Submitted to: Clinical Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/21/2001
Publication Date: 1/1/2002
Citation: LARSON, I.A., ORDOVAS, J.M., SUN, Z., BARNARD, J.R., LOHRMANN, J., FEUSSNER, G., LAMON-FAVA, S., SCHAEFER, E.J. EFFECTS OF APOLIPOPROTEIN A-IV GENOTYPE ON GLUCOSE AND PLASMA LIPOPROTEIN LEVELS. Clinical Genetics. 61:176-84,2002. Interpretive Summary: Apolipoprotein A-IV plays a role in the metabolism of triglyceride-rich lipoprotiens and of high-density lipoprotein (HDL). Apo A-IV is mainly synthesized by the intestine in response to fat absorption. We have studied the effect of two mutations in the apo A-IV gene. Apo A-IV 360 polymorphism is caused by a G --> T mutation resulting in an amino acid change from histidine to glutamine. Apo A-IV 347 polymorphism (A --> T) causes a threonie to serine substitution at amino acid position 347. Our results show that genetic variations at amino acid position 360 and 347 of the apo A-IV gene within the general population do not have a direct physiological influence on plasma cholesterol, triglyceride, LDL or HDl cholesterol levels, the ratio of TC/HDL cholesterol or apo A-IV levels. The rare allele at codon 360 was associated with higher glucose levels in women.
Technical Abstract: The effects of apolipoprotein (apo) A-IV genotype on serum glucose, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, and glucose concentrations were ascertained in a population of 373 men and 361 women with a mean age of about 57 years. Subjects were evaluated at entry into a lifestyle intervention program. Apolipoprotein A-IV genotype variations at residues 347 and 360 were examined, since these mutations affect the sequence of apo A-IV, a major protein constituent of intestinal triglyceride rich lipoprotein and HDL. With regard to the apo A-IV 360 mutation, 16.4% of the females and 13.4% of the males carried the apo A-IV 2-allele, almost entirely in the heterozygous state. No effect of the apo A-IV 1/2 genotype was observed in either men or women on total cholesterol, LDL cholesterol, HDL cholesterol, triglyceride, they total cholesterol (TC)/HDL ratio, or on A-I, A-IV, and apo B levels. This was also the case for the apo A-IV 347 mutation. Women with the apo A-IV 360 1/2 genotype had significantly (p<0.005) higher glucose levels (105.5 mg/dl) compared with the 1/1 wildtype (94.0 mg/dl). All analyses were also adjusted for age, body mass index, medications, alcohol use, and cigarette smoking. The prevalence of the 347 mutation was higher than the 360 mutation, with 29% of females and 32.0% of the males being heterozygous for this mutation, and 3.9% of the females and 5.4% of the males being homozygous for this mutation. These data are consistent with the concept that the apo A-IV 360 and 247 genotypes have no significant effect of apo A-IV levels and other lipid parameters in either gender. Apo A-IV 306 1/2 genotype did have a significant effect on serum glucose levels in women.