bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/657734

Mendelian Randomization Analysis Dissects the Relationship between NAFLD, T2D, and Obesity and Provides Implications to Precision Medicine

Liu, Z.·Zhang, Y.·Graham, S.·Pique-Regi, R.·Dong, X. C.·Chen, Y. E.·Willer, C.·Liu, W.
View original source ↗Export metadata ↓

Abstract

BackgroundNon-alcoholic fatty liver disease (NAFLD) is epidemiologically correlated with both type 2 diabetes (T2D) and obesity. However, the causal inter-relationships among the three diseases have not been completely investigated.\n\nAimWe aim to explore the causal relationships among the three diseases.\n\nDesign and methodsWe performed a genome-wide association study (GWAS) on fatty liver disease in [~]400,000 UK BioBank samples. Using this data as well as the largest-to-date publicly available summary-level GWAS data, we performed a two-sample bidirectional Mendelian Randomization (MR) analysis. This analysis tested the causal inter-relationship between NAFLD, T2D, and obesity, as well as the association between genetically driven NAFLD (with two well-established SNPs at the PNPLA3 and TM6SF2 loci) and glycemic and lipidemic traits, respectively. Transgenic mice expressing the human PNPLA3 I148I (TghPNPLA3-I148I) and PNPLA3 I148M (TghPNPLA3-I148M) isoforms were used to further validate the causal effects.\n\nResultsWe found that genetically instrumented hepatic steatosis significantly increased the risk for T2D (OR=1.3, 95% CI: [1.2, 1.4], p=8.3e-14) but not the intermediate glycemic phenotypes at the Bonferroni-adjusted level of significance (p<0.002). There was a moderate, but significant causal association between genetically driven hepatic steatosis and decreased risk for BMI ({beta}=- 0.027 SD, 95%CI: [-0.043, -0.01], p=1.3e-4), but an increased risk for WHRadjBMI (Waist-Hip Ratio adjusted for BMI) ({beta}=0.039 SD, 95%CI: [0.023, 0.054], p=8.2e-7), as well as a decreased level for total cholesterol ({beta}=-0.084 SD, 95%CI [-0.13, -0.036], p=6.8e-4), but not triglycerides ({beta}=0.02 SD, 95%CI [-0.023, 0.062], p=0.36). The reverse MR analyses suggested that genetically driven T2D (OR=1.1, 95% CI: [1.0, 1.2], p=1.7e-3), BMI (OR=2.3, 95% CI: [2.0, 2.7], p=1.4e-25) and WHRadjBMI (OR=1.5, 95% CI: [1.3, 1.8], p=1.1e-6) causally increase the NAFLD risk. In the animal study, as compared to the TghPNPLA3-I148I controls, the TghPNPLA3-I148M mice developed higher fasting glucose level and reduced glucose clearance. Meanwhile, the TghPNPLA3-I148M mice demonstrated a reduced body weight, increased central to peripheral fat ratio, decreased circulating total cholesterol as compared to the TghPNPLA3-I148I controls.\n\nConclusionThis large-scale bidirectional MR study suggests that lifelong, genetically driven NAFLD is a causal risk factor for T2D (hence potentially a \"NAFLD-driven T2D\" subtype) and central obesity (or \"NAFLD-driven obesity\" subtype), but protects against overall obesity; while genetically driven T2D, obesity, and central obesity also causally increase the risk of NAFLD, hence a \"metabolic NAFLD\". This causal relationship revealed new insights into disease subtypes and provided novel hypotheses for precision treatment or prevention for the three diseases.

Source connections

Explore related subjects

epidemiologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Liu, Z., Zhang, Y., Graham, S., Pique-Regi, R., Dong, X. C., Chen, Y. E., Willer, C., Liu, W.. 2019-06-07. Mendelian Randomization Analysis Dissects the Relationship between NAFLD, T2D, and Obesity and Provides Implications to Precision Medicine. https://doi.org/10.1101/657734

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2019

Determinants of Severe Acute Malnutrition among Children age 6-59 Months Old in Two Public Hospitals, North West Ethiopia: a Case Control Study

