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\begin{document}

\title{Race is a Modifier between Parental Allergy and Food Allergy in
Offspring}



\author[1]{Amy A. Eapen}%
\author[1]{Erica Ridley}%
\author[1]{Alexandra Sitarik}%
\author[1]{Christine Joseph}%
\author[1]{Christian Nageotte}%
\author[1]{Rana Misiak}%
\author[2]{Dennis Ownby}%
\author[1]{Christine Cole Johnson}%
\author[1]{Edward Zoratti}%
\author[1]{Haejin Kim}%
\affil[1]{Henry Ford Health System}%
\affil[2]{Augusta University}%


\vspace{-1em}



  
  \date{June 16, 2024}


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Race is a Modifier between Parental Allergy and Food Allergy in
Offspring

Amy A. Eapen, MD, MS*\textsuperscript{1}, Erica Ridley
MD*\textsuperscript{1}, Alexandra R. Sitarik MS\textsuperscript{2},
Christine Joseph PhD\textsuperscript{2}, Christian Nageotte,
MD\textsuperscript{1}, Rana Misiak, MD\textsuperscript{1}, Dennis Ownby
MD\textsuperscript{3}, Christine Johnson PhD\textsuperscript{2}, Edward
Zoratti MD\textsuperscript{1}, Haejin Kim MD\textsuperscript{1}.

\textsuperscript{1}Division of Allergy and Clinical Immunology, Henry
Ford Health System, Detroit, Michigan

\textsuperscript{2}Department of Public Health Sciences, Henry Ford
Health System, Detroit, Michigan

\textsuperscript{3}Department of Pediatrics, Augusta University,
Augusta, Georgia.

*Dr. Eapen and Dr. Ridley are listed as co-first authors

Corresponding author: Amy A. Eapen, MD, One Ford Place, 4B Detroit, MI
48202; Telephone (313) 971-6182; Fax (313) 876-2094; E-mail:
aeapen1@hfhs.org

Funding: Grants from the National Institute of Allergy and Infectious
Diseases (R01 A1051598 and P01 A1089473) and the Fund for Henry Ford
Hospital.

\textbf{Financial disclosure} : There are no financial disclosures of
conflicts of interest.

\textbf{Word count:} 1191

\textbf{Keywords} : Food allergy, race, parental allergy, total IgE

\emph{To the Editor,}

Studies indicate associations between maternal allergy and development
of food allergy in their offspring\textsuperscript{1}, with higher food
allergy risk among those with more than one first degree relative with
allergic disease\textsuperscript{2}. However, unnecessary food avoidance
among children of allergic parents has important implications since
diverse diets in children may decrease risk for food allergy, and early
food introduction with foods such as peanut, can be protective for food
allergy\textsuperscript{3}. We sought to assess the association between
parental allergic markers and offspring food sensitization and clinical
allergy to milk, egg, or peanut.

We analyzed data from the racially and socioeconomically diverse
population birth cohort, Wayne County Health, Environment, Allergy and
Asthma Longitudinal Study (WHEALS) that enrolled pregnant women between
21 to 45 years of age and their offspring following recruitment between
September 2003 to December 2007. Details regarding the cohort have been
previously published\textsuperscript{4,5}. Institutional Review Board
(IRB) approval was obtained for all aspects of the study.

Parental factors assessed included questionnaire responses regarding
history of allergy or asthma; maternal total IgE and maternal serum
allergen specific IgE (sIgE) levels during pregnancy or one month
postpartum were also evaluated. Atopy was defined as at least one sIgE [?]
0.35 IU/mL to eight allergens (dust mite, dog, cat, grass,
ragweed,\emph{Alternaria} , egg, cockroach). Maternal asthma, atopic
dermatitis, and food allergy were determined by questionnaire. Due to a
paucity of paternal data, only paternal asthma was assessed.

Offspring sensitization to milk, egg, or peanut was determined at 2
years of age by sIgE[?] 0.35 IU/mL and also skin prick testing (SPT; wheal
size [?]3 mm larger than the saline control defined a positive test). As
sensitization to foods does not translate to clinical allergy in all
cases, we formed an algorithm to determine those most likely to have
true IgE-mediated food allergy\textsuperscript{6}. A consensus panel of
allergists determined food allergy status in offspring based on review
of the aforementioned data and abstracted chart informations as
previously described\textsuperscript{7}. Briefly, infant data were
forwarded to the panel only if more than one of the following criteria
were met for milk, egg, or peanut allergens: (1) 1 sIgE [?]0.35 IU/mL; (2)
a positive SPT; or (3) parental report of infant symptoms potentially
related to food allergy plus at least one specific IgE greater than 0.10
IU/mL. To enhance standardization in classifying infants to the presence
of IgE- mediated food allergy (IgE-FA), physicians were asked to combine
professional experience with investigator-developed protocols based on
the Guidelines for the Diagnosis and Management of Food Allergy in the
United States\textsuperscript{8}. A third allergist independently
reviewed and ruled on discordant decisions.

