Genetics of the Metabolic Syndrome

Hospital Physician October 2006 51 Metabolic syndrome is one of the fastest growing health problems worldwide. It is a major risk factor for both diabetes mellitus1 and cardiovascular disease (CVD).2 The etiology is complex, determined by the interplay of both genetic and environmental factors (Figure).3 It is characterized by the clustering of multiple metabolic abnormalities, including abdominal obesity, hypertension, dyslipidemia, insulin resistance, and impaired glucose tolerance.4 This clustering has been referred to as syn­drome X, the deadly quartet, and the in­sulin­ resistan­ce syn­drome. The term in­sulin­ resistan­ce syn­drome was widely used until 1998, when the World Health Organization proposed a unifying definition for the syndrome and chose to call it metabolic syn­drome. In the United States, approximately 25% of the adult population (age > 20 years) and up to 45% of those older than 50 years meet the National Cholesterol Education Program’s Adult Treatment Panel III (NCEP/ ATP III) diagnostic criteria for the metabolic syndrome.5 Metabolic syndrome has a higher prevalence in men. Prevalence varies substantially among ethnic groups, with the highest rate in Mexican-American women.6 Due to the increasing prevalence of obesity, the prevalence of metabolic syndrome continues to increase. An apparent paradox has been observed in African Americans. Although African Americans have a higher prevalence of obesity and hypertension compared to whites, they have a lower prevalence of metabolic syndrome.6 Compared with whites, African-American men have a lower incidence of large waist circumference, high triglyceride levels, and low high-density lipoprotein (HDL) cholesterol levels, and a higher incidence of hypertension and diabetes6; African-American women have a higher frequency of large waist circumference, diabetes, hypertension, and hyperglycemia and a lower frequency of high triglyceride levels. The net result is that by the NCEP/ATP III criteria, the prevalence of metabolic syndrome in African-American men is half that observed in white men, and in African-American women the prevalence is 30% less than that of white women. These differences persist even after adjusting for contributing factors, such as age, body mass index (BMI), smoking and drinking habits, socioeconomic status, and physical inactivity as well as menopausal status among women. The ethnic differences strongly suggest a genetic component in the pathogenesis of metabolic syndrome. This manual, the seventh part in a series on the metabolic syndrome, reviews candidate genes involved in metabolic syndrome and discusses genetic approaches to understanding the genotype/ phenotype interactions in this syndrome. C l i n i c a l R e v i e w A r t i c l e