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</div>
<div class="action-panel-control-wrap">
<label for="email-to" class="action-panel-label required-field-asterisk">
To:
</label>
<input type="email" aria-label="Recipient Email Address" placeholder="email@example.com" id="email-to" class="email-to" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" maxlength="100" required>
</div>
<div class="action-panel-control-wrap">
<label for="email-from" class="action-panel-label">
From:
</label>
<input type="email" aria-label="Sender Email Address" placeholder="email@example.com" id="email-from" class="email-from" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" maxlength="256">
</div>
<div class="action-panel-control-wrap">
<label for="email-citation-format" class="action-panel-label">
Format:
</label>
<select id="email-citation-format" name="citation-format" class="action-panel-selector email-citation-format">
<option selected="selected" value="summary">Summary</option>
<option value="summary-text">Summary (text)</option>
<option value="abstract">Abstract</option>
<option value="abstract-text">Abstract (text)</option>
</select>
</div>
<div class="include-supplemental-container">
<input type="checkbox" aria-label="Include MeSH and other data" name="include-supplemental" id="email-include-supplemental" class="email-include-supplemental">
<label for="email-include-supplemental" class="email-include-supplemental-label">MeSH and other data</label>
</div>
<div class="form-field recaptcha ">
<div class="g-recaptcha" id="id-recaptcha" data-sitekey="6LfsWHMdAAAAAClKbtOpjQ2pMjgsGxvv7NdZW9uI"></div>
</div>
<div id="captcha-error-message" class="usa-input-error-message captcha-validation-message" role="alert"></div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="send">
Send email
</button>
<button class="action-panel-cancel"
aria-label="Close 'Email citations' panel"
ref="linksrc=close_email_panel"
aria-controls="email-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="cancel">
Cancel
</button>
</div>
<input type="hidden" name="email-search-details" value="" />
<input type="hidden" name="email-search-details-hash" value="0e42663a6c3bd85498fcb88798998fed7bfdc45d457db35281e41afe13cc0524" />
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<div id="collections-action-panel"
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aria-hidden="true"
data-collections-open-panel-enabled="false"
data-collections-open-panel-url-hash="#open-collections-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to Collections
</h3>
<form id="collections-action-panel-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
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data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-myncbi-max-collection-name-length="100"
data-add-to-collection-max-amount="1000"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/">
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<div class="choice-group" role="radiogroup">
<ul class="radio-group-items">
<li>
<input type="radio"
id="collections-action-panel-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_new">
<label for="collections-action-panel-new">Create a new collection</label>
</li>
<li>
<input type="radio"
id="collections-action-panel-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_existing">
<label for="collections-action-panel-existing">Add to an existing collection</label>
</li>
</ul>
</div>
<div class="controls-wrapper">
<div class="action-panel-control-wrap new-collections-controls">
<label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label>
<input
type="text"
name="add-to-new-collection"
id="collections-action-panel-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="save_share"
data-ga-action="create_collection"
data-ga-label="non_favorties_collection">
<div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
Name must be less than 100 characters
</div>
</div>
<div class="action-panel-control-wrap existing-collections-controls">
<label for="collections-action-panel-add-to-existing" class="action-panel-label">
Choose a collection:
</label>
<select id="collections-action-panel-add-to-existing"
class="action-panel-selector collections-action-add-to-existing"
data-ga-category="save_share"
data-ga-action="select_collection"
data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'">
</select>
<div class="collections-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your collection due to an error<br>
<a href="#">Please try again</a>
</div>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="add">
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to Collections' panel"
ref="linksrc=close_collections_panel"
aria-controls="collections-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="bibliography-action-panel"
class="bibliography-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-bibliography-open-panel-enabled="false"
data-bibliography-open-panel-url-hash="#open-bibliography-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to My Bibliography
</h3>
<form id="bibliography-action-panel-form"
class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-add-to-bibliography-max-amount="100"
data-add-to-bibliography-batch-size="10"
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<div class="action-panel-control-wrap bibliographies-controls">
<div class="choice-group">
<ul class="bibliographies-action-add radio-group-items">
<li>
<input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/>
<label for="my-bibliography">My Bibliography</label>
</li>
</ul>
</div>
</div>
<div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your delegates due to an error<br>
<a href="#">Please try again</a>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore>
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to bibliography' panel"
ref="linksrc=close_bibliography_panel"
aria-controls="bibliography-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="mybib"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true"
data-saved-search-open-panel-enabled="false"
