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. 2023 Jan;12(2):1922-1934.
doi: 10.1002/cam4.5027. Epub 2022 Jul 16.

Association of serum Klotho levels with cancer and cancer mortality: Evidence from National Health and Nutrition Examination Survey

Yating Qiao  1 , Fubin Liu  1 , Yu Peng  1 , Peng Wang  1 , Bing Ma  1 , Limin Li  1 , Changyu Si  1 , Xixuan Wang  1 , Ming Zhang  2 , Fangfang Song  1
Affiliations

Association of serum Klotho levels with cancer and cancer mortality: Evidence from National Health and Nutrition Examination Survey

Yating Qiao et al. Cancer Med. 2023 Jan.

Abstract

Background: Klotho has both anticancer and hormone-like functions. But the research on Klotho and cancer is mainly based on animal experiments and small-scale clinical research, thus we explored the association between serum Klotho and cancer and cancer mortality based on the National Health and Nutrition Survey (NHANES).

Methods: Participants were employed from the NHANES 2007-2016, excluding pregnant, chronic renal insufficiency, and incomplete data of cancer questionnaire and serum Klotho level. The association of serum Klotho with cancer and mortality was analyzed by weighted Logistic regression, weighted Cox regression and competitive risk model, respectively. Correlations between serum Klotho and testosterone and estradiol levels were analyzed by Spearman correlation and restricted cubic spline respectively.

Results: We found Klotho had an inverse effect with risk of pan-cancer (all p < 0.02), with each unit increase in Klotho (1ug/g creatinine) associated with a 0.9%-2.2% reduction in the risk of cancer, and higher levels showing a stronger negative association (all p-trend <= 0.0005). Whereas, we did not observe any association between serum Klotho level with all-cause mortality and cancer-specific mortality (all p > 0.05). Then, stratified analysis found that people aged 60-79, female, overweight and non-Hispanic whites or Mexican Americans were less likely to develop cancer. In addition, there was a strong nonlinear and linear positive correlation of Klotho with estradiol (p-nonlinear = 0.0178) and testosterone only among male participants (β = -0.513, p = 0.0137), respectively.

Conclusions: We found an inverse association between serum Klotho and cancer, but without cancer mortality. And this effect may be partially mediated by estradiol and testosterone. Further prospective studies are needed to prove these findings.

Keywords: NHANES; Serum Klotho; cancer; cancer mortality; estradiol; testosterone.

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Conflict of interest statement

All authors have made no disclosure.

Figures

FIGURE 1
FIGURE 1
Flowchart displaying selection criteria of the study population. (A) Present population selection for analysis of the association between serum Klotho and cancer. (B) Population selection was presented to analyze the relationship between serum Klotho and all‐cause mortality and specific‐cause mortality. The 10th revised edition (ICD‐10) was based on the International Statistical Classification of Diseases and Related health problems, classified cause of death: diseases of heart (054–064), malignant neoplasms (019–043) or all other causes (Residual) (010)
FIGURE 2
FIGURE 2
Forest plot for the association of serum Klotho with the risk of pan‐cancer and individual cancers from NHANES 2007–2016. Adjusted for age (continuous), gender, race/ethnicity, education levels, PIR, BMI, smoking status, physical activity, alcohol intake, diabetes, cardiovascular diseases, hypertension, dyslipidemia, self‐reported health, total energy intake. Abbreviations: CI, confidence interval; NHANES, National Health and Nutrition Examination Survey; OR, odds ratio
FIGURE 3
FIGURE 3
The association of serum Klotho with mortality. (A) Klotho level by mortality status. (B) Distribution of Klotho by mortality status. (C) Cumulative risk of death by Klotho level. (D) Probability of cancer mortality by Klotho level
FIGURE 4
FIGURE 4
Correlation between serum Klotho and sex steroid hormones: NHANES 2013–2016. (A and B) distribution of estradiol and testosterone by Klotho level. (C and D) restricted cubic spline analysis of the nonlinear relationship between continuous Klotho in estradiol and testosterone
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