Investigation of the Genetic Link Between the Metabolic Diseases Gout and Type 2 Diabetes
Gout is associated with various co-morbidities including insulin resistance and type 2 diabetes. Gout and type 2 diabetes are strongly linked to the individual components of metabolic syndrome. There may be shared pathogenic pathways between gout and type 2 diabetes in which insulin resistance, obesity, hypertension and hyperuricaemia play a central role.Genetic and environmental factors play a crucial role in the development of these diseases. Genetic factors that are associated with type 2 diabetes and metabolic syndrome may be shared with gout. It was hypothesised in this study that genetic variants that influence type 2 diabetes and metabolic syndrome also influence gout. The aim of the study was to find a genetic link between the two diseases by finding novel associations with gout and testing whether or not the effect is independent of diabetes and metabolic syndrome.The case-control study approach was used in this study. In this study 19 variants from 11 genes were examined in a multi-ethnic sample of 1003 gout cases and 1244 controls from the NZ gout population. Two reference datasets were added to provide a comparative group: Framingham Heart Study (FHS) and Atherosclerosis Risk in Communities Study (ARIC). A combined meta-analysis was performed to increase the overall power of the association. Haplotype analysis was also performed and gene-gene interactions were also investigated.The results chapter is divided into three sections. The first section focuses on variants associated with type 2 diabetes. The KCNJ11 gene variant rs2285676 G allele was associated with a reduced risk of gout in the New Zealand European Caucasian (P=0.04, OR=0.73[0.54-0.99]) and Western Polynesian (P=0.03, OR=0.65[0.44-0.96]) sample sets. The miRNA16A gene variant rs2910164 C allele was found to be associated with reduced risk of gout in the New Zealand European Caucasian (P=0.02, OR=0.60[0.39-0.92]) and Eastern Polynesian (P=0.02, OR=0.38[0.16-0.89]) sample sets. All variants either showed weak or non-significant associations with gout. In order to establish a positive link between gout and type 2 diabetes, replication is needed in larger cohorts.The second section is focused on variants associated with obesity. The MC3R gene variant, rs3827103 A allele was significantly associated with a reduced risk of gout in the New Zealand European Caucasian (P=0.0004, OR= 0.30 [0.18-0.50]) and in the mixed Eastern and Western Polynesian (P=0.04, OR=0.01[0.001-0.89]) sample sets. The MC4R gene variant rs17782313 C allele in the Western Polynesian sample set was found to be associated with a reduced risk of gout (P=0.01, OR=0.53[0.32-0.89]). When combined in meta-analysis, the Polynesian sample set was also found to be associated with a reduced risk of gout (P=0.03, OR= 0.73[0.55-0.98]). Another MC4R gene variant, rs17700633 (A allele), showed a significant association (P=0.04, OR=0.60[0.37-0.98]) with a reduced risk of gout in the Western Polynesian sample set. The haplotype analysis of MC4R gene variants rs17782313 and rs921971 showed that minor alleles were associated with an increased risk of gout and the major alleles were associated with a decreased risk of gout. The FTO gene variant rs9922047 C allele was associated (P=0.002, OR=2.23[145-3.43]) with an increased risk of gout in the Western Polynesian sample. When combined in meta-analysis, the Polynesian sample set also showed an increased risk for gout (P=0.003, OR=1.33[1.10-1.59]). One particular haplotype, GAG, of the FTO gene variants rs9922047, rs17817288 and rs9923233 was consistently protective against gout, independent of BMI. The results of this study indicate that obesity-associated variants also influence gout in a manner that is independent of obesity. These genes are expressed in the hypothalamus of the brain and are thought to possibly influence gout by modulating eating behaviour. A high intake of a diet rich in purine and fructose increases serum urate levels, which can ultimately lead to gout.The third section is about PDZK1 gene variants that influence serum urate levels and metabolic syndrome. The T allele of rs1284300 was found to be associated with a reduced risk of gout (P=0.04, OR=0.44[0.20-0.99]) in the New Zealand European Caucasian sample set. Combined meta-analysis of the Caucasian sample set was found to be associated with a reduced risk of gout (P=0.009, OR=0.71[0.56-0.92]). The rs11576685 variant showed a reduced risk for gout in the combined meta-analysis of the Polynesian sample set (P=0.007, OR=0.26[0.10-0.68]). The results of the association analysis suggest that PDZK1 gene variants influence gout. PDZK1 was also tested for gene-gene interactions with urate transporters such as URAT1, ABCG2, OAT4 and NPT1, but this study did not find any significant interactions.This is the first study that has directly investigated the association of type 2 diabetes, obesity and metabolic syndrome variants with gout. This study has found some novel associations with gout, particularly with regard to the MC3R, MC4R and FTO genes, which suggests that metabolic syndrome variants also influence gout independent of type 2 diabetes, obesity and metabolic syndrome. However, to confirm these findings, these variants need to be genotyped in large association studies, as this will be important in exploring the role of common risk variants between gout and type 2 diabetes.