{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T14:13:29Z","timestamp":1789827209355,"version":"4.0.1"},"posted":{"date-parts":[[2026,9,15]]},"group-title":"Nephrology","reference-count":25,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"funder":[{"award":["T32 AG071474"],"award-info":[{"award-number":["T32 AG071474"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U01 AG032984"],"award-info":[{"award-number":["U01 AG032984"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U2C DK129440"],"award-info":[{"award-number":["U2C DK129440"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]},{"award":["TL1 DK132770"],"award-info":[{"award-number":["TL1 DK132770"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]},{"award":["K01 DK128304"],"award-info":[{"award-number":["K01 DK128304"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01 DK127638"],"award-info":[{"award-number":["R01 DK127638"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01 DK135265"],"award-info":[{"award-number":["R01 DK135265"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/01n45xa04","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Healthy Americas Foundation Lucy Delgado Fund"},{"name":"All of Us Research Program","award":["3OT2OD025277"],"award-info":[{"award-number":["3OT2OD025277"]}]},{"id":[{"id":"https:\/\/ror.org\/00baak391","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>\n                    Genetic studies have shown the\n                    <jats:italic>APOL1<\/jats:italic>\n                    variant p.N264K, also called M1, is associated with markedly lower kidney disease risk when co-inherited with the G2-risk allele. Empirical studies show M1 in\n                    <jats:italic>cis<\/jats:italic>\n                    with G2 blocks APOL1 cation channel flux. To date M1 only occurs on a specific APOL1 haplotype defined by three amino acid positions: p.Lys150 (K), p.Ile228 (I) and p.Lys255 (K). We analyzed two large community datasets to determine if M1 occurs on other APOL1 protein haplotypes and used a cell model to assess if the M1 variant alone is sufficient to block channel activity or if its haplotype context modifies its function.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Phased\n                    <jats:italic>APOL1<\/jats:italic>\n                    haplotypes frequencies were examined in the Alzheimer Disease Sequencing Project Release 5 (ASDP R5) participants (n=40,909) and confirmed in All of Us Research Program (All of Us) enrollees (n=72,538). Reported race was compared with genetically inferred ancestry. Local APOL1 genealogies were inferred and allele age determined. Thallium flux was measured in 293 cells after induced expression of\n                    <jats:italic>APOL1<\/jats:italic>\n                    -G2 on natural and engineered haplotype backgrounds.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    The M1 variant occurred exclusively on the KIK APOL1 protein haplotype in all ADSP R5 participants (n=330) and 99.5% of All of Us participants (n=3,560). Local genealogies placed these chromosomes within the lineage carrying p.150K.\n                    <jats:italic>In vitro<\/jats:italic>\n                    thallium flux assays demonstrated that M1 alone and p.Lys150 alone each partially reduced thallium flux but completely abrogated thallium flux when on the same haplotype.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>M1 is inherited almost exclusively with a single haplotype background. Both the p.150K and p.264K (M1) are needed to completely block APOL1-G2-mediated thallium flux. Studies aimed at examining and exploiting the protective mechanisms of M1 for possible treatments need to consider its distinct haplotype context.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Translational Statement<\/jats:title>\n                  <jats:p>\n                    G1 and G2 coding variants in\n                    <jats:italic>APOL1<\/jats:italic>\n                    increase the risk of kidney disease in populations with African ancestry. Another coding variant p.N264K (M1) reduces kidney disease risk when inherited in\n                    <jats:italic>cis<\/jats:italic>\n                    with the APOL1 G2 risk allele. Here we show in large populations that the M1 is almost always inherited on an\n                    <jats:italic>APOL1<\/jats:italic>\n                    haplotype that encodes a p.E150K amino acid change. Otherwise G2 in the absence of M1 is exclusively on a p.150E haplotype. M1 and p.150K functionally interact to block APOL1-mediated thallium flux in cell culture models. These functional interactions highlight the importance of considering the M1 variant in its haplotype context when designing basic research studies and translating results into future approaches for therapeutic intervention.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.14.26362999","type":"posted-content","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T01:35:19Z","timestamp":1789522519000},"source":"Crossref","is-referenced-by-count":0,"title":["The APOL1 protective M1 modifier occurs exclusively with the KIK protein haplotype to suppress channel conductance"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3131-1157","authenticated-orcid":false,"given":"Diya","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA"},{"name":"Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Korey R.","family":"Bartolomeo","sequence":"additional","affiliation":[{"name":"Department of Kidney Medicine, Medical Specialties Institute and Department of Heart, Blood and Kidney Research, Cleveland Clinic, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiying","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA"},{"name":"Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agustin","family":"Gonzalez-Vicente","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas R.","family":"Wheeler","sequence":"additional","affiliation":[{"name":"Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Penelope","family":"Benchek","sequence":"additional","affiliation":[{"name":"Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA"},{"name":"Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofeng","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA"},{"name":"Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan