The CAA Repeat Polymorphism in the ZFHX3 Gene Is Associated with Risk of Coronary Heart Disease in a Chinese Population

Abstract

Coronary heart disease (CHD) is a disease resulting from the interaction between genetic variations and environmental factors. Zinc finger homeobox 3 (ZFHX3) is a transcription factor and contains a poly-glutamine tract in a compositionally biased region that is encoded by exon 9, containing a cluster of CAG and CAA triplets followed by the polymorphic CAA repeats: (CAG)₂(CAA)₂(CAG)₃CAACAG(CAA)_nGCA_. Thus, nine successive glutamine residues precede the poly-glutamine tract, encoded by the polymorphic CAA repeats. The aim of this study was to investigate the association of the CAA repeat polymorphism in exon 9 of the ZFHX3 gene with the risk of CHD in a Chinese population. The CAA repeat polymorphism was determined by polymerase chain reaction followed by DNA sequencing in 321 CHD patients. Genotype frequencies were compared using the non-parametric mood median test. Four alleles of CAG(CAA)₁₀GCA, CAG(CAA)₈GCA, CAG(CAA)₉GCA_, and CAG(CAA)₁₁GCA were found in Chinese CHD patients in exon 9 of the ZFHX3 gene. The CAG(CAA)₁₀GCA was a major allele (95.95%), and the CAG(CAA)₈GCA was a minor allele (3.58%). The CAG(CAA)₉GCA and CAG(CAA)₁₁GCA were rare alleles (0.31% and 0.16%). The CAG(CAA)₁₀GCA allele encodes a poly-glutamine tract of 19 residues. Importantly, the CHD patients homozygous for the CAG(CAA)₁₀GCA allele had a higher risk of CHD, compared to the heterozygous patients carrying a CAG(CAA)₈GCA allele. Moreover, the CAG(CAA)₁₀GCA allele was significantly associated with hypertension, diabetes mellitus, or dyslipidemia (P < 0.05). Thus, the CAA repeat polymorphism in exon 9 of the ZFHX3 gene contributes to the CHD susceptibility in the Chinese population.