Genetic variations in the tenomodulin (TNMD) gene are associated with obesity and metabolic alterations in children in a sex-specific manner, working as a risk factor in boys while being a protective element in girls, a study has found.
Findings suggest that genetic variants of the TNMD gene could be used as early indicators of obesity and type 2 diabetes in boys.
The study, “Effects of X-chromosome Tenomodulin Genetic Variants on Obesity in a Children’s Cohort and Implications of the Gene in Adipocyte Metabolism,” was published in the journal Scientific Reports.
The TNMD gene, located in the human X chromosome, provides instructions for making a membrane protein that inhibits the formation of blood vessels. The levels of TNMD protein are usually high in tissues devoid of blood vessels, like connective tissues such as tendons and cartilage.
Previous studies have shown that TNMD is higher in the adipose tissue of obese people and that genetic variations in the TNMD gene that change its expression are associated with obesity in adults.
Here, a team of Spanish researchers assessed whether TNMD genetic variants are also linked to metabolic alterations and obesity in children.
Genetic variants is the term used to describe slightly different forms of a gene, normally caused by changes in a single DNA letter — a phenomenon called single nucleotide polymorphism (SNP). Genetic variants are the reason why humans have different eye colors, with each variant giving rise to a different color.
Scientists have demonstrated that SNPs in the TNMD gene are associated with changes in body mass index (BMI, a measure of body fat), cholesterol levels, and inflammatory factors in adults. Because the gene is located in the X chromosome, the association differs between women and men.
To address the outcomes of TNMD genetic variants in children, the researchers collected data from 915 Spanish children — 438 were boys and 477 were girls — followed at three health institutions.
Researchers found four variants with a positive association with BMI in boys, but they focused on one particular variant, called rs4828038, which they thought was a good representative of other genetic variants.
This variant was associated with central adiposity — the accumulation of fat in the lower waist — in boys, but correlated with a smaller waist circumference in girls.
In boys, the variant was also associated with higher levels of glucose during fasting and insulin resistance — a risk factor for diabetes — while in girls, it promoted low-grade inflammation.
“Such sex-specific behavior could arise from some X-chromosome particularities including differential gene dosage, the escape from the X-chromosome inactivation (XCI) and the existence of distinct genomic imprint mechanisms,” the researchers said.
To understand the association between TNMD variants and obesity, the team tested TNMD levels during adipocyte formation using adipose-derived stem cells. Adipocytes are the most common cellular constituent of fat.
They observed that TNMD levels were significantly increased in differentiated adipocytes compared with the stem cells. Reducing TNMD levels in adipocytes decreased the breakdown of fat (a process called lipolysis), impaired glucose metabolism, and increased the production of inflammatory markers such as IL1-beta and tumor necrosis factor-α.
These results suggest that genetic variants in the TNMD gene, specifically rs4828038, “are associated with obesity and alterations in glucose metabolism in children,” the researchers wrote.
“These results replicate previous findings that have been observed in adults and suggest that these markers could be potentially useful as early life risk factor indicators for obesity and the occurrence of alterations in glucose metabolism during adulthood,” the study concluded.