Background:
- Short adult leg length (LL) is a marker of adverse early childhood conditions and is associated with higher risk for type 2 diabetes, but it’s not known how this association is metabolically mediated.
- Aim: Identify how components of stature influence metabolic profile and HbA1c.
Methods:
- Cross-sectional analysis of UK Biobank (Application ID 47673): n=367,838, without prevalent diabetes cases.
- Applied causal structure learning algorithm NetCoupler (R package at github.com/NetCoupler), tested on 100 resamples of 10% of dataset.
- Exposures: LL, leg-height ratio (LHR), and height; Outcome: HbA1c.
- Metabolic profile: gamma-glutamyltransferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), TAG, LDL-C, HDL-C, total cholesterol, C-reactive protein (CRP), apolipoprotein A and B, and albumin.
- Confounders: Age, sex, and waist circumference.
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Results:
- Metabolic network links: e.g. HDL-C-LDL-C-Cholesterol-TAG (serum lipid profile) and GGT-ALT-AST (liver function).
- Network to HbA1c: Positive links with ALT, GGT, and CRP.
- Stature to network: Negative links between:
- LL and height on CRP, GGT, and TAG.
- LHR, LL on CRP and ALT.
- NetCoupler algorithm identified GGT, ALT, and CRP as likely metabolic link between stature components and HbA1c.
Conclusion:
- Adverse early childhood growth conditions (leading to shorter legs and shorter stature) may contribute to higher HbA1c through higher liver dysfunction (GGT and ALT) and higher inflammation (CRP).
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