Genetic polymorphisms of innate immunity-related inflammatory pathways and their association with factors related to type 2 diabetes

Abstract

BackgroundType 2 diabetes mellitus (T2DM) has been linked to a state of pre-clinical chronic inflammation resulting from abnormalities in the innate immune pathway. Serum levels of pro-inflammatory cytokines and acute-phase proteins, collectively known as 'inflammatory network', are elevated in the pre-, or early, stages of T2DM and increase with disease progression. Genetic variation can affect the innate immune response to certain environmental factors, and may, therefore, determine an individual's lifetime risk of disease.MethodsWe conducted a cross-sectional study in 6,720 subjects from the TwinsUK Registry to evaluate the association between 18 single nucleotide polymorphisms (SNPs) in five genes (TLR4, IL1A, IL6, TNFA, and CRP) along the innate immunity-related inflammatory pathway and biomarkers of predisposition to T2DM [fasting insulin and glucose, HDL- and LDL- cholesterols, triglycerides (TGs), amyloid-A, sensitive C-reactive protein (sCRP) and vitamin D binding protein (VDBP) and body mass index (BMI)].ResultsOf 18 the SNPs examined for their association with nine metabolic phenotypes of interest, six were significantly associated with five metabolic phenotypes (Bonferroni correction, P ≤ 0.0027). Fasting insulin was associated with SNPs in IL6 and TNFA, serum HDL-C with variants of TNFA and CRP and serum sCRP level with SNPs in CRP. Cross-correlation analysis among the different metabolic factors related to risk of T2DM showed several significant associations. For example, BMI was directly correlated with glucose (r = 0.11), insulin (r = 0.15), sCRP (r = 0.23), LDL-C (r = 0.067) and TGs (r = 0.18) but inversely with HDL-C (r = -0.14). sCRP was also positively correlated (P < 0.0001) with insulin (r = 0.17), amyloid-A (r = 0.39), TGs (r = 0.26), and VDBP (r = 0.36) but inversely with HDL-C (r = -0.12).ConclusionGenetic variants in the innate immunity pathway and its related inflammatory cascade is associated with some metabolic risk factors for T2DM; an observation that may provide a rationale for further studying their role as biomarkers for disease early risk prediction.

Genetic polymorphisms of the TLR4 gene and their association with susceptibility to type 2 diabetes mellitus in the Chinese population

“…Genetic factors play key roles in the pathogenesis of T2DM. TLR4 is one of the most important candidate genes for T2DM, and genetic variants in the TLR4 gene have been reported to be associated with T2DM susceptibility (Illig et al, 2003;Rudofsky et al, 2004;Creely et al, 2007;Kim et al, 2008;Buraczynska et al, 2009;Arora et al, 2011;Maldonado-Bernal et al, 2011;Jiang et al, 2013). In this study, we demonstrated an association between the g.12375A>G and g.14367G>A genetic variants of the TLR4 gene and the risk of T2DM in the Chinese Han population.…”

“…To date, several single nucleotide polymorphisms (SNPs) have been identified in the human TLR4 gene (Raby et al, 2002;Kolz et al, 2008;Arora et al, 2011;Jiang et al, 2013), such as Asp299Gly (Rudofsky et al, 2004;Kim et al, 2008;Buraczynska et al, 2009;Arora et al, 2011;Maldonado-Bernal et al, 2011;Jiang et al, 2013) and Thr399Ile (Rudofsky et al, 2004;Kim et al, 2008;Kolz et al, 2008;Buraczynska et al, 2009;Maldonado-Bernal et al, 2011;Jiang et al, 2013). Furthermore, several studies proved that the TLR4 gene variants were associated with susceptibility to T2DM (Rudofsky et al, 2004;Kim et al, 2008;Kolz et al, 2008;Buraczynska et al, 2009;Arora et al, 2011;Maldonado-Bernal et al, 2011;Jiang et al, 2013). However, the data from these studies are inconsistent, and the exact mechanism is poorly understood.…”

“…The incidence of T2DM is increasing rapidly in the world. It is estimated that six people die from the disease worldwide every minute (Wild et al, 2004;Arora et al, 2011). Recently, studies reported that there is a very high T2DM incidence in China where diabetes has become a major public health problem (Yang et al, 2010), with approximately 92.4 million adults with the disease and 148.2 million with prediabetes (Jiang et al, 2013).…”

“…Recently, studies reported that there is a very high T2DM incidence in China where diabetes has become a major public health problem (Yang et al, 2010), with approximately 92.4 million adults with the disease and 148.2 million with prediabetes (Jiang et al, 2013). A large number of previous studies have shown that the human Toll-like receptor 4 (TLR4) is potentially an important gene influencing the susceptibility to T2DM (Illig et al, 2003;Rudofsky et al, 2004;Creely et al, 2007;Kim et al, 2008;Buraczynska et al, 2009;Arora et al, 2011;Maldonado-Bernal et al, 2011;Jiang et al, 2013). To date, several single nucleotide polymorphisms (SNPs) have been identified in the human TLR4 gene (Raby et al, 2002;Kolz et al, 2008;Arora et al, 2011;Jiang et al, 2013), such as Asp299Gly (Rudofsky et al, 2004;Kim et al, 2008;Buraczynska et al, 2009;Arora et al, 2011;Maldonado-Bernal et al, 2011;Jiang et al, 2013) and Thr399Ile (Rudofsky et al, 2004;Kim et al, 2008;Kolz et al, 2008;Buraczynska et al, 2009;Maldonado-Bernal et al, 2011;Jiang et al, 2013).…”

S-Adenosylmethionine-dependent Protein Methylation Is Required for Expression of Selenoprotein P and Gluconeogenic Enzymes in HepG2 Human Hepatocytes

“…Cellular methylation processes are ubiquitous metabolic events (29 -32) that are linked to redox status (33) and involved in immune processes (34), both processes known to be involved in obesity and the progression of type II diabetes (35,36). SAM and SAH levels as well as protein-arginine methylation are altered in diabetic models (5-9) and in humans (10, 11).…”