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Towns, Laura Katherine (2013) Genetic and functional investigation of sequence variation associated with the related phenotypes: birth weight, obesity, and type 2 diabetes (T2D). Doctoral thesis, London Metropolitan University.
Background: Global incidence of obesity and Type 2 diabetes (T2D) has increased rapidly in the last fifty years and even more rapidly in immigrant ethnic minority communities in Western countries. There is evidence of a connection between birth weight and the subsequent risk of obesity and T2D in adulthood, with several T2D susceptibility loci reported to be associated with fetal birth weight, including the leptin receptor gene (LEPR).
Aims: To ascertain if maternal candidate loci contribute to fetal birth weight variation in a Gujarati South Asian immigrant population in North London and to investigate three variants in the extracellular region of LEPR to determine their effect on LEPR protein structure and function.
Methods: Two commercially-available methods (Sequenom iPLEX and Life Technologies TaqMan) were used to genotype specific polymorphisms in the genes HHEX-IDE, ADCY5 and FTO, while molecular cloning and computer modelling techniques were used to investigate the variants in LEPR.
Results: Significant associations were found with lower birth weight and rs 12765131 in the HHEX-IDE locus (p=0.002) and with higher birth weight and markers in FTO, namely rs9939609 (p=0.001), rsl7817449 (p=0.0273) and rs8050136 (p=0.0231). No significant associations were found with fetal birth weight and markers in the ADCY5 gene. Although molecular cloning of three LEPR variants was unsuccessful, in silico modelling of the LEPR protein revealed that the Gln223Arg polymorphism was predicted to affect the surface electrostatic potential of the receptor and create hydrogen bonding with a neighbouring cysteine residue, potentially lowering the binding affinity with leptin.
Conclusion: These results demonstrate that maternal variants in HHEX-IDE and FTO are associated with birth weight variation in the Gujarati South Asian population. Furthermore, LEPR polymorphisms have been predicted to affect its overall structure and possibly its
leptin signalling function.
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