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Type 2 diabetes‐associated fatty acid binding protein 2 promoter haplotypes are differentially regulated by GATA factors
Author(s) -
Klapper Maja,
Böhme Mike,
Nitz Inke,
Döring Frank
Publication year - 2008
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20618
Subject(s) - biology , fatty acid binding protein , haplotype , type 2 diabetes , genetics , gene , diabetes mellitus , endocrinology , genotype
The human intestinal fatty acid binding protein 2 (FABP2) mediates fat absorption by binding and intracellular trafficking of long‐chain free fatty acids. Studies with knockout mice and association analysis of polymorphisms revealed that FABP2 is a susceptibility gene for type 2 diabetes (noninsulin dependent diabetes mellitus [NIDDM]) and related traits. Relevant FABP2 promoter polymorphisms c.–80_–79insT (rs5861422), c.–136_–132delAGTAG (rs5861423), c.–168_–166delAAGinsT (rs1973598), c.–260G>A (rs6857641), c.–471G>A (rs2282688), and c.–778G>T (rs10034579) result in two haplotypes A and B, whereby B possesses two‐ to three‐fold lower transcriptional activity than A. We show in luciferase reporter gene assays by a series of chimeric FABP2 promoter constructs in intestinal Caco‐2 cells that polymorphism c.–80_–79insT essentially determines different activities of the FABP2 promoter. In accordance, in electrophoretic mobility shift assays (EMSAs), transcriptional factors GATA‐5 and ‐6 bind with higher binding affinities to the FABP2 promoter region containing the −80A allele compared to B. As functional consequence, haplotype A is twice as much more activated by GATA factors than haplotype B in liver Huh7 cells. Additionally, a construct bearing the −80B allele in the background of haplotype A reversed the activity from A to B. Thus, the GATA mediated differential activation of FABP2 haplotypes depends on polymorphism c.–80_–79insT. This provides the molecular basis for the variant specific transcriptional regulation of the diabetes type 2–associated FABP2 gene. Hum Mutat 29(1), 142–149, 2008. © 2007 Wiley‐Liss, Inc.