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Although numerous clinical and environmental risk factors exist, not all patients with risk factors develop ARDS, raising the possibility of genetic underpinnings for ARDS susceptibility. We have previously reported that circulating cell-free hemoglobin (CFH) is elevated during sepsis, and higher levels predict worse outcomes. Excess CFH is rapidly scavenged by haptoglobin (Hp). A common\n                    <jats:italic>HP<\/jats:italic>\n                    genetic variant,\n                    <jats:italic>HP2<\/jats:italic>\n                    , is unique to humans and is common in many populations worldwide. HP2 haptoglobin has reduced ability to inhibit CFH-mediated inflammation and oxidative stress compared with the alternative\n                    <jats:italic>HP1<\/jats:italic>\n                    . We hypothesized that HP2 increases ARDS susceptibility during sepsis when plasma CFH levels are elevated. In a murine model of sepsis with elevated CFH, transgenic mice homozygous for\n                    <jats:italic>Hp2<\/jats:italic>\n                    had increased lung inflammation, pulmonary vascular permeability, lung apoptosis, and mortality compared with wild-type mice. We then tested the clinical relevance of our findings in 496 septic critically ill adults, finding that\n                    <jats:italic>HP2<\/jats:italic>\n                    increased ARDS susceptibility after controlling for clinical risk factors and plasma CFH. These observations identify\n                    <jats:italic>HP2<\/jats:italic>\n                    as a potentially novel genetic ARDS risk factor during sepsis and may have important implications in the study and treatment of ARDS.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.131206","type":"journal-article","created":{"date-parts":[[2019,10,1]],"date-time":"2019-10-01T12:00:42Z","timestamp":1569931242000},"source":"Crossref","is-referenced-by-count":36,"title":["Haptoglobin-2 variant increases susceptibility to acute respiratory distress syndrome during sepsis"],"prefix":"10.1172","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0342-1965","authenticated-orcid":true,"given":"V. 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