IntroductionGlobally sever acute malnutrition affects 16.4 million under five children and more than one quarter of those children live in Africa. In Ethiopia, about 3% of children are severely wasted and continues to be persistent over the past 15 years. To implement an effective intervention, it is essential to identify predictors predispose to it. This study therefore, aimed to identify determinants of severe acute malnutrition among under five children in selected public health facilities, Northwest Ethiopia.\n\nMethodsInstitution based; age matched case control study was conducted on 104 cases and 208 controls. Bivariate and multivariate analyses were done using conditional logistic regression to identify predictors. Variables having P-value [&le;] 0.2 during binary analysis were entered into multivariate analysis. P value < 0.05 was considered as statistically significant.\n\nResultsChildren from households of large family size(AOR=2.7, 95% CI: 1.06 - 6.9), having monthly income less than 1500 birr (AOR = 5.17, 95% CI: 1.7-15.3), which are food insecure (AOR = 2.9, 95% CI:1.17-7.28)), which didnt receive any nutrition information (AOR= 3.47,95% CI: 1.14 - 7.10), didnt practice exclusive breastfeeding (AOR = 2.69, 95% CI: 1.18 - 6.10), and practice infrequent hand washing (AOR= 7.6 95% CI:2.44-23.6) as well as children who had history of diarrhea two weeks prior to the survey (AOR 3.2, 95%CI:1.4-7.2) were more likely to suffer from severe acute malnutrition.\n\nConclusionFamily size, monthly income, food security status, exclusive breastfeeding practice, access to information on child feeding, hand washing practice and history of diarrhea were identified to be predictors of severe acute malnutrition. Due emphasis should be given to promoting family planning, improve household livelihoods and food security, strength awareness creation on exclusive breastfeeding and frequent hand washing practices as well as prevention of diarrhea.

epidemiology↗
bioRxiv2019

Associations between meteorological variables, vector indices and dengue hospitalizations in Can Tho, Vietnam: a field survey

IntroductionDengue is a significant cause of morbidity and mortality in Can Tho, a province in the Mekong Delta in Vietnam. In this region, average temperatures have increased by 0.5{degrees}C since 1980, and river levels have risen. In a time-series analysis, we previously found that relative humidity was the most important meteorological predictor for dengue hospitalizations in Can Tho. To better understand proximate factors mediating this association, this study examines weather variables in relation to dengue hospitalization rates, vector indices, container productivity and larval elimination and mosquito avoidance behaviors.\n\nMethodsFour hundred households were sampled bimonthly for one year in Can Tho. Vector indices of the immature forms of the dengue vector, Aedes aegypti, and the productivity of different types of household containers were determined. Dengue hospitalization rates were determined for the study period. Associations between these variables and mean temperature, relative humidity, precipitation, and the number of hours of sun were estimated using mixed effects Poisson regression analysis. Relative productivity of containers was determined by collecting Ae. aegypti pupae using a sweep method and adjusting by a calibration factor. Ae. aegypti larval density risk factors were determined using multivariate generalized estimating equations with a negative binomial distribution. To examine possible mechanisms mediating the relationship between climate, vectors and dengue, we also interviewed households about mosquito avoidance and larval elimination behaviors.\n\nResultsThe house-(HI), container-(CI), Breteau (BI), and pupal (PI) indices were associated with relative humidity (1-month lag, IRRHI=1.10 (95% CI 1.06, 1.13) per 1% increase), IRRCI=1.10 (95% CI 1.02, 1.19), IRRBI=1.17 (95% CI 1.14, 1.21), IRRPI=1.12 (95% CI 1.10, 1.14)). Vector indices were also associated with precipitation (1-month lag) and to a lesser degree, hours of sun and mean temperature. Ae. aegypti larval density was associated with not cleaning water storage containers (RR=2.50, 95% CI 1.59, 3.66), not having access to municipal waste pick-up (RR=3.15, 95% CI2.09, 4.75), disheveled clothes in the home (RR=1.85, 95% CI 1.24, 2.74) and season (RR[rainy season]=3.10, 95% CI 2.18-4.48). The most productive containers were water storage containers (relative pupal productivity 87%). Dengue hospitalization rates were associated with relative humidity (2-month lag, IRR=1.11 (95% CI 1.06, 1.17) per 1% increase). Only the PI (1-month lag) was significantly associated with dengue hospitalization rates (IRR 1.04, 95% CI 1.00, 1.07). Mosquito avoidance behaviors were more frequent in the dry season (92.5% vs. 86.0% of interviewees endorsed one or more forms of mosquito prevention, p<0.001). There was also less use of larval elimination strategies (39.2% vs. 50.5%, p<0.001) during the rainy versus the dry season.\n\nConclusionOur study reveals a strong effect of relative humidity on vector indices and dengue hospitalization rates. This may be due to the mosquitos vulnerability to desiccation, and the association warrants further study. Our findings also demonstrate, however, that during the rainy season when mosquito prevention is most needed, the use of fans, repellant coils and maintenance of water storage containers is actually reduced. Water storage containers were by far the most productive of pupae, and should be targeted in vector control activities.\n\nAuthor summaryClimate plays an important role in the geographic distribution and burden of disease due to dengue, owing to the vector and virus sensitivity to temperature, humidity, and rainfall. In the Mekong Delta in Vietnam, where dengue poses a significant health burden, average temperatures have increased by 0.5{degrees}C since 1980. To better understand the influence of climate on dengue, this study examines its influence on dengue hospitalization rates, vector breeding behavior and human mosquito avoidance behaviors. We sampled 400 households every 2 months for one year for the presence of the dengue vector, Aedes aegypti, and the productivity of different types of household containers. Human mosquito avoidance behaviors, such as the use of fans, mosquito repellant, and larval elimination strategies were also recorded. The association between dengue hospitalizations, mean temperature, relative humidity, precipitation, and the number of hours of sun were established, and risk factors for the abundance of Ae. aegypti larvae were determined. We found that relative humidity is positively associated with the presence of Ae. aegypti immature forms, and that large jars used for water storage serve as the most important source of this vector. We also determined that people engage in mosquito avoidance/larval elimination strategies more frequently in the dry season versus the rainy season, despite increased vector breeding and dengue hospitalizations during the rainy season. This temporal disconnect between peak vector activity and dengue hospitalization rates vis-a-vis mosquito control strategies is a potential area for intervention.

