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\begin{document}

\title{Global associations of macronutrient supply and asthma disease burden}



\author[1]{Duan Ni}%
\author[1]{Alistair M. Senior}%
\author[2]{David Raubenheimer}%
\author[2]{Stephen J. Simpson}%
\author[1]{Laurence Macia}%
\author[1]{Ralph Nanan}%
\affil[1]{The University of Sydney}%
\affil[2]{The University of Sydney Charles Perkins Centre}%


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  \date{June 18, 2024}


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\textbf{Global associations of macronutrient supply and asthma disease
burden}

Duan Ni\textsuperscript{1,2,3}, Alistair M.
Senior\textsuperscript{3,4,5}, David Raubenheimer\textsuperscript{3,4},
Stephen J. Simpson\textsuperscript{3,4}, Laurence
Macia\textsuperscript{3,6,7}, Ralph Nanan\textsuperscript{1,2,3,*}

1 Sydney Medical School Nepean, The University of Sydney, Sydney, NSW,
Australia

2 Nepean Hospital, Nepean Blue Mountains Local Health District, Sydney,
NSW, Australia

3 Charles Perkins Centre, The University of Sydney, Sydney, NSW,
Australia

4 School of Life and Environmental Sciences, The University of Sydney,
Sydney, NSW, Australia

5 Sydney Precision Data Science Centre, The University of Sydney,
Sydney, NSW, Australia

6 School of Medical Sciences, Faculty of Medicine and Health, The
University of Sydney, Sydney, NSW, Australia

7 Sydney Cytometry Core Research Facility, Charles Perkins Centre, The
University of Sydney and Centenary Institute, Sydney, NSW, Australia

* Correspondence:

Ralph Nanan

ralph.nanan@sydney.edu.au

Sydney Medical School Nepean, The University of Sydney.

Nepean Hospital, Level 5, South Block, Penrith NSW, 2751, Australia

Telephone: +61 2 4734 1614

Fax: +61 2 4734 1144

To the Editor,

We read with interest the work by Shin et al. \textsuperscript{1},
investigating the global disease burden of allergic disorders. They
showed that the age-standardized prevalence of asthma has decreased over
time on a global level.

Following a similar theme, we curated asthma disease burden,
macronutrient (protein, carbohydrate and fat) supply and gross domestic
product (GDP) data around the globe (Supplementary Methods). Our
analysis found that in parallel to changes in asthma disease burden, GDP
per capita \textsuperscript{2} has increased, and the global nutritional
landscape has also changed (Figure 1A-B). Both socioeconomic status and
nutritional factors, are emerging critical confounders for
asthma\textsuperscript{1}. However, so far, most studies have neglected
to consider their correlations and interactions, including among
nutrients within diets (Figure 1C-E). They instead focused on individual
parameters alone, like specific diets or foods \textsuperscript{3}.
Here, we adopted a recently published approach \textsuperscript{2} to
systematically interrogate the relationship between nutrient supply, a
good proxy of food environment, socioeconomic status and asthma disease
burden at a global scale over time. We focused on macronutrient supplies
and their interactions, considering their important associations with
many facets of health.

Various multi-response generalized additive mixed models (GAMMs) were
used to analyze the effects on asthma disease burden from macronutrient
supplies and GDP over time (Supplementary Methods). In all analyses, a
model considering the interactions of macronutrient supply and GDP, and
an additive effect of time was favoured (Supplementary Table 1, 3). This
suggested combinatory effects of macronutrients on asthma and the
impacts of socioeconomic changes.

The most recent year with all data available, 2018, is shown as a
representative (Figure 1F-G, Supplementary Table 1-2). In brief,
predicted association between asthma prevalence and macronutrient
supplies were visualized using response surfaces on macronutrient supply
plots. We focused on the fat (\emph{x} -axis) and carbohydrate (\emph{y}
-axis) supplies while holding protein at 25\%, 50\% and 75\% quantiles
of global supply. Across the response surfaces, red indicated higher
asthma disease burden, while blue indicated lower.

