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{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2023,4,10]],"date-time":"2023-04-10T05:11:28Z","timestamp":1681103488227},"reference-count":68,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,4,10]],"date-time":"2023-04-10T00:00:00Z","timestamp":1681084800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["HI 865\/2-1 TRR296 TRR152 SFB1123 GRK 2816\/1 209933838 SFB1052"]},{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["01G0820 PALGER 2017-33:01DH19010"]},{"DOI":"10.13039\/501100010380","name":"Stiftung Universit\u00e4tsmedizin Essen","doi-asserted-by":"publisher"},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["101044445"]},{"DOI":"10.13039\/501100008349","name":"Universit\u00e4t Duisburg-Essen","doi-asserted-by":"publisher"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>Increased thermogenesis in brown adipose tissue might have an obesity-reducing effect in humans. In transgenic mice, depletion of genes involved in creatine metabolism results in disrupted thermogenic capacity and altered effects of high-fat feeding on body weight. Data analyses of a sex-stratified genome-wide association study (GWAS) for body mass index (BMI) within the genomic regions of genes of this pathway (<jats:italic>CKB<\/jats:italic>, <jats:italic>CKMT1B<\/jats:italic>, and <jats:italic>GATM<\/jats:italic>) revealed one sex-dimorphic BMI-associated SNP in <jats:italic>CKB<\/jats:italic> (rs1136165). The effect size was larger in females than in males. A mutation screen of the coding regions of these three candidate genes in a screening group (192 children and adolescents with severe obesity, 192 female patients with anorexia nervosa, and 192 healthy-lean controls) identified five variants in each, <jats:italic>CKB<\/jats:italic> and <jats:italic>GATM<\/jats:italic>, and nine variants in the coding sequence of <jats:italic>CKMT1B<\/jats:italic>. Non-synonymous variants identified in <jats:italic>CKB<\/jats:italic> and <jats:italic>CKMT1B<\/jats:italic> were genotyped in an independent confirmation study group (781 families with severe obesity (trios), 320 children and adolescents with severe obesity, and 253 healthy-lean controls). <jats:italic>In silico<\/jats:italic> tools predicted mainly benign yet protein-destabilizing potentials. A transmission disequilibrium test in trios with severe obesity indicated an obesity-protective effect of the infrequent allele at rs149544188 located in <jats:italic>CKMT1B<\/jats:italic>. Subsequent correlation analyses in 1,479 individuals of the Leipzig Obesity BioBank revealed distinct correlations of <jats:italic>CKB<\/jats:italic> with the other two genes in omental visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (SAT). Furthermore, between-subject comparisons of gene expression levels showed generally higher expressions of all three genes of interest in VAT than in SAT. Future <jats:italic>in vitro<\/jats:italic> analyses are needed to assess the functional implications of these findings.<\/jats:p>","DOI":"10.3389\/fgene.2023.1128133","type":"journal-article","created":{"date-parts":[[2023,4,10]],"date-time":"2023-04-10T04:28:46Z","timestamp":1681100926000},"update-policy":"http:\/\/dx.doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic variants in genes involved in creatine biosynthesis in patients with severe obesity or anorexia nervosa"],"prefix":"10.3389","volume":"14","author":[{"given":"Luisa S.","family":"Rajcsanyi","sequence":"first","affiliation":[]},{"given":"Anne","family":"Hoffmann","sequence":"additional","affiliation":[]},{"given":"Adhide
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