epidemiology↗
bioRxiv2019

Socioeconomic factors associated with dysentery in children under-five years from developing countries

ObjectiveDysentery represents 10% of all causes of acute diarrhea in the world and recognizing the implied proximal and distal social factors at different levels would impact on every related outcome. Our purpose is to identify mother, household and country characteristics that favor the presence of dysentery in children under 5 years old.\n\nMethodsWe conducted a multilevel analysis of data from phase V of the Demographic and Health Survey and the World Bank, which included 38,762 children from 33 countries.\n\nResultsPrevalence of dysentery was 14.74%. GDP per-capita was negative associated (OR= 0.75; 95% CI 0.71-0.78) and Gini index was positive associated (OR= 1.23; 95% CI 1.19-1.28). Additionally, child age (OR= 0.99; 95% CI 0.99-1.00), mother age (OR= 1.01; 95% CI 1.00-1.01), employed mother (OR= 1.11; 95% CI 1.02-1.20), and number of household members (OR= 1.02; 95% CI 1.01-1.03) have significant positive associations with the presence of dysentery, while complete immunization schedule (OR= 0.88; 95% CI 0.81-0.96), duration of breastfeeding (OR= 0.81; 95% CI 0.75-0.89), and type of residence (OR= 0.87; 95% CI 0.79-0.97) have significant negative associations with having the illness. Finally, each of the categories of wealth index showed a significant association with dysentery (p-value < 0.001).\n\nConclusionsLower per capita GDP and higher Gini coefficient are associated with the development of dysentery, regardless of characteristics of children, their mother, and household. Future and present public health programs should address these issues in order to impact on the occurrence of this illness.\n\nAuthor summaryDysentery represents 10% of all causes of acute diarrheal disease. Diarrhea is the fifth cause of worldwide death in children under five years old. It is particularly important to assess and prevent this condition because the early years of life are critical since it is the period when the brain develops most rapidly and has a high capacity for change. Complications associated with dysentery such as malnutrition and convulsive episodes could have a negative effect in this aspect.\n\nOur purpose is to identify the country proximal and distal socioeconomic factors that favor the presence of dysentery in children under five years old from low and middle-income developing countries in order to impact on the occurrence of this illness and its related outcomes. Studying associated factors with developing dysentery during an episode of acute diarrhea could be the base upon which we can diminish mortality from this illness through national policies to impact on national, community and household aspects.

epidemiology↗