Response to Koker and Ozcelik

We appreciate the correspondence by Koker and Ozcelik¹ regarding our recent publication on drinking patterns and time lag of alcohol consumption in relation to risk of developing colorectal cancer (CRC).

First, we agree that the sex-specific association warrants further investigation. We observed a positive association between light to moderate alcohol consumption and elevated CRC risk, predominantly in men. In line with our findings, a previous meta-analysis of 16 cohort studies from 10 different countries, including those from East Asia, had also reported a significant positive association in men but not in women.² We acknowledge physiological and genetic differences, including alcohol dehydrogenase activity, body composition and folate status, may modulate susceptibility to alcohol-induced colorectal carcinogenesis, particularly among women.^3,4

Second, we agree that more evidence addressing different aspects of drinking, such as beverage type, binge drinking and combination of frequency and quantity, would help polish alcohol-related public health implications. In that regard, we performed the joint analysis of alcohol intake and drinking frequency with CRC risk as well as beverage type-specific analysis and included them as supplementary findings.

Third, we appreciate the interesting points raised to help enhance causal inference; however, we would like to clarify that we have already applied time-dependent Cox proportional hazards models and performed a wide range of sensitivity analyses to add rigorous epidemiologic evidence on this topic to the possible extent.

Finally, we also appreciate the suggestion to consider Mendelian Randomization (MR) approaches; however, MR studies in alcohol research must be interpreted with caution. Alcohol consumption is a multidimensional behavior—encompassing dose, frequency, patterns, etc—and most genetic instruments (eg, variants in ADH1B or ALDH2) may reflect problematic drinking patterns rather than potentially more benign drinking patterns (ie, a drink daily with a meal). Thus, MR analyses may not capture the full behavioral spectrum of alcohol consumption relevant to CRC risk and should be complemented by observational data collectively capturing nuanced drinking patterns. Also, ALDH2 deficiency could be an important effect modifier in alcohol-CRC associations. Although the Nurses’ Health Study and Health Professionals Follow-up Study largely comprise white health professionals, a prior investigation has demonstrated that our cohorts have shown exposure-disease associations highly compatible with the broader literature.⁵ East Asians could be an important group of interest where differences in the association are expected due to the genetic predisposition.

With this response, along with our original article, we hope to underscore the importance of future studies with rigorous methodologies that investigate multifold aspects of light to moderate drinking in relation to a wide range of health outcomes to enhance our understanding of the complicated relationship and help refine public health strategies towards alcohol consumption.

Author contributions

Jinhee Hur (Conceptualization, Writing—original draft, Writing—review & editing), Xinyi Li (Writing—review & editing), and Edward Giovannucci (Conceptualization, Writing—review & editing)

Funding

The Nurses’ Health Study was supported by the National Institutes of Health (NIH) grants UM1 CA186107 and R01 CA49449. The Health Professionals Follow-up Study was supported by the NIH grant U01 CA167552. Jinhee Hur was supported by the National Research Foundation of Korea grant RS-2024-00349274 funded by the Ministry of Science and ICT as well as the research grant from the Otoki Ham Taiho Foundation. Edward Giovannucci was supported by the American Cancer Society Clinical Research Professor grant CRP-23-1014041. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funding sources played no role in study design, collection, analysis and interpretation of the data, manuscript writing or decision to submit the manuscript for publication.

Conflicts of interest

The authors have no conflicts of interest to disclose.

Data availability

No new data were generated or analyzed for this response.