Logistic regression models of parental variables with each outcome were
fit. Interaction terms were added to logistic regression models to
assess differences in associations based on race, (p\textless{}0.10 was
considered a significant interaction). Predicted probabilities were used
to construct receiver operating characteristic (ROC) curves and
calculate area-under-the-curve (AUC) values.

Of 1258 maternal-child pairs, 761 had sufficient data for analysis
(Supplemental Figure el). Participant characteristics indicated that
families not lost to follow up had higher household incomes, as well as
higher maternal education, and a higher proportion of mothers who were
married, kept pets, and breastfed the child. rates (Table e1).

Associations between parental variables and physician panel
determination of food allergy are shown in Table 1. After adjusting for
child race, seven out of eight parental characterics of the were
significant or of borderline signficance. However, the maximum AUC for
ROC curves for any individual variable was 0.54 (maternal total IgE),
indicating poor prognostic value (Supplemental Table e2). Maternal
atopy, multi-sensitization, and total IgE significantly interacted with
race (p=0.012, 0.092, 0.068, respectively) indicating strong
associations among African American (AA) children only (Table 1). For
example, maternal atopy in non-AA children was not associated with food
allergy, but was highly associated among AA children (OR {[}95\%
CI{]}=3.56 {[}1.55, 9.66{]}, p=0.006).

Maternal current asthma was also associated with childhood food allergy
(OR {[}95\% CI{]}=2.27 {[}1.02, 4.71{]}, p=0.034), and patterns varied
by race with history of maternal asthma associated with food allergy
only in non-AA children (OR {[}95\% CI{]}= 4.92 {[}1.22, 17.14{]},
p=0.015), and current asthma among AA children (OR {[}95\% CI{]}=2.64
{[}1.10, 5.92{]}, p=0.022; Table 1).

Combined, parental variables only modestly impacted food allergy ROC
analyses resulting in an AUC of 0.66. However, the ROC curves differed
by race (non-AA AUC 0.36 vs AA AUC 0.71, p=0.002) as shown in Figure 1.

Apart from food allergy, parental variables were analysed for
associations with offspring sensitization (positive sIgE or SPT) to
peanut, milk, or egg at age 2 years. Maternal atopy,
multi-sensitization, and total IgE were associated with offspring
positive food sIgE sensitization to at least one food. Analysis
stratified by race indicated these associations were significant only
among AA children. (Supplemental Table e3). Furthermore, maternal
current asthma was associated with food sIgE sensitization only among
non-AA children (OR {[}95\% CI{]}=4.90 {[}1.69, 16.20{]}, p=0.005). ROC
curves were significantly different between AA and non-AA children
(p=0.036) but predictive ability remained poor in both (AUC 0.55 and
0.44 respectively as in supplemental Figure e2).

Maternal multisensitization, total IgE and current asthma, and paternal
asthma were statistically significantly associated with any positive
food SPTs only among AA children. (Supplemental Table e4). Additionally,
race modified the relationship between maternal atopy and SPTs
(p=0.039); AA children of atopic mothers had elevated odds of food SPT
positivity (OR {[}95\% CI{]}=1.96 {[}1.15, 3.45{]}, p=0.016). Despite
ROC differences by race (p=0.015; Figure e3), parental variables again
had minimal predictive ability.

The importance of genetic factors in food allergy is supported by twin
studies showing higher concordance of peanut allergy among monozygotic
compared with dizygotic twins (64.3\% and 6.8\%,
respectively)\textsuperscript{9}. In addition, heritability among
parents and offspring for overall food sensitization have been
reported\textsuperscript{1}. However, our report indicates parental
variables related to allergy have poor predictive ability for offspring
food sensitization. The results from the physician panel demonstrate a
moderate degree of risk and capability of predicting food allergy in
offspring from parents having clinical characteristics of allergy.

We previously reported similar food allergy prevalence for milk, egg,
and peanut in AA and non-AA children\textsuperscript{7}. We report here
that the inherited risk as measures by parental allergic variables and
predictive ability of parental allergic variables on food allergy
development in offspring varies by race and is more strongly associated
with clinical food allergy versus sensitization, among AA children. The
potential mechanisms behind this racial discrepancy are require further
studies.

