The CYP1A2-164A→C polymorphism (CYP1A2*1F) is …
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FTO Obesity Variant Circuitry and Adipocyte Browning …
Panel A shows gene annotations and LD with array tag variant rs9930506 in a 2.5-Mb window; LD is expressed as r2 values in the CEU population. Arrows indicate the direction of transcription of annotated genes in the locus. Panel B shows chromosome conformation capture (Hi-C) interactions contact probabilities in human IMR90 myofibroblasts, revealing a 2-Mb topologically associating domain, and LD mean r2 statistics for all SNV pairs at 40-kb resolution. Panel C shows box plots for expression levels, after 2 days of differentiation, in human adipose progenitors isolated from 20 risk-allele carriers and 18 nonrisk-allele carriers, evaluated by means of a quantitative polymerase-chain-reaction analysis for all genes in the 2.5-Mb locus. The horizontal line within each box represents the median, the top and bottom of each box indicate the 75th and 25th percentile, and I bars indicate the range.
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On the basis of epigenomic annotations across 127 human cell types, we predicted the cell type in which the genetic variant was likely to act, and we validated the prediction with the use of haplotype-specific enhancer assays. We analyzed long-range chromatin interactions in the region surrounding to define potential target genes, and to validate genetic targets, we conducted an expression quantitative-trait-locus (eQTL) analysis in primary human adipocytes from risk-allele carriers and nonrisk-allele carriers. We predicted the cellular processes affected by the obesity-associated variants on the basis of correlated expression with the target genes across participants, and we validated their genetic control with the use of a trans-eQTL analysis of energy-balance genes (i.e., an eQTL analysis of energy-balance genes at large genomic distances from the locus) in adipocytes, as well as by measuring cellular phenotypes in risk-allele carriers and nonrisk-allele carriers. To examine the causal roles for the predicted target genes, we first used knockdown and overexpression of each target gene in primary human adipocytes from the subcutaneous fat of risk-allele carriers and nonrisk-allele carriers, followed by cellular phenotyping; second, we used generation of mice with a dominant negative allele of one of the target genes expressed in adipose tissue, followed by organism-level phenotyping, histologic measurements, and gene-expression profiling in major fat stores; and third, we used knockdown, overexpression, and knockout in three mouse adipocyte models.
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