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Common Allele Linked to Sugar Consumption Leads to Lower Body Fat, Higher Blood Pressure

NEW YORK (GenomeWeb) – A common allele in the FGF21 gene affects the macronutrients people tend to eat and is associated with lower body fat, but high blood pressure.

FGF21 is a hormone secreted by the liver that sends a signal to the brain to suppress sugar and alcohol consumption, while also stimulating glucose uptake and acting as an insulin sensitizer. Because of this, it has been pursued as the basis of obesity and type 2 diabetes treatments.

Researchers led by the University of Exeter Medical School's Andrew Wood studied the effect of a common FGF21 allele in more than 451,000 people from the Biobank UK study. They theorized that by examining its effects, they could identify potential adverse as well as beneficial effects of therapies that target FGF21. This common allele, they reported today in Cell Reports, was linked to increased consumption of carbohydrates, higher blood pressure, and higher waist-to-hip ratio, but lower body-fat percentage and no effect on type 2 diabetes.

"[H]uman genetic association data provide further insight into the potential multiple metabolic effects of FGF21 and have hypothesis-generating implications for the development of therapies targeting FGF21," Wood and his colleagues wrote.

The FGF21 rs838133 variant has previously been linked to macronutrient intake, coffee and alcohol consumption, and smoking. In this study using a food frequency questionnaire filled out by 176,994 UK Biobank participants and their genetic data, the researchers also found that each copy of the minor A allele was linked to higher carbohydrate and alcohol intake and lower fat and protein intake. The same effect, the researchers said, has been reported in animal models, including non-human primates.

Among the 451,099 UK Biobank participants of European ancestry, the minor rs838133 allele was linked to lower body fat percentage. Lower body fat is typically associated with a lower waist-to-hip ratio, but here the researchers reported that the allele is linked to a higher waist-to-hip ratio, after adjusting for body mass index.

At the same time, the A allele was associated with higher blood pressure, hypertension, and use of blood pressure medication as well as with higher LDL cholesterol and gamma-glutamyl transpeptidase. It was also linked to lower alkaline phosphatase levels. However, the researchers noted no association with coronary artery disease or type 2 diabetes.

The largest effect, the researchers reported, was with systolic blood pressure, as each A allele raised it by 0.29 mm Hg.

Wood and his colleagues also conducted a phenome-wide association study to further test links between the rs838133 allele and 82 traits and behaviors captured within the UK Biobank dataset. In addition to what they'd already found, they noted an association between the allele and evening chronotype, lower physical activity, and lower birth weight. They noted no associations with bone mineral density or reproductive traits.

The researchers added that the A allele likely leads to decreased FGF21 function as it is strongly linked to higher sugar and alcohol preference in people, which would be consistent with the effects of pharmacologically lowering FGF21 in animal models. However, they noted no association with the allele and FGF21 gene expression in the liver, though they said the allele's effects could be subtle.

Their findings also provide a number of hypotheses for the therapeutic effects of FGF21, including that targeting it might not benefit people with type 2 diabetes and that it might have a larger effect on body-fat percentage and weight distribution than on overall weight, the researchers said.

They also noted their study has a number of limitations, including that there is no direct experimental evidence that the variant alters FGF21 gene expression or function.