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=5.8×10-3/0.037). Association analysis with obesity revealed that rs6064099 is associated with reduced susceptibility for obesity (OR=0.48, P=6.8×10-3). Also, haplotype GGC conferred increased susceptibility for obesity (OR=1.27, P/Pperm =9.0×10-3/0.039). 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=7.0x10-3].
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.

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