The combinatorial diversity of KIR and HLA class I allotypes in Peninsular Malaysia
We characterized HLA and KIR combinatorial diversity in Malay and Malay Chinese, identified substantial allelic and structural diversity of the KIR locus in both populations and discovered novel variations at each analysis level. The Malay are more diverse than Malay Chinese, likely representing a u...
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| Veröffentlicht in: | Immunology 2021-04, Vol.162 (4), p.389-404 |
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| creator | Tao, Sudan Kichula, Katherine M. Harrison, Genelle F. Farias, Ticiana Della Justina Palmer, William H. Leaton, Laura Ann Hajar, Che Ghazali Norul Zefarina, Zulkafli Edinur, Hisham Atan Zhu, Faming Norman, Paul J. |
| description | We characterized HLA and KIR combinatorial diversity in Malay and Malay Chinese, identified substantial allelic and structural diversity of the KIR locus in both populations and discovered novel variations at each analysis level. The Malay are more diverse than Malay Chinese, likely representing a unique history that includes admixture with immigrating populations spanning several thousand years. Characterizing the Malay are KIR haplotypes with large structural variants present in 10% individuals, and the Malaysian Chinese, a low frequency of interactions of KIR2DL1 with C2+HLA‐C.
Summary
Killer cell immunoglobulin‐like receptors (KIRs) interact with polymorphic human leucocyte antigen (HLA) class I molecules, modulating natural killer (NK) cell functions and affecting both the susceptibility and outcome of immune‐mediated diseases. The KIR locus is highly diverse in gene content, copy number and allelic polymorphism within individuals and across geographical populations. To analyse currently under‐represented Asian and Pacific populations, we investigated the combinatorial diversity of KIR and HLA class I in 92 unrelated Malay and 75 Malaysian Chinese individuals from the Malay Peninsula. We identified substantial allelic and structural diversity of the KIR locus in both populations and characterized novel variations at each analysis level. The Malay population is more diverse than Malay Chinese, likely representing a unique history including admixture with immigrating populations spanning several thousand years. Characterizing the Malay population are KIR haplotypes with large structural variants present in 10% individuals, and KIR and HLA alleles previously identified in Austronesian populations. Despite the differences in ancestries, the proportion of HLA allotypes that serve as KIR ligands is similar in each population. The exception is a significantly reduced frequency of interactions of KIR2DL1 with C2+HLA‐C in the Malaysian Chinese group, caused by the low frequency of C2+HLA. One likely implication is a greater protection from preeclampsia, a pregnancy disorder associated with KIR2DL1, which shows higher incidence in the Malay than in the Malaysian Chinese. This first complete, high‐resolution, characterization of combinatorial diversity of KIR and HLA in Malaysians will form a valuable reference for future clinical and population studies. |
| doi_str_mv | 10.1111/imm.13289 |
| format | Article |
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Summary
Killer cell immunoglobulin‐like receptors (KIRs) interact with polymorphic human leucocyte antigen (HLA) class I molecules, modulating natural killer (NK) cell functions and affecting both the susceptibility and outcome of immune‐mediated diseases. The KIR locus is highly diverse in gene content, copy number and allelic polymorphism within individuals and across geographical populations. To analyse currently under‐represented Asian and Pacific populations, we investigated the combinatorial diversity of KIR and HLA class I in 92 unrelated Malay and 75 Malaysian Chinese individuals from the Malay Peninsula. We identified substantial allelic and structural diversity of the KIR locus in both populations and characterized novel variations at each analysis level. The Malay population is more diverse than Malay Chinese, likely representing a unique history including admixture with immigrating populations spanning