Sex-specific cancer risk associated with insomnia: a prospective cohort study using the Korean genome and epidemiology study (KoGES) data

The interaction effect of sex and insomnia on the risk of cancer remains unclear. Our study aimed to examine the association between insomnia and cancer development, and through stratified analysis, to determine if this association is modified based on sex. We used the Korean Genome Epidemiology Study (KoGES), which initiated two distinct prospective cohort investigations in 2001. The main exposure variable are sex and insomnia and the main outcome is cancer occurrence. The occurrence of cancer was considered the main outcome, and Cox regression analysis was utilized to estimate hazard ratios and 95% confidence interval. Additionally, stratified analysis was conducted to evaluate the interaction effect of sex and insomnia on cancer risk. In our study, the incidence of cancer per 1000 person-years was 5.23 in the insomnia group and 5.33 in the non-insomnia group, with no significant difference in adjusted hazard ratio (aHR: 1.01 (0.81–1.26)). Stratifying by sex, incidence rates were 4.86 for males and 5.72 for females per 1000 person-years, with females presenting a significantly higher aHR (1.30 (1.03–1.71)). No significant interaction was observed for both “insomnia × sex” and “sex × insomnia”. Notably, females on insomnia medication had a substantially increased cancer risk (aHR: 4.06 (1.95–17.24)). Our study revealed that females, especially those undergoing insomnia medication treatment, exhibited a heightened cancer risk, though insomnia alone did not significantly influence this risk. These findings suggest a potential protective effect of male gender against cancer incidence.

Cancer; Insomnia; Sex

[1] Luengo-Fernandez R, Leal J, Gray A, Sullivan R. Economic burden of cancer across the European Union: a population-based cost analysis. The Lancet Oncology. 2013; 14: 1165–1174.

[2] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians. 2021; 71: 209–249.

[3] Kamra H. CANCER—will molecular methods and bioinformatics help us to reduce cancer mortality or researches have way ahead. Cancer Research and Reports. 2018; 1: e101.

[4] Kolčić I. Double burden of malnutrition: a silent driver of double burden of disease in low- and middle-income countries. Journal of Global Health. 2012; 2: 020303.

[5] Haiman CA, Le Marchand L, Yamamato J, Stram DO, Sheng X, Kolonel LN, et al. A common genetic risk factor for colorectal and prostate cancer. Nature Genetics. 2007; 39: 954–956.

[6] Sun Y, Zhao Z, Yang Z, Xu F, Lu H, Zhu Z, et al. Risk factors and preventions of breast cancer. International Journal of Biological Sciences. 2017; 13: 1387–1397.

[7] Lee YY, Derakhshan MH. Environmental and lifestyle risk factors of gastric cancer. Archives of Iranian Medicine. 2013; 16: 358–365.

[8] Huxley RR, Ansary‐Moghaddam A, Clifton P, Czernichow S, Parr CL, Woodward M. The impact of dietary and lifestyle risk factors on risk of colorectal cancer: a quantitative overview of the epidemiological evidence. International Journal of Cancer. 2009; 125: 171–180.

[9] Lu C, Sun H, Huang J, Yin S, Hou W, Zhang J, et al. Long-term sleep duration as a risk factor for breast cancer: evidence from a systematic review and dose-response meta-analysis. BioMed Research International. 2017; 2017: 4845059.

[10] Leysen L, Lahousse A, Nijs J, Adriaenssens N, Mairesse O, Ivakhnov S, et al. Prevalence and risk factors of sleep disturbances in breast cancersurvivors: systematic review and meta-analyses. Supportive Care in Cancer. 2019; 27: 4401–4433.

[11] Morin CM, Jarrin DC. Epidemiology of insomnia: prevalence, course, risk factors, and public health burden. Sleep Medicine Clinics. 2013; 8: 281–297.

[12] Javaheri S, Redline S. Insomnia and Risk of Cardiovascular Disease. Chest. 2017; 152: 435–444.

[13] Shamim SA, Warriach ZI, Tariq MA, Rana KF, Malik BH. Insomnia: risk factor for neurodegenerative diseases. Cureus. 2019; 11: e6004.

[14] Shi T, Min M, Sun C, Zhang Y, Liang M, Sun Y. Does insomnia predict a high risk of cancer? A systematic review and meta‐analysis of cohort studies. Journal of Sleep Research. 2020; 29: e12876.

[15] Fang H, Miao N, Chen C, Sithole T, Chung M. Risk of cancer in patients with insomnia, parasomnia, and obstructive sleep apnea: a nationwide nested case-control study. Journal of Cancer. 2015; 6: 1140–1147.

[16] Jafari-Koulaee A, Bagheri-Nesami M. The effect of melatonin on sleep quality and insomnia in patients with cancer: a systematic review study. Sleep Medicine. 2021; 82: 96–103.

[17] Sogawa R, Shimanoe C, Tanaka K, Hara M, Nishida Y, Furukawa T, et al. Sex-and age-specific all-cause mortality in insomnia with hypnotics: findings from Japan multi-institutional collaborative cohort study. Sleep Medicine. 2022; 100: 410–418.

