Polygenic index of waist-hip ratio associated with cardiovascular disease

1. Investigating a polygenic index of 48 single nucleotide polymorphisms for Waist-Hip Ratio adjusted for BMI, this study showed an association with increased biomarkers for cardiovascular and metabolic risk.

2. The polygenic index for WHR-B was also associated with increased risk of Coronary Heart Disease and Type II Diabetes but not 38 other unrelated diseases.

Evidence Rating Level: 2 (Good)

Study Rundown: The Waist-Hip Ratio adjusted for BMI (WHR-B) has been shown to be correlated with cardiovascular and metabolic diseases. However, confounding environmental factors have made it difficult to discern whether WHR-B is a predictor of these diseases or simply related to disease development. Previous genome-wide association studies (GWAS) have determined that an underlying group of 48 single nucleotide polymorphisms (SNPs) may be causally linked with WHR-B. Thus, if independent of confounding factors like smoking status, eating habits, and lifestyle, these SNPs could provide a clearer association between WHR-B and coronary heart disease (CHD) and type II diabetes (DM-II).

This study utilized a previously developed polygenic index of these 48 SNPs and analyzed the genetic markers of a large number of tissues contained in a biobank. After validating the index as being strongly associated with WHR-B, the group showed that many biomarkers of cardiovascular and metabolic disease, such as triglycerides and cholesterol, were elevated in patients with more positive polygenic index scores. In addition, the risk of CHD and DM-II but not 38 other unrelated diseases were significantly increased with a 1 standard deviation difference in the WHR-B index.

The results of this study add to the evidence that WHR-B is a mechanistic predictor of later cardiovascular and metabolic disease, as opposed to a biomarker that is representative of other environmental processes.

The greatest confounder underlying this current method of validating WHR-B is one of pleiotropy, which tempers the conclusions due to shared genetic factors causing WHR-B and other endpoints, such as triglycerides or CHD. Though this paper makes many attempts to address this issue, it is difficult to completely mitigate concern. Still, this study should be accepted into the canon of evidence suggesting WHR-B as a more accurate predictor of cardiovascular and metabolic diseases compared to BMI.

Click to read the study, published today in JAMA

Relevant Reading: Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study

In-Depth [retrospective cohort]: The 48 SNP WHR-B polygenic index was developed from the Genome-Wide Investigation of Anthropometric Traits (GIANT) Consortium. The index had an F-score of 1713 and described 1.5% of the variance in WHR-B, validating it as an appropriate marker for WHR-B. Using data from the UK Biobank, the WHR-B polygenic index was not associated with confounders of WHR-B, such as smoking, alcohol use, physical activity, vegetable consumption, red meat consumption, and breastfeeding status as a child. The WHR-B polygenic index was associated with many biomarkers of CHD and DM-II, and for every 1 standard deviation increase in the WHR-B index there was an associated 1-point decrease in BMI (CI₉₅ 0.87-1.1), a 2-cm increase in waist circumference (CI₉₅ 1.5-2.4), and a 4.1-cm decrease in hip circumference (CI₉₅ 3.8-4.4). Likewise, each standard deviation increase in the index was associated with higher total cholesterol levels (5.6 mg/dL, CI₉₅ 3.9-7.3), higher LDL (5.7 mg/dL, CI₉₅ 4.1-7.2), higher triglyceride levels (27 mg/dLCI₉₅ 25-30), lower HDL level (6.0 mg/dL, CI₉₅ 5.3-6.6), higher log-transformed fasting insulin levels (0.07 log[pmol/L], CI₉₅ 0.05-0.08) log[pmol/L]), higher 2-hour glucose levels (4.1mg/dL, CI, 1.6-6.5), and higher systolic blood pressure (2.1 mmHg, CI₉₅ 1.2-3.0 mm Hg). The WHR-B polygenic index was also associated with a higher risk of DM-II (OR 1.77 CI₉₅ 1.57-2.00) and CHD (OR 1.46, CI₉₅ 1.32-1.62). 4 out of 5 sensitivity analyses for pleiotropy showed similar results and a phenome-wide association to 38 other unrelated disease were not significantly associated with the WHR-B polygenic index.

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