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Using Genomics to Modify Genetic Diseases

Is it possible to modify someone’s disease risk or impact from a genetic mutation or other highly penetrant gene variant?

This is a question we hear often from both clinicians and our own patients. When you understand the biochemistry of our bodies – including the enzymes, cofactors and cell signaling pathways – it is very clear that the answer is often yes.

Why? Because our complex biology relies on multiple systems to perform critical functions. And very often there are backup systems built in so that if one system is down or not functioning as it should, other systems can pick up the slack. It also means that since multiple biological systems are involved in so many diseases, how well backup systems are working can make a big difference in how a disease actually manifests.

Take hereditary breast cancer related to BRCA gene mutations, for example.

Back in 2014, Dr. Veltmann gave a presentation estrogen metabolism and breast cancer at the first International Latin American Personalized Medicine conference. He introduced the concept of genes influencing the impact of BRCA gene mutations on breast cancer risk, focusing on the potential modifying impact of Nrf2. Early research was looking at how SNPs in the gene that codes for this “master antioxidant” gene might influence the development of hereditary breast cancer.

While this was met with a lot of skepticism at the time, we knew we were on the right track with our deep knowledge of the genomics and biochemistry involved. Further research has confirmed this concept.

A recent study published in Nature is providing support for what we have observed clinically and based our approach on: the polygenic model. Our deep knowledge of genomics and biochemistry, combined with our 25+ years of experience in Genomic Medicine led us to this conclusion more than a decade ago: that using a polygenic approach gives us the best assessment and most powerful tools.

Now with this recent study we are now starting to document on a quantitative level just how much impact a polygenic approach can have on a disease process.

They looked at 3 diseases with a strong genetic link: hereditary breast and ovarian cancer, familial hypercholesterolemia, and Lynch syndrome.

In this study, they looked at over 80,000 individuals of primarily European ancestry to examine the interaction between variants in multiple genes in other systems (called the polygenic background) and monogenic variants for these specific inherited diseases. They found that carriers of a monogenic risk variant had substantial variability in disease risk based on the polygenic background.

And what they were able to quantify is astounding: the probability of disease by the age of 75 ranged from 17 percent to 78 percent for coronary artery disease; 13 percent to 76 percent for breast cancer; and 11 percent to 80 percent for colon cancer (Lynch syndrome).

Breast cancer

For individuals with BRCA1 or BRCA2 mutations, they found a baseline 3.48-fold increased risk of breast cancer.

The investigators then calculated a polygenic risk for breast cancer and found that disease risk was strongly affected by these other gene variants, even for individuals who carried a pathogenic BRCA1 or BRCA2 mutation. Compared to non-carriers with intermediate polygenic score, there was an increased risk among carriers that ranged from 2.40-fold for those in the lowest quintile of the polygenic score distribution to 6.85-fold in the highest quintile.

Familial Hypercholesterolemia

The presence of a familial hypercholesterolemia variant in any of the LDLR, APB or PCSK9 genes conferred a baseline 3.21-fold increased risk of coronary artery disease.

But the actual observed risk varied substantially according to the polygenic score. For example, the risk among mutation carriers ranged from 1.30-fold for those in the lowest quintile of the polygenic score distribution to 12.61-fold in the highest quintile of the polygenic score distribution, when compared to non-mutation carriers with intermediate polygenic scores.

Colorectal Cancer

 A pathogenic or likely pathogenic Lynch syndrome variant in any of four genes (MLH1MSH2MSH6, and PMS2) conferred a baseline increased risk of colorectal cancer of 27.86-fold.

But when they factored in polygenic scores, absolute risk of colorectal cancer by age 75 years ranged from 11.3% to 79.7% for carriers and 0.7% to 8.7% for noncarriers.

So what does this all mean in practical terms?

We can potentially modify the outcome of inherited diseases by understanding the multiple biochemical pathways and mechanisms involved, the genes that impact them, and using a polygenic model for genomics. This may make a difference as to what surveillance and intervention strategies are chosen for an individual.

And – perhaps most importantly – how to use a person’s genomic map to be able to upregulate or downregulate genes and their biological systems and modify the polygenic impact to potentially reduce risk even further.

While we do not perform genetic testing for inherited diseases, we DO use the polygenic model in our genomic testing for assessing genes impacting our biological systems and disease predispositions. This is why our comprehensive genomic testing is so powerful for creating personalized solutions for optimal health.

And now we know that having certain genetic mutations may not leave us as helpless as we thought.

We have the tools and the power right now to make a difference. 

Apply for a professional account to offer this life-changing service in your practice.

Learn more about using genomics in our Genomic Medicine Certification Program.

Contact us to find a clinician near you.

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