Common variants in CNDP1 and CNDP2, and risk of nephropathy in type 2 diabetes

Abstract

Aims/hypothesis Several genome-wide linkage studies have shown an association between diabetic nephropathy and a locus on chromosome 18q harbouring two carnosinase genes, CNDP1 and CNDP2. Carnosinase degrades carnosine (β-alanyl-L-histidine), which has been ascribed a renal protective effect as a scavenger of reactive oxygen species. We investigated the putative associations of genetic variants in CNDP1 and CNDP2 with diabetic nephropathy (defined either as micro-or macroalbuminuria) and estimated GFR in type 2 diabetic patients from Sweden. Methods We genotyped nine single nucleotide polymorphisms (SNPs) and one trinucleotide repeat polymorphism (D18S880, five to seven leucine repeats) in CNDP1 and CNDP2 in a case-control set-up including 4,888 unrelated type 2 diabetic patients (with and without nephropathy) from Sweden (Scania Diabetes Registry). Results Two SNPs, rs2346061 in CNDP1 and rs7577 in CNDP2, were associated with an increased risk of diabetic nephropathy (rs2346061 p=5.07×10 −4 ; rs7577 p=0.021).

Carnosine decreases IGFBP1 production in db/db mice through suppression of HIF-1

“…We therefore provide a new mechanism by which carnosine improves the metabolic control in diabetes and protect against the development of complications in diabetes. Even though carnosine shown protective effect in several animal models for complications of diabetes (Pfister et al 2011, Riedl et al 2011, Ansurudeen et al 2012, Yapislar & Aydogan 2012, Brown et al 2014, Peters et al 2014, Menini et al 2015 and strongly suggested to be relevant for diabetes complications in humans (Ahluwalia et al 2011, Kurashige et al 2013) the exact mechanism of action is still unraveled. Here we suggest a potential mechanism by showing that carnosine complexly modulates IGFBP1 by different mechanisms, i.e.…”

Energy metabolism, proteotoxic stress and age-related dysfunction – Protection by carnosine

“…therein;Gallant et al, 2000;Rajanikant et al, 2007;Tang et al, 2007;Yasuhara et al, 2008), including when added after the ischaemic episode (Dobrota et al, 2005;Tang et al, 2007;Rajanikant et al, 2007), and type-2 diabetes has been obtained mostly from the study of animal models and cell culture (Lee et al, 2005;Shi et al, 2009;Kamel et al, 2008;Tanida et al, 2004). Evidence supporting a role for carnosine in controlling diabetic kidney disease in humans has emerged from a study of carnosinase polymorphisms which suggest that lower levels of serum carnosinase activity decreases the incidence of kidney disease in type-2 diabetics (Ahluwalia et al, 2011;Janssen et al, 2005;Freedman et al, 2007;Sauerhoefer et al, 2005). There is also a report stating that the serum AGE levels are higher in diabetic vegetarians than in diabetic omnivores (Krajcovicova-Kudlackova et al, 2002); this is possible due to lower carnosine intake by vegetarians; alternatively it is also possible that fructose (a potent glycating agent and MG precursor) intake is high in vegetarians.…”

The Combined Effects of Genetic Variation in the CNDP1 and CNDP2 Genes and Dietary Carbohydrate and Carotene Intake on Obesity Risk

“…Previously, the genotypes for CNDP1 and CNDP2 were reported to be genetic risk factors for diabetic nephropathy, neurological disorders, and cancer [11,23,24,25]. Moreover, oxidative stress and subsequent inflammation increase the risk of development of such diseases [7,8,9,18].…”

“…The linkage disequilibriums among these 4 SNPs were not observed (online supplemental table; see www.karger.com/doi/10.1159/000485798). It was also described that these 4 SNPs do not exist in the same linkage disequilibrium block [23,24]. Therefore, these 4 SNPs were regarded as tag SNPs.…”