data-saved-search-open-panel-url-hash="#open-saved-search-panel">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your saved search
</h2>
<form id="saved-search-action-panel-form"
class="saved-search-action-panel-form action-panel-content action-form"
data-create-saved-search-url="/create-saved-search/"
data-try-search-terms-url="/try-search-term/"
data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/">
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<div class="action-panel-control-wrap">
<label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk">
Name of saved search:
</label>
<input maxlength="200"
type="text"
name="saved-search-name"
id="saved-search-name"
class="saved-search-name"
value=""
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-term" class="action-panel-label required-field-asterisk">
Search terms:
</label>
<textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea>
</div>
<div class="test-search-term-wrap">
<a href="#" class="try-search-term">Test search terms</a>
</div>
<div class="choice-group action-panel-extra-margin-top">
<span class="action-panel-label" id="fieldset-label">
Would you like email updates of new search results?
</span>
<fieldset id="saved-search-alert" aria-describedby="fieldset-label">
<legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend>
<ul class="radio-group-items">
<li>
<input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked>
<label for="saved-search-alert-yes" class="action-panel-label">Yes</label>
</li>
<li>
<input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no">
<label for="saved-search-alert-no" class="action-panel-label">No</label>
</li>
</ul>
</fieldset>
</div>
<div class="alert-schedule-wrap">
<div class="action-panel-control-wrap">
<label class="action-panel-label">
Email:
</label>
<span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span>
</div>
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="saved-search-frequency" class="action-panel-label">
Frequency:
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<select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency">
<option value="monthly">Monthly</option>
<option value="weekly">Weekly</option>
<option value="daily">Daily</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-monthly-additional">
<label for="saved-search-monthly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-monthly-on-day" class="no-border-panel-selector">
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<option value="Monday">The first Monday</option>
<option value="Tuesday">The first Tuesday</option>
<option value="Wednesday">The first Wednesday</option>
<option value="Thursday">The first Thursday</option>
<option value="Friday">The first Friday</option>
<option value="Saturday">The first Saturday</option>
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<div class="action-panel-control-wrap saved-search-weekly-additional">
<label for="saved-search-weekly-on-day" class="action-panel-label">
Which day?
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<option value="Sunday">Sunday</option>
<option value="Monday">Monday</option>
<option value="Tuesday">Tuesday</option>
<option value="Wednesday">Wednesday</option>
<option value="Thursday">Thursday</option>
<option value="Friday">Friday</option>
<option value="Saturday">Saturday</option>
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</div>
<div class="action-panel-control-wrap">
<label for="saved-search-report" class="action-panel-label">
Report format:
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<select id="saved-search-report" class="no-border-panel-selector saved-search-report">
<option value="DocSum">Summary</option>
<option value="DocSumText">Summary (text)</option>
<option value="Abstract">Abstract</option>
<option value="AbstractText">Abstract (text)</option>
<option value="MEDLINE">PubMed</option>
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</div>
<div class="action-panel-control-wrap">
<label for="saved-search-amount" class="action-panel-label">
Send at most:
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<option value="5" selected>5 items</option>
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<option value="20">20 items</option>
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<option value="200">200 items</option>
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</div>
<div>
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Send even when there aren't any new results
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Optional text in email:
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id="saved-search-email-text"
class="saved-search-email-text"></textarea>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Saving..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Save
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<button class="action-panel-cancel"
aria-label="Close 'Your saved search' panel"
ref="linksrc=close_saved_search_panel"
aria-controls="saved-search-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Create a file for external citation management software
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class="action-panel-content action-form"
action="/results-export-ids/"
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data-by-ids-action="/results-export-ids/"
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<input name="results-format" type="hidden" value="pubmed"/>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="save">
Create file
</button>
<button class="action-panel-cancel"
aria-label="Close 'Send citations to citation manager' panel"
ref="linksrc=close_citation_manager_panel"
aria-controls="citation-manager-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your RSS Feed
</h2>
<form id="rss-action-panel-form"
class="rss-action-panel-form action-panel-content action-form"
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<div class="action-panel-control-wrap">
<label for="rss-name" class="action-panel-label required-field-asterisk">
Name of RSS Feed:
</label>
