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The N363S and ER22/23EK polymorphisms of the NR3C1 gene are negatively associated with parameters of β-cell function in women, but not in men.

Genetic and biochemical studies were carried out in 96 relatives of six independently ascertained probands with familial dysbetalipoproteinemia (FD) carrying the APOE *2 (Lysl46-+Gln) allele. Compared to noncarriers, the 40 heterozygous APOE*2(Lysl46-+G1n) allele carriers exhibited markedly increased mean levels of cholesterol and triglyceride in the very low density lipoproteins (VLDL) (1.89+0.37 vs 0.30±0.27 and 1.86±0.37 vs 0.68±0.27 mmol/liter, respectively) and plasma apolipoprotein (apo)E levels (28.1+1.6 vs 4.6±1.1 mg/dl), which is characteristic for FD.By means of a pedigree-based maximum likelihood method we calculated that carrier-status accounted for 57% and 71%, respectively, of the total variance of the ratio (VLDL + IDL)-cholesterol/plasma triglyceride and plasma apoE levels. APOE*2(Lys146-+Gln) and APOE*3-Leiden allele carriers were found to differ significantly in: (a) plasma apoE levels, (b) in the amounts of triglycerides in the VLDL and VLDL + IDL fraction, and (c) in the amount of cholesterol in the VLDL and VLDL + IDL fraction relative to the amount of triglyceride in these fractions. In the APOE*2 (Lysl46-+Gln) allele carriers the VLDL and VLDL + IDL fraction is relatively rich in triglycerides as compared with that in APOE*3-Leiden carriers. We hypothesize that these two rare mutations of apoE both lead to dominantly inherited forms of FD along different underlying metabolic defects. (J. Clin. Invest. 1994.94:1252-1262.) Key words: dominant mode of inheritance * family studies -apoE3-Leiden * type m hyperlipoproteinemia

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