Ahmad et al. (1) in their study aim to identify the interactions between adiposity and triglyceride associated genetic variants in the apparently healthy women from the Women’s Genome Health Study (WGHS). The purpose of this study was to identify the link between lifestyle-related exposures and an inherent risk for higher triglyceride levels. Given the immense burden of cardiovascular disease (CVD) as the leading cause of mortality globally, it is important to understand and dissect contributing factors of CVD. Increased triglyceride levels that are generally found with obesity [body mass index (BMI) ≥25.0] have been correlated with higher risk for development of CVD (2). Two studies done in Denmark (3) and Sweden (4) as referenced by Ahmad et al. (1) attempt to explain this variability in that adiposity [BMI and waist circumference (WC)] in interaction with triglyceride associated single-nucleotide polymorphisms (SNPs) can accentuate the risk of developing higher triglyceride levels which in return leads to a higher risk of CVD. Ahmad et al. attempt to replicate these findings in the US population. The group analyzes blood samples of 23,294 American women in the WGHS database and calculates a triglyceride-weighted genetic risk score (TG-wGRS) based on the prevalence of 40 SNPs that have been associated with hypertriglyceridemia. They then do a meta-analysis combining results from WGHS with four Scandinavian Cohorts (INTER99, HEALTH2006, GlACIER, MDC) analyzing triglycerides levels based on the calculated TG-wGRS, BMI, and WC. The results of this study are remarkable in that they discover the following:
- Each unit increase in TG-wGRS was associated with a 1.011% increase in TG of normal BMI individuals vs. 1.013% in higher BMI individuals (Pinteraction =0.014);
- Each unit increase of TG-wGRS was associated with a 1.010 increase in TG of normal WC individuals vs. 1.012% in higher WC individuals. (Pinteraction =0.06);
- They found highly significant interaction of TG-wGRS and BMI with TG-rich lipoprotein (TRLP) Pinteraction <0.001).
These results demonstrate that the effects of genetic predisposition to a high TG level appear to be augmented by adiposity (BMI/WC). Epidemiologic and clinical data align with genetic data and support a causative role for TG and TRLPs in CVD (2). In the genome wide association studies, triglyceride effect size was significantly associated with CVD (r=0.46, P=0.02) (5). In a study using data from three Copenhagen population cohorts, three common APOA5 variants used to define 10 common genotype combinations were associated stepwise increase in triglyceride and cholesterol remnant. With each doubling of non-fasting triglyceride levels and calculated remnant (which is the cholesterol content of TRLPs) risk of myocardial infarction (MI) approximately doubled [odds ratios of 1.94 (95% CI: 1.40–1.85) and 2.23 (95% CI: 1.48–3.35), respectively] (6).
In conclusion, study by Ahmad et al. supports the previous data, that adiposity accentuates the effects of interaction between genetic factors and serum triglyceride and TRLPs. Previously, in studies conducted by Pollin et al. (7) and Zubair et al. (8) found that intensive lifestyle modification and weight loss might partially alleviate interaction between genetic risk score and higher triglycerides. Thus, obese individuals with high triglycerides and TG-wGRS might benefit the most from intense lifestyle modifications and triglyceride lowering products such as omega 3 fatty acids. Further multiethnic population-based studies are needed to assess the effects of weight loss and triglyceride lowering medications across different genetic risk profiles.
Conflicts of Interest: The authors have no conflicts of interest to declare.
- Ahmad S, Mora S, Franks PW, et al. Adiposity and Genetic Factors in Relation to Triglycerides and Triglyceride-Rich Lipoproteins in the Women's Genome Health Study. Clin Chem 2018;64:231-41. [Crossref] [PubMed]
- Budoff M. Triglycerides and Triglyceride-Rich Lipoproteins in the Causal Pathway of Cardiovascular Disease. Am J Cardiol. 2016;118:138-45. [Crossref] [PubMed]
- Justesen JM, Allin KH, Sandholt CH, et al. Interactions of Lipid Genetic Risk Scores With Estimates of Metabolic Health in a Danish Population. Circ Cardiovasc Genet 2015;8:465-72. [Crossref] [PubMed]
- Ali A, Varga TV, Stojkovic IA, et al. Do Genetic Factors Modify the Relationship Between Obesity and Hypertriglyceridemia? Findings From the GLACIER and the MDC Studies. Circ Cardiovasc Genet 2016;9:162-71. [Crossref] [PubMed]
- Willer CJ, Schmidt EM, Sengupta S, et al. Discovery and refinement of loci associated with lipid levels. Nat Genet 2013;45:1274-83. [Crossref] [PubMed]
- Jørgensen AB, Frikke-Schmidt R, West AS, et al. Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction. Eur Heart J 2013;34:1826-33. [Crossref] [PubMed]
- Pollin TI, Jablonski KA, McAteer JB, et al. Triglyceride response to an intensive lifestyle intervention is enhanced in carriers of the GCKR Pro446Leu polymorphism. J Clin Endocrinol Metab 2011;96:E1142-7. [Crossref] [PubMed]
- Zubair N, Mayer-Davis EJ, Mendez MA, et al. Genetic risk score and adiposity interact to influence triglyceride levels in a cohort of Filipino women. Nutr Diabetes 2014;4. [Crossref] [PubMed]
Cite this article as: Sheikh MS, Shaikh K, Budoff MJ. Interaction of genetic risk scores and adiposity: a significant influence on triglyceride levels. J Lab Precis Med 2018;3:82.