medwireNews: A mendelian randomization analysis published in JAMA implicates abdominal obesity as a direct cause of type 2 diabetes and coronary heart disease (CHD), independently of body mass index (BMI).
“[T]hese results suggest that body fat distribution, beyond simple measurement of BMI, could explain part of the variation in risk of type 2 diabetes and CHD noted across individuals and subpopulations,” say Sekar Kathiresan (Massachusetts General Hospital, Harvard Medical School, Boston, USA) and co-researchers.
The researchers used a weighted polygenic risk score comprising 48 single-nucleotide polymorphisms linked to waist-to-hip ratio (WHR) adjusted for BMI in a study from the Genome-Wide Investigation of Anthropometric Traits (GIANT) Consortium. They found that each genetically determined 1 standard deviation (SD) increase in WHR was associated with a significant 1.73-fold increased risk for type 2 diabetes among the 111,986 participants of the UK Biobank and a 1.79-fold increased risk among the 149,821 DIAGRAM participants.
Likewise, there were 1.64- and 1.42-fold increased risks for CHD among the UK Biobank and the 184,305 CARDIOGRAMplusC4D participants, respectively. The risk score was not, however, associated with potential confounders, such as smoking, alcohol consumption, and physical activity.
And data from the UK Biobank plus an additional four large cohorts (GIANT, GLCC, MAGIC, CKDGen) showed that higher genetically determined WHR was associated with higher blood pressure and poorer lipid and glycemic measures, in particular for triglycerides, high-density lipoprotein (HDL) cholesterol, and 2-hour glucose. Renal function was unaffected.
Each SD increase in WHR was associated with a 0.42 and 0.40 SD increase in triglycerides and 2-hour glucose, and a 0.39 reduction in HDL cholesterol, equivalent to 27 mg/dL, 4.1 mg/dL, and 6.0 mg/dL, respectively.
George Davey Smith (University of Bristol, UK) and co-authors of an accompanying editorial, say that “Mendelian randomization is slowly beginning to generate data of clear clinical and public health relevance,” and suggest that its use before committing to major clinical trials should be “actively encouraged.”
With respect to the current analysis, they note: “In public health terms, it has proved difficult to reduce obesity levels through interventions, and the same may be true for abdominal adiposity.”
For this reason, they believe the focus should be on causal mediators, such as blood pressure and cholesterol levels, with mendelian randomization used to identify which to target with treatment to reap the largest benefit.
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