Metabolic Syndrome, a combination of high blood pressure, being over-weight, and diabetes, affects millions of people. A new study finds that the casual link between these three conditions is, instead, genetic. That also lends focus to obesity being genetic, rather than just eating too many calories, and may well lead to new treatment approaches to the Syndrome.

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Endocrinology

Metabolic Syndrome: Genetic Trigger?

Published: May 14, 2014 | Updated: May 14, 2014

By Crystal Phend, Senior Staff Writer, MedPage Today

 

 

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Genetic mutations causing an inherited form of the metabolic syndrome have been found, with implications for drug development across diabetes, heart disease, and obesity.

A substitution error in the gene DYRK1B tracked exactly with early-onset coronary artery disease, abdominal obesity, hypertension, and type 2 diabetes running in three large families in Iran, Arya Mani, MD, of Yale, and colleagues found.

A second substitution mutation in the same gene was found in affected, but not unaffected, members in a fourth family of a different ethnic background, the group reported in the May 15 issue of the New England Journal of Medicine.

The specific mutations found are likely rare, but genome-wide association studies have also linked DYRK1B to type 2 diabetes and traits associated with the metabolic syndrome, which may implicate common variants in the general population, the group noted.

While there have been plenty of causative mutations found for individual cardiovascular risk factors, that hadn't been the case for susceptibility genes for clusters of cardiovascular risk traits, such as those in the metabolic syndrome, the researchers noted.

Approximately 3% to 4% of the population may carry these mutations impacting metabolic syndrome risk, Mani predicted, although there does appear to be an interaction with environment.

Now with these results, it's time for a search into mechanisms that could be exploited to treat the whole gamut, he told MedPage Today.

"With a single drug, one may actually find treatment for different metabolic risk factors, such as high blood pressure, in certain instances, and hypercholesterolemia and reduce the risk for coronary artery disease and diabetes," he said.

There are broader implications for how we view obesity too, Chin Jou, PhD, a science historian at Harvard, wrote in an accompanying editorial.

"These studies, of course, reinforce what some physician-researchers have been insisting for more than a century: that obesity is innate, that weight regulation is not governed by a uniform tally of 'calories in-calories out,' and to quote Jules Hirsch, that 'there is a biochemical or basic biological element in what it is that we call 'willpower,'" she wrote.

That's not a view shared by the majority of Americans, Jou noted.

He cited a 2012 online poll by Reuters and the market research firm Ipsos that found 61% of U.S. adults believed that "personal choices about eating and exercise" were responsible for the obesity epidemic.

While they, "it seems, remain unaware of or unconvinced by scientific research suggesting that 'personal choices' may not account for all cases of obesity," she noted, "...weight is clearly far from being entirely within an individual's control. Genetic predispositions, in tandem with the development of food environments that facilitate overeating and built environments requiring minimal energy expenditure, may help explain why so many Americans are obese today."

The study examined three unrelated families in a community in southwest Iran on the basis of an "unusual constellation" of juvenile-onset abdominal obesity and other aspects of the metabolic syndrome.

"These families were considered to be outliers because of the low prevalence of early-onset coronary artery disease and obesity in the local community," Mani's group noted.

In these families, 25 members (21 with genetic samples) had the metabolic syndrome not explained by neurohormonal activation and early-onset myocardial infarction or coronary artery disease. Onset was at a mean age of 45 in men and 44 in women.

Each of them had a mutation substituting cysteine for arginine at position 102 in the highly conserved kinase-like domain of DYRK1B, the gene encoding dual-specificity tyrosine-phosphorylation-regulated kinase 1B.

None of the 12 unaffected family members had the mutation, dubbed R102C.

Nor was the mutation found in 2,000 DNA samples from ethnically-matched Iranian controls, 3,600 U.S. white controls, 2,500 persons of diverse ethnic backgrounds in the Allele Frequency Database (ALFRED), 5,000 exomes from the Yale Center for Genome Analysis database, or 5,400 exomes in the NHLBI ESP5400 database.

Linkage analysis and whole-exome sequencing showed that all three affected families shared identical haplotype markers, "indicative of their common ancestral origin," although no family member was homozygous for this haplotype.

"In each family, affected members could trace their descent from a common ancestor," the researchers noted. "The familial clustering and pattern of inheritance of these clinical features were consistent with the effect of a highly penetrant autosomal dominant trait and suggested that the affected family members might share a common founder mutation."

Functional characterization of the disease gene revealed that normally the "nutrient-sensing" protein encoded by DYRK1B boosts fat formation via inhibition of the SHH (sonic hedgehog) and Wnt signaling pathways.

The gene also appeared to kick up generation of glucose by increasing expression of the key enzyme glucose-6-phosphatase.

The R102C mutation discovered in the families was a gain-of-function allele that boosted both effects.

"Our findings suggest that DYRK1B plays a central role in the biologic pathways that are disrupted in the disorder known as the metabolic syndrome," the researchers concluded.

No other genetic variant was found in more than five affected family members, and some were found in unaffected members.

The study was funded by the National Institutes of Health.
Mani disclosed NIH grant support but no relevant relationships with industry.
Jou disclosed no relevant relationships with industry.