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C-reactive protein levels and body mass index: elucidating direction of causation through reciprocal Mendelian randomization.

ABSTRACT: The assignment of direction and causality within networks of observational associations is problematic outside randomized control trials, and the presence of a causal relationship between body mass index (BMI) and C-reactive protein (CRP) is disputed.Using reciprocal Mendelian randomization, we aim to assess the direction of causality in relationships between BMI and CRP and to demonstrate this as a promising analytical technique.The study was based on a large, cross-sectional European study from Copenhagen, Denmark. Genetic associates of BMI (FTO(rs9939609)) and circulating CRP (CRP(rs3091244)) have been used to reexamine observational associations between them.Observational analyses showed a strong, positive association between circulating CRP and BMI (change in BMI for a doubling in log CRP of 1.03 kg m(-2) (95% confidence interval (95% CI): 1.00, 1.07), P<0.0001). Analysis using CRP(rs3091244) to re-estimate the causal effect of circulating CRP on BMI yielded null effects (change in BMI for a doubling in log CRP of -0.24 kg m(-2) (95% CI: -0.58, 0.11), P=0.2). In contrast, analysis using FTO(rs9939609) to assess the causal effect of BMI on circulating CRP confirmed observational associations (ratio of geometric means of CRP per s.d. increase in BMI 1.41 (95% CI: 1.10, 1.80), P=0.006).Taken together, these data suggest that the observed association between circulating CRP and measured BMI is likely to be driven by BMI, with CRP being a marker of elevated adiposity. More generally, the method of reciprocal randomization has general applicability in determining the direction of causation within inter-correlated networks of metabolic components.

SUBMITTER: Timpson NJ

PROVIDER: S-EPMC4783860 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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C-reactive protein levels and body mass index: elucidating direction of causation through reciprocal Mendelian randomization.

Timpson N J NJ Nordestgaard B G BG Harbord R M RM Zacho J J Frayling T M TM Tybjærg-Hansen A A Smith G Davey GD

International journal of obesity (2005) 20100817 2

<h4>Context</h4>The assignment of direction and causality within networks of observational associations is problematic outside randomized control trials, and the presence of a causal relationship between body mass index (BMI) and C-reactive protein (CRP) is disputed.<h4>Objective</h4>Using reciprocal Mendelian randomization, we aim to assess the direction of causality in relationships between BMI and CRP and to demonstrate this as a promising analytical technique.<h4>Participants and methods</h4 ...[more]

PMID: 20714329

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Project description:BackgroundWhile an association between gut microbiota composition and thyroid cancer (TC) has been observed, the directionality and causality of this relationship remain unclear.MethodsWe conducted a bidirectional two-sample Mendelian randomization (MR) analysis to investigate the causal effect between gut microbiota composition and TC. Gut microbiota data were derived from a diverse population encompassing various ethnicities (n = 18,340 samples), while TC data were sourced from an European population (n = 218,792 samples). Instrumental variables, represented by single nucleotide polymorphisms (SNPs), were employed to assess the causal relationship using multiple MR methods, including inverse-variance weighting (IVW), weighted median, weighted mode, MR-Egger, and simple mode. F-statistics and sensitivity analyses were performed to evaluate the robustness of the findings.ResultsOur investigation identified a comprehensive set of 2934 instrumental variables significantly linked to gut microbiota composition (p < 1 × 10-5). The analysis illuminated notable candidates within the phylum Euryarchaeota, including families Christensenellaceae and Victivallaceae, and genera Methanobrevibacter, Ruminococcus2, and Subdoligranulum, which emerged as potential risk factors for TC. On the other hand, a protective influence against TC was attributed to class Betaproteobacteria, family FamilyXI, and genera Anaerofilum, Odoribacter, and Sutterella, alongside order Burkholderiales. Further enhancing our insights, the integration of 7 instrumental variables from TC data (p < 1 × 10-5) disclosed the regulatory potential of one family and five genera. Notably, the genus Coprobacter innocuum group (p = 0.012, OR = 0.944) exhibited the highest probability of regulation. Our meticulous analyses remained free from significant bias, heterogeneity, or horizontal pleiotropy concerns.ConclusionThrough a bidirectional two-sample Mendelian randomization approach, we elucidated a potential bidirectional causal relationship between gut microbiota composition and TC. Specific microbial taxa were associated with an increased risk or conferred protection against TC. These findings advance our understanding of the complex interplay between the gut microbiota and TC pathogenesis, offering new insights into the therapeutic potential of modulating the gut microbiota for managing TC.

Dataset Information

C-reactive protein levels and body mass index: elucidating direction of causation through reciprocal Mendelian randomization.

Publications

C-reactive protein levels and body mass index: elucidating direction of causation through reciprocal Mendelian randomization.

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