Table 3. Effect of Metabolic Biomarker Levels on the relationship between IGF-I/IR signaling pathways–relevant SNPs (in IRS1 gene) and CRC risk, stratified by selected lifestyle factors‡.
| SNP_¥ | Effect allele/Other allele | Active or Nonuser Group | Inactive or User Group | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CRC risk in relation to SNP | CRC risk in relation to SNP adjusted by biomarker | Proportion of relationship between CRC and SNP explained by biomarker * | CRC risk in relation to SNP | CRC risk in relation to SNP adjusted by biomarker | Proportion of relationship between CRC and SNP explained by biomarker * | ||||||||||
| HR£ | 95% CI | HR£ | 95% CI | % | HR£ | 95% CI | HR£ | 95% CI | % | ||||||
| A. Physical activity level | |||||||||||||||
| Active Group (MET ≥ 10, n = 348) | Inactive Group (MET < 10, n = 356) | ||||||||||||||
| Total IGF-I level | Total IGF-I level | ||||||||||||||
| IRS1RS1801123_D | G/A | 0.92 | 0.51 | 1.65 | 1.01 | 0.56 | 1.82 | 9.43 | 1.58 | 0.91 | 2.74 | 1.98 | 1.11 | 3.53 | 69.49 |
| Insulin level | Insulin level | ||||||||||||||
| IRS1RS1801278_AD | T/C | 1.28 | 0.65 | 2.49 | 1.27 | 0.64 | 2.51 | 3.85 | 1.63 | 0.84 | 3.19 | 2.20 | 1.10 | 4.38 | 89.01 |
| IRS1RS1801278_D | T/C | 1.10 | 0.53 | 2.28 | 1.08 | 0.51 | 2.28 | 16.37 | 1.85 | 0.90 | 3.79 | 2.54 | 1.21 | 5.31 | 82.25 |
| HOMA-IR level | HOMA-IR level | ||||||||||||||
| IRS1RS1801278_D | T/C | 1.12 | 0.54 | 2.32 | 1.10 | 0.52 | 2.32 | 12.23 | 1.85 | 0.90 | 3.79 | 2.20 | 1.06 | 4.56 | 41.58 |
| B. Exogenous estrogen use | |||||||||||||||
| Nonusers (n = 273) | E only users (n = 205) | ||||||||||||||
| Total IGF-I level | Total IGF-I level | ||||||||||||||
| IRS1RS1801278_AD | T/C | 1.25 | 0.60 | 2.59 | 1.32 | 0.62 | 2.84 | 32.07 | 2.71 | 1.05 | 6.97 | 3.10 | 1.15 | 8.36 | 22.72 |
| Free IGF-I level | Free IGF-I level | ||||||||||||||
| IRS1RS1801278_AD | T/C | 1.12 | 0.53 | 2.36 | 1.08 | 0.51 | 2.30 | 30.83 | 2.81 | 1.11 | 7.10 | 2.80 | 1.11 | 7.10 | 0.47 |
| Insulin level | Insulin level | ||||||||||||||
| IRS1RS1801278_D | T/C | 1.36 | 0.61 | 3.01 | 1.47 | 0.66 | 3.29 | 32.03 | 3.48 | 1.08 | 11.26 | 4.87 | 0.72 | 32.98 | 55.58 |
| Glucose level | Glucose level | ||||||||||||||
| IRS1RS1801278_D | T/C | 1.38 | 0.62 | 3.06 | 1.57 | 0.70 | 3.55 | 50.51 | 3.58 | 1.10 | 11.60 | 3.55 | 1.09 | 11.55 | 1.10 |
| HOMA-IR level | HOMA-IR level | ||||||||||||||
| IRS1RS1801278_AD | T/C | 1.23 | 0.59 | 2.57 | 1.37 | 0.65 | 2.90 | 59.91 | 2.59 | 0.99 | 6.76 | 3.05 | 1.03 | 9.07 | 28.96 |
| IRS1RS1801278_D | T/C | 1.36 | 0.61 | 3.01 | 1.50 | 0.67 | 3.37 | 39.59 | 3.48 | 1.08 | 11.26 | 4.40 | 1.10 | 17.62 | 36.98 |
CI, confidence interval; CRC, colorectal cancer; HOMA-IR, homeostatic model assessment–insulin resistance; HR, hazard ratio; IGF-I, insulin-like growth factor-I; IR, insulin resistance; MET, metabolic equivalent; SNP, single–nucleotide polymorphism. Note: Among SNPs having statistically significant association with cancer in either subgroup, the SNPs with ≥ 30% of indirect effect in this subgroup or its counterpart are included. Numbers in bold face are statistically significant.
‡ Lifestyle modifiers whose strata include statistically significant association between SNP and cancer only are presented.
¥ Tag attached to the SNP name indicates the SNP-analysis approach (AD: additive; D: minor-allele dominant; and R: minor-allele recessive).
£ Multivariate regression was adjusted by covariates (age, education, family income, family histories of diabetes mellitus or colorectal cancer, heart failure ever, high cholesterol requiring pills ever, smoking status, alcohol intake, and reproductive history [oral contraceptive and history of hysterectomy or oophorectomy, ages at menarche and menopause, and history of pregnancy]); effect-modifier variables (physical activity, BMI, and exogenous estrogen use), when not evaluated as effect modifier variables, were adjusted as a covariate; when stratified via waist circumference or waist-to-hip ratio, body mass index was not adjusted.
* Proportional difference was estimated via difference in the HRs without (total effect) and with (direct effect) accounting for hormone.