<input maxlength="200"
placeholder="Name"
type="text"
name="rss-name"
id="rss-name"
class="rss-name"
value=''
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="rss-limit-wrap">
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="rss-limit" class="action-panel-label">
Number of items displayed:
</label>
<select id="rss-limit" class="no-border-panel-selector rss-limit">
<option value="5">5</option>
<option value="10">10</option>
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<option value="20">20</option>
<option value="50">50</option>
<option value="100">100</option>
</select>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Creating..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Create RSS
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your RSS' panel"
ref="linksrc=close_rss_panel"
aria-controls="rss-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
<div class="action-panel-control-wrap rss-link-copy-wrap">
<label for="rss-link" class="usa-sr-only">RSS Link</label>
<input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link">
<button
type="button"
disabled
class="rss-link-copy-button disabled"
data-ga-category="save_share"
data-ga-action="rss"
data-ga-label="copy">
Copy
</button>
</div>
</form>
</div>
</div>
</div>
</div>
<div class="article-page" id="article-page" data-article-pmid="39643614">
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Full text links
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<div class="full-text-links-list">
<a class="link-item
dialog-focus"
href="https://doi.org/10.1038/s42003-024-07115-3"
target="_blank"
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Full text links
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<div class="actions-buttons sidebar"><h3 class="title">Actions</h3><div class="inner-wrap"><button class="citation-button citation-dialog-trigger"
aria-label="Open dialog with citation text in different styles"
data-ga-category="save_share"
data-ga-action="cite"
data-ga-label="open"
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aria-label="Save article in MyNCBI collections."
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data-ga-action="click"
data-ga-label="collections_button"
data-collections-open-dialog-enabled="false"
data-collections-open-dialog-url="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F39643614%2F%23open-collections-dialog"
data-in-collections="false"><span class="button-label">Collections</span></button><div class="overlay" role="dialog"><div id="collections-action-dialog"
class="dialog collections-dialog"
aria-hidden="true"><div class="title">Add to Collections</div><div class="collections-action-panel action-panel"><form id="collections-action-dialog-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-myncbi-max-collection-name-length="100"
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id="collections-action-dialog-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_new"><label for="collections-action-dialog-new">Create a new collection</label></li><li><input type="radio"
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class="collections-existing"
name="collections"
value="existing"
checked="true"
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<h1 class="heading-title">
Novel loci and biomedical consequences of iron homoeostasis variation
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23
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark." href="#full-view-affiliation-24" ref="linksrc=author_aff">
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</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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23
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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25
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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24
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Immunology, Zealand University Hospital, Køge, Denmark." href="#full-view-affiliation-26" ref="linksrc=author_aff">
26
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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27
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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27
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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28
</a></sup><span class="semicolon">;&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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29
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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29
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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29
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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29
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Neurology, General Central Hospital, Bolzano, Italy." href="#full-view-affiliation-30" ref="linksrc=author_aff">
30
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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31
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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32
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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32
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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33
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Institute of Epidemiology, Helmholtz Munich, Neuherberg, Germany." href="#full-view-affiliation-34" ref="linksrc=author_aff">
34
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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34
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="German Center for Diabetes Research (DZD), Neuherberg, Germany." href="#full-view-affiliation-35" ref="linksrc=author_aff">
35
