Associations of combined phenotypic aging and genetic risk with incident cancer: A prospective cohort study

  1. Lijun Bian
  2. Zhimin Ma
  3. Xiangjin Fu
  4. Chen Ji
  5. Tianpei Wang
  6. Caiwang Yan
  7. Juncheng Dai
  8. Hongxia Ma
  9. Zhibin Hu
  10. Hongbing Shen  Is a corresponding author
  11. Lu Wang  Is a corresponding author
  12. Meng Zhu  Is a corresponding author
  13. Guangfu Jin  Is a corresponding author
  1. Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, China
  2. Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health Nanjing Medical University, China
  3. Department of Chronic Non-Communicable Disease Control, The Affiliated Wuxi Center for Disease Control and Prevention of Nanjing Medical University, Wuxi Center for Disease Control and Prevention, Wuxi Medical Center, Nanjing Medical University, China
  4. Research Units of Cohort Study on Cardiovascular Diseases and Cancers, Chinese Academy of Medical Sciences, China
5 figures, 3 tables and 2 additional files

Figures

Flowchart for filtering participants from the UK Biobank cohort.

Participants who had withdrawn their consent, had been diagnosed with cancer before baseline, failed to be genotyped, reported a mismatch sex with genetic data, or with missing data on Phenotypic …

Association results of Phenotypic Age Acceleration (PhenoAgeAccel) with site-specific cancer risk per 5 years increased.

Cox proportional hazards regression adjusted for age, height, cancer family history, Townsend deprivation index at recruitment, and the first 10 principal components of ancestry. Error bars are 95% …

Effect of Phenotypic Age Acceleration (PhenoAgeAccel) on the risk of incident cancer in the UK Biobank.

The distribution of PhenoAgeAccel between participants with incident cancer and those without incident cancer in the UK Biobank for men(A) and women (B). Participants in the UK Biobank were divided …

Figure 4 with 1 supplement
Risk of incident cancer according to genetic and Phenotypic Age Acceleration (PhenoAgeAccel) categories in the UK Biobank for men (A) and women (B).

The hazard ratios (HRs) were estimated using Cox proportional hazard models with adjustment for age, height, family history of cancer, Townsend deprivation index, and the first 10 principal …

Figure 4—figure supplement 1
Risk of incident cancer according to genetic and Phenotypic Age Acceleration (PhenoAgeAccel) categories (quintiles) in the UKB cohort for men (A) and women (B).

The hazard ratios (HRs) were estimated using Cox proportional hazard models with adjustment for age, height, family history of cancer, Townsend deprivation index, and the first 10 principal …

Absolute risk estimates of overall cancer based on the UK Biobank for men (A) and women (B).

The x-axis is chronological age. The curves describe the average risk of participants in younger and older Phenotypic Age (PhenoAge) groups. The dashed curve represents the average risk of the whole …

