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Genetically elevated fetuin-A levels, fasting glucose levels, and risk of type 2 diabetes: the cardiovascular health study.

ABSTRACT: OBJECTIVE:Fetuin-A levels are associated with higher risk of type 2 diabetes, but it is unknown if the association is causal. We investigated common (>5%) genetic variants in the fetuin-A gene (AHSG) fetuin-A levels, fasting glucose, and risk of type 2 diabetes. RESEARCH DESIGN AND METHODS:Genetic variation, fetuin-A levels, and fasting glucose were assessed in 2,893 Caucasian and 542 African American community-living individuals 65 years of age or older in 1992-1993. RESULTS:Common AHSG variants (rs4917 and rs2248690) were strongly associated with fetuin-A concentrations (P<0.0001). In analyses of 259 incident cases of type 2 diabetes, the single nucleotide polymorphisms (SNPs) were not associated with diabetes risk during follow-up and similar null associations were observed when 579 prevalent cases were included. As expected, higher fetuin-A levels were associated with higher fasting glucose concentrations (1.9 mg/dL [95% CI, 1.2-2.7] higher per SD in Caucasians), but Mendelian randomization analyses using both SNPs as unbiased proxies for measured fetuin-A did not support an association between genetically predicted fetuin-A levels and fasting glucose (-0.3 mg/dL [95% CI, -1.9 to 1.3] lower per SD in Caucasians). The difference between the associations of fasting glucose with actual and genetically predicted fetuin-A level was statistically significant (P=0.001). Results among the smaller sample of African Americans trended in similar directions but were statistically insignificant. CONCLUSIONS:Common variants in the AHSG gene are strongly associated with plasma fetuin-A concentrations, but not with risk of type 2 diabetes or glucose concentrations, raising the possibility that the association between fetuin-A and type 2 diabetes may not be causal.

SUBMITTER: Jensen MK

PROVIDER: S-EPMC3781539 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Genetically elevated fetuin-A levels, fasting glucose levels, and risk of type 2 diabetes: the cardiovascular health study.

Jensen Majken K MK Bartz Traci M TM Djoussé Luc L Kizer Jorge R JR Zieman Susan J SJ Rimm Eric B EB Siscovick David S DS Psaty Bruce M BM Ix Joachim H JH Mukamal Kenneth J KJ

Diabetes care 20130625 10

<h4>Objective</h4>Fetuin-A levels are associated with higher risk of type 2 diabetes, but it is unknown if the association is causal. We investigated common (>5%) genetic variants in the fetuin-A gene (AHSG) fetuin-A levels, fasting glucose, and risk of type 2 diabetes.<h4>Research design and methods</h4>Genetic variation, fetuin-A levels, and fasting glucose were assessed in 2,893 Caucasian and 542 African American community-living individuals 65 years of age or older in 1992-1993.<h4>Results</ ...[more]