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Institute for Medical Information Processing, Biometry and Epidemiology, Medical Faculty, Ludwig-Maximilians-Universität München, München, Germany." href="#full-view-affiliation-36" ref="linksrc=author_aff">
36
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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37
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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38
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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39
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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38
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Centre for Cardiovascular Sciences, Queens Medical Research Institute, University of Edinburgh, Edinburgh, Scotland, UK." href="#full-view-affiliation-40" ref="linksrc=author_aff">
40
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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38
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Genomics Research Centre, Human Technopole, Milan, Italy." href="#full-view-affiliation-41" ref="linksrc=author_aff">
41
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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38
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK." href="#full-view-affiliation-39" ref="linksrc=author_aff">
39
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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42
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Public and Occupational Health, Amsterdam Public Health Research Institute, Amsterdam UMC, Amsterdam, The Netherlands." href="#full-view-affiliation-43" ref="linksrc=author_aff">
43
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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42
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Public and Occupational Health, Amsterdam Public Health Research Institute, Amsterdam UMC, Amsterdam, The Netherlands." href="#full-view-affiliation-43" ref="linksrc=author_aff">
43
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Luigi Ferrucci">Luigi Ferrucci</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Longitudinal studies section, National Institute on Aging, Baltimore, MD, USA." href="#full-view-affiliation-44" ref="linksrc=author_aff">
44
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Stefania Bandinelli">Stefania Bandinelli</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy." href="#full-view-affiliation-45" ref="linksrc=author_aff">
45
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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44
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Giorgia Girotto">Giorgia Girotto</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Institute for Maternal and Child Health - IRCCS, Burlo Garofolo, Trieste, Italy." href="#full-view-affiliation-46" ref="linksrc=author_aff">
46
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy." href="#full-view-affiliation-47" ref="linksrc=author_aff">
47
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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46
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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46
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Niek Verweij">Niek Verweij</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands." href="#full-view-affiliation-48" ref="linksrc=author_aff">
48
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Regeneron Genetics Center, Tarrytown, NY, USA." href="#full-view-affiliation-49" ref="linksrc=author_aff">
49
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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48
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands." href="#full-view-affiliation-50" ref="linksrc=author_aff">
50
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=van+de+Vegte+YJ&amp;cauthor_id=39643614"
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48
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Kiemeney+LA&amp;cauthor_id=39643614"
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51
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands." href="#full-view-affiliation-52" ref="linksrc=author_aff">
52
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Fred C Sweep">Fred C Sweep</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands." href="#full-view-affiliation-53" ref="linksrc=author_aff">
53
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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51
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Sulem+P&amp;cauthor_id=39643614"
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<div class="publication-type" >Meta-Analysis</div>
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Novel loci and biomedical consequences of iron homoeostasis variation
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Iron homoeostasis is tightly regulated, with hepcidin and soluble transferrin receptor (sTfR) playing significant roles. However, the genetic determinants of these traits and the biomedical consequences of iron homoeostasis variation are unclear. In a meta-analysis of 12 cohorts involving 91,675 participants, we found 43 genomic loci associated with either hepcidin or sTfR concentration, of which 15 previously unreported. Mapping to putative genes indicated involvement in iron-trait expression, erythropoiesis, immune response and cellular trafficking. Mendelian randomisation of 292 disease outcomes in 1,492,717 participants revealed associations of iron-related loci and iron status with selected health outcomes across multiple domains. These associations were largely driven by HFE, which was associated with the largest iron variation. Our findings enhance understanding of iron homoeostasis and its biomedical consequences, suggesting that lifelong exposure to higher iron levels is likely associated with lower risk of anaemia-related disorders and higher risk of genitourinary, musculoskeletal, infectious and neoplastic diseases.
