.84) | 0.317 | -3.08 (-7.39, 1.22) | 0.160 | 45.84 (-14.95, 106.64) | 0.139 | 37.64 (-21.03, 96.31) | 0.209 | |
3rd | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | |||||
4th | -0.76 (-6.00, 4.49) | 0.778 | 0.61 (-3.21, 4.43) | 0.755 | -31.00 (-80.02, 18.02) | 0.215 | -30.44 (-72.34,11.46) | 0.155 | |
5th | -0.87 (-6.38, 4.65) | 0.758 | -0.07 (-3.94, 3.80) | 0.972 | 17.10 (-35.25, 69.44) | 0.522 | 2.43 (-43.66, 48.53) | 0.918 |
SNP, single-nucleotide polymorphism; CRP, C-reactive protein; Chr, chromosome; CRC, colorectal cancer; EA, effective allele; EAF, effective allele frequency; GWAS, genome-wide association study; HD, hazard difference; PY, person-year; RA, reference allele. The positions of the SNPs were derived from GRCh37. Age, sex, study centers, survey years, and first 10 principal components were adjusted in all models. Age, sex, genotyping array, tumor, node, metastasis stage, and first 10 principal components were adjusted in all models.
Values are presented as hazard difference per 1,000 person-year (95% confidence interval). CRC, colorectal cancer; CRP, C-reactive protein; GRS, genetic risk score; IVW, inverse-variance weighted method; SD, standard deviation; SNP, single-nucleotide polymorphism. Results are expressed per 2-fold increase in serum CRP levels. Age, sex, genotyping array, and tumor, node, metastasis stage were adjusted.
Values are presented as hazard difference per 1,000 person-year (95% confidence interval). CRC, colorectal cancer; CRP, C-reactive protein; GRS, genetic risk score; IVW, inverse-variance weighted method; SD, standard deviation. Results are expressed per 2-fold increase in serum CRP levels. Age, sex, and genotyping array were adjusted.