RBP4 variants are significantly associated with plasma RBP4 levels and hypertriglyceridemia risk in Chinese Hans

Abstract

We previously found that plasma RBP4 levels were strongly associated with metabolic syndrome components. This study aimed to determine whether RBP4 variants are associated with the metabolic syndrome components and plasma RBP4 levels, and to investigate whether the associations between plasma RBP4 and the metabolic syndrome components are causal. Five tagSNPs were tested for their associations with plasma RBP4 levels and metabolic syndrome components in a population-based sample of 3,210 Chinese Hans. A possible causal relationship between plasma RBP4 levels and hypertriglyceridemia was explored by Mendelian randomization. Plasma RBP4 levels were significantly associated with rs10882273 (bz 20.10SD[20.17,20.03], P 5 0.0050), rs3758538 (bz 20.13SD[20.24,20.02], P 5 0.0249) in all participants, and with rs17108993 in Shanghai participants (bz 20.19SD[20.32,20.05], P 5 0.0061). The single nucleotide polymorphism (SNP) rs3758538 was significantly associated with hypertriglyceridemia ], P 5 0.0026) and triglycerides (bz 20.19SD [20.30,20.07], P 5 0.001) in all participants. In Mendelian randomization analysis, the observed effect size of association between rs3758538 and hypertriglyceridemia was different from the expected effect size (P 5 0.0213). This is the first study to show that the RBP4 variants are significantly associated with plasma RBP4 levels and hypertriglyceridemia risk in Chinese Hans. However, results of Mendelian randomization do not support the hypothesis that RBP4 levels are causally related to hypertriglyceridemia risk. Retinol-binding protein 4 (RBP4), initially known as the specific carrier of retinol, has recently been identified as a new adipokine that is robustly associated with visceral fat and insulin resistance (1). The potential link between RBP4 and insulin resistance was first suggested by the observations that serum RBP4 levels were elevated in adipose-Glut4 2/2 mice and completely normalized by the antidiabetic agent rosiglitazone (2), whereas genetic deletion of Rbp4 (Rbp4 2/2 mice) improved insulin sensitivity (2). These findings in mice were strongly supported by clinical data in humans from the same group (3), showing that serum RBP4 levels were elevated in insulin-resistant individuals with obesity, impaired glucose tolerance, type 2 diabetes, and even in lean nondiabetic individuals with a strong family history of type 2 diabetes. Several recent genetic association studies also found an association between common RBP4 variants and insulin resistance or type 2 diabetes (4-7). However, results of subsequent clinical and cross-sectional studies were inconsistent, as many failed to confirm the inverse correlation between RBP4 and insulin resistance, or some found opposite results (8-13). Apparently, the role of RBP4 as a mediator of insulin resistance in humans remains to be clarified.Growing evidence suggests that RBP4 may play a more important role in lipid metabolism than insulin resistance. For example, most of the previous human studies that confirmed the association ...

Association of Retinol-Binding Protein-4 (RBP4) with Lipid Parameters in Obese Women

“…On the other hand, again, it is possible that in the independent association that we found with lipid parameters, there was a contribution of genetic factors since recent studies suggest an important genetic component in these associations [37,38].…”

Relation of Absolute or Relative Adiposity to Insulin Resistance, Retinol Binding Protein-4, Leptin, and Adiponectin in Type 2 Diabetes

“…While RBP4 released from adipocytes is an adipokine released from adipocytes [21], it is more strongly associated with intestinal fat mass than with total fat mass, and is known to increase in an elevated insulin resistance setting [22]. Graham et al [23] investigated the relationship between serum RBP4 concentration and insulin resistance in obese and diabetic subjects and found that RBP4 concentrations are strongly associated with insulin resistance in both type 2 diabetic and non-diabetic subjects, while also influencing metabolic syndrome and cardiovascular heart disease.…”

RBP4: a controversial adipokine

“…It was also considered a promising adipokine in humans possibly linking adiposity, insulin resistance, T2D, and certain components of the metabolic syndrome (32,33,35,47,48,(51)(52)(53)(54). However, in several clinical studies, associations and/or causality of observed RBP4 expression changes with these states could not be shown (9-11, 35, 71, 72, 93).…”

“…Circulating RBP4 levels also correlate with other components of the metabolic syndrome (32,(51)(52)(53)(54). It is suggested that RBP4 is a predictor of atherosclerosis and its clinical manifestations -cardiovascular diseases.…”