Does a Genetic Risk Score for Waist-to-Hip Ratio Confirm Relationship to Diabetes and Heart Disease?
BACKGROUND AND PURPOSE:
Observational studies demonstrate an association between waist-to-hip ratio (WHR), type 2 diabetes and coronary heart disease
Evidence still lacking as to whether this is a truly a causal relationship or associative
Genetic variants are randomly assorted and determined at conception and would therefore be less likely to be affected by common biases seen in observational studies
Emdin et al. (JAMA, 2018) sought to determine if genetic evidence could be used to help establish causality by developing a genetic risk score for abdominal adiposity in relationship to diabetes/ coronary heart disease
A polygenic risk score for WHR, adjusted for BMI, was constructed with 48 SNPs
A mendelian randomization analysis that combined case-control and cross-sectional data sets was used to test the strength of the association between the polygenic risk score and different cardiometabolic traits, coronary heart disease and type 2 diabetes
Is an epidemiologic methodology that uses genetic variation in known genes to help establish causality of a modifiable exposure on disease (in this case, diabetes and coronary heart disease) previously seen in observational studies
Mendelian randomization analysis requires genetic variants to be associated with the exposure of interest, not be associated with confounders and not associated with outcome independently of the exposure
Estimated cardiometabolic traits were based on data from 4 genome-wide association studies
Estimates for type 2 diabetes and coronary heart disease were based on 2 separate genome-wide association studies
The primary outcomes were Type 2 diabetes and coronary heart disease
Blood lipids, blood pressure, and glycemic phenotypes were used as potential intermediates for these disorders
Data was collected form 111,986 individuals (mean age = 57; 53.5% women)
1 standard deviation increase in WHR adjusted for BMI mediated by the polygenic risk score was associated with (P<0.001 for each)
27 mg/dL higher triglyceride levels
4.1 mg/dL higher 2-hour glucose levels
2.1 mm Hg higher systolic blood pressure
1 standard deviation increase in WHR adjusted for BMI was also associated with
Higher risk for type 2 diabetes odds ratio (OR) 1.77 (95% Cl, 2.57-2.00)
Higher risk for coronary heart disease OR 1.46 (95% Cl, 1.3-2.4)
A genetic predisposition to higher WHR adjusted for BMI was associated with an increased risk of type 2 diabetes and coronary heart disease
This study supports a causal relationship between abdominal adiposity and type 2 diabetes and coronary heart disease
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