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Common genetic variants in the FETUB locus, genetically predicted fetuin-B levels, and risk of insulin resistance in obese Chinese adults.

ABSTRACT: Elevated serum fetuin-B is suggested to be associated with insulin resistance, but it is unknown if this association is causal. The aim of this study was to explore the potential causal relationship between fetuin-B and insulin resistance.We used Mendelian randomization analysis by incorporating information of genetic variants in FETUB and serum fetuin-B concentrations with insulin resistance in 1148 obese Chinese adults.Common genetic variants (FETUB rs4686434, rs6785067, and rs3733159) were significantly associated with serum fetuin-B concentrations but not with insulin resistance. Higher serum fetuin-B levels were significantly associated with increased homeostasis model assessment of insulin resistance (HOMA-IR) (0.17 [95%CI: 0.01 to 0.32, P?=?.037] 10 mol?IU?L higher per SD). However, Mendelian randomization analysis using 3 single-nucleotide polymorphisms as instrumental variables did not support a significant association between genetically predicted fetuin-B levels and HOMA-IR (-0.09 [95%CI: -0.62 to 0.44, P?=?.738] 10 mol?IU?L lower per SD). The regression coefficients for measured and genetically predicted fetuin-B concentrations on HOMA-IR were significantly different (P?<.001).This study suggests the association between fetuin-B and insulin resistance may not be causal. Future studies on the nongenetic determinants of serum fetuin-B concentration to assess if such unmeasured factors may confound the association between fetuin-B and insulin resistance as well as more pathway analysis for this association are warranted.

SUBMITTER: Li Z

PROVIDER: S-EPMC5815766 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Common genetic variants in the FETUB locus, genetically predicted fetuin-B levels, and risk of insulin resistance in obese Chinese adults.

Li Zhibin Z Liu Changqin C Shi Xiulin X Chen Zheng Z Wang Dongmei D Li Long L Tu Yichang Y Lin Mingzhu M Liu Suhuan S Yang Shuyu S Li Xuejun X

Medicine 20171201 50

Elevated serum fetuin-B is suggested to be associated with insulin resistance, but it is unknown if this association is causal. The aim of this study was to explore the potential causal relationship between fetuin-B and insulin resistance.We used Mendelian randomization analysis by incorporating information of genetic variants in FETUB and serum fetuin-B concentrations with insulin resistance in 1148 obese Chinese adults.Common genetic variants (FETUB rs4686434, rs6785067, and rs3733159) were si ...[more]

PMID: 29390354

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Project description:BackgroundInflammation plays a pivotal role in the pathogenesis of cancer. Though previous studies have reported a link between several inflammatory biomarkers and risk of certain types of cancer, there is a lack of systematic investigation. Therefore, we aimed to assess the role of circulating cytokines on the risk of cancer using a two-sample Mendelian randomization (MR) approach.MethodWe used genetic variants associated with circulating levels of cytokines from a meta-analysis of genome-wide association studies (GWASs) of 8,293 Finns as instrumental variables. Summary level data of 20 site-specific cancer were obtained from the UK BioBank including up to 456,348 participants of European ancestry. We performed two-sample MR analyses using inverse-variance weighted (IVW) method as the main method, followed by weighted-median and likelihood-based methods as sensitivity analysis. Pleiotropic and outlier variants were assessed by MR-Egger regression and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test.Results224 genetic variants associated with 27 circulating cytokines achieving genome-wide significance (P<5×10-8) were used as IVs. After Bonferroni correction, genetically predicted high levels of interleukin-18 (IL-18) were associated with a decreased risk of acute myeloid leukemia (odds ratio (OR) per 1 standard deviation (SD) increase = 0.55, 95% confidence interval (CI):0.43-0.69, P=5.39×10-7), and circulating levels of IL-17 were associated with altered stomach cancer risk (OR per 1 SD increase = 0.15, 95% CI: 0.07-0.36, P=1.25×10-5) by IVW. Results were stable across sensitivity analyses, and MR-Egger regression did not suggest the presence of directional pleiotropy. Additionally, we found suggestive evidence for 48 cytokine-cancer associations including tumor necrosis factor related apoptosis-inducing ligand (TRAIL) and cutaneous T-cell attracting chemokine (CTACK) with the risk of several types of cancer (9.26×10-5≤P<0.05).ConclusionsBy using a genetic epidemiological approach, our study systematically evaluated the role of circulating cytokines on the risk of cancer, and provided clues for potential therapeutic targets. However, the exact underlying biological mechanism warrants further investigation.

Project description:OBJECTIVE: Pigment epithelium-derived factor (PEDF) belongs to the serpin family of peptidase inhibitors (serpin F1) and is among the most abundant glycoproteins secreted by adipocytes. In vitro and mouse in vivo data revealed PEDF as a candidate mediator of obesity-induced insulin resistance. Therefore, we assessed whether common genetic variation within the SERPINF1 locus contributes to adipose tissue-related prediabetic phenotypes in humans. SUBJECTS/METHODS: A population of 1,974 White European individuals at increased risk for type 2 diabetes was characterized by an oral glucose tolerance test with glucose and insulin measurements (1,409 leptin measurements) and genotyped for five tagging SNPs covering 100% of common genetic variation (minor allele frequency ? 0.05) in the SERPINF1 locus. In addition, a subgroup of 486 subjects underwent a hyperinsulinaemic-euglycaemic clamp and a subgroup of 340 magnetic resonance imaging (MRI) and spectroscopy (MRS). RESULTS: After adjustment for gender and age and Bonferroni correction for the number of SNPs tested, SNP rs12603825 revealed significant association with MRI-derived total adipose tissue mass (p?=?0.0094) and fasting leptin concentrations (p?=?0.0035) as well as nominal associations with bioelectrical impedance-derived percentage of body fat (p?=?0.0182) and clamp-derived insulin sensitivity (p?=?0.0251). The association with insulin sensitivity was completely abolished by additional adjustment for body fat (p?=?0.8). Moreover, the fat mass-increasing allele of SNP rs12603825 was significantly associated with elevated fasting PEDF concentrations (p?=?0.0436), and the PEDF levels were robustly and positively associated with all body fat parameters measured and with fasting leptin concentrations (p<0.0001, all). CONCLUSION: In humans at increased risk for type 2 diabetes, a functional common genetic variant in the gene locus encoding PEDF contributes to overall body adiposity, obesity-related insulin resistance, and circulating leptin levels.

Dataset Information

Common genetic variants in the FETUB locus, genetically predicted fetuin-B levels, and risk of insulin resistance in obese Chinese adults.

Publications

Common genetic variants in the FETUB locus, genetically predicted fetuin-B levels, and risk of insulin resistance in obese Chinese adults.

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