What is Individual Heterogeneity in Human Diseases?
Why is it Important to Understand Human Diseases at the Individual Level?
Why One-Size-Fits-All Treatment Approaches do not Always Work
What is individual heterogeneity in human diseases?
The degree of susceptibility, as well as the prognosis of human diseases, are not evenly distributed at the population level. In other words, not every individual in a given population is equally susceptible to a specific disease or expected to have a similar disease outcome.
This individual heterogeneity in diseases could be due to genetic, epigenetic, environmental, or demographic (age, sex, ethnicity) factors. Thus, understanding human diseases at the individual level is important for better disease management.
Why is it important to understand human diseases at the individual level?
Individual heterogeneity is defined as variations in responses to a particular disease. The currently ongoing coronavirus disease 2019 (COVID-19) pandemic has showcased a perfect example of individual heterogeneity, with some people developing asymptomatic or mild infections and some developing severe and life-threatening infections.
Clinical burdens of both infectious and chronic diseases are unevenly distributed within a population because of individual-level variation in disease susceptibility. The genetic heterogeneity among individuals has the highest impact on disease susceptibility and outcome.
Although multiple causative factors drive the development of human diseases, genetic factors are considered to be the strongest risk factors for complex diseases, such as cancer, diabetes, cardiovascular and pulmonary diseases, psychiatric disorders, and autoimmune disorders.
In complex diseases, crosstalk between genetic, environmental, demographic, and lifestyle factors plays a crucial role in disease development. These diseases do not follow the standard Mendelian patterns of inheritance. A person may have a genetic predisposition or genetic susceptibility to develop a certain disease due to inheritance of the disease-related genes, the actual development of the disease depends significantly on environmental, lifestyle and demographic factors.
The importance of interplay between these factors in disease development is well evident in many human diseases. Fair-skinned individuals have a higher susceptibility to developing skin cancer than dark-skinned individuals when exposed to the sun’s ultraviolet radiation. This is due to the mutations in the melanocortin 1 receptor gene.
Similarly, alcohol dehydrogenase deficiency caused by a mutation in the ADH1C gene is very common among Asian individuals. Such deficiency is associated with acute sensitivity to alcohol ingestion.
The human genome project has immensely helped researchers to understand the genetic pathogenesis of diseases and individual variability in them. The human genomic sequences have several variations, with single nucleotide polymorphisms (single DNA base-pair changes) having the highest prevalence. A significant variation in single nucleotide polymorphism (SNP) is commonly observed between individuals.
Scientists have determined the locations of SNPs in each human chromosome to identify disease-related mutations. If an SNP located in a protein-coding genetic sequence impairs the production of a functional protein, the SNP is expected to demonstrate a phenotypic effect.
The advancement in high-throughput genotyping has made it possible to determine specific genetic differences at the individual level. The genome-wide association studies (GWAS) are very useful in understanding how a specific genetic variation influences disease risk. These studies primarily involve the identification of SNPs and subsequently determining their prevalence in samples from populations.
Apart from genetic predisposition, pre-existing health conditions can influence disease susceptibility and the course of progression in an individual. Certain pre-existing conditions, including cardiovascular and pulmonary diseases, obesity, diabetes, autoimmune diseases, cancer, and liver and kidney diseases, can significantly increase the risk of developing severe infections.
The main causative factor is a weakened immune system together with hyperinflammation. Studies conducted during the COVID-19 pandemic have shown that individuals with certain comorbidities have a higher risk of developing severe and often life-threatening infections.
Taken together, understanding individual heterogeneity in disease susceptibility and outcome is important for better disease management. Understanding genotype-phenotype relationships at the individual level are vital for identifying and developing personalized diagnostic biomarkers and therapeutic agents.
Why one-size-fits-all treatment approaches do not always work
Many people die annually because of adverse drug reactions. Because of the variations in demographic characteristics, environmental exposure, and genetic make-up, each individual responds to a particular treatment differentially.
Since drug responses are driven by genotype, determining individual-level relationships between genotypes and drug responses is vital for developing personalized medicines. In this context, researchers are investigating the interaction patterns of therapeutic agents with a single gene (pharmacogenetics) or multiple genes (pharmacogenomics) to identify biomarkers that can predict which patients will respond positively, negatively, or remain unresponsive to a particular treatment.
Cancer is highly heterogenous with diverse groups of cells containing distinct mutations. The disease also varies significantly among individuals. Even in the same patient, cancer cells can acquire new mutations during progression to develop drug resistance. More advanced genetic testing has made it possible to identify mutations responsible for tumor recurrence, which in turn has immensely facilitated the development of personalized medicines.
The real advancement in the field of personalized medicine can be achieved by understanding the combined effects of genetic, demographic, environmental, and lifestyle factors. Wearable or implantable devices that monitor the physical parameters of individuals in real-time can provide useful information on the impacts of environmental factors, which can be integrated with genetic information to develop personalized treatment interventions.