Do Seed Oils Cause Heart Disease?

tl:dr—Seed oils are associated, and probably causal, in cardiovascular disease.

"Figure 3. Mendelian randomization analysis. A significant deviation from zero of the estimate of causal effect using all SNPs (solid red line) suggests a causal relationship between the metabolite and CHD." (Ganna et al., 2014)

Oh dear. So sorry... *

"The Mendelian randomization analysis... suggested a weak, but positive causal effect of MG 18:2 on CHD risk (odds ratio, 1.05... per SD increment in MG 18:2; P-value = 0.05) and a lack of causal effect for LysoPC 18:1, 18:2 and SM 28:1."

Even worse:

"...In the multivariable analysis for association with CHD, we separately included two covariates in addition to the main cardiovascular risk factors: [CRP] and statin treatment. The associations between the four metabolites and incident CHD were essentially the same...

"Lysophosphatidylcholines were negatively associated with BMI, markers of inflammations and subclinical cardiovascular disease, while a reverse pattern was observed for MG 18:2."

“We found evidences [sic] for a causal effect of MG 18:2 on CHD independently of triglycerides levels."

And: "We observed a strong positive association between MG 18:2 and CHD."

So what are they saying? A few terms, so you can understand the jargon:

• Mendellian randomization is a way of correlating observational (epidemiological) data cross-referenced to genetic data. This is supposed to establish “causation” using epidemiology. **
• MG 18:2 is monoglyceride linoleic acid (LA, chemical symbol C18:2). Linoleic acid attached to a glycerol molecule, in other words.
  LA is the most common fat found in seed oils. Fats are generally consumed as either triglycerides or phospholipids, in this case two fats have been removed from a tri-glyceride, leaving one, a mono-glyceride.
• CHD is coronary heart disease.
• CRP is c-reactive protein, part of the body’s inflammatory response, and used as a marker of inflammation.
• Phosphatidylcholines (PC) are a way of packaging fats, used extensively in the body’s cellular membranes. Tri-, di-, or mono-glycerides attach three, two, or one fat(s) to a glyceride backbone, here two fats are attached to a choline backbone. You’ve heard of lecithin? This is the chemical name for lecithin.
  
• Lysophosphatidylcholine (LysoPC) is a PC from which one fat has been removed.

So they looked at metabolites of various things in the body (Metabolomics) and found a correlation between a form of linoleic acid (LA) and heart disease. LA is generally found in triglycerides (TG), but here they found the association with TG was weaker than that of LA with heart disease. TG is an established risk factor for heart disease.

Moreover they found that this effect became stronger as the amount of LA increased: “a weak, but positive causal effect of MG 18:2 on CHD risk (odds ratio, 1.05... per SD [standard deviation] increment in MG 18:2…” This is known as a dose-response, and suggests that causation is present (criteria 5 in the Bradford Hill list of criteria for determining possible causation from observed data).

More:

"Several observations suggest an involvement of MG 18:2 in the pathogenesis of CHD. First, MG 18:2 is central in the synthesis and breakdown of triglycerides and a causal effect of plasma triglyceride levels on CHD risk have recently been supported by a large Mendelian randomization analysis [11]. Although highly correlated, when both MG 18:2 and triglycerides were included in the same model, both showed independent significant associations with CHD. Moreover, when separately added to a model with main cardiovascular risk factors, MG 18:2 was a better predictor of CHD than triglycerides. Second, MG 18:2 was associated with higher levels of cardiovascular risk factors and markers of subclinical CVD and oxidative stress. Third, Mendelian randomization analysis suggested a weak, but positive causal effect of MG 18:2 on CHD risk. Several SNPs reported for association with CHD remained associated with MG 18:2 (in the PCSK9, HHIPL1, PLG, ApoE/ApoC1, COL4A1/COL4A2 regions, P-values,0.05), even after adj. for main cardiovascular risk factors.”

"Our study has several strengths. To our knowledge, this is the largest study investigating the metabolome in relation to incident CHD."

"In conclusion, in the largest study of the metabolome in relation to incident CHD to date, we identified [LysoPC]s 18:1, 18:2, monoglyceride 18:2 and sphingomyelin 28:1 as risk factors of coronary heart disease and suggested a causal effect for monoglyceride 18:2 on CHD."

