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Regulation of alternative splicing in human obesity loci
Author(s) -
Kaminska Dorota,
Käkelä Pirjo,
Nikkola Elina,
Venesmaa Sari,
Ilves Imre,
Herzig KarlHeinz,
Kolehmainen Marjukka,
Karhunen Leila,
Kuusisto Johanna,
Gylling Helena,
Pajukanta Päivi,
Laakso Markku,
Pihlajamäki Jussi
Publication year - 2016
Publication title -
obesity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.438
H-Index - 199
eISSN - 1930-739X
pISSN - 1930-7381
DOI - 10.1002/oby.21587
Subject(s) - rna splicing , alternative splicing , obesity , human obesity , medicine , genetics , medline , computational biology , biology , bioinformatics , gene , exon , rna , biochemistry
Objective Multiple obesity susceptibility loci have been identified by genome‐wide association studies, yet the mechanisms by which these loci influence obesity remain unclear. Alternative splicing could contribute to obesity by regulating the transcriptomic and proteomic diversity of genes in these loci. Methods Based on a database search, 72 of the 136 genes at the 13 obesity loci encoded multiple protein isoforms. Thus, alternative splicing of these genes in adipose tissue samples was analyzed from the Metabolic Syndrome in Men population‐based study and from two weight loss intervention studies (surgical and very low calorie diet). Results Alternative splicing was confirmed in 11 genes with PCR capillary electrophoresis in human subcutaneous adipose tissue. Interestingly, differential splicing of TRA2B, BAG6, and MSH5 was observed between lean individuals with normoglycemia and overweight individuals with type 2 diabetes. Of these genes, we detected fat depot‐dependent splicing of TRA2B and BAG6 and weight loss‐induced regulation of MSH5 splicing in the intervention studies. Finally, body mass index was a major determinant of TRA2B, BAG6, and MSH5 splicing in the combined data. Conclusions This study provides evidence for alternative splicing in obesity loci, suggesting that alternative splicing at least in part mediates the obesity‐associated risk in these loci.