Genetic variation of the adenylyl cyclase 3 (AC3) locus and its influence on type 2 diabetes and obesity susceptibility in Swedish men

Abstract

Objective: Our previous study using the Goto-Kakizaki rat implicates that the adenylyl cyclase 3 (AC3) is a candidate gene for genetic study of metabolic disorders. The present study aimed to investigate the susceptibility of genetic variation of the AC3 gene in type 2 diabetes (T2D) patients and obese subjects. Subjects and methods: Variation screening in the putative promoter and validation of single nucleotide polymorphisms (SNPs) covering the AC3 gene were performed. In total, 630 Swedish men, including 243 T2D patients (BMI from 18.4 to 45.6 kg m À2 ), 199 obese subjects with normal glucose tolerance (NGT, BMIX30 kg m À2 ) and 188 control subjects (NGT, BMIp26 kg m À2 ), were genotyped. Results: A novel variant -17A/T in the promoter was identified, but no significant association of this polymorphism with T2D was found. SNPs rs2033655 C/T and rs1968482 A/G were found to be significantly associated with obesity when T2D patients had BMIX30 kg m À2 (P ¼ 0.003 and 0.005). The significance was borderline in T2D patients with BMIo30 kg m À2 (P ¼ 0.051 and 0.084) and disappeared in T2D patients with BMIp26 kg m À2 . Importantly, analysis in obese subjects with NGT demonstrated that these two polymorphisms were strongly associated with obesity per se (P ¼ 0.028 and 0.003). Furthermore, analyses for diplotypes (haplotypic genotypes) predicted an association with BMI in obese subjects. Conclusions:The present study provides the first evidence that AC3 polymorphisms confer the risk susceptibility to obesity in Swedish men with and without type 2 diabetes.

International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases

“…However, there is no effect on renal sodium or water excretion after selective deletion of AC3 in collecting ducts, suggesting compensation by other ACs (Kittikulsuth et al, 2014b). ADCY3 gene polymorphisms have been associated with obesity (Nordman et al, 2008;Wang et al, 2009Wang et al, , 2010Wen et al, 2012;Stergiakouli et al, 2014;Warrington et al, 2015), depression (Wray et al, 2012), and inflammatory bowel disease (Hulur et al, 2015).…”

The cilium: a cellular antenna with an influence on obesity risk

“…Links between the ADCY3 gene and obesity have been reported both in humans and in mice. In a Swedish cohort, genetic association was found between variants of the ADCY3 gene and men with obesity and type 2 diabetes (111) . In the Han population, genetic association with obesity was also observed (112) .…”

AC3: A Novel Gene Plays a Role in the Regulation of Body Weight

“…In order to evaluate the genetic defect of AC3 in the development of type 2 diabetes and obesity, we have conducted a genetic association study for the AC3 gene in type 2 diabetes patients and obese subjects in a Swedish population [15]. Initially, we have carried out variation screening for the putative promoter region of human AC3 gene with a direct-sequencing analysis approach.…”