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<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">Competing interests: R.S. is currently employed at Astra Zeneca. N.V. is an employee and stockholder of Regeneron Pharmaceuticals. J.Da. serves on scientific advisory boards for AstraZeneca, Novartis, and UK Biobank, and has received multiple grants from academic, charitable, and industry sources outside of the submitted work. All other authors declare no competing interests.</p>
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<p> Fig. 1. Study overview. </p>
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<p> Fig. 1. Study overview. </p>
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<div class="figure-caption-contents"><p> GWAS, genome-wide association study. sTfR soluble transferrin receptor, TSAT transferrin saturation,… </p></div>
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Fig. 1. Study overview.
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<div class="figure-caption-contents">GWAS, genome-wide association study. sTfR soluble transferrin receptor, TSAT transferrin saturation, TIBC total iron-binding capacity, eQTL expression quantitative trait loci, pQTL protein quantitative trait loci, MR Mendelian randomisation, MVP Million Veteran Programme. The genetic variants from Moksnes 2022 were obtained from the papers Supplementary Data 1.</div>
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<p> Fig. 2. Results of GWAS meta-analysis of… </p>
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<p> Fig. 2. Results of GWAS meta-analysis of hepcidin and sTfR and correlations with common iron… </p>
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Fig. 2. Results of GWAS meta-analysis of hepcidin and sTfR and correlations with common iron traits.
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<div class="figure-caption-contents"><b>A</b> Miami plot for hepcidin (upper plot, <i>N</i>=91,675 participants) and sTfR (lower plot, <i>N</i>=45,330 participants). For each locus (<i>N</i>=16 loci for hepcidin, <i>N</i>=27 for sTfR), we show the candidate gene name for the sentinel variant with the lowest <i>p</i> value. <b>B</b> Genetic and phenotypic correlations between the iron traits analysed in this study (hepcidin, sTfR) and those investigated in previous studies (ferritin, iron, TIBC, TSAT). Phenotypic correlations were estimated in the INTERVAL study (up to 40,197 participants). Genetic correlations were estimated using associations from the present study (hepcidin, sTfR; up to 91,675 participants) and Moksnes et al. 2022 (ferritin, iron, TIBC, TSAT; up to 257,953 participants).</div>
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<p> Fig. 3. Established and potential candidate genes mapped to variants associated with hepcidin or sTfR:… </p>
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Fig. 3. Established and potential candidate genes mapped to variants associated with hepcidin or sTfR: summary of their role and contextual information.
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<div class="figure-caption-contents"><b>A</b> This figure summarises the genes mentioned in Table 2 of this study, as well as other iron-homoeostasis genes provided for contextual information. Genes with an established role in iron homoeostasis are shown in red and italic; genes with a potential role are presented in dark grey and italic. Relevant references to other studies are included in Supplementary Data 8 ❶ Hepcidin is tightly regulated by several pathways. <i>TMPRSS6, ERFE</i> (via the BMP pathway), and <i>ZFPM1</i> suppress hepcidin expression in hepatocytes. <i>HFE</i>, <i>TFR2</i>, the Wnt pathway, and the JAK/STAT pathway increase hepcidin expression. Activation of the Wnt pathways is observed in iron overload, with involvement of <i>AXIN1</i>. Activation of JAK/STAT signalling has been proposed as a possible link between inflammation and iron homoeostasis. ❷ In presence of iron abundance, hepcidin suppresses function of ferroportin (FPN), an iron transporter coded by <i>SLC40A1</i> that mediates dietary intestinal iron uptake and iron recycling by macrophages from senescent erythrocytes. <i>NDFIP1</i> prevents degradation of ferroportin in vitro. ❸ Hypoxia-inducible factor 2α (HIF-2 α), coded by <i>EPAS1</i> and regulated by <i>EGLN3</i>, also controls duodenal iron absorption by promoting the expression of divalent metal transporter 1 (DMT1), coded by <i>SLC11A2</i>, on