Familial Risk of Graves Disease Among First-Degree Relatives and Interaction With Smoking: A Population-Based Study

Hyun Jung Kim, Gahwi Hong, Jungyun Hwang, Sayada Zartasha Kazmi, Kyoung Hoon Kim, Taeuk Kang, Heather Swan, Jaewoo Cha, Young Shin Kim, Kyeong Uoon Kim, Hoo Jae Hann, Hyeong Sik Ahn

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Context: Population-based studies on the familial aggregation of Graves disease (GD) are scarce and gene-environment interactions are not well-studied. Objective: We evaluated the familial aggregation of GD and assessed interactions between family history and smoking. Methods: Using the National Health Insurance database, which includes information on familial relationships and lifestyle risk factors, we identified 5 524 403 individuals with first-degree relatives (FDRs). Familial risk was calculated using hazard ratios (HRs), comparing the risk of individuals with and without affected FDRs. Interactions between smoking and family history were assessed on an additive scale using relative excess risk due to interaction (RERI). Results: The HR among individuals with affected FDRs was 3.39 (95% CI, 3.30-3.48) compared with those without affected FDR, and among individuals with affected twin, brother, sister, father, and mother, the HRs were 36.53 (23.85-53.54), 5.26 (4.89-5.66), 4.12 (3.88-4.38), 3.34 (3.16-3.54), and 2.63 (2.53-2.74), respectively. Individuals with both a positive family history and smoking had an increased risk of disease (HR 4.68) with statistically significant interaction (RERI 0.94; 95% CI, 0.74-1.19). Heavy smokers with a positive family history showed a nearly 6-fold increased risk, which was higher than moderate smoking, suggesting a dose-response interaction pattern. Current smoking also showed a statistically significant interaction with family history (RERI 0.52; 95% CI, 0.22-0.82), while this was not observed for former smoking. Conclusion: A gene-environment interaction can be suggested between smoking and GD-associated genetic factors, which diminishes after smoking cessation. Smokers with a positive family history should be considered a high-risk group and smoking cessation should be advised.

Original languageEnglish
Pages (from-to)e502-e511
JournalJournal of Clinical Endocrinology and Metabolism
Issue number8
StatePublished - 1 Aug 2023

Bibliographical note

Publisher Copyright:
© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved.


  • Graves disease
  • additive interaction
  • familial risk


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