The evidence of polymorphisms of the liver X receptor gene as a DNA-based biomarker for susceptibility to coronary artery disease in a Japanese population

抄録

Coronary artery disease (CAD) is a multifactorial and polygenic disorder, which arises due to atherosclerosis of the coronary arteries. Both numerous genetic factors and environmental risk factors may contribute to the pathogenesis of atherosclerosis. Thus, in order to identify the genetic determinants of CAD, an association of genetic polymorphisms of the liver X receptoralpha (NR1H3) and -beta (NR1H2) genes with susceptibility to CAD was examined in a Japanese population. Eight tag single nucleotide polymorphisms (SNPs) in NR1H3 and NR1H2 were analyzed by PCR-restriction fragment length polymorphism or PCR-direct DNA sequencing method in 143 Japanese patients with CAD and 164 healthy control subjects with normal coronary arteries. Subsequently, haplotypes composed of the two tag SNPs in NR1H2 were constructed. Significant differences in the clinical risk factors, dyscholesteremia and diabetes mellitus, were observed between CAD patients and controls (P = 0.040 and P = 0.005, respectively). The frequencies of a C allele in the multiplicative model and its homozygous C/C genotype in the recessive model at rs2279238 in NR1H3 were significantly higher in CAD patients as compared to those in controls (P = 0.039 and P = 0.016, respectively). Furthermore, the frequency of a Hap 4/any diplotype of NR1H2 was significantly higher in CAD patients in comparison to controls (P = <0.0001, OR = 17.16). Multivariate logistic regression analysis revealed that these polymorphisms, dyscholesteremia, and diabetes mellitus independently contributed to susceptibility to CAD. In conclusion, NR1H3 and NR1H2 appears to be the genetic determinants of CAD. Furthermore, the genetic polymorphisms of NR1H3 and NR1H2 may be useful as new DNA-based diagnostic biomarkers for identifying high-risk individuals susceptible to CAD.