Factors Linked to LDL-Cholesterol Levels Differ by Gender

Liam Davenport

May 29, 2019

MAASTRICHT, The Netherlands — Differences in the impact of an unhealthy lifestyle and genetic factors on levels of low-density-lipoprotein (LDL) cholesterol between men and women, as well as their association with key disease targets, could be used to individualize cardiovascular treatment between the sexes, say Dutch investigators.

Antoine Rimbert, PhD, University Medical Center Groningen, the Netherlands, and colleagues looked at data on more than 600 men and women who had either very low, normal range, or very high LDL-cholesterol levels.

Presenting the findings here at the European Atherosclerosis Society 2019 Congress, they showed that an unhealthy lifestyle was significantly associated with high LDL-cholesterol levels in women but not in men.

Moreover, a genetic cause for low LDL-cholesterol levels was identified for almost 70% of women, but only just over half of men.

In contrast, there was a significant association between high LDL-cholesterol levels and levels of the atherogenic lipoprotein(a) in men but not in women.

Although both sexes had a significant association between levels of the dyslipidemia treatment target proprotein convertase subtilisin/kexin type 9 (PCSK9) and LDL-cholesterol levels, PCSK9 levels were, on average, higher in women than in men.

Rimbert said that their findings have "strong repercussions for the healthcare of these individuals, who are at high risk of developing atherosclerosis later on in life."

Gerard Pasterkamp, MD, PhD, professor and head of the Experimental Cardiology Laboratory, University Medical Centre Utrecht, the Netherlands, who chaired the session, questioned, however, whether treatment could indeed be modified for men and women.

"The question is more about: Can we understand the sex-specific differences, because we do see differences sometimes in the pathogenesis in studies," he told theheart.org | Medscape Cardiology.

Pasterkamp believes, however, that "we can't make the next step based on these results to change therapy, because you would still treat males and females exactly the same."

This is for two reasons, the first being that the study data were not individualized, so it is not possible to say who would benefit from which treatment, he explained.

The other reason is that "if you look at all the demographic statistics, we see a decline in myocardial infarction and strokes, but the decline is similar for males and females, so the mechanisms do not affect so much the outcome of the disease."

Still, Pasterkamp added, "it's very important to understand what is driving the mechanism because, if we have the tools, let's say genetics or biomarkers, to do more individualized or risk-stratified therapies, then you can adapt them, but at present that's still a challenge."

Main Factor

Atherosclerotic cardiovascular disease (ASCVD) is a disorder of aging that begins in childhood, with LDL cholesterol as the main risk factor, Rimbert said.

One of the main drivers of ASCVD is lifestyle, he said, noting that, although major gender differences are also seen, the treatment of the disorder is the same regardless of age and gender.

To examine how drivers of low and high LDL levels differ between genders, the researchers conducted an observational study using data from the Dutch Lifelines bio- and databank.

From this database, which contains information on more than 167,000 individuals over a 30-year period, they selected men and women 25 to 39 years of age who had completed extensive questionnaires and provided DNA and plasma samples.

They included 121 women and 120 men who were in the first percentile for LDL-cholesterol levels, 60 men and 60 women who had average LDL-cholesterol levels and acted as controls sunjects, and 121 women and 120 men who were in the 99th percentile for LDL-cholesterol levels.

The results showed that body mass index was significantly associated with high LDL-cholesterol levels in women (P < .01), but not in men and not with medium or low LDL-cholesterol levels.

HDL-cholesterol levels were significantly inversely associated with high LDL-cholesterol levels in women (P < .01), but, again, not in men and not with medium or low LDL-cholesterol levels.

In contrast, there was a significant association between triglycerides and high LDL-cholesterol levels that was stronger in men (< .01) than in women (< .05).

This pattern was also seen for apolipoprotein E, with the association with LDL-cholesterol levels stronger in men (< .001) than in women (< .05).

Rimbert and colleagues also found that, although there was a significant association between high LDL-cholesterol levels and PCSK9 levels in both sexes, average levels in women were significantly higher than in men (P < .001).

Interestingly, LDL-cholesterol levels were not associated with lipoprotein(a) levels in women.

However, they were in men, with significant differences in lipoprotein(a) levels seen between those with low, control, and high LDL cholesterol (P < .001).

Next, the team used a lifestyle score in which individuals were rated as healthy or unhealthy, depending on the combination of their smoking status, their weight, whether they exercised regularly, and their eating habits.

This showed that an unfavorable lifestyle was positively and significantly associated with LDL-cholesterol levels in women (P < .05), but not in men, where there were no significant differences across the groups.

Finally, they looked at the prevalence of common and rare genetic variants associated with cholesterol levels, finding that there was a gender difference in the degree of genetic predisposition.

Specifically, 68% of women with hypocholesterolemia were found to have a genetic explanation for their low LDL-cholesterol levels, compared with just 55% of men (P = .03).

There was no difference in the degree of genetic predisposition for high LDL-cholesterol levels, at 32% in women and 30% in men.

Rimbert and colleagues are now examining a number of other parameters, including the size of lipoproteins in plasma, to develop a "fingerprint" of individuals with known or unknown genetic cases, or favorable or favorable lifestyles.

The aim is "to better understand what is going here, and how we can select the right persons to focus on for the identification of new pathways."

No conflicts of interest or funding reported.

European Atherosclerosis Society (EAS) 2019 Congress: Abstract EAS19-1010. Presented May 27, 2019.

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