Genetic and functional analyses of diabetic nephropathy with focus on chromosome 3q

Abstract

Diabetic nephropathy (DN) is a complex disease affected by both genetic and environmental factors. Genetic and functional analyses of the susceptibility and/or resistance genes in DN may provide useful information for better understanding the pathogenesis and further developing novel therapeutic approaches in this disease.

This thesis concerns about genetic and functional analyses of the candidate genes, which are selected from a region in chromosome 3q linked to DN. Genetic association studies are performed mainly with type 1 diabetes (T1D) patients with or without DN. They come from European descent and are selected from Genetics of Kidney Disease in Diabetes (GoKinD) collection. Gene expression analyses at both mRNA and protein levels were ex-amined with kidney tissues of db/db mice. The ADIPOQ gene is located in chromosome 3q27.3. A promoter single nucleotide polymorphism (SNP) rs266729 in the gene was found to be associated with DN in female T1D patients. This polymorphism altered the se-quence for SP1 binding site and subsequently caused the reduction of ADIPOQ promoter activity. The MCF2L2 gene is located in chromosome 3q27.1. A non-synonymous SNP rs7639705 (Leu359Ile) was associated with DN in females. This polymorphism together with SNPs rs266729 in the ADIPOQ and rs11915160 in the SOX2 (in chromosome 3q26.3) gene had combined effects on the association with DN in females. The MME gene is lo-cated in chromosome 3q25.1-25.2. A significant advance of MME expression at both mRNA and protein levels in kidney tissues of db/db mice were observed. Genetic polymor-phisms rs3796268 and rs3773885 in the MME gene were found to be associated with DN in females. The TRPC1 gene is located in chromosome 3q22-24. Although TRPC1 mRNA expression in kidney tissues of db/db mice was significantly decreased in comparison with the controls, no association between the gene polymorphisms and DN was found.

Data from the studies in this thesis indicate that the ADIPOQ, MCF2L2 and MME genetic polymorphisms but not TRPC1 are associated with DN with the protective effect in female T1D patients among the GoKinD population. Thus, the evidence provided by this thesis may partially explain the linkage with DN in chromosome 3q. Further investigation on the studied genes and other candidates in the linkage region of this chromosomal arm will be interesting to explore the genetic association with gender-specificity and functional conse-quence in the development of DN.