New research, published in the Nature journal, Communications Medicine has identified rare genetic variants that may contribute to the increased prevalence of type 2 diabetes (T2D) in multiple generations of Asian Indian families.1 The findings could provide new insights into the genetic basis of T2D and could pave the way for more targeted treatments.
Led by Dharambir Sanghera (Professor of Pediatric Genetics, University of Oklahoma College of Medicine) the study focused on Punjabi Sikh families, using targeted sequencing of ten known T2D-related genes. The research revealed rare and ultra-rare variants in KCNJ11-ABCC8 and HNF4A, genes previously associated with maturity-onset diabetes of the young (MODY), as well as two newly associated genes, SLC38A11 and ANPEP. These variants were found to co-segregate with late-onset T2D, suggesting they could play a role in disease progression.
A gene-burden analysis showed that HNF4A carried the highest burden of rare variants (p= 0.0003), followed by KCNJ11/ABCC8 (p=0.0061) and SLC38A11 (p=0.03). Interestingly, some of these rare variants were also found in Agarwal families from Northern India but were monomorphic in the two other South Indian groups studied. Further functional analysis identified an intronic regulatory variant in ABCC8, which influences downstream gene expression by affecting the binding of key transcription factors such as Pax4 and NF-kB.
One of the unexpected findings was that many of the genetic variants linked to T2D in these families were found to be non-coding, so they do not directly produce proteins but instead regulate when and where proteins are made. Sanghera noted that this suggests a form of oligogenic diabetes, where multiple rare gene variants significantly influence disease risk, independent of common polygenic factors.
Additionally, three of the genes with high rare variant frequencies were MODY genes; genes typically linked to early-onset diabetes. Although MODY genes are known to cause monogenic diabetes, their role in T2D is not well understood.2 The study also found that in families with multiple cases of late-onset T2D had fewer common polygenic risk factors than expected, challenging the conventional understanding of genetic risk in diabetes.
“These findings suggest we need to study the role of MODY genes in type 2 diabetes more closely by looking at the genes of families affected by it,” Sanghera said. “The more we understand about the genetics of diabetes, the closer we move to precision medicine—treating people according to the specific type of diabetes that they have.”2
References
- Rout M, Ramu D, Mariana M, et al. Excess of rare noncoding variants in several type 2 diabetes candidate genes among Asian Indian families. Commun Med. 2025; 5:47.
- FirstWord Pharma. Discovery of rare gene variants provides window into tailored type 2 diabetes treatment. [Press release] Available at: https://firstwordpharma.com/story/5938161 (accessed 26 February 2025)
Disclosure: This article was created by the touchENDOCRINOLOGY team utilizing AI as an editorial tool (ChatGPT (GPT-4o) [Large language model]. https://chat.openai.com/chat.) The content was developed and edited by human editors. No funding was received in the publication of this article.
Editor: Gina Furnival, Senior Editorial Director.
Support: No funding was received in the publication of this short article.
Cite: Rare genetic variants identified that could uncover new therapeutic targets for type 2 diabetes. touchENDOCRINOLOGY. 27 February 2025.
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