A﻿ gene linked to diabetes and cholesterol is being called a "master regulator" gene that controls the behavior of other genes found within fat in the body, U.K. researchers found.

An examination of more than 20,000 genes in subcutaneous fat biopsies from 776 female twin volunteers in the U.K. showed an association between the KLF14 locus and the expression levels of multiple distant genes found in fat tissue, reported Kerrin S. Small, PhD, from King's College in London, and colleagues.

This finding was confirmed in a further independent sample of 600 subcutaneous fat biopsies from Icelandic subjects, researchers reported in a letter published online in Nature Genetics.

The authors wrote that while "cis regulatory patterns of gene expression have been extensively explored, the identification of trans regulatory effects in humans has attracted less attention."

Cis regulatory elements are present on the same molecule of DNA as the gene they regulate, whereas trans regulatory elements can regulate genes distant from the gene from which they were transcribed.

Scientists had already known that the KLF14 gene is linked to type 2 diabetes and cholesterol levels, but until now they didn't know how it did this or how far-reaching its control of other genes was.

"Here we show that the type 2 diabetes and high-density lipoprotein cholesterol-associated cis-acting expression quantitative trait locus (eQTL) of the maternally expressed transcription factor KLF14 acts as a master trans regulator of adipose gene expression," they wrote.

They found that genes regulated by KLF14 are highly correlated with certain metabolic traits. Furthermore, "a subset of the trans regulated genes harbor variants directly associated with metabolic phenotypes."

Having an understanding of the genetic network associated with metabolism and fat offers a way to further comprehend the overall effect the KLF14 locus has on metabolic disease risk, researchers said.

Using the samples from the twins, Small and colleagues tested the association of the single-nucleotide polymorphism (SNP) rs4731702 with KLF14. "The enrichment of rs4731702 trans associations for low P values suggests that KLF14 is a master regulator of gene expression in adipose tissue," they concluded.

"These findings indicate that the same set of SNPs (and presumably the same causal variant) underlies the cis, trans and metabolic trait associations at this locus," they added.

Researchers then focused on 10 genes associated with the SNP rs4731702. They first replicated its association with KLF14 in an independent set of adipose tissue samples.

Using another database, they obtained further support for the hypothesis that KLF14 mediates regulation of other genes. Although this database did not contain KLF14, it did contain KLF4, which has been shown to compete for the same binding sites as KLF14, and was used as a surrogate for KLF14 for this part of the study.

Having shown that the same set of SNPs influences cis expression of KLF14, trans expression of members of the genome-wide significant trans gene network, and a variety of metabolic traits including type 2 diabetes and HDL cholesterol, researchers sought to clarify the causal connections between these effects and, in particular, to establish whether or not the trans effects were likely to be mediating the metabolic associations at KLF14.

They found that six of the 10 genes were associated with body mass index and HDL cholesterol, five with triglycerides and fasting insulin levels, four with HOMA-IR (an index of insulin sensitivity), and two with fasting glucose and adiponectin levels. "Compared to all genes on the array, this represents an enrichment for expression and metabolic phenotype associations, with significance ranging from P=0.001 to P=3.3 × 10–5."

Such strong associations are consistent with a causal link between trans gene expression and metabolic phenotypes and "provide clues to the biological processes in which these genes may participate."

Next, Small and colleagues found associations of SNPs near one or more of the 10 genes that were linked with insulin-resistance-related traits such as HDL, body mass index (BMI)-adjusted waist-to-hip ratio, LDL, and triglycerides.

"This pattern of association shows that variation involving genome-wide significant trans genes has the potential to affect insulin-resistance-related traits and thereby supports the notion that a subset of these genes are directly implicated in mediating the effects of KLF14 variation on disease susceptibility," they wrote.

The authors also found that SLC7A10, which mediates transport of neutral amino acids and is highly heritable, is negatively correlated with BMI, insulin, HOMA-IR, glucose, and triglycerides and is positively correlated with HDL and adiponectin levels.

"Our data provide convincing evidence of a bona fide adipose trans eQTL and implicate this trans expression network in the link between KLF14 variation and risk of metabolic disease," the authors concluded. "This trans regulation uncovers new biological links between previously identified genome-wide significant associations at KLF14 ... and additional signals where metabolic trait associations have not yet been established to genome-wide significance."