Potential study limitations include the physician panel to determine
clinical food allergy status as opposed to performing oral food
challenges. These challenges are time consuming and impractical to
implement in large epidemiological studies\textsuperscript{10}. Another
limitation is that non-AA children included multiple ethnicites, which
was done to preserve sample size. These groups may have different
incidences of disease, and risk may vary. Finally, included and excluded
WHEALS participants differed by demographic variables, so findings may
not be generalizable to the target population.

Parental allergy and atopy, although associated with offspring food
allergy, is only a weak predictor and depends upon race. Further studies
of familial factors contributing to food allergy and these disparities
are needed to precisely identify children at risk for food allergy.

Amy A. Eapen, MD, MS*\textsuperscript{1}, Erica Ridley
MD*\textsuperscript{1}, Alexandra R. Sitarik MS\textsuperscript{2},
Christine Joseph PhD\textsuperscript{2}, Christian Nageotte,
MD\textsuperscript{1}, Rana Misiak, MD\textsuperscript{1}, Dennis Ownby
MD\textsuperscript{3}, Christine Johnson PhD\textsuperscript{2}, Edward
Zoratti MD\textsuperscript{1}, Haejin Kim MD\textsuperscript{1}.

\textsuperscript{1}Division of Allergy and Clinical Immunology

\textsuperscript{2}Department of Public Health Sciences, Henry Ford
Health System, Detroit, Michigan

\textsuperscript{3}Department of Pediatrics, Augusta University,
Augusta, Georgia.

*Dr. Eapen and Dr. Ridley are listed as co-first authors

\textbf{References}

1. Tsai HJ, Kumar R, Pongracic J, et al. Familial aggregation of food
allergy and sensitization to food allergens: a family-based
study.\emph{Clin Exp Allergy} . Jan 2009;39(1):101-9.
doi:10.1111/j.1365-2222.2008.03111.x

2. Koplin JJ, Allen KJ, Gurrin LC, et al. The impact of family history
of allergy on risk of food allergy: a population-based study of
infants.\emph{Int J Environ Res Public Health} . Oct 25
2013;10(11):5364-77. doi:10.3390/ijerph10115364

3. Randomized Trial of Peanut Consumption in Infants at Risk for Peanut
Allergy. \emph{N Engl J Med} . Jul 28 2016;375(4):398.
doi:10.1056/NEJMx150044

4. Wegienka G, Joseph CL, Havstad S, Zoratti E, Ownby D, Johnson CC.
Sensitization and allergic histories differ between black and white
pregnant women. \emph{J Allergy Clin Immunol} . Sep 2012;130(3):657-662
e2. doi:10.1016/j.jaci.2012.06.024

5. Havstad S, Wegienka G, Zoratti EM, et al. Effect of prenatal indoor
pet exposure on the trajectory of total IgE levels in early
childhood.\emph{J Allergy Clin Immunol} . Oct 2011;128(4):880-885 e4.
doi:10.1016/j.jaci.2011.06.039

6. Sampson HA, Ho DG. Relationship between food-specific IgE
concentrations and the risk of positive food challenges in children and
adolescents. \emph{J Allergy Clin Immunol} . Oct 1997;100(4):444-51.
doi:10.1016/s0091-6749(97)70133-7

7. Joseph CL, Zoratti EM, Ownby DR, et al. Exploring racial differences
in IgE-mediated food allergy in the WHEALS birth cohort. \emph{Ann
Allergy Asthma Immunol} . Mar 2016;116(3):219-224 e1.
doi:10.1016/j.anai.2015.12.019

8. Boyce JA, Assa'ad A, Burks AW, et al. Guidelines for the Diagnosis
and Management of Food Allergy in the United States: Summary of the
NIAID-Sponsored Expert Panel Report. \emph{J Allergy Clin Immunol} . Dec
2010;126(6):1105-18. doi:10.1016/j.jaci.2010.10.008

9. Sicherer SH, Furlong TJ, Maes HH, Desnick RJ, Sampson HA, Gelb BD.
Genetics of peanut allergy: a twin study. \emph{J Allergy Clin Immunol}
. Jul 2000;106(1 Pt 1):53-6. doi:10.1067/mai.2000.108105

10. Asero R, Ballmer-Weber BK, Beyer K, et al. IgE-mediated food allergy
diagnosis: Current status and new perspectives. \emph{Mol Nutr Food Res}
. Jan 2007;51(1):135-47. doi:10.1002/mnfr.200600132

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