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An approach to estimate bidirectional mediation effects with application to body mass index and fasting glucose.

ABSTRACT: Obesity and type 2 diabetes are major public health issues with known interdependence. Genetic variants have been associated with obesity, type 2 diabetes, or both; thus, we hypothesize that some single nucleotide polymorphisms (SNPs) associated with both conditions may be mediated through obesity to affect type 2 diabetes or vice versa. We propose a framework for bidirectional mediation analyses. Simulations show that this approach accurately estimates the parameters, whether the mediation is unidirectional or bidirectional. In many scenarios, when the mediator is regressed on the initial variable and the outcome is regressed on the mediator and the initial variable, the resulting residuals are correlated because of other unmeasured covariates not in the model. We show that the proposed model provides accurate estimates in this scenario, too. We applied the proposed approach to investigate the mediating effects of SNPs associated with type 2 diabetes and obesity using genetic data from the Multi-Ethnic Study of Atherosclerosis cohort. Specifically, we used body mass index (BMI) as a measure for obesity and fasting glucose as a measure for type 2 diabetes. We evaluated the top 6 SNPs associated with both BMI and fasting glucose. Two SNPs (rs3752355 and rs6087982) had indirect effects on BMI mediated through fasting glucose [0.2677; 95% confidence interval (CI) (0.0007, 0.6548) and 0.3301; 95% CI (0.0881, 0.8544), respectively]. The remaining four SNPs (rs7969190, rs4869710, rs10201400, and rs12421620) directly affect BMI and fasting glucose without mediating effects.

SUBMITTER: Talluri R

PROVIDER: S-EPMC6188813 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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An approach to estimate bidirectional mediation effects with application to body mass index and fasting glucose.

Talluri Rajesh R Shete Sanjay S

Annals of human genetics 20180711 6

Obesity and type 2 diabetes are major public health issues with known interdependence. Genetic variants have been associated with obesity, type 2 diabetes, or both; thus, we hypothesize that some single nucleotide polymorphisms (SNPs) associated with both conditions may be mediated through obesity to affect type 2 diabetes or vice versa. We propose a framework for bidirectional mediation analyses. Simulations show that this approach accurately estimates the parameters, whether the mediation is u ...[more]

PMID: 29993118

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Project description:Abstract Background: The uncoupling proteins (UCPs) belong to the mitochondrial inner membrane anion carrier superfamily and play an important role in energy homeostasis. UCP-1 is expressed mostly in brown adipose tissue (BAT) and act in the thermogenesis and regulation of energy expenditure. UCP-2 has a role in the metabolism of fatty acids direct and indirectly path insulin secretion. UCP-3 is specific of skeletal muscle and BAT and may affects the adaptive and translocation of fatty acids. Genetic polymorphisms in these proteins have been associated with obesity, as rs1800592 (-3826 A/G) in UCP-1 gene. The rs659366 (-866GA) UCP-2 has being associated with high expression of its RNAm, decrease of obesity risk, and increase of energy expenditure. The rs1800849 (-55CT) UCP-3 has been associated with low risk of type 2 Diabetes Mellitus, but its association with body mass index is controversial. Objective: To analyze the association of the polymorphisms rs1800592 UCP-1, rs659366 UCP-2, and rs1800849 UCP-3 with BMI and resting energy expenditure (REE). Material and Methods: We included 120 subjects with BMI>30kg/m2 and 100 subjects with BMI between18.5 -24.9 kg/m2, aged 20 to 50 years. Anthropometric data were recorded and the REE was measure for indirect calorimetric. Fasting glucose and lipid profile were assessed. Leptin, insulin and acylated-ghrelin were quantified by ELISA. Genomic DNA was extracted using comercial kit. Genotyping for three polymorphisms was performed by allelic discrimination using Taqman probes. Results: All the three polymorphisms of UCPs showed distribution in accordance with Hardy-Weinberg equilibrium. The weight, BMI, glucose, triglycerides, leptin, insulin, HOMA-IR, and REE levels were signitifcantly higher in obese subjects. There was a strong correlation between REE with BMI (r=0.42, p<0.00001) and with insulin levels (r=0.229, p=0.001) in all group. No differences in genotypic and allelic frequencies of rs1800592 UCP-1, rs659366 UCP-2 and rs180084 UCP-3 polymorphisms between obese and lean subjects. No differences among the genotypes rs1800592 UCP-1 and rs1800849 UCP-3 with metabolic variables. In rs659366 UCP-2 polymorhism, the REE and glucose concentrations were lower in carriers of rs659366AA genotype (F=3.11, p=0.046; F=2.97, p=0.053, respectively) in whole group. In obese subjects with rs659366AA UCP-2 genotype, the REE was significantly low (F=4.15, P=0.017). Conclusion. In this work the obese subjects with rs659366AA genotype had low REE. We found low glucose concentrations in the carries of rs659366 AA genotype.

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An approach to estimate bidirectional mediation effects with application to body mass index and fasting glucose.

Publications

An approach to estimate bidirectional mediation effects with application to body mass index and fasting glucose.

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