Abstract 3452: Impact of Upstream Transcription Factor 1 Gene Variant on Genetically Confirmed Familial Hypercholesterolemia (K790X)
Objective: Lipid profiles of patients with familial hypercholesterolemia (FH) are sometimes heterogeneous even with same LDL-receptor mutations, and other genetic backgrounds may affect them. Upstream transcription factor 1 gene (USF1) is a most promising genetic background for familial combined hyperlipidemia (FCHL), and major allele of its 3′UTR variant usf1s1 (rs3737787) and functional intronic variant usf1s2 (rs2073658) have been shown to link with FCHL phenotypes in many ethnic groups. Therefore, we investigated clinical influences of USF1 polymorphism in coronary high-risk patients including genetically confirmed FH.
Methods: A total of 99 FH patients (M/F=51/48) with LDL-receptor K790X mutation, and 210 patients (M/F=122/88) with suspected coronary artery disease with ischemic findings or multiple coronary risk factors (CAD group) were enrolled to genotype usf1s1/2, and to analyze metabolic profiles. In CAD group, 50 patients were diagnosed as FCHL. Coronary stenosis index (CSI) was evaluated with angiography in 23 patients in FH group and in 113 patients in CAD group. Also 250 general males were genotyped as control group.
Results: Usf1s1 and usf1s2 were in perfect linkage disequilibrium as reported in other ethnic groups. The frequencies of major allele were 0.84 in FH, 0.71 in CAD group, and 0.78 in control group (ns). In CAD group, usf1s1/2 major allele homozygotes showed higher apo-B (137 ± 27 vs. 128 ± 33 mg/dl, p<0.05), higher LDL-C (159 ± 54 vs. 146 ± 52 mg/dl, p<0.05), higher HOMA-IR (2.17 ± 1.53 vs. 1.57 ± 1.30, p<0.01), and higher CSI (15 ± 11 vs. 11 ± 9, p<0.05) than minor allele carriers. FCHL was more frequent in major allele homozygotes than in minor allele carriers (24% vs. 19%, ns). In FH group, major allele homozygotes showed higher TG (153 ± 106 vs. 106 ± 70 mg/dl, p<0.05), lower HDL-C (48 ±16 vs. 56 ± 17 mg/dl, p<0.05), and tendencies for higher CSI (15 ± 9 vs. 10 ± 8, ns) and higher apo-B/LDL-C ratio (0.72 ± 0.13 vs. 0.65 ± 0.14, ns). But no differences were observed in LDL-C and apo-B levels in FH group, probably because of their extremely high levels.
Conclusion: Usf1s1/2 were associated with advanced coronary atherosclerosis in coronary high-risk patients, and worsen lipid profiles even in genetically confirmed FH patients.