Excess of rare noncoding variants in several type 2 diabetes candidate genes among Asian Indian families.

Summary

Targeted sequencing in Punjabi Sikh families revealed rare/ultra-rare variants in KCNJ11-ABCC8 and HNF4A co-segregating with late-onset T2D, and enrichment of rare variants in SLC38A11 and ANPEP. Gene-burden was strongest for HNF4A (p=0.0003), then KCNJ11/ABCC8 (p=0.0061) and SLC38A11 (p=0.03). Despite high T2D and rare variant burden, families had lower PRS. An intronic ABCC8 regulatory variant altered Pax4 and NF-κB binding, supporting functional impact.

Key Findings

• Rare and ultra-rare variants in KCNJ11-ABCC8 and HNF4A co-segregated with late-onset T2D in Sikh families.
• Rare variant enrichment identified in SLC38A11 and ANPEP; gene-burden strongest for HNF4A (p=0.0003), followed by KCNJ11/ABCC8 (p=0.0061) and SLC38A11 (p=0.03).
• Families had a significantly lower polygenic risk score burden despite high T2D prevalence and rare variant burden.
• Functional assays showed an intronic ABCC8 regulatory variant alters Pax4 and NF-κB binding, affecting downstream gene regulation.

Clinical Implications

Encourages tailored genetic risk assessment in South Asian populations and consideration of MODY gene rare variants in late-onset T2D; suggests PRS alone underestimates risk. Findings may guide future screening and therapeutic target discovery.

Limitations

• Targeted sequencing limited to ten GWAS/candidate regions may miss other loci
• Sample sizes per subgroup and exact numbers are not fully specified in the abstract
• Generalizability beyond the studied endogamous groups requires further validation

Future Directions

Expand to genome/exome-wide approaches in diverse South Asian populations; integrate functional assays at scale for noncoding variants; develop ancestry-aware risk models combining rare variants and PRS.