Tables

Table 1
Baseline characteristics of participants stratified by Phenotypic Age Acceleration (PhenoAgeAccel) categories.
Men (n=173,431)Women (n=201,032)
Biologically younger
n=81,242
Biologically older
n=92,189
Biologically younger
n=123,648
Biologically older
n=77,384
PhenoAgeAccel, median (IQR), years–2.61 (−4.35–-1.25)3.28 (1.50–6.06)–3.55 (−5.64–-1.81)3.07 (1.33–5.79)
Age at baseline, median (IQR), years57.00 (49.00–62.00)58.00 (50.00–64.00)58.00 (51.00–63.00)56.00 (48.00–62.00)
Height, median (IQR), centimeters176.00 (171.00–181.00)175.00 (171.00–180.00)162.50 (158.00–167.00)162.00 (158.00–166.50)
Townsend deprivation index, median (IQR)–2.34 (−3.76–0.16)–1.86 (−3.52–1.10)–2.33 (−3.73–0.07)–1.79 (−3.44–1.10)
Family history of cancer, n (%)
 No53907 (66.35)60654 (65.79)79800 (64.54)50924 (65.81)
 Yes27335 (33.65)31535 (34.21)43848 (35.46)26460 (34.19)
Healthy lifestyle factors, n (%)
 No current smoking46412 (57.13)43216 (46.88)78743 (63.68)45416 (58.69)
 No alcohol consumption2064 (2.54)2828 (3.07)6221 (5.03)5459 (7.05)
 Normal BMI66120 (81.39)62654 (67.96)103054 (83.34)49003 (63.32)
 Regular physical activity54346 (66.89)57733 (62.62)80629 (65.21)46468 (60.05)
 Healthy diet18540 (22.82)15486 (16.80)39547 (31.98)19826 (25.62)
Healthy lifestyle*, n (%)
 Favorable7781 (9.58)5255 (5.70)17781 (14.38)7178 (9.28)
 Intermediate57683 (71.00)57489 (62.36)87272 (70.58)49324 (63.74)
 Unfavorable15778 (19.42)29445 (31.94)18595 (15.04)20882 (26.98)
Albumin, median (IQR), (g/L)46.20 (44.62–47.85)44.95 (43.28–46.64)45.47 (43.87–47.12)44.04 (42.42–45.70)
Alkaline phosphatase, median (IQR), (U/L)75.00 (64.30–87.40)82.80 (70.10–97.90)78.70 (65.10–93.90)86.20 (70.60–104.00)
Creatinine, median (IQR), (umol/L)77.60 (70.90–84.70)82.50 (74.40–91.60)61.70 (56.00–67.90)65.50 (58.90–73.20)
Glucose, median (IQR), (mmol/l)4.82 (4.49–5.14)5.09 (4.72–5.60)4.84 (4.54–5.14)5.05 (4.70–5.55)
C-reactive protein, median (IQR), (mg/dL)0.09 (0.05–0.16)0.19 (0.10–0.36)0.10 (0.05–0.20)0.25 (0.12–0.51)
Lymphocyte percent, median (IQR), (%)29.86 (25.48–34.48)25.60 (21.22–30.24)31.09 (26.58–35.80)27.00 (22.62–31.61)
Mean cell volume, median (IQR), (fL)90.90 (88.46–93.30)91.90 (89.10–94.74)91.10 (88.60–93.54)90.98 (87.64–94.02)
Red cell distribution width, median (IQR), (%)13.01 (12.70–13.37)13.63 (13.21–14.11)13.10 (12.71–13.50)13.90 (13.40–14.55)
White blood cell count, median (IQR), (1000 cells/uL)6.12 (5.29–7.10)7.27 (6.17–8.51)6.24 (5.37–7.26)7.41 (6.30–8.73)
  1. *

    Healthy lifestyle was defined as favorable (4–5 healthy lifestyle factors), intermediate (2–3 healthy lifestyle factors), and unfavorable (0–1 healthy lifestyle factor).

Table 2
Association between Phenotypic Age Acceleration (PhenoAgeAccel) and cancer risk.
Model 1*Model 2
n (cases)Person-YearsHR (95% CI)p valueHR (95% CI)value
MenPer 5 years increase173431 (11532)11906281.15 (1.13–1.17)1.55×10–541.13 (1.11–1.15)5.46×10–44
Category
 Biologically younger81242 (4649)564818Ref.Ref.
 Biologically older92189 (6883)6258101.22 (1.18–1.27)5.31×10–261.19 (1.15–1.24)3.18×10–20
Quintiles
 Low34687 (1864)242519Ref.Ref.
 Intermediate104058 (6668)7163121.15 (1.09–1.21)2.17×10–71.12 (1.07–1.18)8.01×10–6
 High34686 (3000)2317971.44 (1.36–1.53)1.01×10–341.39 (1.31–1.47)1.99×10–27
p for trend3.03×10–371.65×10–29
WomenPer 5 years increase201032 (10838)13935621.15 (1.13–1.17)1.80×10–531.13 (1.11–1.15)1.35×10–41
Category
 Biologically younger123648 (6229)861570Ref.Ref.
 Biologically older77384 (4609)5319931.26 (1.22–1.31)5.91×10–331.23 (1.18–1.28)2.71×10–25
Quintiles
 Low40207 (1946)281912Ref.Ref.
 Intermediate120618 (6351)8363411.15 (1.09–1.21)1.46×10–71.13 (1.07–1.18)5.89×10–6
 High40207 (2541)2753091.46 (1.38–1.55)2.54×10–361.40 (1.32–1.49)5.94×10–28
p for trend4.23×10–371.36×10–28
  1. *

    Cox proportional hazards regression adjusted for Model 1, as well as cancer polygenic risk score and healthy lifestyle.

