Effects of adiposity on the human plasma proteome: observational and Mendelian randomisation estimates

Goudswaard, Lucy J; Bell, Joshua A.; Hughes, David A.; Corbin, Laura J; Walter, Klaudia; Smith, George Davey; Soranzo, Nicole; Danesh, John; Angelantonio, Emanuele Di; Ouwehand, Willem H.; Watkins, Nicholas A.; Roberts, David; Butterworth, Adam S.; Hers, Ingeborg; Timpson, Nicholas J.

doi:10.1038/s41366-021-00896-1

Cited by 39 publications

(67 citation statements)

References 53 publications

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“…We replicated this positive correlation between BMI and IL-6 in all subgroups. Estimates from linear regression in the adult subgroups (24-year-olds and the mothers) were comparable to published estimates in adults, however the slope of linear model and correlation coefficients indicated the relationship was slightly stronger than published estimates [26][27][28] . These associations were weaker when analyses were restricted to the Olink IL-6 values >LOD.…”

Section: Discussionsupporting

confidence: 59%

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Inflammation proteomics datasets in the ALSPAC cohort

Goulding

Goudswaard²,

Hughes³

et al. 2022

Wellcome Open Res

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Proteomics is the identification, detection and quantification of proteins within a biological sample. The complete set of proteins expressed by an organism is known as the proteome. The availability of new high-throughput proteomic technologies, such as Olink Proteomic Proximity Extension Assay (PEA) technology has enabled detailed investigation of the circulating proteome in large-scale epidemiological studies. In particular, the Olink® Target 96 inflammatory panel allows the measurement of 92 circulating inflammatory proteins. The Avon Longitudinal Study of Parents and Children (ALSPAC) is a prospective population-based cohort study which recruited pregnant women in 1991-1992 and has followed these women, their partners, and their offspring ever since. In this data note, we describe the proteomic data available in ALSPAC. Ninety-two proteins were analysed in 9000 blood plasma samples using the Olink® Target 96 inflammatory panel. Samples were derived from 2968 fasted mothers (mean age 47.5; Focus on Mothers 1 (FOM1)), 3005 non-fasted offspring at age 9 (Focus@9) and 3027 fasted offspring at age 24 (Focus@24). Post sample filtering, 1834 offspring have data at both timepoints and 1119 of those have data from their mother available. We performed quality control analyses using a standardised data processing workflow (metaboprep) to produce a filtered dataset of 8983 samples for researchers to use in future analyses. Initial validation analyses indicate that IL-6 measured using the Olink® Target 96 inflammatory panel is highly correlated with IL-6 previously measured by clinical chemistry (Pearson’s correlation = 0.77) and we are able to reproduce the reported positive correlation between body mass index (BMI) and IL-6. The pre-processing and validation analyses indicate a rich proteomic dataset to further characterise the role of inflammation in health and disease.

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Section: Discussionsupporting

confidence: 59%

“…This was supported by our validation analyses. For example, BMI and IL-6 have been shown to be positively associated in observational studies 26 . We replicated this positive correlation between BMI and IL-6 in all subgroups.…”

Section: Discussionmentioning

confidence: 99%

Inflammation proteomics datasets in the ALSPAC cohort

Goulding

Goudswaard²,

Hughes³

et al. 2022

Wellcome Open Res

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“…We compared our MR findings for NPNT with results from the INTERVAL study, which evaluated the associations between BMI and 3,622 plasma protein levels among 2,729 individuals 6 . In the INTERVAL study, a one SD increase in BMI was observationally associated with NPNT (beta = 0.127, 95% CI: 0.088–0.167, P = 4.52 × 10 -10 ), which was directionally consistent with the MR findings.…”

Section: Resultsmentioning

confidence: 99%

“…The derived beta estimates represented normalized SD-unit difference in each protein level per one SD (4.8 kg/m 2 ) increase in BMI. Further details of the study have been described in detail previously 6 .…”

Section: Methodsmentioning

confidence: 99%

Proteome-wide Mendelian randomization implicates nephronectin as an actionable mediator of the effect of obesity on COVID-19 severity

Yoshiji

Butler‐Laporte

et al. 2022

Preprint

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Obesity is a major risk factor for COVID-19 severity; however, the underlying mechanism is not fully understood. Considering that obesity influences the human plasma proteome, we sought to identify circulating proteins mediating the effects of obesity on COVID-19 severity. We first screened 4,907 plasma proteins to identify proteins influenced by body mass index (BMI) using Mendelian randomization (MR). This yielded 1,216 proteins, whose effects on COVID-19 severity were assessed, again using MR. This two-step approach identified nephronectin (NPNT), for which a one standard deviation increase was associated with severe COVID-19 (odds ratio = 1.71, 95% CI: 1.45–2.02, P = 1.63 × 10-10). Colocalization analyses indicated that an NPNT splice isoform drove this effect. Overall, NPNT mediates 3.7% of the total effect of BMI on severe COVID-19. Finally, we found that decreasing body fat mass and increasing fat-free mass can lower NPNT levels and thus may improve COVID-19 outcomes. These findings provide actionable insights into how obesity influences COVID-19 severity.

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“…Third, our study is a hypothesis-driven study focusing on whether genetic associations with CRP differ across three common cardiometabolic diseases. A recent MR study has provided evidence for a widespread influence of BMI on the human proteome 14 . Our MR results suggested that increasing BMI level is associated with increased CRP level, which confirmed the finding from a previous MR study using an FTO SNP as instrument 7 .…”

Section: Discussionmentioning

confidence: 99%

Genetic effect modification of cis-acting C-reactive protein variants in cardiometabolic disease status

Zheng

Tang

Lyon

et al. 2021

Preprint

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Mendelian randomization (MR) studies carried out among patients with a particular health condition should establish the genetic instrument influences the exposure in that subgroup, however this is normally investigated in the general population. Here, we investigated whether the genetic associations of four cis-acting C-reactive protein (CRP) variants differed between participants with and without three cardiometabolic conditions: obesity, type 2 diabetes, and cardiovascular disease. Associations of cis-genetic variants with CRP differed between obese and non-obese individuals. A multivariable analysis suggested strong independent associations of the gene-by-body mass index (BMI) interaction on CRP (P<1.18×10−8 for the CRP variants). Applying MR, we observed strong causal effect of BMI on CRP (P=2.14×10−65). In summary, our study indicates that genetic associations with CRP differ across disease sub-groups, with evidence to suggest that BMI is an effect modifier. MR studies of disease progression should report on the genetic instrument-exposure association in the disease subgroup under investigation.

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Effects of adiposity on the human plasma proteome: observational and Mendelian randomisation estimates

Cited by 39 publications

References 53 publications

Inflammation proteomics datasets in the ALSPAC cohort

Inflammation proteomics datasets in the ALSPAC cohort

Proteome-wide Mendelian randomization implicates nephronectin as an actionable mediator of the effect of obesity on COVID-19 severity

Genetic effect modification of cis-acting C-reactive protein variants in cardiometabolic disease status

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