L.","family":"Haines","sequence":"additional","affiliation":[{"name":"Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA"},{"name":"Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA"},{"name":"Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica N.","family":"Cooke Bailey","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Toxicology, East Carolina University, Greenville, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Nader","sequence":"additional","affiliation":[{"name":"Department of Kidney Medicine, Medical Specialties Institute and Department of Heart, Blood and Kidney Research, Cleveland Clinic, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nurdan","family":"Cam","sequence":"additional","affiliation":[{"name":"Department of Kidney Medicine, Medical Specialties Institute and Department of Heart, Blood and Kidney Research, Cleveland Clinic, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie A.","family":"Bruggeman","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University School of Medicine, Cleveland, OH, USA"},{"name":"Department of Kidney Medicine, Medical Specialties Institute and Department of Heart, Blood and Kidney Research, Cleveland Clinic, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott M.","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA"},{"name":"Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana C.","family":"Crawford","sequence":"additional","affiliation":[{"name":"Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA"},{"name":"Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA"},{"name":"Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9729-6519","authenticated-orcid":false,"given":"William S.","family":"Bush","sequence":"additional","affiliation":[{"name":"Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA"},{"name":"Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA"},{"name":"Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5929-1947","authenticated-orcid":false,"given":"John F.","family":"O\u2019Toole","sequence":"additional","affiliation":[{"name":"Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA"},{"name":"Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University School of Medicine, Cleveland, OH, USA"},{"name":"Department of Kidney Medicine, Medical Specialties Institute and Department of Heart, Blood and Kidney Research, Cleveland Clinic, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6780-9168","authenticated-orcid":false,"given":"John R.","family":"Sedor","sequence":"additional","affiliation":[{"name":"Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA"},{"name":"Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA"},{"name":"Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University School of Medicine, Cleveland, OH, USA"},{"name":"Department of Kidney Medicine, Medical Specialties Institute and Department of Heart, Blood and Kidney Research, Cleveland Clinic, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026091907000448000_2026.09.14.26362999v1.1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1193032"},{"key":"2026091907000448000_2026.09.14.26362999v1.2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-042325-051210"},{"key":"2026091907000448000_2026.09.14.26362999v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.05.014"},{"key":"2026091907000448000_2026.09.14.26362999v1.4","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1400699111"},{"key":"2026091907000448000_2026.09.14.26362999v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2015.151"},{"key":"2026091907000448000_2026.09.14.26362999v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2019.07.010"},{"key":"2026091907000448000_2026.09.14.26362999v1.7","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2022020213"},{"key":"2026091907000448000_2026.09.14.26362999v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-53298-4"},{"key":"2026091907000448000_2026.09.14.26362999v1.9","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.0000000000000219"},{"key":"2026091907000448000_2026.09.14.26362999v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-43020-9"},{"key":"2026091907000448000_2026.09.14.26362999v1.11","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2026.1452"},{"key":"2026091907000448000_2026.09.14.26362999v1.12","doi-asserted-by":"publisher","DOI":"10.26508\/lsa.202503570"},{"key":"2026091907000448000_2026.09.14.26362999v1.13","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.0000001159"},{"key":"2026091907000448000_2026.09.14.26362999v1.14","doi-asserted-by":"publisher","DOI":"10.1093\/G3JOURNAL\/JKAE290"},{"key":"2026091907000448000_2026.09.14.26362999v1.15","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000000194"},{"key":"2026091907000448000_2026.09.14.26362999v1.16","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMsr1809937"},{"key":"2026091907000448000_2026.09.14.26362999v1.17","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-022-02767-8"},{"key":"2026091907000448000_2026.09.14.26362999v1.18","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2016121322"},{"key":"2026091907000448000_2026.09.14.26362999v1.19","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-55408-2"},{"key":"2026091907000448000_2026.09.14.26362999v1.20","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2202396"},{"key":"2026091907000448000_2026.09.14.26362999v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.ekir.2019.11.022"},{"key":"2026091907000448000_2026.09.14.26362999v1.22","doi-asserted-by":"publisher","DOI":"10.1159\/000537948"},{"key":"2026091907000448000_2026.09.14.26362999v1.23","doi-asserted-by":"publisher","DOI":"10.64898\/2026.04.04.26350158"},{"key":"2026091907000448000_2026.09.14.26362999v1.24","doi-asserted-by":"publisher","DOI":"10.1172\/JCI172262"},{"key":"2026091907000448000_2026.09.14.26362999v1.25","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-013-1415-z"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.09.14.26362999","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T14:00:13Z","timestamp":1789826413000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.09.14.26362999"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,15]]},"references-count":25,"URL":"https:\/\/doi.org\/10.64898\/2026.09.14.26362999","relation":{},"subject":[],"published":{"date-parts":[[2026,9,15]]},"subtype":"preprint"}}