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Title: Genetic studies of syndromes of severe insulin resistance and type 2 diabetes : a candidate gene approach
Author: Fawcett, K. A.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2009
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The lipin 1 gene has been suggested to influence human insulin sensitivity and adiposity. I sequenced human LIPIN1, 2 and 3 in insulin resistant patients to identify potential pathogenic mutations and tested for association of common variation in LPIN1 with metabolic traits underlying T2D. These studies demonstrated that variants in the lipid family are unlikely to be common causes of severe insulin resistance, and that LPIN1  common variants do not importantly contribute to risk of T2D. Sequencing genes in the mTOR pathway revealed a number of rare variants in insulin resistant patients. Some of these variants may be contributing to insulin resistance. More detailed genetic and functional studies are needed to confirm this. In the PARL gene the polymorphism Leu262Val had previously been reported to associate with fasting insulin levels. Despite a larger sample size (N=3666) I could not replicate this result in UK populations. I contributed to a large candidate gene association study that investigated 1536 SNPs in 84 genes involved in pancreatic β-cell function for association with T2D. This study identified common variants in WFS1, a gene response for an autosomal recessive form of diabetes, impacting T2D risk. I initiated re-sequencing and genotyping efforts to refine the association signal and investigated whether rare variants in WFS1 also impact T2D risk. There was no evidence for association between rare variants and disease risk. Recently, genome-wide association studies (GWAS), have identified a number of genes underlying T2D and related traits. My work, which identified a novel T2D susceptibility gene not detected in initial GWAS results, WFS1, suggests that candidate gene studies can sometimes complement genome-wide approaches.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available