  2. Defined by quintiles of PhenoAgeAccel: low (the bottom quintile), intermediate (quintiles 2–4), and high (the top quintile).

  3. Cox proportional hazards regression adjusted for age, height, cancer family history, Townsend deprivation index at recruitment, and the first 10 principal components of ancestry.

  4. CI, confidence interval; HR, hazards ratio; Ref, reference.

Table 3
Risk of incident cancer according to Phenotypic Age Acceleration (PhenoAgeAccel) categories within each genetic risk level*.
GenderPhenoAgeAccel categoryLow genetic riskIntermediate genetic riskHigh genetic risk
Biologically youngerBiologically olderBiologically youngerBiologically olderBiologically youngerBiologically older
MenNo. of cases/Person years668/1149621031/1245262606/3389504012/3767821375/1109071840/124502
Hazards ratioRef.1.29
(1.17–1.42)
Ref.1.27
(1.21–1.33)
Ref.1.10
(1.02–1.18)
(95% CI)
p value3.53×10–73.15×10–211.07×10–2
Absolute risk (%)-
5 years (95% CI)
2.71
(2.49–2.94)
3.87
(3.60–4.14)
3.57
(3.41–3.72)
4.95
(4.78–5.13)
5.78
(5.44–6.11)
6.90
(6.55–7.26)
Absolute risk increase (%)-
5 years (95% CI)
Ref.1.16
(0.84–1.46)
Ref.1.39
(1.19–1.60)
Ref.1.13
(0.68–1.52)
WomenNo. of cases/Person years1030/173195761/1069373579/5186112704/3187531620/1697641144/106303
Hazards ratioRef.1.25
(1.14–1.38)
Ref.1.30
(1.24–1.37)
Ref.1.19
(1.10–1.28)
(95% CI)
p value2.65×10–61.84×10–248.19×10–6
Absolute risk (%) -
5 years (95% CI)
2.83
(2.63–3.02)
3.39
(3.12–3.65)
3.27
(3.15–3.39)
4.02
(3.86–4.19)
4.58
(4.33–4.83)
5.17
(4.84–5.49)
Absolute risk increase (%)-
5 years (95% CI)
Ref.0.56
(0.26–0.86)
Ref.0.76
(0.57–0.93)
Ref.0.59
(0.23–0.98)
  1. *

    Cox proportional hazards regression is adjusted for age, height, family history of cancer, Townsend deprivation index, height, and the first 10 principal components of ancestry.

  2. CI, confidence interval; Ref, reference.

Additional files

Supplementary file 1

Supplementary Tables a - k for additional results.

(a) Association results of Phenotypic Age Acceleration (PhenoAgeAccel) with site-specific cancer risk per 5 years increased. (b) Sensitivity analysis of association between different risk levels of PhenoAgeAccel and cancer risk. (c) Sensitivity analysis of association between PhenoAgeAccel and cancer risk by excluding of patients diagnosed in the first two follow-ups. (d) Sensitivity analysis of association between PhenoAgeAccel and cancer risk in unimputed data. (e) Sensitivity analysis of association between PhenoAgeAccel and cancer risk in the unrelated white British population. (f) Sensitivity analysis of association between PhenoAgeAccel and cancer risk using retrained PhenoAge in cancer-free participants. (g) Relative excess risk due to interaction (RERI) and attributable proportion (AP) for additive interaction between genetic and PhenoAgeAccel categories. (h) Risk of incident cancer according to PhenoAgeAccel categories within each genetic risk level. (i) PhenoAgeAccel of participants stratified by lifestyle factors. (j) Association results of PhenoAgeAccel with lifestyle factors of participants. (k) RERI and AP for additive interaction between genetic and lifestyle factors on PhenoAgeAccel.

https://cdn.elifesciences.org/articles/91101/elife-91101-supp1-v1.docx
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https://cdn.elifesciences.org/articles/91101/elife-91101-mdarchecklist1-v1.docx

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