Dataset Information

Causal relationships between NAFLD, T2D and obesity have implications for disease subphenotyping.

ABSTRACT:

Background & aims

Non-alcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D) and obesity are epidemiologically correlated with each other but the causal inter-relationships between them remain incompletely understood. We aimed to explore the causal relationships between the 3 diseases.

Methods

Using both UK Biobank and publicly available genome-wide association study data, we performed a 2-sample bidirectional Mendelian randomization analysis to test the causal inter-relationships between NAFLD, T2D, and obesity. Transgenic mice expressing the human PNPLA3-I148M isoforms (TghPNPLA3-I148M) were used as an example to validate causal effects and explore underlying mechanisms.

Results

Genetically driven NAFLD significantly increased the risk of T2D and central obesity but not insulin resistance or generalized obesity, while genetically driven T2D, body mass index and WHRadjBMI causally increased NAFLD risk. The animal study focusing on PNPLA3 corroborated these causal effects: compared to the TghPNPLA3-I148I controls, the TghPNPLA3-I148M mice developed glucose intolerance and increased visceral fat, but maintained normal insulin sensitivity, reduced body weight, and decreased circulating total cholesterol. Mechanistically, the TghPNPLA3-I148M mice demonstrated decreased pancreatic insulin but increased glucagon secretion, which was associated with increased pancreatic inflammation. In addition, transcription of hepatic cholesterol biosynthesis pathway genes was significantly suppressed, while transcription of thermogenic pathway genes was activated in subcutaneous and brown adipose tissues but not in visceral fat in TghPNPLA3-I148M mice.

Conclusions

Our study suggests that lifelong, genetically driven NAFLD causally promotes T2D with a late-onset type 1-like diabetic subphenotype and central obesity; while genetically driven T2D, obesity, and central obesity all causally increase the risk of NAFLD. This causal relationship revealed new insights into how nature and nurture drive these diseases, providing novel hypotheses for disease subphenotyping.

Lay summary

Non-alcoholic fatty liver disease, type 2 diabetes and obesity are epidemiologically correlated with each other, but their causal relationships were incompletely understood. Herein, we identified causal relationships between these conditions, which suggest that each of these closely related diseases should be further stratified into subtypes. This is important for accurate diagnosis, prevention and treatment of these diseases.

SUBMITTER: Liu Z

PROVIDER: S-EPMC7371536 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceNeonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain.ObjectiveTo test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight.Design, setting, and participantsMendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30,487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included.ExposuresGenetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level.Main outcome and measureOffspring birth weight from 18 studies.ResultsAmong the 30,487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele (P = .008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele (P = 7 × 10(-14)) and -4 g (95% CI, -6 to -2 g) per SBP-raising allele (P = 1×10(-5)), respectively. A 1-SD ( ≈ 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD ( ≈ 7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD ( ≈ 10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, -394 to -21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions.Conclusions and relevanceIn this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.