Tiange Wang1,2,3, Tao Huang1,2, Yanping Li2, Yan Zheng2, JoAnn E Manson4,5,6, Frank B Hu2,6, Lu Qi7,8,9. 1. Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, 1440 Canal Street, New Orleans, LA, 70112, USA. 2. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 3. Shanghai Institute of Endocrine and Metabolic Diseases, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China. 4. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 5. Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. 6. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. 7. Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, 1440 Canal Street, New Orleans, LA, 70112, USA. lqi1@tulane.edu. 8. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA. lqi1@tulane.edu. 9. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. lqi1@tulane.edu.
Abstract
AIMS/HYPOTHESIS: Low birthweight has been associated with a high risk of type 2 diabetes mellitus in observational studies. However, it remains unclear whether this relation is causal. METHODS: The present study included 3627 individuals with type 2 diabetes and 12,974 control participants of European ancestry from the Nurses' Health Study and the Health Professionals Follow-Up Study. A genetic risk score (GRS) was calculated based on five low-birthweight-related single nucleotide polymorphisms (SNPs). We assessed the evidence for causality first by examining the association of the GRS and the individual SNPs with type 2 diabetes, and second by performing a Mendelian randomisation analysis to estimate the potentially causal effect size of low birthweight on type 2 diabetes. RESULTS: In a meta-analysis of the two studies, each 1 point increment in the GRS was associated with a 6% (95% CI 3%, 9%) higher risk of type 2 diabetes. CCNL1 rs900400 and 5q11.2 rs4432842 showed dose-response associations with risk of type 2 diabetes; the corresponding ORs and 95% CIs were 1.09 (1.03, 1.16) and 1.09 (1.02, 1.16), respectively. Furthermore, we observed an overall Mendelian randomisation OR of 2.94 (95% CI 1.70, 5.16; p < 0.001) for type 2 diabetes per 1 SD lower genetically determined birthweight. CONCLUSIONS/ INTERPRETATION: A genetically lowered birthweight was associated with increased susceptibility to type 2 diabetes. Our findings support a potential causal relation between birthweight and risk of type 2 diabetes, providing new evidence to support the role of intrauterine exposures in the pathogenesis of type 2 diabetes.
AIMS/HYPOTHESIS: Low birthweight has been associated with a high risk of type 2 diabetes mellitus in observational studies. However, it remains unclear whether this relation is causal. METHODS: The present study included 3627 individuals with type 2 diabetes and 12,974 control participants of European ancestry from the Nurses' Health Study and the Health Professionals Follow-Up Study. A genetic risk score (GRS) was calculated based on five low-birthweight-related single nucleotide polymorphisms (SNPs). We assessed the evidence for causality first by examining the association of the GRS and the individual SNPs with type 2 diabetes, and second by performing a Mendelian randomisation analysis to estimate the potentially causal effect size of low birthweight on type 2 diabetes. RESULTS: In a meta-analysis of the two studies, each 1 point increment in the GRS was associated with a 6% (95% CI 3%, 9%) higher risk of type 2 diabetes. CCNL1rs900400 and 5q11.2 rs4432842 showed dose-response associations with risk of type 2 diabetes; the corresponding ORs and 95% CIs were 1.09 (1.03, 1.16) and 1.09 (1.02, 1.16), respectively. Furthermore, we observed an overall Mendelian randomisation OR of 2.94 (95% CI 1.70, 5.16; p < 0.001) for type 2 diabetes per 1 SD lower genetically determined birthweight. CONCLUSIONS/ INTERPRETATION: A genetically lowered birthweight was associated with increased susceptibility to type 2 diabetes. Our findings support a potential causal relation between birthweight and risk of type 2 diabetes, providing new evidence to support the role of intrauterine exposures in the pathogenesis of type 2 diabetes.
Entities:
Keywords:
Birthweight; Mendelian randomisation; Type 2 diabetes
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