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We undertook this study to investigate the potential causal nature and direction between insulin resistance and hyperuricemia, along with gout, by using bidirectional Mendelian randomization (MR) analyses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We used genome\u2010wide association data (n = 288,649 for serum urate [SU] concentration; n = 763,813 for gout risk; n = 153,525 for fasting insulin) to select genetic instruments for 2\u2010sample MR analyses, using multiple MR methods to address potential pleiotropic associations. We then used individual\u2010level, electronic medical record\u2013linked data from the UK Biobank (n = 360,453 persons of European ancestry) to replicate our analyses via single\u2010sample MR analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Genetically determined SU levels, whether inferred from a polygenic score or strong individual loci, were not associated with fasting insulin concentrations. In contrast, genetically determined fasting insulin concentrations were positively associated with SU levels (0.37 mg\/dl per log\u2010unit increase in fasting insulin [95% confidence interval (95% CI) 0.15, 0.58];\n                      <jats:italic>P<\/jats:italic>\n                      = 0.001). This persisted in outlier\u2010corrected (\u03b2 = 0.56 mg\/dl [95% CI 0.45, 0.67]) and multivariable MR analyses adjusted for BMI (\u03b2 = 0.69 mg\/dl [95% CI 0.53, 0.85]) (\n                      <jats:italic>P<\/jats:italic>\n                      &lt; 0.001 for both). Polygenic scores for fasting insulin were also positively associated with SU level among individuals in the UK Biobank (\n                      <jats:italic>P<\/jats:italic>\n                      &lt; 0.001). Findings for gout risk were bidirectionally consistent with those for SU level.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings provide evidence to clarify core questions about the close association between hyperuricemia and insulin resistance syndrome: hyperinsulinemia leads to hyperuricemia but not the other way around. Reducing insulin resistance could lower the SU level and gout risk, whereas lowering the SU level (e.g., allopurinol treatment) is unlikely to mitigate insulin resistance and its cardiometabolic sequelae.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.41779","type":"journal-article","created":{"date-parts":[[2021,5,13]],"date-time":"2021-05-13T07:12:07Z","timestamp":1620889927000},"page":"2096-2104","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":163,"title":["Assessing the Causal Relationships Between Insulin Resistance and Hyperuricemia and Gout Using Bidirectional Mendelian Randomization"],"prefix":"10.1002","volume":"73","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4147-8348","authenticated-orcid":false,"given":"Natalie","family":"McCormick","sequence":"first","affiliation":[{"name":"Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, and Arthritis Research Canada  Richmond British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6973-1926","authenticated-orcid":false,"given":"Mark J.","family":"O\u2019Connor","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital  Boston"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7557-3303","authenticated-orcid":false,"given":"Chio","family":"Yokose","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital and Harvard Medical School  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0844-8726","authenticated-orcid":false,"given":"Tony R.","family":"Merriman","sequence":"additional","affiliation":[{"name":"University of Otago, Dunedin, New Zealand, and University of Alabama at Birmingham"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David B.","family":"Mount","sequence":"additional","affiliation":[{"name":"Brigham and Women\u2019s Hospital VA Boston Healthcare System, and Harvard Medical School  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3353-9454","authenticated-orcid":false,"given":"Aaron","family":"Leong","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, and Broad Institute of MIT and Harvard  Cambridge Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2862-0442","authenticated-orcid":false,"given":"Hyon K.","family":"Choi","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, and Arthritis Research Canada  Richmond British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,9,26]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.41404"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2006.06.040"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2011.09.033"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1991.03470210076036"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1047-2797(97)00204-4"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kws002"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1042\/cs0920051"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.aje.a116768"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyy262"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0504-x"},{"key":"e_1_2_6_12_1","unstructured":"ChenJ SpracklenCN MarenneG VarshneyA CorbinLJ LuanJ et al.The trans\u2010ancestral genomic architecture of glycaemic traits. 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