several thousand years. Characterizing the Malay population are KIR haplotypes with large structural variants present in 10% individuals, and KIR and HLA alleles previously identified in Austronesian populations. Despite the differences in ancestries, the proportion of HLA allotypes that serve as KIR ligands is similar in each population. The exception is a significantly reduced frequency of interactions of KIR2DL1 with C2+HLA‐C in the Malaysian Chinese group, caused by the low frequency of C2+HLA. One likely implication is a greater protection from preeclampsia, a pregnancy disorder associated with KIR2DL1, which shows higher incidence in the Malay than in the Malaysian Chinese. This first complete, high‐resolution, characterization of combinatorial diversity of KIR and HLA in Malaysians will form a valuable reference for future clinical and population studies.</description><identifier>ISSN: 0019-2805</identifier><identifier>EISSN: 1365-2567</identifier><identifier>DOI: 10.1111/imm.13289</identifier><identifier>PMID: 33283280</identifier><language>eng</language><publisher>England: Wiley Subscription Services, Inc</publisher><subject>Alleles ; Allotypes ; Antigens ; Asian People ; Combinatorial analysis ; Copy number ; DNA Copy Number Variations ; Female ; Gene Frequency ; Gene polymorphism ; Genetic diversity ; Genetic Predisposition to Disease ; Genetic Variation ; Genotype ; Haplotypes ; High-Throughput Nucleotide Sequencing ; Histocompatibility antigen HLA ; HLA ; HLA-C Antigens - genetics ; Humans ; Incidence ; KIR ; Leukocytes ; Loci ; Malaysia ; Malaysia - epidemiology ; Malaysia - ethnology ; Male ; Native Hawaiian or Other Pacific Islander ; Natural killer (NK) cells ; Natural killer cells ; Original ; Polymorphism ; Population ; Population genetics ; Population studies ; Populations ; Potassium channels (inwardly-rectifying) ; Pre-eclampsia ; Pre-Eclampsia - epidemiology ; Pre-Eclampsia - genetics ; Pregnancy ; Receptors, KIR2DL1 - genetics</subject><ispartof>Immunology, 2021-04, Vol.162 (4), p.389-404</ispartof><rights>2020 John Wiley & Sons Ltd</rights><rights>2020 John Wiley & Sons Ltd.</rights><rights>Copyright © 2021 John Wiley & Sons Ltd</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4439-c1214f0ca6fe059db2e2968a50419325e75659989376d0fb5e4c1e33c753e9333</citedby><cites>FETCH-LOGICAL-c4439-c1214f0ca6fe059db2e2968a50419325e75659989376d0fb5e4c1e33c753e9333</cites><orcidid>0000-0002-3606-2428 ; 0000-0003-3386-8159 ; 0000-0003-2029-2234 ; 0000-0002-0348-6339 ; 0000-0001-5152-1883 ; 0000-0002-3379-6063 ; 0000-0001-8370-7703</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968402/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968402/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,1417,1433,27924,27925,45574,45575,46409,46833,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33283280$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tao, Sudan</creatorcontrib><creatorcontrib>Kichula, Katherine M.</creatorcontrib><creatorcontrib>Harrison, Genelle F.</creatorcontrib><creatorcontrib>Farias, Ticiana Della Justina</creatorcontrib><creatorcontrib>Palmer, William H.</creatorcontrib><creatorcontrib>Leaton, Laura Ann</creatorcontrib><creatorcontrib>Hajar, Che Ghazali Norul</creatorcontrib><creatorcontrib>Zefarina, Zulkafli</creatorcontrib><creatorcontrib>Edinur, Hisham Atan</creatorcontrib><creatorcontrib>Zhu, Faming</creatorcontrib><creatorcontrib>Norman, Paul J.</creatorcontrib><title>The combinatorial diversity of KIR and HLA class I allotypes in Peninsular Malaysia</title><title>Immunology</title><addtitle>Immunology</addtitle><description>We characterized HLA and KIR combinatorial diversity in Malay and Malay Chinese, identified substantial allelic and structural diversity of the KIR locus in both populations and discovered novel variations at each analysis level. The Malay are more diverse than Malay Chinese, likely representing a unique history that includes admixture with immigrating populations spanning several thousand years. Characterizing the Malay are KIR haplotypes with large structural variants present in 10% individuals, and the Malaysian Chinese, a low frequency of interactions of KIR2DL1 with C2+HLA‐C.
