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The effect of liver enzymes on adiposity: a Mendelian randomization study.

ABSTRACT: Poorer liver function is positively associated with diabetes in Mendelian randomization (MR) studies. Observationally, adiposity is associated with poorer liver function. To clarify the etiology, we assessed the association of liver enzymes with adiposity observationally and using two-sample MR for validation. In the "Children of 1997" birth cohort, we used multivariable linear regression to assess the associations of alanine transaminase (ALT) and alkaline phosphatase (ALP) at ~17.5 years with body mass index (BMI) (n?=?3,458). Using MR, genetic predictors of ALT, ALP and gamma glutamyltransferase (GGT), were applied to genome-wide association studies of BMI (n?=?681,275), waist circumference (WC) (n?=?224,459) and waist-hip ratio (WHR) (n?=?224,459) to obtain unconfounded estimates. Observationally, ALT was positively associated with BMI (0.10?kg/m2 per IU/L, 95% confidence interval (CI) 0.09 to 0.11). ALP was inversely associated with BMI (-0.018?kg/m2 per IU/L, 95% CI -0.024 to -0.012). Using MR, ALT was inversely associated with BMI (-0.14 standard deviation per 100% change in concentration, 95% CI -0.20 to -0.07), but not WC or WHR. ALP and GGT were unrelated to adiposity. Poorer liver function might not cause adiposity; instead higher ALT might reduce BMI, raising the question as to the role of ALT in body composition.

SUBMITTER: Liu J

PROVIDER: S-EPMC6856156 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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The effect of liver enzymes on adiposity: a Mendelian randomization study.

Liu Junxi J Au Yeung Shiu Lun SL Kwok Man Ki MK Leung June Yue Yan JYY Lin Shi Lin SL Hui Lai Ling LL Leung Gabriel Matthew GM Schooling C Mary CM

Scientific reports 20191114 1

Poorer liver function is positively associated with diabetes in Mendelian randomization (MR) studies. Observationally, adiposity is associated with poorer liver function. To clarify the etiology, we assessed the association of liver enzymes with adiposity observationally and using two-sample MR for validation. In the "Children of 1997" birth cohort, we used multivariable linear regression to assess the associations of alanine transaminase (ALT) and alkaline phosphatase (ALP) at ~17.5 years with ...[more]

PMID: 31727910

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Project description:Background Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. Methods We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N?=?806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N?=?24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. Results In sex-specific MR analyses, higher BMI (per 4.2?kg/m2) was associated with 1.23 (95% confidence interval (CI)?=?1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2?kg/m2) was associated with 1.09 (95% CI?=?0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR?=?1.25, 95% CI?=?1.08, 1.43) than men (IVW OR?=?1.05, 95% CI?=?0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P???0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI?=?1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. Conclusions Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways. Supplementary information The online version contains supplementary material available at 10.1186/s12916-020-01855-9.

Project description:Background: The incidence of type 1 diabetes (T1D) is increasing globally. One hypothesis is that increasing childhood obesity rates may explain part of this increase, but, as T1D is rare, intervention studies are challenging to perform. The aim of this study was to assess this hypothesis with a Mendelian randomization approach that uses genetic variants as instrumental variables to test for causal associations.Methods and findings: We created a genetic instrument of 23 single nucleotide polymorphisms (SNPs) associated with childhood adiposity in children aged 2-10 years. Summary-level association results for these 23 SNPs with childhood-onset (<17 years) T1D were extracted from a meta-analysis of genome-wide association study with 5,913 T1D cases and 8,828 reference samples. Using inverse-variance weighted Mendelian randomization analysis, we found support for an effect of childhood adiposity on T1D risk (odds ratio 1.32, 95% CI 1.06-1.64 per standard deviation score in body mass index [SDS-BMI]). A sensitivity analysis provided evidence of horizontal pleiotropy bias (p = 0.04) diluting the estimates towards the null. We therefore applied Egger regression and multivariable Mendelian randomization methods to control for this type of bias and found evidence in support of a role of childhood adiposity in T1D (odds ratio in Egger regression, 2.76, 95% CI 1.40-5.44). Limitations of our study include that underlying genes and their mechanisms for most of the genetic variants included in the score are not known. Mendelian randomization requires large sample sizes, and power was limited to provide precise estimates. This research has been conducted using data from the Early Growth Genetics (EGG) Consortium, the Genetic Investigation of Anthropometric Traits (GIANT) Consortium, the Tobacco and Genetics (TAG) Consortium, and the Social Science Genetic Association Consortium (SSGAC), as well as meta-analysis results from a T1D genome-wide association study.Conclusions: This study provides genetic support for a link between childhood adiposity and T1D risk. Together with evidence from observational studies, our findings further emphasize the importance of measures to reduce the global epidemic of childhood obesity and encourage mechanistic studies.

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Project description:Observational studies have reported an association between obesity, as measured by elevated body mass index (BMI), in early adulthood and risk of multiple sclerosis (MS). However, bias potentially introduced by confounding and reverse causation may have influenced these findings. Therefore, we elected to perform Mendelian randomization (MR) analyses to evaluate whether genetically increased BMI is associated with an increased risk of MS.Employing a two-sample MR approach, we used summary statistics from the Genetic Investigation of Anthropometric Traits (GIANT) consortium and the International MS Genetics Consortium (IMSGC), the largest genome-wide association studies for BMI and MS, respectively (GIANT: n = 322,105; IMSGC: n = 14,498 cases and 24,091 controls). Seventy single nucleotide polymorphisms (SNPs) were genome-wide significant (p < 5 x 10-8) for BMI in GIANT (n = 322,105) and were investigated for their association with MS risk in the IMSGC. The effect of each SNP on MS was weighted by its effect on BMI, and estimates were pooled to provide a summary measure for the effect of increased BMI upon risk of MS. Our results suggest that increased BMI influences MS susceptibility, where a 1 standard deviation increase in genetically determined BMI (kg/m2) increased odds of MS by 41% (odds ratio [OR]: 1.41, 95% CI 1.20-1.66, p = 2.7 x 10-5, I2 = 0%, 95% CI 0-29). Sensitivity analyses, including MR-Egger regression, and the weighted median approach provided no evidence of pleiotropic effects. The main study limitations are that, while these sensitivity analyses reduce the possibility that pleiotropy influenced our results, residual pleiotropy is difficult to exclude entirely.Genetically elevated BMI is associated with risk of MS, providing evidence for a causal role for obesity in MS etiology. While obesity has been associated with many late-life outcomes, these findings suggest an important consequence of childhood and/or early adulthood obesity.

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The effect of liver enzymes on adiposity: a Mendelian randomization study.

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The effect of liver enzymes on adiposity: a Mendelian randomization study.

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