Genetics of the Metabolic Syndrome in Japanese Americans

BACKGROUND:

Although each of the risk factors have recently been associated with increased risk of CHD and are known to be genetically influenced, none of them have been investigated in a large sample of American families of Japanese ancestry. The project represents a unique and timely opportunity to characterize the genetic epidemiology of CHD risk factors among Japanese Americans. The findings could lead to the development of effective preventive strategies targeted to subgroups of individuals with high risk due to underlying genetic susceptibility.

DESIGN NARRATIVE:

In the original study, several hypotheses were tested, including: 1) that a predominance of small LDL particles (ALP phenotype B), as determined by gradient gel electrophoresis, was inherited as a single gene trait in Japanese-American kindreds and to compare these results with previous studies in Caucasian families; 2) that ALP-B was associated with risk factors characteristic of the insulin resistance syndrome and NIDDM among individual Japanese-American family members. 3) that plasma levels of Lp(a) were inversely associated with apo(a) size phenotypes, as determined by high- resolution SDS-agarose-gel electrophoresis followed by immunoblotting, in individual Japanese-American subjects, and to compare and contrast these associations with those previously reported in Caucasians and other ethnic groups; 4) that in addition to apo(a) gene effects, the segregation of plasma levels of Lp(a) in families was nherited consistent with the presence of another single major gene effect. The study also established a repository of frozen white cells for future genetic studies of candidate genes associated with risk of CHD in Japanese Americans. These hypotheses were all tested based on blood samples, blood pressure and anthropometric measurements, and questionnaire data from 33 Japanese-American kindreds identified through participants in the ongoing Japanese-American Community Diabetes Study in Seattle. The kindreds consist of 126 nuclear families and 443 individual family members, including probands, siblings, spouses, offspring and nieces and nephews of full Japanese descent.

In 1998, the renewal has three specific aims. The first aim was to identify genetic influences on the risk factors that characterize ther metabolic insulin resistance syndrome (including fasting insulin, proinsulin, C-peptide and glucose; body weight and waist circumference; lipoproteins; blood pressure; fibrinogen; factor VII and plasminogen activator inhibitor. Statistical genetic analysis approaches used in the first aim included univariate complex segregation analysis, factor analysis, and quantitative multivariate genetic analysis. The second specific aim was to test for genetic linkage between specific candidate genes involved in lipid metabolism, carbohydrate metabolism, blood pressure, obesity, and hemostasis with genetically influenced risk factors of the metabolic syndrome in Japanese-Americans. The third specific aim was, when the DNA repository had been completed (750 samples by the end of year four), to apply to the NHLBI Mammalian Genotyping Service to perform a whole genome screen to identify new genes involved in susceptibility to the metabolic syndrome.