The global concern is the alarming increase in the high proportion of Diabetes Mellitus affecting nearly all populations which in turn emphasized the urge to investigate the role of susceptibility genes contributing to the disease burden. The highly vulnerable genes accountable for promoting type 2 Diabetic Kidney Disease (T2DKD) in South Indians are not well studied. This study is an attempt to research the possible association between (CTG)n trinucleotide repeats in Carnosinase or Carnosine dipeptidase 1 (CNDP1) gene and Diabetic Kidney disease (DKD) in South Indian population. The repetitive sequence of CTG in CNDP1 gene was amplified from the genomic DNA of total 285 [T2DKD, n:85; Type 2 Diabetes Mellitus (T2DM), n:100; healthy controls (HC), n:100] subjects using DNA sequencing method and was examined by a case-control approach. The significant trinucleotide repeats in our study were homozygous 5/5 leucine, heterozygous 5/6 leucine and homozygous 6/6 leucine. T2DKD had a lower frequency of homozygous 5/5 leucine genotype (23.5%) than T2DM (37%, P=0.047) and HC (41%, P=0.011). Likewise, five leucine allele (5L) recurrence was lower in T2DKD (45.9%) when compared with T2DM (59.5%, P=0.008) and HC (62.5%, P=0.001). T2DKD showed lower frequencies of homozygous 5/5 leucine genotype and five leucine allele (5L) of CNDP1 gene when compared to T2DM and HC. These findings established that this allele may offer defence against the onset of kidney disease in South Indians. © 2024 Elsevier B.V., All rights reserved.