An association study of C9orf3, a novel component of the renin-angiotensin system, and hypertension in diabetes

Abstract

The renin-angiotensin system (RAS) is important in the onset and course of cardiovascular, kidney, and metabolic disorders. Previous reports showed that the RAS blockade protects organs and suppress the development of type 2 diabetes mellitus. A novel component of the RAS, namely, chromosome 9 open reading frame 3 (C9orf3), was recently identified, however, its effects are unclear. We evaluated whether the genetic variant of C9orf3 is associated with morbidity of hypertension among subjects with type 2 diabetes. We enrolled 382 subjects with type 2 diabetes, 222 of whom were diagnosed with hypertension. Human leukocyte genomic DNA was isolated and a genetic variant was analyzed for a C/T variant of C9orf3 (rs4385527) via PCR analysis. The relationship between the genotype and hypertension morbidity among subjects with diabetes was examined. The proportion of the respective C9orf3 genetic variants were as follows 247 CC, 119 CT, and 16 TT. The risk of hypertension was determined to be 1.58, with a 95% confidence interval of 1.11–2.27. Moreover, the p value was 0.012 for allelic comparison and for Armitage’s trend test, with the C allele identified as the risk factor. Consequently, hypertension was markedly associated with type 2 diabetes in subjects with the C9orf3 variant, exhibiting a nearly 1.6-fold increased risk. The C variant of a new component of the RAS, C9orf3 (rs4385527) might have a considerable impact on the pathogenesis of hypertension in diabetes.

Biallelic AOPEP Loss‐of‐Function Variants Cause Progressive Dystonia with Prominent Limb Involvement

“…This may reflect the fact that these genes are more likely to play a critical role for dystonia pathogenesis during brain development and less so in the adult mature brain 30 . Single‐nucleotide polymorphism‐based association studies have shown that more common variations in AOPEP may influence susceptibility to prevalent disease traits, such as arterial hypertension, polycystic ovary syndrome, and atrial fibrillation 31‐33 . We believe, however, that it is currently not possible to bring these observations into a direct pathophysiological context with dystonia because the herein identified loss‐of‐function alterations are likely to have molecular consequences different from those encountered in association to common (non‐neurological) disease risk alleles.…”

Suicide Related Phenotypes in a Bipolar Sample: Genetic Underpinnings

“…Even though this prediction highlights the potential variability caused by rs2767403, the AOPEP gene encodes a metallo protease linked to the renin-angiotensin system [47]. In particular, it is able to cleave angiotensin III (but not I and II) to generate Angiotensin IV.…”

Comparative Multi-omic Mapping of Human Pancreatic Islet Endoplasmic Reticulum and Cytokine Stress Responses Provides Insights into Type 2 Diabetes Genetics

“…Twenty-one and 24 T2D- associated variants overlapped ER stress- or cytokine-specific opening CREs, respectively (Figure 4A; Supplementary Table 5) . Among these, 11 variants overlapped ER stress-specific opening CREs that are within 500kb of an ER stress response gene (Figure 4B; Supplementary Table 5), including AOPEP - a key gene involved in peptide processing 70 and robustly induced by ER stress in beta cells (Figure 4C; Supplementary Tables 2-3) . We detected an ER stress-specific induced CRE in the AOPEP intron, which harbors the T2D-associated variant rs4744423 (Figure 4D; Supplementary Tables 4-5) .…”