Summary
Killer cell immunoglobulin‐like receptors (KIRs) interact with polymorphic human leucocyte antigen (HLA) class I molecules, modulating natural killer (NK) cell functions and affecting both the susceptibility and outcome of immune‐mediated diseases. The KIR locus is highly diverse in gene content, copy number and allelic polymorphism within individuals and across geographical populations. To analyse currently under‐represented Asian and Pacific populations, we investigated the combinatorial diversity of KIR and HLA class I in 92 unrelated Malay and 75 Malaysian Chinese individuals from the Malay Peninsula. We identified substantial allelic and structural diversity of the KIR locus in both populations and characterized novel variations at each analysis level. The Malay population is more diverse than Malay Chinese, likely representing a unique history including admixture with immigrating populations spanning several thousand years. Characterizing the Malay population are KIR haplotypes with large structural variants present in 10% individuals, and KIR and HLA alleles previously identified in Austronesian populations. Despite the differences in ancestries, the proportion of HLA allotypes that serve as KIR ligands is similar in each population. The exception is a significantly reduced frequency of interactions of KIR2DL1 with C2+HLA‐C in the Malaysian Chinese group, caused by the low frequency of C2+HLA. One likely implication is a greater protection from preeclampsia, a pregnancy disorder associated with KIR2DL1, which shows higher incidence in the Malay than in the Malaysian Chinese. This first complete, high‐resolution, characterization of combinatorial diversity of KIR and HLA in Malaysians will form a valuable reference for future clinical and population studies.</description><subject>Alleles</subject><subject>Allotypes</subject><subject>Antigens</subject><subject>Asian People</subject><subject>Combinatorial analysis</subject><subject>Copy number</subject><subject>DNA Copy Number Variations</subject><subject>Female</subject><subject>Gene Frequency</subject><subject>Gene polymorphism</subject><subject>Genetic diversity</subject><subject>Genetic Predisposition to Disease</subject><subject>Genetic Variation</subject><subject>Genotype</subject><subject>Haplotypes</subject><subject>High-Throughput Nucleotide Sequencing</subject><subject>Histocompatibility antigen HLA</subject><subject>HLA</subject><subject>HLA-C Antigens - genetics</subject><subject>Humans</subject><subject>Incidence</subject><subject>KIR</subject><subject>Leukocytes</subject><subject>Loci</subject><subject>Malaysia</subject><subject>Malaysia - epidemiology</subject><subject>Malaysia - ethnology</subject><subject>Male</subject><subject>Native Hawaiian or Other Pacific Islander</subject><subject>Natural killer (NK) cells</subject><subject>Natural killer cells</subject><subject>Original</subject><subject>Polymorphism</subject><subject>Population</subject><subject>Population genetics</subject><subject>Population studies</subject><subject>Populations</subject><subject>Potassium channels (inwardly-rectifying)</subject><subject>Pre-eclampsia</subject><subject>Pre-Eclampsia - epidemiology</subject><subject>Pre-Eclampsia - genetics</subject><subject>Pregnancy</subject><subject>Receptors, KIR2DL1 - genetics</subject><issn>0019-2805</issn><issn>1365-2567</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kV1rFDEUhoNY7Fq98A9IwBu9mDYfk5nkRihF28VdWmx7HbKZMzYlk6zJTGX-vWm3FisYAuGQh-ecw4vQO0oOaTlHbhgOKWdSvUALyhtRMdG0L9GCEKoqJonYR69zvi0lJ0K8Qvu8wOWSBbq8ugFs47BxwYwxOeNx5-4gZTfOOPb42_I7NqHDZ6tjbL3JGS-x8T6O8xYydgFfQHAhT94kvDbezNmZN2ivNz7D28f3AF1__XJ1clatzk-XJ8erytY1V5WljNY9sabpgQjVbRgw1UgjSE0VZwJa0QilpOJt05F-I6C2FDi3reCgOOcH6PPOu502A3QWwpiM19vkBpNmHY3Tz3-Cu9E_4p1uS5uasCL4-ChI8ecEedSDyxa8NwHilDWrm1bWvJGyoB_-QW_jlEJZTzNBqJT3aKE-7SibYs4J-qdhKNH3UekSlX6IqrDv_57-ifyTTQGOdsAv52H-v0kv1-ud8jezYZxF</recordid><startdate>202104</startdate><enddate>202104</enddate><creator>Tao, Sudan</creator><creator>Kichula, Katherine M.</creator><creator>Harrison, Genelle F.</creator><creator>Farias, Ticiana Della Justina</creator><creator>Palmer, William H.</creator><creator>Leaton, Laura Ann</creator><creator>Hajar, Che Ghazali Norul</creator><creator>Zefarina, Zulkafli</creator><creator>Edinur, Hisham Atan</creator><creator>Zhu, Faming</creator><creator>Norman, Paul J.