DNA shows why being short can be bad for your heart

It's true: Genetic analysis confirms link between short stature and risk of coronary artery disease

When Randy Newman sang his tongue-in-cheek tune about short people, he called attention to their “little hands, little eyes” and their “little baby legs.” Nowhere does his 1978 hit mention that short people also have an increased risk of coronary artery disease.

But scientists have established this link in several large studies, and a new one shows that it’s not just a coincidence. Some of the genetic variants that cause people to have short stature also tend to boost their levels of “bad” cholesterol and triglycerides – two risk factors for coronary artery disease.

After examining the DNA of 65,066 people with coronary artery disease along with that of 128,383 controls, researchers calculated that the risk for the condition rose by 13.5% for each 2.5-inch drop in height below the average. They also found that LDL cholesterol and triglycerides explain about one-third of this unfortunate relationship.

The results were published this week by the New England Journal of Medicine.

Coronary artery disease is a condition in which cholesterol and other substances in the blood form plaques that build up inside the vessels that supply the heart. This narrows the vessels and, over time, can weaken the heart muscle by depriving it of oxygen and nutrients. It also makes people vulnerable to a heart attack because it’s easier for an errant clot to cut off the blood supply altogether.

Coronary artery disease is the most common cause of death for men and women in the United States, according to the National Heart Lung and Blood Institute.

Some people had speculated that the link between shortness and coronary artery disease was a matter of geometry. Tall people have bigger coronary arteries, and short people have smaller ones. Therefore, it stands to reason that any given amount of plaque has the potential to do more damage to someone with petite arteries than it does to someone with wider ones.

But the research team found a problem with this theory. Women have “smaller-caliber” arteries than men, they noted. That should mean that short women have the greatest risk of coronary artery disease. Instead, the researchers discovered that the genetic link between height and the disease was weaker in women than in men.

The researchers began their analysis by focusing on 180 places in the human genome that were shown to be associated with height in a 2010 study known as the Genetic Investigation of Anthropometric Traits, or GIANT. None of these 180 genetic variants had any previously known connection to the risk of coronary artery disease.

The researchers estimated how much a change in each of these height-related variants changed the odds of the disease among thousands of people who had already participated in genome-wide association studies and clinical trials related to coronary artery disease. Most of the variants had little to no effect on their own. But once all of them were added together, the net effect was that the risk of coronary artery disease rose as height fell.

When the researchers restricted their analysis to patients who had suffered a heart attack, the association between height and risk of the disease was the same.

The researchers had enough data on 18,249 people to cluster them into four groups depending on how many of their 180 height-related variants were of a type that would make them taller. Once again, there was a linear relationship. Compared with those with the fewest “tall” variants, those with the most were 26% less likely to have been diagnosed with coronary artery disease.

The study “validates the epidemiologic observation of an inverse association between height and CAD,” the researchers concluded. But for the most part, it doesn’t explain why this association exists.

The strongest signal was for LDL cholesterol, which accounts for about 19% of the link between genetically determined height and CAD. Another 12% is due to the effect of triglycerides. Still, scientists don’t yet understand how these 180 variants influence the body’s production of either LDL or triglycerides.

And the explanation for the remaining 69% remains a mystery. One thing the analysis did not find was a link between the height-related DNA and body mass index. That suggests obesity is not the reason shorter people are more likely to have heart disease.

It’s possible that short people make lifestyle choices that make them more susceptible to coronary artery disease, the study authors wrote. Perhaps they drink more than tall people, or exercise less. So far there’s no evidence that either of these things is true. The researchers did note that short people who smoke do not smoke more cigarettes than tall people who smoke.

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