Skip to main content
Premium Trial:

Request an Annual Quote

Linkage Analysis, Exome Sequencing Uncover Novel Variants Associated with Metabolic Syndrome

NEW YORK (GenomeWeb News) — Through both linkage analysis and whole-exome sequencing, an international team of researchers has linked mutations in the protein kinase DYRK1B gene to metabolic syndrome.

As reported yesterday in the New England Journal of Medicine, the team led by Yale University's Arya Mani studied three families with members who inherited a suite of metabolic-related disorders, including early onset cardiovascular disease, obesity, hypertension, and diabetes. Through a linkage analysis, the team homed in on a region of chromosome 19q13 associated with the syndrome, and subsequent exome sequencing uncovered a novel variant in DYRK1B present in all affected family members.

"[W]e found that mutations in DYRK1B are associated with a clinical phenotype that is characterized by central obesity, hypertension, type 2 diabetes, and early-onset coronary artery disease," Mani and his colleagues wrote in their paper. "Our findings suggest that DYRK1B plays a central role in the biologic pathways that are disrupted in the disorder known as metabolic syndrome."

Metabolic syndrome, which is marked by increased risk of heart disease, stroke, and diabetes, may affect some 47 million people in the US, according to the American Heart Association. By focusing on three families with a pattern of disease, the researchers sought to identify rare mutations linked to the phenotype and tease out biological processes involved in the disorder.

Mani and his colleagues focused in particular on three families in southwest Iran with metabolic syndrome, presenting symptoms that were largely absent in the rest of the community and seemed to follow an autosomal dominant inheritance pattern. The researchers collected DNA samples from 21 living family members with early onset coronary heart disease, two with central obesity, hypertension, and diabetes, and five unaffected family members.

Through a genome-wide linkage analysis drawing on data obtained using Illumina's HumanOmni10Quad BeadChips, the researchers linked a stretch of chromosome 19q13 to the disorder. All three families, they noted, had identical markers across a 6.1-megabase pair haplotype region of chromosome 19q13. Additionally, all affected family members were heterozygous for the hapolotype; no one was homozygous for it.

Then, turning to the exomes of two index patients from two of the families, the researchers narrowed in on a potential causal variant. After capturing exome DNA from the patients using the Sequence Capture Human Exome 2.1 M Array from Roche NimbleGen, the researchers sequenced those libraries on the Illumina Genome Analyzer. From this, they pinpointed a novel variant in DYRK1B, a gene that encodes dual-specificity tyrosine-phosphorylation-regulated kinase 1b.

DYRK1B is part of the Dyrk family of proteins that are involved in cell differentiation, survival, and proliferation, and is expressed ubiquitously in both mice and humans, the researchers said. Its expression, though, also increases during adipogenic differentiation.

This variant, the researchers noted, swaps a cysteine for arginine at position 102, a spot that is highly conserved in species from lizards to people. The R102C variant, they added, was absent in samples from 2,000 ethnically matched Iranians and 3,600 white controls in the US. Additionally, it was not found in some 2,500 ethnically diverse samples included in the Allele Frequency Database, nor was it in the 5,000 samples at the Yale Cancer for Genome Analysis database or in the 5,400 exomes of the NHLBI ESP5400 database.

Both PolyPhen-1 and PolyPhen-2 predicted this variant to be deleterious, Mani and his colleagues added.

In 3T3-L1 preadipocyte cell lines, they examined how non-mutant DYRK1B, DYRK1B R102C, and shRNA knockdown of DYRK1B affected adipogenic differentiation.

Overall, the researchers found that total expression levels of non-mutant DYRK1B and DYRK1B R102C were similar, but that intracellular lipids accumulated faster in cells expressing DYRK1B R102C than the non-mutant form or the empty control vector. Further, cells expressing DYRK1B R102C had lower Wnt signaling than non-mutant-expressing cells or controls, and cells expressing the mutant DYRK1B could transform into mature adipocytes, even without any addition of adipogenic medium.

DYRK1B also affects the induction of glucose-6-phosphatase, an important gluconeogenic enzyme, the increased expression of which has been linked to higher fasting glucose levels in people with type 2 diabetes. Using a luciferase reporter assay, Mani and his colleagues found that the DYRK1B R102C mutant dramatically potentiated the induction of glucose-6-phosphatase, which they confirmed through mRNA and protein level analysis. They noted that this appears to represent a dose-dependent and gain-of-function effect of the R102C mutant.

The researchers also screened an additional 300 morbidly obese white patients with coronary artery disease and multiple metabolic phenotypes for this DYRK1B R102C allele. From this, however, they identified another novel DYRK1B allele — H90P — in five unrelated patients. After examining one carrier's family, they noted that this novel allele also co-segregated with metabolic syndrome and followed an autosomal dominant pattern.

"These results show that rare alleles may underlie an association with a cluster of metabolic risk factors of coronary artery disease known as the metabolic syndrome," Mani and his colleagues said.

Additionally, they noted that their findings raised the possibility that common variants in DYRK1B may also be associated with metabolic syndrome traits in the general population.

The Scan

Steps for Quick Review

The US Food and Drug Administration is preparing for the quick review of drugs and vaccines for the Omicron variant, according to the Wall Street Journal.

Moving Away From Using Term 'Race'

A new analysis finds that geneticists are using the term "race" in their papers less than in years past, as Science reports.

Point of the Program

The Guardian writes that some scientists have called the design of a UK newborn sequencing program into question.

Science Papers Present Multi-Omic Analysis of Lung Cells, Regulation of Cardiomyocyte Proliferation

In Science this week: a multi-omic analysis of lung cells focuses on RIT1-regulated pathways, and more.