Life & Health insurers are striving to streamline the application process by asking as few questions as possible. Among the new technologies being explored to help ascertain an applicant’s health status is a technique known as epigenetic testing.

Epigenetics is a rapidly evolving field of molecular biology that aims to understand how gene expression is influenced by environmental changes. Epigenetics is not identical to genetics, however. Epigenetics describes reversible and heritable processes that regulate gene function without changing the primary DNA sequence.¹

Genetics is the study of heritable characteristics coded in the DNA of individuals. Unlike genetics, epigenetics is prone to reversible changes with time, influenced by a multitude of environmental factors, such as smoking.^2,3

Importantly for insurers, certain epigenetic marks might reflect how fast an individual is ageing, and by proxy, how long the individual will remain healthy. Some risk factors relevant to insurance underwriting might be potentially linked to epigenetics, including BMI, smoking, alcohol consumption, and even certain diseases such as type 2 diabetes and breast cancer.

But can underwriting be replaced by a simple epigenetic saliva test? Several studies do show a link between epigenetic outcomes such as different DNA methylation patterns and certain lifestyle aspects of individuals. But to decide if epigenetic tests can help in the risk assessment process, we need to know which risk factors can be reliably revealed by epigenetics.

Ageing

Age is one of the basic questions asked in any insurance application and certain questions could be removed by using epigenetic analyses. For example, some epigenetic marks (e. g. DNAmGrimAge) may be used to predict age based on a biological sample from the applicant.⁴ Saliva can be such a biological sample – it contains sufficient high-quality DNA that is suitable for the assessment of DNAmAge.⁵

Epigenetics can predict a set of epigenetic clocks which predict the individual’s chronological age (elapsed time since birth), biological age (decline of biological functions), and accelerated age (difference between the chronological and biological age).^6,7 Nevertheless, using epigenetic clocks as an underwriting tool comes with limitations as ongoing clinical trials are still attempting to optimise them for efficacy, efficiency, scalability, and affordability.⁸

Body Mass Index (BMI)

Obesity is one of the main causes of diseases such as heart disease and cancer. A 2021 study has shown that obesity can alter DNA methylation and that this alteration could affect inflammation and lipoprotein levels in obese individuals.⁹

In another study, the relationship between obesity and DNA methylation was analysed in 991 healthy individuals, demonstrating the importance of using epigenetics as a diagnostic tool for obesity and the risk of certain diseases associated with abnormal BMI as well as potential consequences.¹⁰ BMI-related DNA methylation is well studied and shows relevance to the development of obesity-related cardiometabolic diseases.¹¹ Since particular methylation patterns are observed in the context of obesity, this information could be useful in the risk assessment of applicants with a high BMI.

Smoking

Studies have shown that tobacco smoking causes extensive changes in the epigenetics of the individual via changes in the pattern of DNA methylation.¹² For instance, cg05575921 (a specific CpG site) methylation is shown to decrease with smoking.^13,14 Therefore, theoretically, the identification of changes in these smoking-related gene loci would also indicate the smoking status of an individual.

As with other epigenetic changes, smoke-induced DNA methylation is reversible and a study indicated that a comparison of methylation levels of the mentioned loci of interests between never smokers and former smokers showed little to no difference five years after cessation of smoking.¹⁵ Thus, relying on epigenetic information alone might mask formerly heavy smokers, allowing for negative selection.

Moreover, quitting smoking presumably allows regaining the DNA methylation state of never smokers. This remains, however, dependent on cessation time and pack-years of these former smokers.¹⁶ While some studies link the smoking intensity to DNA methylation levels, these studies are mostly done on mice or only small samples of human whole blood DNA or saliva DNA. More data need to be accumulated to have higher confidence in the correlation between epigenetic changes in the loci and smoking or even vaping.¹⁷

Alcohol Consumption

If it were possible to use a simple salivary epigenetic test to detect past behaviour of addiction or heavy drinking, why not use epigenetics for the underwriting process? Several studies have mentioned the association between certain DNA methylation patterns and alcohol dependence.^18,19

It is known that certain changes in lifestyle would be able to change the DNA methylation, and this was also observed in alcohol consumers. Further, a 2018 study showed that daily exercise in hazardous and binge drinkers was able to positively reverse DNA methylation and could therefore be a way to prevent alcohol abuse.²⁰

Type 2 Diabetes

Type 2 diabetes is a prevalent comorbidity, particularly among the obese population. It is also responsible for a myriad of adverse health outcomes such as cardiovascular disease and is closely evaluated in underwriting. Some studies have found differences in the epigenetic pattern (i. e. DNA methylation and gene expression) in blood cells, skeletal muscle, adipose tissue, the liver and pancreatic islets from subjects with type 2 diabetes compared with nondiabetic controls.²¹

It is crucial to point out that epigenetic patterns are cell and tissue specific. To have insight into the diabetic status of an individual, epigenetic samples from the disease-relevant tissues are needed. Obtaining such tissue-specific samples in addition to blood or saliva to get a more accurate epigenetic pattern for diseases such as type 2 diabetes and obesity is not very practical for insurance purposes.

Breast Cancer

Nowadays, different DNA methylation patterns are used for risk stratification in breast cancer and the association has been analysed in various studies.²² Trimethylation of lysine 27 on histone H3 (H3 K27 me) is an epigenetic mark which was shown to be able to predict cancer survival. H3 K27 me3 expression was found to be significantly lower in breast cancer tissues than in normal tissues. Additionally, individuals with breast cancer and lower expression of H3 K27 me3 were seen to have significantly shorter overall survival than individuals with higher expression.²³

When comparing methylation of normal breast tissue with ductal carcinoma in situ and invasive carcinoma of the breast, DNA methylation was highly altered in 5,000 genes of the in‑situ breast tissue. Moreover, approximately 1,000 genes were altered in invasive carcinoma of the breast. This indicates that DNA methylation could be used as biomarker even in early stages of breast cancer.²⁴

It is important to note that other meta-analyses don’t show any association between certain DNA methylation levels and a higher risk of breast cancer or breast cancer survival.²⁵ So, scientific results are not yet conclusive enough to say whether insurers should use epigenetic information to predict the survival or risk of breast cancer patients based on epigenetic information alone.

Social and Moral Questions

In epigenetics, a simple saliva or blood test, provides information on whether a person’s gene expression has changed due to certain lifestyle habits or environmental changes. In underwriting, for certain diseases we need laboratory values to check the health of the applicant. It is clear from the beginning which lab values are required. Use of epigenetics could lead to policy applicants receiving new information about their health they would otherwise have preferred to keep private. Also, a third party has received information that could be unfavourable but was not intended to be made public; unexpected information from epigenetics could lead to discrimination, or difficulty in ignoring the unfavourable factors.²⁶

If a test reveals certain unfavourable factors, how should this information be conveyed to the person? Can insurance companies use this information that was not previously known, including for underwriting purposes? The field of epigenetics is in its infancy and many challenges lie ahead; the epigenetic mechanisms are mostly poorly known and isolating a single environmental factor is still a problem. Additionally, the handful of available studies are limited to a small number of participants and to specific populations which negatively affects the statistical power of the findings. Therefore, it is very important that the scientific reliability of epigenetics will be further researched and analysed to be certain of its validity – especially when evidence-based information on epigenetics is used as a solid background for insurance and underwriting purposes.