A RECENT study has uncovered rare genetic variants that may explain the significantly higher risk of Type 2 diabetes (T2D) in Asian Indian populations, particularly among Punjabi Sikh families. The research, which focuses on genetic sequencing, reveals insights into the hereditary factors influencing diabetes prevalence in these communities.
Scientists have long observed that Asian Indian individuals are up to six times more likely to develop T2D than their European counterparts. However, the genetic and biological reasons behind this disparity have remained unclear. To address this, researchers conducted targeted sequencing on ten known diabetes-related genetic regions using endogamous Punjabi Sikh families and extended their investigation to three other Indian ethnic groups.
The study identified rare and ultra-rare genetic variants in the KCNJ11-ABCC8 and HNF4A genes—both associated with Maturity-Onset Diabetes of the Young (MODY)—which were found to be linked with late-onset T2D. Additionally, researchers discovered new rare variant enrichments in the SLC38A11 and ANPEP genes, further implicating them in diabetes risk.
Gene burden analysis demonstrated that HNF4A contributed the highest rare variant burden (p = 0.0003), followed by KCNJ11/ABCC8 (p = 0.0061) and SLC38A11 (p = 0.03). Notably, while some rare variants identified in Sikh individuals were also found in Agarwals from Jaipur (another Northern Indian group), they were absent in South Indian ethnic groups, suggesting regional genetic distinctions.
Despite a high prevalence of diabetes-related rare variants, many of the studied families exhibited a significantly lower burden of polygenic risk scores (PRS), indicating that the condition in these populations is influenced by a combination of oligogenic inheritance and polygenic susceptibility. Further functional studies demonstrated that a rare intronic regulatory variant in the ABCC8 gene affects key transcription factor binding, impacting gene regulation linked to diabetes development.
These findings underscore the urgent need to investigate diabetes genetics in non-European populations to uncover novel therapeutic targets and devise effective prevention strategies. The study’s authors emphasize that understanding these genetic differences can help develop more tailored approaches to diabetes management for Asian Indian individuals, who continue to bear a disproportionately high burden of the disease.
Reference
Rout M et al. Excess of rare noncoding variants in several type 2 diabetes candidate genes among Asian Indian families. Commun Med. 2025;5(1):47.
