Jeffrey Bland explains why genetic test results like BRCA1/2 and APOE4 aren't destiny. Women born after 1940 with BRCA mutations had lower cancer risk than those born before, and APOE4 can actually protect you in harsh environments. Lifestyle changes exercise, diet, avoiding obesity in adolescence can shift your genetic risk.
Genetic testing, what an enigma. You know, it's interesting, isn't it, because there's still those individuals that when they get their genetic tests, feel that this is like cast in stone and whatever it says is going to be their lot in life. And I've asked myself the question, why is that? What have we learned about that and why is that wrong? And it led me to ask the question, what are the two genes from a common genetic test that you really have to give permission before they give you the data, because it's so alarming potentially for the recipient if they have a positive to those two genes, as if those genes were so cast in stone for something so dreaded that there is nothing you can do about it. What are those two genes? You know what they are? They're the BRCA1 and 2 gene and it's the APOE4 gene. So what do we really know about those two genes? Are they really that tied to deterministic outcome? In the case of BRCA 1 and 2, as Mary Claire King had first discovered this gene as a postdoctoral student at the University of California, Berkeley, and then later found its association with the mutated forms of it as associated with ovarian and breast cancer and in males now with prostate cancer, it was as if, oh, my word, this is a death sentence. I have this double hit of bad news in my genetic history and there certainly is a very significant relative concern about that gene as it relates to cancer risk. But is it in and of itself absolutely deterministic? And similarly, if we ask about the ApoE4 double allele, is it absolutely then a kind of a criteria that says a person will get Alzheimer's disease or cardiovascular disease or both. Interesting questions. And the lesson that we can take away from these, I think are very powerful as it relates to all of the genetic information. Why do I say that? Well, let's first go to BRCA 1 and 2, Mary Claire King, and let's ask the question, what has she helped us to understand about that? She points out in this article that was actually published back in 2003, October 24 issue of the Science magazine entitled Breast and Ovarian Cancer Risk due to inherited mutations in BRCA 1 and 2. And yes, she points out in this article that certainly there is a very significant risk, but the risk and the incidence of breast and ovarian cancer in women that carry that mutation has significantly changed whether they were born before 1940 or after 1940 at age of 50, the risk of a woman getting breast cancer today, if they carry those Double alleles of mutated BRCA 1 and 2 is in excess of 75% if they were born before 1940. However, the risk is only 24%. Some 1/3 of the same gene mutated in women that were born later after 1940. Why? Well, she goes and points out in this article, it's very interesting that sometimes we miss this lifetime range. Risks of ovarian cancer were 54% for BRCA1 and 2 and 23% for BRCA for BRCA1 and 23% for BRCA2. However, physical exercise and lack of obesity in adolescents were associated with significantly delayed breast cancer events in women who carry those genes. Meaning there is a lifestyle principle associated with the expression of those genes. Hold that just if you will for a moment, because now let's examine BRCA. Go from BRCA 1 and 2 to APOE. So we'll move from Mary Claire King to Caleb Finch at the University of Southern California Longevity Institute there, who has been studying with his colleagues around the world the correlation between the double APOE4 allele and the association with Alzheimer's disease. Because there are those individuals who are so fearful that if they were to get a positive on this genetic test, they feel it's a death sentence the that they will get Alzheimer's. Yet, however, in recent publications by Finch and others in his group and collaborators around the world, they found that APOE 4 is actually associated with a reduced incidence of dementia in indigenous populations that are exposed to high infection from various microbes or parasites. In fact, those that have high eosinophil counts, which is an indicator, clinical indicator of, of being infected with a parasite, they have much higher incidence of early stage dementia. And if they have an APOE 4, they have lower in the same area, the same place where infection is rampant and endemic, they have much lower eosinophils and they have much lower incidence of dementia because APOE 4 provides a protection against infection. And in fact, in certain indigenous areas within the world, the dominant APOE pattern is that of A four pattern which has provided protection against infection. Now what do they say? Well, there's a paper that appeared in the FASEP journal in 2017. The title of it is clearly evident. APOE 4 is associated with improved cognitive function in Amazonian forager horticulturists with a high parasite burden. That's one paper. The other is a similar paper in plos1 in 2017. ApoE4 allele on survival and fertility in adverse environments. And what does this paper show? Women who have APOE4 have higher fertility in challenging environments where there's a lot of infection in parasites and they have lower dementia. And, and in fact, the last little sentence in this paper I think is quite fascinating. As a summary, the authors say the following and I think you'll get this. They say we conclude that contemporary observations in affluent societies showing the late life detrimental effects of ApoE4 are best considered as an example of specific gene environment interactions. What does that mean? It means lifestyle and environment play very significant roles in how the APOE4 gene is expressed into the function of the individual, either as a protection factor or as a risk factor. And similarly, if we go Back to the BRCA 1 and 2 example, what have we learned? We know that that is a specific gene that controls enzymes that regulate DNA repair. And one of the things that's most at risk in a BRCA 1 and 2 mutated situation is lower DNA repair when it's damaged. And what have we found is one of the most significant damaging factors for which BRCA1 facilitates DNA repair? It's exposure to chemicals like formaldehyde and acetaldehyde. So could there be an environmental connection to the increasing prevalence of breast canc ovarian cancer with women that carry the BRCA 1 and 2 that's not particularly related exclusively to their genetics, but but related to the uniqueness of their gene. In an imperfect environment, the gene can't be changed, but the environment can. What I'm trying to say is that Even with the two most dreaded genetic bits of information, a double E4 or a BRCA1 and 2, there is more evidence of plasticity than we ever fully understood. It's not genetically hardwired. And this is a whole new concept as it relates to how we evaluate much less severe genetic risk factors as it pertains to how they're expressed by modulating the environment and lifestyle. This is the age of personalized lifestyle healthcare.