</creator><general>Wiley Subscription Services, Inc</general><general>John Wiley and Sons Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QR</scope><scope>7T5</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-3606-2428</orcidid><orcidid>https://orcid.org/0000-0003-3386-8159</orcidid><orcidid>https://orcid.org/0000-0003-2029-2234</orcidid><orcidid>https://orcid.org/0000-0002-0348-6339</orcidid><orcidid>https://orcid.org/0000-0001-5152-1883</orcidid><orcidid>https://orcid.org/0000-0002-3379-6063</orcidid><orcidid>https://orcid.org/0000-0001-8370-7703</orcidid></search><sort><creationdate>202104</creationdate><title>The combinatorial diversity of KIR and HLA class I allotypes in Peninsular Malaysia</title><author>Tao, Sudan ; Kichula, Katherine M. ; Harrison, Genelle F. ; Farias, Ticiana Della Justina ; Palmer, William H. ; Leaton, Laura Ann ; Hajar, Che Ghazali Norul ; Zefarina, Zulkafli ; Edinur, Hisham Atan ; Zhu, Faming ; Norman, Paul J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4439-c1214f0ca6fe059db2e2968a50419325e75659989376d0fb5e4c1e33c753e9333</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Alleles</topic><topic>Allotypes</topic><topic>Antigens</topic><topic>Asian People</topic><topic>Combinatorial analysis</topic><topic>Copy number</topic><topic>DNA Copy Number Variations</topic><topic>Female</topic><topic>Gene Frequency</topic><topic>Gene polymorphism</topic><topic>Genetic diversity</topic><topic>Genetic Predisposition to Disease</topic><topic>Genetic Variation</topic><topic>Genotype</topic><topic>Haplotypes</topic><topic>High-Throughput Nucleotide Sequencing</topic><topic>Histocompatibility antigen HLA</topic><topic>HLA</topic><topic>HLA-C Antigens - genetics</topic><topic>Humans</topic><topic>Incidence</topic><topic>KIR</topic><topic>Leukocytes</topic><topic>Loci</topic><topic>Malaysia</topic><topic>Malaysia - epidemiology</topic><topic>Malaysia - ethnology</topic><topic>Male</topic><topic>Native Hawaiian or Other Pacific Islander</topic><topic>Natural killer (NK) cells</topic><topic>Natural killer cells</topic><topic>Original</topic><topic>Polymorphism</topic><topic>Population</topic><topic>Population genetics</topic><topic>Population studies</topic><topic>Populations</topic><topic>Potassium channels (inwardly-rectifying)</topic><topic>Pre-eclampsia</topic><topic>Pre-Eclampsia - epidemiology</topic><topic>Pre-Eclampsia - genetics</topic><topic>Pregnancy</topic><topic>Receptors, KIR2DL1 - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tao, Sudan</creatorcontrib><creatorcontrib>Kichula, Katherine M.</creatorcontrib><creatorcontrib>Harrison, Genelle F.</creatorcontrib><creatorcontrib>Farias, Ticiana Della Justina</creatorcontrib><creatorcontrib>Palmer, William H.</creatorcontrib><creatorcontrib>Leaton, Laura Ann</creatorcontrib><creatorcontrib>Hajar, Che Ghazali Norul</creatorcontrib><creatorcontrib>Zefarina, Zulkafli</creatorcontrib><creatorcontrib>Edinur, Hisham Atan</creatorcontrib><creatorcontrib>Zhu, Faming</creatorcontrib><creatorcontrib>Norman, Paul J.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Immunology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tao, Sudan</au><au>Kichula, Katherine M.</au><au>Harrison, Genelle F.</au><au>Farias, Ticiana Della Justina</au><au>Palmer, William H.</au><au>Leaton, Laura Ann</au><au>Hajar, Che Ghazali Norul</au><au>Zefarina, Zulkafli</au><au>Edinur, Hisham Atan</au><au>Zhu, Faming</au><au>Norman, Paul J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The combinatorial diversity of KIR and HLA class I allotypes in Peninsular Malaysia</atitle><jtitle>Immunology</jtitle><addtitle>Immunology</addtitle><date>2021-04</date><risdate>2021</risdate><volume>162</volume><issue>4</issue><spage>389</spage><epage>404</epage><pages>389-404</pages><issn>0019-2805</issn><eissn>1365-2567</eissn><abstract>We characterized HLA and KIR combinatorial diversity in Malay and Malay Chinese, identified substantial allelic and structural diversity of the KIR locus in both populations and discovered novel variations at each analysis level. The Malay are more diverse than Malay Chinese, likely representing a unique history that includes admixture with immigrating populations spanning several thousand years. Characterizing the Malay are KIR haplotypes with large structural variants present in 10% individuals, and the Malaysian Chinese, a low frequency of interactions of KIR2DL1 with C2+HLA‐C.
