Determining Risk for Disease – HMX Genetics

Determining Risk for Disease – HMX Genetics

Dr. DeGennaro:
Mendelian conditions are rare and often quite severe. But complex traits like high
cholesterol, type 2 diabetes, rheumatoid arthritis,
depression, coronary heart
disease, and obesity are more common
in the population. Many families seem to have
a high incidence of one of these traits, indicating
that they have one or more risk variants for that condition. Each complex trait
has a different amount of heritability, which tells
us how much of the variation observed in that trait can
be accounted for by genetics. Genome-wide association studies
can provide further insight into the genetic
basis of a disease by allowing identification of
disease-associated variants and calculation of
an odds ratio, which provides an estimate of how
much a variant increases or decreases risk
of a condition. However, most traits still
have a substantial amount of missing heritability,
meaning that we don’t yet understand all of the
genetic risk factors. In addition, while
heritability and odds ratios are predictive at
the population level, many questions remain about
how to use this information to predict risk
in an individual. Predicting the risks associated
with genetic diseases requires an understanding
of conditional risk. Every trait has a
general population risk. For example, nearly 10% of all
Americans have type 2 diabetes. However, the risk
that an individual will develop diabetes
within the next decade may be considerably different
than the general population risk based on factors like
age, weight, ethnicity, physical activity, diet,
and family history. To determine the risk of an
individual based on one or more of these factors, you
can look at the risk of a subset of the population
with that same characteristic or set of characteristics and
adjust the risk prediction of the individual accordingly. Let’s look at an example of
how this works in more detail. Let’s look at the risk of
coronary heart disease, or CHD, which is the buildup of plaque
in the arteries of the heart and which substantially
increases risk of heart attack and stroke. CHD is a complex trait
determined by genetics and the environment. The risk of an American adult
developing complications of CHD, such as heart attack
or stroke, is about 6% over a 10-year period. However, if we look at these
two individuals, Adriana and Joseph, you might
imagine that their risk is quite different. How can we use information
about both their genetics and environment to give
them a more accurate picture of their risk? To determine the risk of having
a CHD-related complication in the next 10 years, we
can take their sex and age into account. Adriana is 31 and female, and
this lowers her risk compared to the general population. Taking only his age
and sex into account, Joseph, who is 47 and male,
also has a slight decrease in his risk. Now let’s consider how
traditional risk factors might impact their individual risks. Cholesterol levels,
particularly high levels of LDL, or bad cholesterol,
and low levels of HDL, or good cholesterol,
increase their risk. Adding on high blood
pressure, smoking, and the onset of
diabetes increases risk further,
though you’ll notice that there is a
differential effect on each of their risks based
on their age and sex. Now let’s compare an estimate of
risk based on traditional risk factors to an estimate based
on genetic variants associated with CHD. There are, of course,
Mendelian variants that can lead to
drastically increased risk. For example, certain
rare variants that impact cholesterol
levels lead to early onset CHD, and increased risk
of fatal heart attack, 50 to 100-fold if left untreated. However, most cases of
increased genetic risk are due to a number of
small effect variants. We don’t know all of the
variants associated with CHD, but a risk score
can be estimated by combining the effects of
the variants that are currently known. In extreme cases,
where an individual has a version of each of these
variants that increases risk, the maximum risk is
estimated to be about four times the baseline risk. This might seem
like a large number, especially when
presented in percent form as 400% of baseline
risk, or a 300% increase over baseline risk. But it’s important to remember
that in a healthy individual, the baseline risk is relatively
low, and the increase in risk is less than the increase
that can be attributed to traditional risk factors. In addition, few people carry
all of the risk alleles. More commonly,
these variants might increase risk twofold or less. Twofold might still sound
like a large increase, but looking at the absolute
rather than the relative risk can provide a more
intuitive understanding of the odds of developing
a particular condition. If you consider the
baseline risk of individuals of similar age,
sex, and ethnicity, which is 4%, or four
out of every 100 people, and convert this twofold
increase in relative risk to an absolute risk, you
can see that in the subset of these individuals who have
a similar genetic makeup, 8%, or eight out of every 100,
will experience complications from CHD over the
course of 10 years, while the other 92 will not. While this is an increase
from the baseline risk, the odds are still low
for any individual. It’s also important to keep
the relative magnitude of these effects in mind,
because although an individual’s genetics
cannot be changed, lifestyle and medical
intervention can often alleviate risk from
traditional risk factors, which can play a much larger
role in determining risk. Thinking about the
probabilities in this way will give you a more
accurate picture of risk. At present, many questions
remain about the variants that underlie complex diseases. What can account for the
missing heritability? How can we combine the
risks of different variants in a way that’s informative? What’s the interplay between
the genetic and environmental risks? As we continue to learn more
about the underlying genetic and environmental causes
of complex diseases, we’ll be able to
use this information to make better predictions
about the risk of an individual. Ultimately, risk is predictive
on a population level, but refining our predictions
by categorizing individuals into more and more
specific subpopulations, by physiological, genetic, and
environmental characteristics could allow for
personalized risk assessment and more targeted
treatment of complex diseases.

2 comments on “Determining Risk for Disease – HMX Genetics

  1. Muhammad Jasim Post author

    We can reduce these risks by balanced diet, physical exercises, spiritual meditation etc.And Islam says us to do these things regularly 🙂


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