the luminal side of enterocytes. <i>NDFIP1</i> regulates DMT1 expression in mice. <i>EGLN3</i> hydroxylates key prolyl residues on HIF-2α, providing a recognition motif for its degradation. ❹ Several genes appear relevant to intestinal iron absorption: (i) <i>DUOX2</i> regulates interactions between the intestinal microbiota and the mucosa to maintain immune homoeostasis in mice, which likely enables intestinal iron absorption; (ii) <i>FUT2</i> codes for fucosyltransferase 2, an enzyme responsible for maintaining host-microbiota symbiosis via fucosylation of intestinal epithelial cells; (iii) <i>VANGL1</i> encodes a protein involved in mediating intestinal trefoil factor-induced wound healing in the intestinal mucosa. ❺ Iron released through ferroportin is bound to iron carrier transferrin (referred to as apotransferrin when not bound to iron), forming iron-loaded transferrin (holotransferrin), which delivers iron to most cells, especially erythrocytes. ❻ In presence of hypoxia, raised levels of HIF-2 α result in increased erythropoietin (EPO) production. ❼ EPO stimulates erythropoiesis, which is also modulated by several genes involved in erythroblast proliferation and differentiation: (i) the <i>HBS1L/MYB</i> intergenic region regulates erythroid cell proliferation, maturation, and foetal haemoglobin expression; (ii) <i>HK1</i> mutations lead to haemolytic anaemia via hexokinase deficiency, which in turn likely affects erythropoiesis; (iii) <i>IRS2</i> expression plays a role in erythroid cell differentiation through binding to cellular receptors involved in normal haematopoiesis; (iv) <i>ARHGAP9</i> regulates adhesion of haematopoietic cells to the extracellular matrix, which can influence their localisation and differentiation potential, and <i>R3HDM2</i> has been mapped to haemoglobin and red blood cell traits in large-scale GWASs; (v) <i>CPS1</i> is directly related to glycine, which is an essential requirement for haem synthesis; (vi) <i>SLC22A5</i> is involved in the active cellular uptake of carnitine, which stimulates erythropoiesis; (vii) <i>SOX7</i> blocks differentiation of hematopoietic progenitors to erythroid and myeloid lineages. In erythroblasts, <i>TFR2</i> is a sensor of holotransferrin, and is thought to protect against excessive erythrocytosis in the presence of iron deficiency. ❽ Finally, the immune response to external pathogens, which compete for iron, may also influence overall iron availability. Among the genes identified, <i>LVRN</i> may play a role in the synthesis of defensins and defensin-like peptides such as hepcidin, potentially contributing to iron homoeostasis via immune response; (ii) <i>MFSD6</i> recognises major histocompatibility complex type I (MHC-I) molecules and mediates MHC-I restricted killing by macrophages; (iii) <i>MPO</i> catalyses the production of hypohalous acids, primarily hypochlorous acid in physiologic situations, and other toxic intermediates that greatly enhance microbicidal activity. Images from Servier Medical Art (<ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://smart.servier.com">https://smart.servier.com</ext-link>), licensed under a Creative Commons Attribution 3.0 Unported (CC BY 3.0) Licence. <b>B</b> This figure summarises the genes mentioned in Table 2 of this study, as well as other iron-homoeostasis genes provided for contextual information. Genes with an established role in transferrin receptor synthesis, recycling, or degradation are shown in red and italic; genes with a potential role are presented in dark grey and italic. Relevant references to other studies are included in Supplementary Data 8. ❶ <i>TFRC</i> codes for transferrin receptor 1, which is constitutively expressed in most cells, especially erythrocytes. <i>TFR2</i> codes for transferrin receptor 2, linked to iron sensing and maintenance of body iron homoeostasis. <i>PGS1</i> is involved in the synthesis of cardiolipin, a phospholipid of mitochondrial membranes implicated in the regulation of transferrin receptor expression. ❷ After O-linked glycosylation, possibly mediated by the protein product of <i>GALNT6</i>, transferrin receptor 1 is expressed on the external surface of the cytoplasmic membrane. ❸ <i>HFE</i> interactswith transferrin receptor 1, facilitating cellular iron-sensing function and playing an important part in the regulation of hepcidin expression in response to body iron status. ❹ Iron-loaded transferrin (holotranferrin) binds to the receptor and the complex is