{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T04:28:23Z","timestamp":1787372903686,"version":"build-2736575974"},"reference-count":29,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100013995","name":"Sanofi Genzyme","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100013995","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>The GLA IVS4+919G&gt;A founder variant causes a late-onset, cardiac-predominant form of Fabry disease, yet the severity of cardiac remodeling varies markedly among affected men. We studied 167 unrelated male carriers. Genome-wide association analyses included 81 men aged \u226550 years for left ventricular hypertrophy (LVH; left ventricular mass index [LVMI] \u2265 51 g\/m2.7) and septal hypertrophy (interventricular septal thickness at end-diastole [IVSd] \u2265 1.2 cm), and 149 men with plasma globotriaosylsphingosine (lyso-Gb3) measurements. Genotyping was performed with the Axiom Genome-Wide TPM 2.0 Array. Mean LVMI increased from 34.6 \u00b1 11.3 g\/m2.7 at 20\u201339 years to 75.1 \u00b1 34.0 g\/m2.7 at \u226560 years, although substantial variability persisted within each age stratum. rs1435166 and rs2572260, located in the adjacent EGLN1\/SPRTN region, showed identical associations with LVH (both p = 4.14 \u00d7 10\u22128) and concordant genotypes in all 81 participants (dosage r2 = 1.00; D\u2032 = 1.00), indicating a single regional association signal. The association remained evident in exact testing, Firth logistic regression, and an age-adjusted continuous-LVMI analysis yielded concordant results. In the age-adjusted analysis, each rs1435166 T allele was associated with a 12.8 g\/m2.7 lower LVMI. Two intergenic variants met the exploratory threshold for septal hypertrophy, whereas no variant reached genome-wide significance for lyso-Gb3. These findings support the hypothesis that inherited genetic background contributes to variation in cardiac remodeling severity among carriers of the same pathogenic GLA variant. Independent replication, regional fine-mapping, and functional validation are required.<\/jats:p>","DOI":"10.3390\/ijms27167447","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T09:48:31Z","timestamp":1787219311000},"page":"7447","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic Modifiers of Cardiac Remodeling Severity in IVS4+919G&gt;A-Associated Fabry Cardiomyopathy"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7032-9731","authenticated-orcid":false,"given":"Kuo-Tzu","family":"Sung","sequence":"first","affiliation":[{"name":"Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan"},{"name":"Division of Cardiology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei 104217, Taiwan"},{"name":"Department of Medicine, MacKay Medical University, New Taipei City 252005, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Yen","family":"Hsu","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yung-Hsiu","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Taipei Veterans General Hospital, Taipei 112201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung-Lieh","family":"Hung","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei 104217, Taiwan"},{"name":"Institute of Biomedical Sciences, MacKay Medical University, New Taipei City 252005, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dau-Ming","family":"Niu","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan"},{"name":"Department of Pediatrics, Taipei Veterans General Hospital, Taipei 112201, Taiwan"},{"name":"Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli 350401, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/1750-1172-5-30","article-title":"Fabry disease","volume":"5","author":"Germain","year":"2010","journal-title":"Orphanet J. 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