Association Between Promoter Polymorphisms of the GRP78 Gene and Risk of Type 2 Diabetes in a Chinese Han Population

Abstract

There are large amounts of unfolding or misfolding protein accumulation in the endoplasmic reticulum in patients with type 2 diabetes (T2D), which in turn induces the expression of the glucose-regulated protein 78 (GRP78) that plays a key role in influencing insulin secretion and maintaining glucose homeostasis in pancreatic beta cells. The aim in the study is to analyze the potential association between single-nucleotide polymorphisms (SNPs) of GRP78 and the risk of T2D. To assess the association between GRP78 polymorphisms and T2D, a casecontrol study was conducted among 1058 consecutive unrelated subjects. Of the 1058 subjects, 523 of them were diagnosed with T2D and 535 of them were healthy controls. Four SNPs with R 2 > 0.8 and the minor allele frequency > 0.05 (rs391957, rs17840761, rs17840762, and rs11355458) in the GRP78 gene promoter were analyzed. Overall, no associations of GRP78 polymorphisms with T2D were observed in genotypic analyses. In addition, haplotypes combining those SNPs in the promoter in high linkage disequilibrium were also not associated with a T2D risk. However, the levels of fasting plasma glucose and HbA1c in patients with the -415AA/-180GG genotype were significantly lower than those of the patients with -415GG/-180deldel and -415AG/-180Gdel genotypes, and the level of fasting insulin in patients with the -415AA/-180GG genotype was significantly lower than that of the patients with -415GG/ -180deldel. The study does not support a role for promoter polymorphisms of GRP78 in T2D in a Chinese Han population, but it does provide a clue for association between low levels of fasting plasma glucose, HbA1c and fasting insulin, and the -415AA/-180GG model.

The regulatory roles of NADPH oxidase, intra- and extra-cellular HSP70 in pancreatic islet function, dysfunction and diabetes

“…Patients with the −415AA/ −180GG genotype have lower levels of fasting plasma glucose and haemoglobin A1c (HbA1C) than the patients with −415GG/−180deldel and −415AG/ −180Gdel, suggesting that the first yield a higher activity and more GRP78 protein, inhibiting β-cell apoptosis and maintaining glucose homoeostasis [56]. Furthermore, iHSP70 was also shown to protect against ER stress in pancreatic β-cells [57].…”

Human gene polymorphisms and their possible impact on the clinical outcome of SARS-CoV-2 infection

“…Bioinformatic modeling has predicted favorable binding between GRP78 and the III (C391-C525) and IV (C480-C488) regions of the SARS-CoV-2 S protein [ 158 ]. In cells harboring the -415A/-180G allele, expression of HSPA5 was significantly increased compared to cells harboring the -415 G/-180 del allele following ER stress [ 159 ]. GRP78 expression and its polymorphisms may be associated with SARS-CoV-2 infection and mortality rates, but their role in COVID-19 is still poorly understood.…”