internalised through clathrin-mediated endocytosis. ❺ A proton pump acidifies the endosome, which causes release of iron from holotransferrin; iron-deprived transferrin (apotransferrin) remains bound to its receptor. ❻ The endosome is usually recycled to the plasma membrane, a process likely regulated by (i) <i>LRBA</i>, known to influence recycling of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) via the classical recycling pathway used by receptors such as transferrin and (ii) <i>UBXN6</i>, which negatively regulates the adenosine triphosphate (ATP) hydrolytic activity of valosin containing protein (VCP), an ATP-driven segregase; VCP depletion delays transferrin receptor recycling. ❼ At neutral pH, apotransferrin dissociates from transferrin receptor and is ready to bind to free iron. The transferrin receptor may also be ubiquitinated and directed to lysosomal degradation, which is mediated by <i>MARCH8</i>, a membrane-associated zinc-finger factor, and, possibly, also by <i>RPS6KB1</i>, a protein kinase involved in the mammalian target of rapamycin-protein S6 kinase (mTOR-S6K) pathway, which is implicated in the degradation of transferrin receptor 1. ❽ Finally, <i>PCSK7</i> mediates the shedding of soluble transferrin receptor (sTfR) from the transferrin receptor. When iron availability is limited, sTfR levels increase at least in part by downregulating expression of <i>PCSK7</i> or neighbouring genes. Images from Servier Medical Art (<ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://smart.servier.com">https://smart.servier.com</ext-link>), licensed under a Creative Commons Attribution 3.0 Unported (CC BY 3.0) Licence.</div>
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Fig. 4. Putative causal effects of genetically predicted iron-related loci: Bonferroni-significant and nominal associations (null findings not presented).
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<div class="figure-caption-contents"><b>A</b> Locus-based MR associations with disease outcomes in up to 1,469,361 deCODE, FinnGen, MVP, and UK Biobank participants. Only loci that are associated (<i>P</i>&lt;5.2×10<sup>6</sup>) with at least one disease and have suggestive evidence of colocalization are shown. The terms in parenthesis indicate the trait that has been used for rescaling. <b>B</b> Locus-based MR associations with biomedical traits in up to 854,977 MVP and UK Biobank participants. Only loci that are associated with at least one disease outcome are shown. The terms in parenthesis indicate the trait that has been used for rescaling.</div>
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Fig. 5. Putative causal effects of genetically predicted systemic iron status: Bonferroni-significant and nominal associations (null findings not presented).
</strong>
<div class="figure-caption-contents"><b>A</b> MR associations of systemic iron status with disease outcomes in up to 1,492,717 deCODE, FinnGen, MVP, and UK Biobank participants. The estimates are expressed in odds ratio per one standard deviation (SD) higher transferrin saturation (TSAT) with confidence intervals shown between brackets. The plot shows estimates with the pC282Y variant in <i>HFE</i> (left-hand Forest plot) and without that variant (right-hand Forest plot), presenting diseases that have MR point estimates with the same direction in all the biobanks included in the meta-analysis. The instrument was generated using six variants mapped to <i>ERFE</i>, <i>HAMP</i>, <i>HFE</i>, <i>SLC25A37</i>, <i>TFR2</i> and <i>TMPRSS6</i> not affected by horizontal pleiotropy, indirect vertical pleiotropy, or collider bias and that: (i) were associated (<i>P</i>&lt;5×10<sup>8</sup>) with at least one trait; (ii) were nominally associated (<i>P</i>&lt;0.05) with all the other iron traits except for hepcidin (as its levels are influenced by systemic iron status); and (iii) displayed a direction of association consistent across all traits. <b>B</b> MR associations of systemic iron status, using the same instrument, with biomedical traits in up to 860,060 MVP and UK Biobank participants. The estimates are expressed in mean change (beta) per one SD higher TSAT. The plot shows estimates with the pC282Y variant in <i>HFE</i> (left-hand Forest plot) and without that variant (right-hand Forest plot), presenting traits that have MR point estimates with the same direction in all the biobanks included in the meta-analysis.</div>
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