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Although several studies have reported that the X allele of the\n                      <jats:italic>ACTN3<\/jats:italic>\n                      R577X polymorphism is associated with reduced muscle mass, others have found no significant relationship between genotype and muscle mass. These inconsistencies may be explained by differences in background characteristics of the study populations, such as sex, age, ethnicity, and measurement site. This systematic review and meta-analysis aimed to clarify the association between the\n                      <jats:italic>ACTN3<\/jats:italic>\n                      R577X polymorphism and skeletal muscle mass. In addition, we investigated whether the effect of the\n                      <jats:italic>ACTN3<\/jats:italic>\n                      gene is modified by population background.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Main body<\/jats:title>\n                    <jats:p>\n                      A total of 34 cohorts (9,496 participants) derived from 24 studies were included in the meta-analysis. In the overall analysis under the dominant model for the X allele (RR vs. RX\u2009+\u2009XX), the\n                      <jats:italic>ACTN3<\/jats:italic>\n                      genotype showed a significant effect on skeletal muscle mass (SMD [95% CI]\u2009= \u2212\u20090.08 [\u2212\u20090.15 to\u2009\u2212\u20090.02],\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.014), with the RX\u2009+\u2009XX group exhibiting lower skeletal muscle mass compared with the RR group. In contrast, the recessive model (RR\u2009+\u2009RX vs. XX) did not yield a statistically significant effect (SMD [95% CI]\u2009=\u2009\u2212\u00a00.02 [\u2212\u00a00.12 to 0.07],\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.616). Under the additive model, a trend toward an effect was observed (per-allele; \u03b2 [95% CI]\u2009=\u2009\u2212\u00a00.05 [\u2212\u00a00.10 to 0.01],\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.078). Moderate heterogeneity was observed across all models (dominant:\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      \u2009=\u200938.8%; recessive:\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      \u2009=\u200955.8%; additive:\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      \u2009=\u200952.5%). No significant subgroup effects were observed for sex, age, or ethnicity. Meta-regression for measurement site indicated that the association became more pronounced as lower-limb specificity increased, although residual heterogeneity remained.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic>ACTN3<\/jats:italic>\n                      R577X polymorphism showed a small association with skeletal muscle mass under the X-allele dominant model, suggesting that this association may be detectable even in heterozygous individuals. Although measurement site may modulate this association, none of the examined factors substantially explained the observed heterogeneity when considered individually. The remaining variability may reflect combinations of background characteristics that were not fully captured by single-factor analyses. Further studies accounting for background characteristics are warranted to clarify the genetic contribution of\n                      <jats:italic>ACTN3<\/jats:italic>\n                      R577X to skeletal muscle mass.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s40101-026-00439-5","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T05:44:35Z","timestamp":1785131075000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Association between the ACTN3 R577X polymorphism and skeletal muscle mass: a systematic review and meta-analysis"],"prefix":"10.1186","volume":"45","author":[{"given":"Sakura","family":"Hattori","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mika","family":"Kamiya-Saito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Kikuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Nakazato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"key":"439_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3803\/EnM.2020.35.1.1","volume":"35","author":"G Kim","year":"2020","unstructured":"Kim G, Kim JH. 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