Genetic variants affect the HDL-c and triglyceride response to lifestyle modification

Do Genetic Modifiers of HDL-C and Triglyceride Levels also Modify Their Response to a Lifestyle Intervention in the Setting of Obesity and Type-2 Diabetes Mellitus? The Look AHEAD Study.

Literature - Huggins GS, Papandonatos GD, Erar B et al. - Circ Cardiovasc Genet. 2013 Jul 16

Huggins GS, Papandonatos GD, Erar B et al.
Circ Cardiovasc Genet. 2013 Jul 16


Weight loss inducing life style changes can improve insulin resistance and other biological markers relevant to CV disease risk in obese patients with type 2 diabetes mellitus (T2DM). Treatment efforts in these patients are aimed at raising HDL-c and lowering triglyceride (TG) levels. However, not everybody responds in the same way to behavioural intervention. Not only are HDL-C and TG levels heritable [1,2], so are lipid responses to overfeeding [3] and exercise [4]. Thus, genetic factors appear to contribute to the lipid response to behavioural intervention.
Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) in at least 95 genetic loci, which together account for about 10-12% of the variance in HDL-c and TG levels [5].
The Action for Health in Diabetes (Look AHEAD) study randomly assigned overweight or obese participants with T2DM to an Intensive Lifestyle Intervention (ILI). The goal was 7% weight loss through caloric restriction and physical activity. Alternatively, participants were randomised to Diabetes Support and Education (DSE) without weight loss or physical activity goals [6]. After one year, participants in the ILI-arm had lost significantly more weight and showed better improvements in fitness, waist circumference and indices of diabetes control than did people in the DSE arm [7]. Improvements in HDL-c and TG levels after one year were better in the ILI arm.
This study aimed to test the hypothesis that GWAS-identified SNPs associated with HDL-c and TG levels are also associated with the response of HDL-C and TG levels to the behavioural intervention in the Look AHEAD trial.

Main results

  • Out of 82 SNPs selected for analysis based on previous HDL-C or TG GWASs, 20 SNPs were associated with baseline HDL-c levels. 12 SNPs showed effect modification as a result of the behavioural treatment. A SNP in CETP showed both an association with baseline HDL-c and an interaction with treatment.
    27 SNPs were associated with baseline TG levels, while 6 showed evidence for treatment effect modification.
Polymorphisms in CETP and lecithin-cholesterol acyltransferase (LCAT) were only associated with baseline HDL-c, whereas 6 SNPs were only associated with baseline TG levels.
  • Several SNPs in lipoprotein lipase (LPL) and phospholipid transfer protein (PLTP) were associated with both baseline HDL-c and TG levels. Changes in lipid traits were however the same in both treatment arms, for carriers of the LPL and PLTP minor allele carriers. No significant treatment interaction was seen for these genetic variants.
  • Three SNPs in hepatic lipase (LIPC) showed evidence of behavioural treatment effect modification after 1 year: a significantly larger increase in HDL-c levels was seen in the ILI arm than in the DSE group, as well as a stronger decrease in TG levels.
  • A genetic variation in CETP strongly affected HDL-C response to ILI. Indeed carriers of the minor allele showed a greater increase in HDL-c in response to ILI than did non-carriers (0.81 mg/dl per minor allele copy, 95%CI: 0.26-1.36), while no difference in response was seen in the DSE group.
Similar effects were seen for some other SNPs, with some of the minor alleles actually being associated with reduced HDL-c in response to ILI.

Several genetic factors were identified to interact with a randomly assigned behavioural intervention, to affect lipid trait change in the setting of established T2DM. SNPs that are associated with baseline HDL-c and TG levels do not necessarily predict the response to behavioural interventions. Certain SNPs even predicted ‘resistance’ to HDL-C improvement. However, all of the individual genetic effects were smaller than the aggregate HDL-C and TG response to ILI. Thus, individual genetic variations do not prevent a favourable HDL-c and TG response to lifestyle changes aimed at reducing obesity and increasing physical fitness.


1. Perusse L, Rice T, Despres JP, et al. Familial resemblance of plasma lipids, lipoproteins and postheparin lipoprotein and hepatic lipases in the HERITAGE Family Study. Arterioscler Thromb Vasc Biol. 1997;17:3263-3269.
2. Pilia G, Chen WM, Scuteri A, et al. Heritability of cardiovascular and personality traits in 6,148 Sardinians. PLoS Genet. 2006;2:e132.
3. Bouchard C, Tremblay A, Despres JP, et al. Sensitivity to overfeeding: the Quebec experiment with identical twins. Prog Food Nutr Sci. 1988;12:45-72. 
4. Despres JP, Moorjani S, Tremblay A, et al. Heredity and changes in plasma lipids and lipoproteins after short-term exercise training in men. Arteriosclerosis. 1988;8:402-409.
5. Teslovich TM, Musunuru K, Smith AV, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010;466:707- 713.
6. Bray G, Gregg E, Haffner S, et al. Baseline characteristics of the randomised cohort from the Look AHEAD (Action for Health in Diabetes) study. Diab Vasc Dis Res. 2006;3:202-215.
7. Pi-Sunyer X, Blackburn G, Brancati FL, et al, Yanovski SZ. Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one-year results of the look AHEAD trial. DiabetesCare. 2007;30:1374-1383.

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