The putative role of the hormone-sensitive lipase gene in the pathogenesisof Type II diabetes mellitus and abdominal obesity

Impaired lipolysis has been proposed as a pathogenic factor contributing to clustering of abdominal obesity and dyslipidaemia in Type II (noninsulin-d ependent) diabetes mellitus - that is, the metabolic syndrome (MSDR). As th is syndrome clusters in families, alterations in the hormone-sensitive lipa se (HSL) gene could contribute to the genetic predisposition to MSDR. To te st this hypothesis we carried out population and intrafamily association st udies in individuals with MSDR, using a polymorphic marker (LIPE) in the HS L gene. There was a significant difference in allele frequency distribution between 235 Type II diabetic patients and 146 control subjects (p = 0.002) , particularly between 78 abdominally obese Type II diabetic patients with MSDR and the control group (p = 0.010). An extended transmission disequilib rium test (TDT) showed transmission disequilibrium of 66 alleles to 42 nond iabetic. abdominally obese offspring in families with Type II diabetes (p < 0.05). A slight difference in allele frequency distribution was seen betwe en 71 individuals from the lowest and 71 from the highest tertile of isopre naline-induced lipolysis in fat tissue (p = 0.07). NO missense mutations we re found with single-strand conformational polymorphism (SSCP) in 20 abdomi nally obese subjects with MSDR. In conclusion, our population and intrafami ly association studies suggest that the LIFE marker in the HSL gene is in l inkage disequilibrium with an allele and/or gene which increases susceptibi lity to abdominal obesity and thereby possibly to Type II diabetes.