2025
@article{Decina2025.04.09.25325484,
vgclass = {refpap},
author = {Decina, Caitlin S. and Warrington, Nicole M. and Beaumont, Robin N. and Bian, Beilei and Nunes, Caroline Brito and Wang, Geng and Lowe, William L. and Squire, David and Vukcevic, Damjan and Leslie, Stephen and Freathy, Rachel M. and Evans, David M.},
title = {Examining the association between fetal HLA-C, maternal KIR haplotypes and birth weight},
journal = {medRxiv},
year = {2025},
note = {(preprint)},
doi = {https://doi.org/10.1101/2025.04.09.25325484},
url = {https://www.medrxiv.org/content/early/2025/04/10/2025.04.09.25325484},
abstract = {Human birth weight is under
stabilizing selection, seeking balance between extremes of high and low,
thereby reducing fetal and maternal perinatal mortality risk. Certain
combinations of maternal killer immunoglobulin-like receptor (KIR) and
paternally derived fetal human leuokocyte antigen-C (HLA-C) alleles were
previously associated with higher risk of high and low birth weight in a
study with limited sample size (n=1,316). Using recently developed
methods to impute HLA and KIR haplotypes using single nucleotide
polymorphism (SNP) genotype data, we tested associations of fetal HLA and
maternal KIR genotypes with offspring birth weight in a large sample. We
imputed KIR haplotypes using the KIR*IMP imputation software in 10,602
mother-offspring pairs of European descent from singleton pregnancies
from five studies. Using mixed linear regression models to account for
mothers with multiple children, we tested associations between maternal
KIR A vs B haplotypes (AA, AB/BA, BB genotypes) as well as copy number of
activating receptor gene KIR2DS1 (0, 1, 2 copies of the gene) in the
presence of fetal HLA C1/C2 alleles, and offspring birth weight.
Associations were analyzed in each cohort before performing a
meta-analysis to estimate the interaction effects between maternal KIR
and fetal HLA-C2 on birth weight across the entire sample. The KIR
haplotypes achieved imputation accuracy estimated at \>95\% in most of
the cohorts. No interaction effects were observed between either the
maternal A vs. B haplotype or the maternal KIR2DS1 locus and fetal HLA-C.
When specifically trying to replicate the previously associated
combination of maternal KIR2DS1 and paternally inherited fetal HLA-C2,
there was a negligible change in offspring birth weight for each
additional KIR2DS1 allele and HLA-C2 of paternal origin (7g lower birth
weight per allele [95\% CI: -54, 40], P = 0.78). We found little evidence
of association between birth weight and maternal KIR haplotypes or fetal
HLA-C2 and were unable to replicate previously reported findings. Our
observations reinforce the importance of replication and the use of large
sample sizes in the validation of genetic associations.Author Summary
Babies born with very high or low birth weights and their mothers are at
a higher risk of illness and death than babies with weights close to
average. Genes involved in the maternal immune system, called
{\textquotedblleft}KIR{\textquotedblright}, and the fetal immune system,
called {\textquotedblleft}HLA-C{\textquotedblright}, are important for
early development of the placenta. Previously published research using a
small sample has provided evidence for the role of interacting
combinations of these genes in driving the spectrum of birth weight and
maintaining the balancing selection of mother-child physiology that
results in healthy birth outcomes. Here we harness recently developed
methods to impute these genetic data to test associations of maternal KIR
and fetal HLA with child{\textquoteright}s birth weight in a larger
sample. By examining \>10,000 European ancestry mother-child pairs, we
found no relationship between child{\textquoteright}s birth weight and
any of the genetic combinations we tested of KIR in the mother and HLA-C
in the fetus. We show that despite biological plausibility, it is
important to validate genetic associations through replication and using
the largest sample sizes possible. Future research could benefit from
including birth weights in the true extremes of the spectrum, using
methods such as high throughput genome sequencing technologies which
could provide more accurate data for these gene regions on a larger
scale, and investigation in ancestrally diverse populations.Competing
Interest StatementThe authors have declared no competing interest.Funding
StatementThis work was supported by a PhD studentship granted to C.S.D by
the QUEX Institute, a collaborative program between the University of
Exeter and the University of Queensland. R.M.F. and R.N.B were supported
by a Wellcome Senior Research Fellowship (WT220390). R.M.F. is also
supported by a grant from the Eunice Kennedy Shriver National Institute
of Child Health \& Human Development of the National Institutes of
Health under Award Number R01HD101669. N.M.W and G.W. were supported by
an Australian National Health and Medical Research Council (NHMRC)
Investigator grant (APP2008723). D.M.E. is supported by an NHMRC
Investigator grant (APP2017942). The contents of the published material
are solely the responsibility of the authors and do not reflect the views
of the NHMRC. Genotyping of the EFSOCH study samples was funded by the
Wellcome Trust and Royal Society (grant 104150/Z/14/Z). The UK Medical
Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the
University of Bristol provide core support for ALSPAC. This publication
is the work of the authors and C.S.D, R.M.F. and D.M.E will serve as
guarantors for the contents of this paper. A comprehensive list of grants
funding (PDF, 330KB) is available on the ALSPAC website. This research
was specifically funded by the Wellcome Trust (Grant ref: WT088806). HAPO
was supported by grants from the Eunice Kennedy Shriver National
Institute of Child Health and Human Development and the National
Institute of Diabetes and Digestive and Kidney Diseases (R01-HD34242 and
R01-HD34243); the National Center for Research Resources (M01-RR00048 and
M01-RR00080); and the American Diabetes Association. Genotyping of the
HAPO study samples was funded by Wellcome Trust and Royal Society grant
104150/Z/14/Z. BiB data used in this research were funded by the Wellcome