[18] Ge L, Guyatt G, Tian J, Pan B, Chang Y, Chen Y, et al. Insomnia and risk of mortality from all-cause, cardiovascular disease, and cancer: systematic review and meta-analysis of prospective cohort studies. Sleep Medicine Reviews. 2019; 48: 101215.

[19] Savard J, Villa J, Ivers H, Simard S, Morin CM. Prevalence, natural course, and risk factors of insomnia comorbid with cancer over a 2-month period. Journal of Clinical Oncology. 2009; 27: 5233–5239.

[20] Kim Y, Han B. Cohort profile: the Korean genome and epidemiology study (KoGES) consortium. International Journal of Epidemiology. 2017; 46: e20.

[21] Siegel RL, Jemal A. Percentage of colorectal cancer diagnosed in adults aged younger than 50 years. Cancer. 2016; 122: 1462–1463.

[22] Dorak MT, Karpuzoglu E. Gender differences in cancer susceptibility: an inadequately addressed issue. Frontiers in Genetics. 2012; 3: 268.

[23] Torre LA, Islami F, Siegel RL, Ward EM, Jemal A. Global cancer in women: burden and trends. Cancer Epidemiology, Biomarkers & Prevention. 2017; 26: 444–457.

[24] Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global patterns and trends in colorectal cancer incidence and mortality. Gut. 2017; 66: 683–691.

[25] Lenis AT, Lec PM, Chamie K, MSHS M. Bladder cancer. JAMA. 2020; 324: 1980.

[26] Kim W, Ryan CJ. Quo vadis: advanced prostate cancer—clinical care and clinical research in the era of multiple androgen receptor‐directed therapies. Cancer. 2015; 121: 361–371.

[27] Gillies GE, McArthur S. Estrogen actions in the brain and the basis for differential action in men and women: a case for sex-specific medicines. Pharmacological Reviews. 2010; 62: 155–198.

[28] Devore EE, Warner ET, Eliassen AH, Brown SB, Beck AH, Hankinson SE, et al. Urinary melatonin in relation to postmenopausal breast cancer risk according to melatonin 1 receptor status. Cancer Epidemiology, Biomarkers & Prevention. 2017; 26: 413–419.

[29] Cotreau MM, von Moltke LL, Greenblatt DJ. The influence of age and sex on the clearance of cytochrome P450 3A substrates. Clinical Pharmacokinetics. 2005; 44: 33–60.

[30] Greenblatt D, Harmatz J, Vonmoltke L, Wright C, Shader R. Age and gender effects on the pharmacokinetics and pharmacodynamics of triazolam, a cytochrome P450 3A substrate. Clinical Pharmacology & Therapeutics. 2004; 76: 467–479.

[31] Kao CH, Sun LM, Liang JA, Chang SN, Sung FC, Muo CH. Relationship of zolpidem and cancer risk: a Taiwanese population-based cohort study. Mayo Clinic Proceedings. 2012; 87: 430–436.

[32] Zhang J, Zhang Z, Huang S, Qiu X, Lao L, Huang Y, et al. Acupuncture for cancer-related insomnia: a systematic review and meta-analysis. Phytomedicine. 2022; 102: 154160.

[33] Jiao L, Duan Z, Sangi-Haghpeykar H, Hale L, White DL, El-Serag HB. Sleep duration and incidence of colorectal cancer in postmenopausal women. British Journal of Cancer. 2013; 108: 213–221.

[34] Sigurdardottir FD, Bertisch SM, Reid ML, deFilippi CR, Lima JAC, Redline S, et al. Association between insomnia phenotypes and subclinical myocardial injury: the multi-ethnic study of atherosclerosis. Sleep. 2023; 46: zsac318.

[35] Jaussent I, Dauvilliers Y, Ancelin M, Dartigues J, Tavernier B, Touchon J, et al. Insomnia symptoms in older adults: associated factors and gender differences. The American Journal of Geriatric Psychiatry. 2011; 19: 88–97.

[36] Lee M, Lee S, Lee G, Ryu H, Chung S, Chung Y, et al. Gender differences in the effect of comorbid insomnia symptom on depression, anxiety, fatigue, and daytime sleepiness in patients with obstructive sleep apnea. Sleep and Breathing. 2014; 18: 111–117.

[37] Troxel WM, Buysse DJ, Matthews KA, Kip KE, Strollo PJ, Hall M, et al. Sleep symptoms predict the development of the metabolic syndrome. Sleep. 2010; 33: 1633–1640.

[38] Brabbins CJ, Dewey ME, Copeland JRM, Davidson IA, McWilliam C, Saunders P, et al. Insomnia in the elderly: prevalence, gender differences and relationships with morbidity and mortality. International Journal of Geriatric Psychiatry. 1993; 8: 473–480.

[39] Shi T, Min M, Sun C, Zhang Y, Liang M, Sun Y. Does insomnia predict a high risk of cancer? a systematic review and meta‐analysis of cohort studies. Journal of Sleep Research. 2020; 29: e12876.

[40] Kim H, Myung S, Park YC, Park B. Use of benzodiazepine and risk of cancer: a meta-analysis of observational studies. International Journal of Cancer. 2017; 140: 513–525.

[41] Greenblatt DJ, Harmatz JS, Roth T. Zolpidem and gender: are women really at risk? Journal of Clinical Psychopharmacology. 2019; 39: 189–199.