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

作者：Madhusmita Rout, Deepika Ramu, Mendez Mariana, Teena Koshy, Vettriselvi Venkatesan, Juan Carlos López-Alvarenga, Rector Arya, Umarani Ravichandran, Surendra K. Sharma, Sailesh Lodha, Amaresh Reddy ­Ponnala, Krishna Kumar Sharma, Mahaboob Vali Shaik, Roy G. Resendez, Priyanka Venugopal, R Parthasarathy, S. NOELTA, Juliet A. Ezeilo, Marcio Almeida, Juan Paralta, Srinivas Mummidi, Natesan Chidambaram, N. K. Mehra, Jai Rup Singh, Gurpreet Singh Wander, Sarju Ralhan, Piers R. Blackett, John Blangero, Krishna Mohan Medicherla, Sadagopan Thanikachalam, Thyagarajan Sadras Panchatcharam, Dileep Kumar K, Rajeev Gupta, Solomon F.D. Paul, Asish K. Ghosh, Christopher E. Aston, Ravindranath Duggirala, Dharambir K. Sanghera · 发表于：Communications Medicine · 年份：2025 · DOI：10.1038/s43856-025-00750-9 · 被引用次数：7 · 研究领域：Genetic Associations and Epidemiology、Genomics and Rare Diseases、BRCA gene mutations in cancer

Type 2 diabetes (T2D) etiology is highly complex due to its multiple roots of origin. Polygenic risk scores (PRS) based on genome-wide association studies (GWAS) can partially explain T2D risk. Asian Indian people have up to six times higher risk of developing T2D than European people, and underlying causes of this disparity are unknown. We have performed targeted sequencing of ten T2D GWAS/candidate regions using endogamous Punjabi Sikh families and replication studies using unrelated Sikh people and families from three other Indian endogamous ethnic groups (EEGs). We detect rare and ultra-rare variants (RVs) in KCNJ11-ABCC8 and HNF4A (MODY genes) cosegregated with late-onset T2D. We also identify RV enrichment in two new genes, SLC38A11 and ANPEP, associated with T2D. Gene-burden analysis reveals the highest RV burden contributed by HNF4A (p = 0.0003), followed by KCNJ11/ABCC8 (p = 0.0061) and SLC38A11 (p = 0.03). Some RVs detected in Sikh people are also found in Agarwals from Jaipur, both from Northern India, but were monomorphic in other two EEGs from South Indian people. Despite carrying a high burden of T2D and RVs, most families have a significantly lower burden of PRS. Functional studies show that an intronic regulatory variant (RV) in ABCC8 affects the binding of Pax4 and NF-kB transcription factors, influencing downstream gene regulation. The high burden of T2D in these families may stem from the enrichment of noncoding RVs in a small number of major known genes (i...