Deeper Dive: A Mendelian randomization study sheds light on the effects of polyunsaturated fatty acids on heart disease

Coronary artery disease (CAD) is caused by the accumulation of atherosclerotic plaques in the circulatory system^[1] — commonly called “clogged arteries”. Eventually, CAD can lead to heart attacks, stroke, and related cardiovascular diseases. The drivers of coronary artery disease in industrialized countries are primarily lifestyle factors^[2]. One factor that has received significant experimental and epidemiological attention is diet. Specifically, the nutritional makeup of a diet and dietary fat in^[3] particular^[4].

Polyunsaturated fatty acids (PUFAs) are essential fats with multiple unsaturated carbon bonds. The two best known and most relevant types of PUFAS are omega-3 and omega-6 fatty acids. Omega-6 fatty acids include arachidonic acid (AA), the predominant PUFA in cell membranes that contributes to both pro-inflammatory and pro-resolution cellular processes^[5], and its shorter chain relatives, linoleic acid, adrenic acid, gamma-linolenic acid (GLA), and dihomo-gamma-linolenic acid (GDLA). In contrast to AA, the latter two are considered anti-inflammatory, anti-atherogenic omega-6 fatty^[6] acids^[7]. The most studied omega-3 fatty acids, on the other hand, have been found to be predominantly anti-inflammatory and pro-resolution in function^[8], suggesting a positive effect on heart health. Their most prominent members ordered from shortest to longest chain-length are alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA).

Figure 1: The main PUFAs examined in this study

Each of these polyunsaturated fatty acids acts as a substrate and a regulator in pathways that mediate anti-inflammatory, pro-inflammatory, and pro-resolution activities within cells. All three activities are relevant to the development of heart disease. After initial cholesterol lipoproteins accumulate in damaged artery walls, inflammatory signals tell immune cells to accumulate, resulting in further inflammation^[9]. Anti-inflammatory signals prevent inflammation of artery walls by reducing the synthesis of inflammatory molecules and directly blocking inflammatory signaling by competing for shared enzymes in the omega-3 and omega-6 biosynthetic pathways. Pro-resolving signals end inflammation by preventing LDL-cholesterol uptake and removing dead cells, foreign material, and white blood cells that accumulate in atherosclerotic plaques^[8]. PUFAs can also affect blood clotting ability, serum triglyceride levels, and, to an extent, LDL cholesterol levels.

Research has been unclear on the individual roles of these different fats. The American Heart Association suggests that the risk of heart disease can be lowered by substituting any PUFA in place of saturated fat^[5]. Previous meta-analyses of randomized controlled trials have shown positive^[10] effects^[4] or no effect^[11] of supplemental high EPA and DHA marine oils on coronary heart disease, but they have not identified clear roles for individual omega-3 PUFAs. Other meta-analyses have shown that some omega-6 fatty acids may have beneficial^[12] effects^[3] on heart disease. This effect is most consistent for linoleic acid^[13], but the relationship between arachidonic acid and heart disease outcomes is far from fully understood, with one short-term clinical trial showing no effect^[14], one showing a positive effect^[15], a meta-analysis of observational data showing a strong positive effect^[16], and another showing either no effect or a potentially negative effect^[17], all laid on top of contradictory mechanistic data.

Mendelian randomization is a study design that compares outcomes between one group of people with a genetic variant and another group with a different variant, each of which has a different effect on an outcome of interest. Mendelian randomization does a remarkably good job at minimizing bias compared to other analyses of observational studies. Even though no intervention takes place, you might think of Mendelian randomization as a randomized controlled trial in which one group is randomly “assigned” one variant at birth, while another is randomly “assigned” a different variant, and then followed through time^[18]. For example, a Mendelian randomization study on fats and heart disease risk would look at a group of people with genes that increase specific circulating fatty acids relative to a group of people with genes that do not and compare their relative risk of coronary artery disease.

Despite being powerful tools in determining whether a variable truly causes an outcome, Mendelian randomization studies have been infrequently used to investigate the effects of different fatty acids in heart disease. The present study compares the risk of coronary artery disease in groups with genetic mutations that increase specific omega-3 and omega-6 polyunsaturated fatty acids.

Previous studies have pointed to a beneficial effect of omega-3 polyunsaturated fatty acids and either a beneficial effect, no effect, or a potentially negative effect of omega-6 polyunsaturated fatty acids. Mendelian randomization, by which groups are compared based on their genetic predisposition for higher or lower specific fatty acids, may help relate the genetically determined levels of specific PUFAs to risk of coronary artery disease and heart attack, even though the method says nothing about the effect of dietary fatty acids on heart disease risk.