Evaluation of DOK5 as a susceptibility gene for type 2 diabetes and obesity in North Indian population.
BACKGROUND
Type 2 diabetes is a complex metabolic disorder with obesity being a major contributing factor in its development. Susceptibility loci for type 2 diabetes and obesity have been localized on different chromosomal regions by various genome-wide linkage scans. Of these chromosomal regions, 20q13 is one of the strongest linked regions for type 2 diabetes as well as obesity. On 20q13 lies DOK5 that seems to be a strong functional and positional candidate for type 2 diabetes and obesity because of its involvement in insulin signaling and immune responses. Hence, for the first time, we explored DOK5 as a potential type 2 diabetes and obesity susceptibility gene.


METHODS
We sequenced 43 subjects for polymorphisms in functionally relevant regions of DOK5. A total of 10 SNPs that included 5 that were identified by sequencing and 5 additional SNPs from NCBI Variation Database were genotyped in 2,115 participants comprising of 1,073 patients with type 2 diabetes and 1,042 controls of Indo-European ethnicity from North India.


RESULTS
We identified a novel variant in intron 7 referred to as DK176673. We found nominal association of three SNPs-rs6064099 (OR = 0.75, P = 0.019), rs873079 (OR = 0.76, P = 0.036) and DK176673 (OR = 1.55, P = 0.037) with type 2 diabetes among normal-weight subjects [BMI < 23 kg/m2]. The haplotype GGC harboring rs6068916, rs6064099 and rs873079 showed strong association with type 2 diabetes among normal-weight subjects (OR = 1.37, P/Pperm = 5.8 x 10-3/0.037). Association analysis with obesity revealed that rs6064099 is associated with reduced susceptibility for obesity (OR = 0.48, P = 6.8 x 10-3). Also, haplotype GGC conferred increased susceptibility for obesity (OR = 1.27, P/Pperm = 9.0 x 10-3/0.039). Also, rs6064099 was significantly associated with reduced BMI [median(IQR) = 24.0(20.7-27.1) vs 23.9(20.2-26.8) vs 21.8(19.2-24.7) for GG vs GC vs CC, P = 7.0 x 10-3].


CONCLUSIONS
We identified DOK5 as a novel susceptibility gene for obesity and type 2 diabetes in North Indian subjects. Association of DOK5 variants both with obesity and type 2 diabetes suggests that these variants might modulate type 2 diabetes susceptibility through obesity.
Tabassum
Rubina
R
Functional Genomics Unit, Institute of Genomics and Integrative Biology (CSIR), Delhi- 110 007, India.
Mahajan
Anubha
A
Chauhan
Ganesh
G
Dwivedi
Om Prakash
OP
Ghosh
Saurabh
S
Tandon
Nikhil
N
Bharadwaj
Dwaipayan
D
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D016022:Case-Control Studies; D002890:Chromosomes, Human, Pair 20; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007194:India / Q000453:epidemiology / Q000208:ethnology; D009765:Obesity / Q000453:epidemiology / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
D048868:Adaptor Proteins, Signal Transducing; C432912:DOK5 protein, human