Summary
Killer cell immunoglobulin‐like receptors (KIRs) interact with polymorphic human leucocyte antigen (HLA) class I molecules, modulating natural killer (NK) cell functions and affecting both the susceptibility and outcome of immune‐mediated diseases. The KIR locus is highly diverse in gene content, copy number and allelic polymorphism within individuals and across geographical populations. To analyse currently under‐represented Asian and Pacific populations, we investigated the combinatorial diversity of KIR and HLA class I in 92 unrelated Malay and 75 Malaysian Chinese individuals from the Malay Peninsula. We identified substantial allelic and structural diversity of the KIR locus in both populations and characterized novel variations at each analysis level. The Malay population is more diverse than Malay Chinese, likely representing a unique history including admixture with immigrating populations spanning several thousand years. Characterizing the Malay population are KIR haplotypes with large structural variants present in 10% individuals, and KIR and HLA alleles previously identified in Austronesian populations. Despite the differences in ancestries, the proportion of HLA allotypes that serve as KIR ligands is similar in each population. The exception is a significantly reduced frequency of interactions of KIR2DL1 with C2+HLA‐C in the Malaysian Chinese group, caused by the low frequency of C2+HLA. One likely implication is a greater protection from preeclampsia, a pregnancy disorder associated with KIR2DL1, which shows higher incidence in the Malay than in the Malaysian Chinese. This first complete, high‐resolution, characterization of combinatorial diversity of KIR and HLA in Malaysians will form a valuable reference for future clinical and population studies.</abstract><cop>England</cop><pub>Wiley Subscription Services, Inc</pub><pmid>33283280</pmid><doi>10.1111/imm.13289</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0002-3606-2428</orcidid><orcidid>https://orcid.org/0000-0003-3386-8159</orcidid><orcidid>https://orcid.org/0000-0003-2029-2234</orcidid><orcidid>https://orcid.org/0000-0002-0348-6339</orcidid><orcidid>https://orcid.org/0000-0001-5152-1883</orcidid><orcidid>https://orcid.org/0000-0002-3379-6063</orcidid><orcidid>https://orcid.org/0000-0001-8370-7703</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Immunology, 2021-04, Vol.162 (4), p.389-404 |
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| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7968402 |
| source | MEDLINE; Wiley Online Library Free Content; Access via Wiley Online Library; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Alleles Allotypes Antigens Asian People Combinatorial analysis Copy number DNA Copy Number Variations Female Gene Frequency Gene polymorphism Genetic diversity Genetic Predisposition to Disease Genetic Variation Genotype Haplotypes High-Throughput Nucleotide Sequencing Histocompatibility antigen HLA HLA HLA-C Antigens - genetics Humans Incidence KIR Leukocytes Loci Malaysia Malaysia - epidemiology Malaysia - ethnology Male Native Hawaiian or Other Pacific Islander Natural killer (NK) cells Natural killer cells Original Polymorphism Population Population genetics Population studies Populations Potassium channels (inwardly-rectifying) Pre-eclampsia Pre-Eclampsia - epidemiology Pre-Eclampsia - genetics Pregnancy Receptors, KIR2DL1 - genetics |
| title | The combinatorial diversity of KIR and HLA class I allotypes in Peninsular Malaysia |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-22T13%3A23%3A15IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20combinatorial%20diversity%20of%20KIR%20and%20HLA%20class%20I%20allotypes%20in%20Peninsular%20Malaysia&rft.jtitle=Immunology&rft.au=Tao,%20Sudan&rft.date=2021-04&rft.volume=162&rft.issue=4&rft.spage=389&rft.epage=404&rft.pages=389-404&rft.issn=0019-2805&rft.eissn=1365-2567&rft_id=info:doi/10.1111/imm.13289&rft_dat=%3Cproquest_pubme%3E2501884678%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2501884678&rft_id=info:pmid/33283280&rfr_iscdi=true |