Although the genetic determinants of the individual risk factors involved in the metabolic syndrome are reasonably well-understood, the causal genetic factors that unite them—resulting in manifestation of the disorder—are unknown. To identify such a factor, Arya Mani and colleagues looked for families with many affected members and the presence of early-onset disease. Three large families in southwest Iran were identified with co-inheritance of early-onset CAD, type 2 diabetes mellitus, abdominal obesity, hypertension and elevated levels of serum triglycerides—satisfying the criteria of the metabolic syndrome. Due to the low prevalence of CAD and obesity in the local community, the families were considered to be outliers. The researchers first performed linkage analysis on DNA samples from affected members of the three families and identified chromosome region 19q13 as being linked to CAD, abdominal obesity, hypertension and type 2 diabetes mellitus. All three families shared common genetic markers within the linkage region, suggesting a common ancestry of the families and the existence of a founder mutation for the metabolic syndrome.
Next, the researchers used whole-exome sequencing to identify protein-altering genetic variants within affected members of the three families. Of the 18 rare variants identified, only one—causing an Arg102Cys mutation in DYRK1B—mapped to chromosome region 19q13, segregating with the metabolic syndrome phenotype in affected members of all three families. Specificity of the Arg102Cys mutation for the metabolic syndrome was confirmed by its absence in DNA samples obtained from unaffected family members and unrelated controls (2,000 ethnically matched Iranian individuals, 3,600 white US individuals and 2,500 individuals of diverse ethnic backgrounds).
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