In our modelling, carbohydrate supply was most strongly associated with
increases of asthma prevalence rates, while fat supply had the opposite
effects (Figure 1F). This is reflected by the purple isocaloric line,
along which the total energy from macronutrients remained constant but
increasing fat:carbohydrate ratio decreased the allergy prevalence.
Protein supply conferred less influences. Similar patterns were found
for asthma incidences (Figure 1G, Supplementary Table 3-4) independent
of gender (Supplementary Figure 1-2) and were not confounded by the
total macronutrient energy supply, as changing total energy while
holding fat:carbohydrate ratio constant (red radial in figures)
minimally impacted asthma disease burden.

This represents the first study to link asthma to global food
environment. Our results imply a driving role of carbohydrate supply for
the asthma disease burden, after adjusting for the plausible
interactions between macronutrients, total energy supply and
socioeconomic status.

Interestingly, previous studies found that ketogenic diets, low in
carbohydrates, might ameliorate established asthma \textsuperscript{4},
supporting our findings that ketogenic-like food environments are
associated with lower asthma disease burden. Although further in-depth
investigations are needed, diet quality might be an intriguing
explanation for the positive association between carbohydrate supply and
asthma. For example, high- and ultra-processed foods low in fibre have
been found to be related to asthma development \textsuperscript{3,5},
while we have previously shown that dietary fibre exhibited a strong
immune regulatory influence, protecting against
asthma\textsuperscript{6}.

Hence, future studies in more depth are warranted to investigate the
associations between macronutrient supply and asthma, including also
other related socioeconomic and environmental factors. Such studies will
be critical for guidance to future clinical research and practice and
public health interventions.

\textbf{Figure 1. Association of global macronutrient supply and asthma
disease burden. A.} Age-standardized asthma prevalence (blue) and
incidence rate (red) of both sexes as functions of year.
\textbf{B.}Global GDP per capita (in US dollars, black) and supplies of
carbohydrate (green), protein (red) and fat (brown) as functions of
year. \textbf{C-E.} Correlations among variables for global data from
1990-2018 (\textbf{C} ) and for different countries in 1990 (\textbf{D}
) and 2018 (\textbf{E} ). Correlation coefficients are shown.
\textbf{F-G.}Predicted effects of macronutrient supply on
age-standardized asthma prevalence rate (\textbf{F} ) and incidence rate
(\textbf{G} ) of both sexes (See Supplementary Information for
statistics and interpretation).

\textbf{Author contributions}

\emph{Concept and design:} Duan Ni, and Ralph Nanan

\emph{Acquisition, analysis and interpretation of data:} Duan Ni,
Alistair M. Senior, Ralph Nanan

\emph{Drafting of the manuscript:} Duan Ni, and Ralph Nanan

\emph{Critical revision of the manuscript for important intellectual
content:} All authors

\textbf{Acknowledgements}

This project is supported by the Norman Ernest Bequest Fund.

\textbf{Conflict of interest}

Non reported.

\textbf{References}

1. Shin YH, Hwang J, Kwon R, et al. Global, regional, and national
burden of allergic disorders and their risk factors in 204 countries and
territories, from 1990 to 2019: A systematic analysis for the Global
Burden of Disease Study 2019. \emph{Allergy.} 2023;78(8):2232-2254.

2. Senior AM, Nakagawa S, Raubenheimer D, Simpson SJ. Global
associations between macronutrient supply and age-specific
mortality.\emph{Proc Natl Acad Sci U S A.} 2020;117(48):30824-30835.

3. Reyes-Angel J, Han YY, Litonjua AA, Celedon JC. Diet and asthma: Is
the sum more important than the parts? \emph{J Allergy Clin
Immunol.}2021;148(3):706-707.

4. Al-Rebdi M, Rabbani U. Alleviation of Asthma Symptoms After Ketogenic
Diet: A Case Report. \emph{Cureus.} 2023;15(2):e34526.

5. Melo B, Rezende L, Machado P, Gouveia N, Levy R. Associations of
ultra-processed food and drink products with asthma and wheezing among
Brazilian adolescents. \emph{Pediatr Allergy
Immunol.}2018;29(5):504-511.

6. Thorburn AN, McKenzie CI, Shen S, et al. Evidence that asthma is a
developmental origin disease influenced by maternal diet and bacterial
metabolites. \emph{Nat Commun.} 2015;6:7320.\selectlanguage{english}
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