Trust (WT101597MA), a joint grant from the UK Medical Research Council
(MRC) and UK Economic and Social Science Research Council (ESRC)
(MR/N024397/1) and the National Institute for Health Research (NIHR)
under its Applied Research Collaboration for Yorkshire and Humber
(NIHR200166) and the Clinical Research Network (CRN). This project
utilised high-performance computing funded by the UK Medical Research
Council (MRC) Clinical Research Infrastructure Initiative (award number
MR/M008924/1). This study was supported by the National Institute for
Health and Care Research Exeter Biomedical Research Centre. The views
expressed are those of the authors and not necessarily those of the NIHR
or the Department of Health and Social Care. This research was funded in
part, by the Wellcome Trust (Grant number: WT220390). For the purpose of
Open Access, the author has applied a CC BY public copyright licence to
any Author Accepted Manuscript version arising from this
submission.Author DeclarationsI confirm all relevant ethical guidelines
have been followed, and any necessary IRB and/or ethics committee
approvals have been obtained.YesThe details of the IRB/oversight body
that provided approval or exemption for the research described are given
below:The UK Biobank has approval from the North West Multi-Centre
Research Ethics Committee (MREC) as a Research Tissue Bank (RTB)
approval. Participants provided written informed consent. Ethical
approval for the Exeter Family Study of Childhood Health was given by the
North and East Devon (UK) Local Research Ethics Committee (approval
number 1104), and informed consent was obtained from the parents of the
newborns. Ethical approval for the study was obtained from the ALSPAC
Ethics and Law Committee and the Local Research Ethics Committees.
Informed consent for the use of data collected via questionnaires and
clinics was obtained from participants following the recommendations of
the ALSPAC Ethics and Law Committee at the time. Consent for biological
samples has been collected in accordance with the Human Tissue Act
(2004). Study participants have the right to withdraw their consent for
elements of the study or from the study entirely. Full details of the
ALSPAC consent procedures are available on the study website
(http://www.bristol.ac.uk/alspac/researchers/research-ethics/). Ethics
approval was obtained for the main platform study and all of the
individual sub-studies from the Bradford Research Ethics Committee.I
confirm that all necessary patient/participant consent has been obtained
and the appropriate institutional forms have been archived, and that any
patient/participant/sample identifiers included were not known to anyone
(e.g., hospital staff, patients or participants themselves) outside the
research group so cannot be used to identify individuals.YesI understand
that all clinical trials and any other prospective interventional studies
must be registered with an ICMJE-approved registry, such as
ClinicalTrials.gov. I confirm that any such study reported in the
manuscript has been registered and the trial registration ID is provided
(note: if posting a prospective study registered retrospectively, please
provide a statement in the trial ID field explaining why the study was
not registered in advance).YesI have followed all appropriate research
reporting guidelines, such as any relevant EQUATOR Network research
reporting checklist(s) and other pertinent material, if applicable.YesThe
genetic and phenotype datasets generated by UK Biobank used in the
current study are available via the UK Biobank data access process (see
http://www.ukbiobank.ac.uk/register-apply/). Detailed information about
the genetic data available from UK Biobank is available at
http://www.ukbiobank.ac.uk/scientists-3/genetic-data/ and
http://biobank.ctsu.ox.ac.uk/crystal/label.cgi?id=100314. The exact
number of samples with genetic data currently available in UK Biobank may
differ slightly from those described in this paper. Summary statistics
from EFSOCH are available on request. Researchers interested in accessing
the data are expected to send a reasonable request by sending an email to
the Exeter Clinical Research Facility at crf{at}exeter.ac.uk. For access
to the HAPO data used in this study, please contact Dr Rachel Freathy
(r.freathy{at}exeter.ac.uk) and Prof. William Lowe Jr
(wlowe{at}northwestern.edu). The website describing the study and other
data available is
https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000096.v4.p1
The ALSPAC data management plan describes in detail the policy regarding
data sharing, which is through a system of managed open access. The data
used in this study are linked to ALSPAC project number B2388. To request
access to the data included in this paper and all other existing ALSPAC
data: (i) Please read the ALSPAC access policy, which describes the
process of accessing the data and samples in detail and outlines the
costs associated with doing so, (ii) you may also find it useful to
browse the fully searchable ALSPAC research proposals database, which
lists all research projects that have been approved since April 2011, and
(iii) please submit your research proposal for consideration by the
ALSPAC Executive Committee. You will receive a response within 10 working
days to advise you whether your proposal has been approved. If you have
any questions about accessing data, please email
alspac-data@bristol.ac.uk. Please note that the study website contains
details of all the data that is available through a fully searchable data
dictionary and variable search tool:
http://www.bristol.ac.uk/alspac/researchers/our-data/. Scientists are
encouraged and able to use BiB data. Data requests are made to the BiB
executive using the form available from the study website
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website. All requests are carefully considered and accepted where
possible. http://www.ukbiobank.ac.uk/register-apply/
http://www.ukbiobank.ac.uk/scientists-3/genetic-data/
http://biobank.ctsu.ox.ac.uk/crystal/label.cgi?id=100314
https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000096.v4.p1
http://www.bristol.ac.uk/alspac/researchers/our-data/
http://www.borninbradford.nhs.uk},
}