Metabolic syndrome, and the associated type 2 diabetes, has become an epidemic in all 'westernized'world cultures, with minority populations at the greatest risk. While considered a disease of mid-age,incidence in pediatric populations is rapidly increasing. Current risk estimates by the CDC predict thatchildren bom in 2000 will have a 50% risk of developing type 2 diabetes, with an average loss of 20 yrs ofquality adjusted life. The rapid increases are due to inactivity, and easy availability of calorie-rich food,however there are significant genetic contributions to each of the five component risk factors (bloodpressure, glycemic index, HDL, LDL, waist circumference). Identification of genetic risk factors are felt to beimportant both for understanding of the biology of predispositions, and also to enable more personalizedinterventions to targeted populations.We present preliminary data on identification of the first major metabolic syndrome risk genetic locus. A15kb haplotype was identified that contains multiple SNPs, each in evolutionary conserved regulatoryregions. Haplotype 2 simultaneously alters three regions away from evolutionary conserved ancestralsequence. Testing of 6 subject cohorts, totaling 9,200 individuals, for this haplotype shows that Haplotype 2confers protection from metabolic syndrome (relative risk RR=0.5 p<0.0001). We have found manyadditional phenotypes associated with this locus, including muscle strength, bone volume, adiposity,circulating insulin, circulating glucose, and insulin resistance. We have also shown that the componentSNPs alter enhancer and represser function differentially in bone, muscle, and fat cells.
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