PMID: 23801724

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Project description:ObjectiveTo collectively evaluate the association of glucose-6-phosphatase catalytic unit 2 (G6PC2) allele variants with elevated fasting glucose (FG) and type 2 diabetes (T2D).DesignMeta-analysis.Data sourcesPubMed, Web of Knowledge and Embase databases.Study selectionFull text articles of studies that identified an association of G6PC2 with T2D and elevated FG.Patient involvementThere was no T2D patient involvement in the analyses on the association of FG with G6PC2, there were T2D patients and non-diabetes patient involvement in the analyses on the association of T2D with G6PC2.Statistical analysisRandom-effects meta-analyses were used to calculate the pool effect sizes. I2 metric and H2 tests were used to calculate the heterogeneity. Begg's funnel plot and Egger's linear regression test were done to assess publication bias.ResultsOf the 423 studies identified, 21 were eligible and included. Data on three loci (rs560887, rs16856187 and rs573225) were available. The G allele at rs560887 in three ethnicities, the C allele at rs16856187 and the A allele at rs573225 all had a positive association with elevated FG. Per increment of G allele at rs560887 and A allele at rs573225 resulted in a FG 0.070 mmol/l and 0.075 mmol/l higher (ß (95% CI) = 0.070 (0.060, 0.079), p = 4.635e-50 and 0.075 (0.065, 0.085), p = 5.856e-48, respectively). With regard to the relationship of rs16856187 and FG, an increase of 0.152 (95% CI: 0.034-0.270; p = 0.011) and 0.317 (95% CI: 0.193-0.442, p = 6.046e-07) was found in the standardized mean difference (SMD) of FG for the AC and CC genotypes, respectively, when compared with the AA reference genotype. However, the G-allele of rs560887 in Caucasians under the additive model and the C-allele of rs16856187 under the allele and dominant models were associated with a decreased risk of T2D (OR (95% CI) = 0.964 (0.947, 0.981), p = 0.570e-4; OR (95% CI) = 0.892 (0.832, 0.956), p = 0.001; and OR (95% CI) = 0.923(0.892, 0.955), p = 5.301e-6, respectively).ConclusionsOur meta-analyses demonstrate that all three allele variants of G6PC2 (rs560887, rs16856187 and rs573225) are associated with elevated FG, with two variants (rs560887 in the Caucasians subgroup and rs16856187 under the allele and dominant model) being associated with T2D as well. Further studies utilizing larger sample sizes and different ethnic populations are needed to extend and confirm these findings.

Project description:Previous studies have demonstrated a positive relationship between liver cancer and diabetes mellitus. However, elevated fasting blood glucose (FBG) itself may be a risk factor for the development of hepatocellular carcinoma (HCC) rather than diabetes, and during the follow-up period, death is an event that may occur before the occurrence of HCC, which should be dealt with competing risk models. Our study aims to investigate the relationship between FBG and new-onset HCC by using competing risk regression models.We prospectively studied the relationship between FBG concentrations and risk of HCC in a cohort of 93,447 participants who were free of prior HCC, and whose demographic characteristics and biochemical parameters were recorded. Cox proportional hazards regression models and competing risk regression models were used to evaluate the association between FBG concentrations and risk of incident HCC.A total of 302 participants were diagnosed with HCC among 93,447 subjects during 810,499 person-years of follow-up. The multivariable hazard ratios (HRs) [95% confidence interval (95% CI)] for the association of FBG and log(FBG) with HCC were 1.07 (1.01∼1.12), 1.84 (1.23∼2.74) in an analysis adjusted for other potential variables. In the multivariable adjusted analysis, participants who were in 4.82 mmol/L≤FBG≤5.49 mmol/L group and FBG >5.49 mmol/L group would have increased the risk of HCC by 47% and 69%, respectively. In a cause-specific hazard model (CS model), the multivariable HRs (95% CI) for the association of FBG with HCC were 1.46 (1.09∼1.98), 1.69 (1.27∼2.27) in the multivariable adjusted analysis. Similar results were also observed in sub-distribution hazard function model (SD model) with corresponding multivariate HRs (95% CI) of 1.46 (1.09∼2.00), 1.69 (1.25∼2.27) in 4.82 mmol/L≤FBG≤5.49 mmol/L group and FBG >5.49 mmol/L group, respectively.Higher FBG concentrations itself were positively associated with new-onset HCC in the Cox proportional hazards regression models and competing risk models. FBG concentrations can be used as a scientific and important way to identify individuals with a higher risk of HCC and control of FBG concentrations might serve as a possible way to decrease the risk of HCC among Chinese population.Trial registration: ChiCTR-TNRC-11001489. Registered August 24, 2011 (retrospectively registered).

Dataset Information

Genetically elevated fetuin-A levels, fasting glucose levels, and risk of type 2 diabetes: the cardiovascular health study.

Publications

Genetically elevated fetuin-A levels, fasting glucose levels, and risk of type 2 diabetes: the cardiovascular health study.

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