In a publication in Nature Genetics with an impact factor of 31.7, a research team comprising of Harvard Medical School, the Broad Institute of MIT and Harvard, and Dr. Lukasz Szczerbinski from the UMB Clinical Research Center, presented ground-breaking discoveries pertaining to the genetic factors that influence diabetes.
The study aimed to understand better how monogenic forms of diabetes (including MODY) and multi-gene type 2 diabetes intersect, which may have direct clinical relevance for the diagnosis and treatment of these diseases.
The researchers used advanced imputation of rare genetic variants and large-scale databases such as the UK Biobank to identify new genes associated with type 2 diabetes. During the analysis, eight rare variants that had not previously been associated with diabetes were discovered, and their presence turned out to have a significant impact on its development. An example is the variant that affects the action of leptin — a key hormone regulating body weight and insulin sensitivity. The study highlights that patients carrying these rare variants may have very different susceptibility to developing the disease, which results from the additional influence of polygenic risk. For example, in people with a mutation in the HNF4A gene (typical for MODY), the risk of developing type 2 diabetes increases significantly if the patients have a high polygenic risk score. This shows that the presence of the mutation itself does not always lead to the disease — the overall genetic profile of the patient is also important. In clinical practice, this means the need for an individual approach to diagnostics, considering not only individual mutations but also the cumulative polygenic risk.
The methodology used also allowed for a more precise classification of genetic variants. Thanks to this analysis, many variants that previously had ambiguous interpretations were classified as mild or with intermediate penetrance.
The study results indicate that the border between monogenic and polygenic diabetes is fluid, emphasizing the importance of thoroughly analyzing the patient's genetic profile. This is a significant step towards personalized medicine and shows that a comprehensive approach to the genetic diagnosis of diabetes is necessary, considering both single genetic variants and their interactions with polygenic risk. A better understanding of these relationships will enable the development of more personalized therapies and the identification of patients who will best respond to specific therapeutic interventions.
Link to the article: Rare variant analyses in 51,256 type 2 diabetes cases and 370,487 controls reveal the pathogenicity spectrum of monogenic diabetes genes.
