{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T16:36:20Z","timestamp":1781109380195,"version":"3.54.1"},"reference-count":54,"publisher":"National Academy of Sciences","issue":"8","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,2,21]]},"abstract":"<jats:p>\n                    The outcome of exposure to infectious microbes or their toxins is influenced by both microbial and host genes. Some host genes encode defense mechanisms, whereas others assist pathogen functions. Genomic analyses have associated host gene mutations with altered infectious disease susceptibility, but evidence for causality is limited. Here we demonstrate that human genetic variation affecting capillary morphogenesis gene 2 (\n                    <jats:italic>CMG2<\/jats:italic>\n                    ), which encodes a host membrane protein exploited by anthrax toxin as a principal receptor, dramatically alters toxin sensitivity. Lymphoblastoid cells derived from a HapMap Project cohort of 234 persons of African, European, or Asian ancestry differed in sensitivity mediated by the protective antigen (PA) moiety of anthrax toxin by more than four orders of magnitude, with 99% of the cohort showing a 250-fold range of sensitivity. We find that relative sensitivity is an inherited trait that correlates strongly with\n                    <jats:italic>CMG2<\/jats:italic>\n                    mRNA abundance in cells of each ethnic\/geographical group and in the combined population pool (\n                    <jats:italic>P<\/jats:italic>\n                    = 4 \u00d7 10\n                    <jats:sup>\u221211<\/jats:sup>\n                    ). The extent of\n                    <jats:italic>CMG2<\/jats:italic>\n                    expression in transfected murine macrophages and human lymphoblastoid cells affected anthrax toxin binding, internalization, and sensitivity. A\n                    <jats:italic>CMG2<\/jats:italic>\n                    single-nucleotide polymorphism (SNP) occurring frequently in African and European populations independently altered toxin uptake, but was not statistically associated with altered sensitivity in HapMap cell populations. Our results reveal extensive human diversity in cell lethality dependent on PA-mediated toxin binding and uptake, and identify individual differences in\n                    <jats:italic>CMG2<\/jats:italic>\n                    expression level as a determinant of this diversity. Testing of genomically characterized human cell populations may offer a broadly useful strategy for elucidating effects of genetic variation on infectious disease susceptibility.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1121006109","type":"journal-article","created":{"date-parts":[[2012,2,7]],"date-time":"2012-02-07T03:14:58Z","timestamp":1328584498000},"page":"2972-2977","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":21,"title":["Human genetic variation altering anthrax toxin sensitivity"],"prefix":"10.1073","volume":"109","author":[{"given":"Mikhail","family":"Martchenko","sequence":"first","affiliation":[{"name":"Departments of aGenetics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie I.","family":"Candille","sequence":"additional","affiliation":[{"name":"Departments of aGenetics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Tang","sequence":"additional","affiliation":[{"name":"Departments of aGenetics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley N.","family":"Cohen","sequence":"additional","affiliation":[{"name":"Departments of aGenetics and"},{"name":"Medicine, Stanford University School of Medicine, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2012,2,6]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.23.13206"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198803243181202"},{"key":"e_1_3_3_3_2","first-page":"632","article-title":"Absence of serum gamma globulins","volume":"84","author":"Bruton OC","year":"1952","unstructured":"OC Bruton, L Apt, D Gitlin, CA Janeway, Absence of serum gamma globulins. 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