So much for the claims there’s no epidemiology supporting the hypothesis that LA from seed oils is causal in heart disease.

"Large-scale metabolomic profiling identifies novel biomarkers for incident coronary heart disease" (Ganna et al., 2014)

Of course linoleic acid is hardly "novel"... The link between LA and heart disease goes all the way back to the 1950s:

“Our results are in accord with the recent work of [(Böttcher et al., 1960)] who showed conclusively that human atherosclerotic plaques have a high content of linoleic acid which increases with the severity of the disease….

“This result would support the view that linoleic acid is essential for the production of atherosclerotic plaques.” (Gresham & Howard, 1961)

If you want more information on the link between seed oil and heart disease, see our work here (Zero Acre Editorial Team, 2022)

I discussed with Prof. Tom Brenna the importance of choline and phospholipids in the metabolism of fat in the body (Goodrich,2022), and I find it very interesting that the correlations between LA in phospholipid form (LysoPC 18:2) and triglyceride form (MG 18:2) is different. Monoglycerides can have very distinct effects on the body (Poursharifiet al., 2017), this may be such a case.

So what's the most messed up thing about this analysis?

They never mention the word "linoleic," or any part of it.

I found this while pulling threads, I never would have found it looking for any useful search term.

* Came across this paper today, while working on something concerning diabetes (Al-Sariet al., 2021). Really, you shouldn’t have to dig into something like this (ChEBITeam, 2018) to find a pretty important paper, but the Tower of Babel story is true in every important way, except perhaps for not actually having happened.

** I have some serious issues with MR, which I will not go into here, but since I have been told that there is no evidence using MR that LA causes CVD, I found this satisfying.

References

Al-Sari, N., Schmidt, S., Suvitaival, T., Kim, M., Trošt, K., Ranjan, A. G., Christensen, M. B., Overgaard, A. J., Pociot, F., Nørgaard, K., & Legido-Quigley, C. (2021). Changes in the lipidome in type 1 diabetes following low carbohydrate diet: Post-hoc analysis of a randomized crossover trial. Endocrinology, Diabetes & Metabolism, 4(2), e00213. https://doi.org/10.1002/edm2.213

Böttcher, C. J. F., Woodford, F. P., Romeny-Wachter, C. C. T., Houte, E. B., & Gent, C. M. V. (1960). Fatty-Acid Distribution In Lipids Of The Aortic Wall. The Lancet, 275(7139), 1378–1383. https://doi.org/10.1016/S0140-6736(60)91153-3

ChEBI Team. (2018). Phosphatidylcholine 35:4 (CHEBI:91322) [Informational]. European Molecular Biology Laboratory; Chemical Entities of Biological Interest. https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:91322#25502724

Ganna, A., Salihovic, S., Sundström, J., Broeckling, C. D., Hedman, A. K., Magnusson, P. K. E., Pedersen, N. L., Larsson, A., Siegbahn, A., Zilmer, M., Prenni, J., Arnlöv, J., Lind, L., Fall, T., & Ingelsson, E. (2014). Large-scale metabolomic profiling identifies novel biomarkers for incident coronary heart disease. PLoS Genetics, 10(12), e1004801. https://doi.org/10.1371/journal.pgen.1004801

Goodrich, T. D. (2022, September 1). Podcast Ep. 5: Prof. Tom Brenna on Omega-3 and Omega-6 in Human Health—with Dr Brian Kerley [Blog]. Yelling Stop. http://yelling-stop.blogspot.com/2022/09/podcast-ep-5-prof-tom-brenna-on-omega-3.html

Gresham, G. A., & Howard, A. N. (1961). The Effect of Dietary Fats and Synthetic Glycerides on the Production of Atherosclerosis and Thrombosis in the Rat. British Journal of Experimental Pathology, 42(2), 166–170. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2082415/

Poursharifi, P., Madiraju, S. R. M., & Prentki, M. (2017). Monoacylglycerol signalling and ABHD6 in health and disease. Diabetes, Obesity & Metabolism, 19 Suppl 1, 76–89. https://doi.org/10.1111/dom.13008

Zero Acre Editorial Team. (2022, August 12). Seed Oils as a Driver of Heart Disease [Advertisement]. Zero Acre. https://www.zeroacre.com//white-papers/seed-oils-as-a-driver-of-heart-disease