A functional polymorphism in the promoter region of the microsomal triglyceride transfer protein (MTP-493G/T) influences lipoprotein phenotype in familial hypercholesterolemia

The microsomal triglyceride transfer protein (MTP) has a key function in in tracellular apolipoprotein (apo) B lipidation and secretion of very low den sity lipoprotein (VLDL). A recently discovered functional polymorphism in t he promoter of the MTP gene (-493G/T) affects the plasma concentration of l ow density lipoprotein (LDL) cholesterol and the VLDL distribution between large and small particle species in healthy men. This phenotype is likely t o be explained by an effect on VLDL synthesis. Against this background, we studied the effect of the MTP-493G/T polymorphism in a large cohort (217 me n and 211 women) with heterozygous familial hypercholesterolemia (FH). A 40 % to 50% lower serum triglyceride level was observed in homozygous carriers of the MTP-493 T allele (T/T, 0.93 +/- 0.34; G/T, 1.53 +/- 1.40; and G/G, 1.56 +/- 1.24 mmol/L; T/T vs G/T P = 0.04, T/T vs G/G P = 0.02). In contras t to the situation in healthy subjects, the MTP promoter polymorphism did n ot have a significant effect on the LDL cholesterol levels in FH subjects, although the same trend was observed (T/T, 7.31 +/- 1.87; G/T, 7.80 +/- 2.1 2; and G/G, 7.91 +/- 2.31 mmol/L, NS). Adjustment for the apo E gene polymo rphism by inclusion of subjects homozygous for the apo E3 allele only revea led a reciprocal high density lipoprotein cholesterol-elevating effect (T/T , 1.41 +/- 0.73; G/T, 1.18 +/- 0.27; and G/G, 1.16 +/- 0.29 mmol/L; T/T vs G/T P = 0.06, T/T vs G/G P = 0.04), This effect seemed to be sex-specific b ecause it was accounted for by the female patients. In conclusion, the LDL cholesterol-lowering effect of the rare MTP gene promoter variant (MTP -493 T) present in healthy subjects is shifted to a triglyceride-lowering effect in FH. These data suggest that the MTP gene has a role in modulating the c linical phenotype of FH.