Fat-Absorbing XX Chromosomes Raise Heart Disease Risk in Women

Fat-Absorbing XX Chromosomes Raise Heart Disease Risk in Women


LISA CASSIS: The leading cause of death in
women is coronary artery disease by far. But having said that, women develop coronary artery
disease almost 10 years later than men. Now for many, many years, research focused on
sex hormones, like estrogen and progesterone, as contributors to why women might be protected
and then why, after menopause, they might have more risk. And there is a lot to be said
and a lot of evidence that estrogen is indeed protective against coronary artery disease
and also promotes a more favorable lipid profile–so good lipids rather than bad lipids. YASIR AL-SIRAJ: circulating lipids are fat
molecules that are transported by the blood. But if they are too high, they will start
to accumulate in and on the wall of the artery. And that accumulation will lead to building
up plaques. These plaques hardens and narrows the artery, and this will lead to reduced
amount of blood flow to the vital organs. And this is what’s called atherosclerosis. LISA CASSIS: And it sets into play a lot of
inflammation and other processes that can then give you ultimately a heart attack.
There are two major ways you make these lipids. You absorb them from your diet. Or you make
them in your liver. So we looked at both of those as how our X sex chromosomes were influencing
the levels of lipids in the blood and in the arteries. And what we found is that actually an XX sex
chromosome complement pretty much sets you totally into place to efficiently use fat.
What our hypothesis would suggest is that we have evolved to be very efficient at absorbing
and storing fat as women. We need it for childbearing purposes. We’re mothers. We feed babies. We’re
set up, potentially through our XX sex chromosomes, to make us effectively absorb that lipid from
the diet and put it into our fat cells and maybe even make it in the liver. Now, we’re
OK because estrogen is protecting us from getting it into the arteries and getting trapped
there. But once we go through menopause and those levels of those sex hormones decline,
then all we have, this is our hypothesis, is that XX, thrifty, fat absorbing kind of
genotype. YASIR AL-SIRAJ: we found that the presence
of two X chromosomes increase the circulating lipids and atherosclerosis in mice.
We believe that results from our studies provide important information to clinical care because
this suggests that the female gonadal hormones, like estrogens, are unlikely to be the only
determinants of the sex differences to the risk of coronary artery disease. So that
means that there is another determinant of the sex differences– basically, its genetic
components, specifically genes on the sex chromosomes. And that could lead to the development
of sex-specific therapy that could work in one sex, but not in the other. 
Well, the next step in this research, we are going to study the role of number of X chromosomes
in atherosclerosis because the results from these studies, we don’t know if it’s due to
the presence of two X chromosomes or due to the absence of the Y chromosome. LISA CASSIS: we’re looking at genes that are
changed in the liver and in the intestine. We’re trying to find those targets. What kind
of a target relates to serum lipids and atherosclerosis that might be a novel target that we haven’t
thought about before that we could then go after with either an available drug or creating
a new drug for that purpose? We may also use this information to guide women on the choice
of their diet. For example, if they’re very effective fat absorbers, obviously, once they
get postmenopausal, they need to be careful about the fat content. It might drive certain
types of diets, depending on your age and your menopausal status. And I guess one of
the exciting things for me is there are others that are studying this sort of area. But there
are not that many in the cardiovascular system. So I’m excited because I think we have, with
our tools and our knowledge, maybe a very defined path to get at, how we can use this
information to drive therapy and prevent disease.