Effects of obesity on the association between common variations in the TBX5 gene and matrix metalloproteinase 9 levels in Taiwanese

Yaw-Tsan Ho^a, Semon Wu^{b, c}, Ching-Feng Cheng^{d, e}, Lung-An Hsu^f, Ming-Sheng Teng^b, Ching-Hua Yeh^g, Jeng Feng Lin^g, Yu-Lin Ko^{b, e, g}

^a Department of Emergency Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
^b Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
^c Department of Life Science, Chinese Culture University, Taipei, Taiwan
^d Department of Pediatrics, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
^e School of Medicine, Tzu Chi University, Hualien, Taiwan
^f First Cardiovascular Division, Department of Internal Medicine, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan
^g Division of Cardiology, Department of Internal Medicine and Cardiovascular Medical Center, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan

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Open Access funded by Buddhist Compassion Relief Tzu Chi Foundation

Abstract

Objectives

The TBX5 gene, a member of the T-box family, is associated with congenital heart disease, electrocardiographic parameters, and development of atrial fibrillation in the general population. This study aimed to elucidate the role of TBX5 gene polymorphisms in metabolic and inflammatory profiles possibly linked to TBX5-related pathologies.

Materials and Methods

A sample population of 597 individuals having routine health examinations was enrolled. Five tagging TBX5 single nucleotide polymorphisms (SNPs) were analyzed using polymerase chain reaction and restriction enzyme digestion or TaqMan SNP genotyping assays. Associations between genotypes/haplotypes and matrix metalloproteinase 9 (MMP9) levels were investigated using generalized linear model analysis. Interactions between each genotype/haplotype, MMP9 level, and obesity status were tested using two-way analysis of variance with Golden Helix SVS Win32 7.3.1 software.

Results

After adjusting for clinical covariates, TBX5 genotypes were found to be associated with MMP9 levels (p = 0.002 and p = 0.001 for rs4113925 and rs3825214, respectively) in a dominant inheritance model. Haplotype analysis using three tag SNPs (rs11067101, rs1247973, and rs3825214) revealed a significant association between TBX5 haplotype GCG and MMP9 levels (uncorrected p = 0.0093 and the corrected false discovery rate p = 0.0435). Multivariate analysis identified that SNP rs3825214, in addition to the MMP9 and E-selectin genotypes, was independently associated with MMP9 levels (p < 0.001). Using a dominant inheritance model, subgroup and interaction analysis showed associations between the rs4113925, rs3825214, and MMP9 levels only in nonobese individuals (p = 1.04 × 10−4 and p = 7.11 × 10−5, respectively; interaction p = 0.009 and 0.018, respectively). Subgroup analysis showed a borderline significant association between haplotype GCG and MMP9 levels (uncorrected p = 0.020 and corrected false discovery rate p = 0.073), but with no evidence of interaction.

Conclusion

TBX5 genotypes/haplotypes are independently associated with MMP9 in Taiwanese individuals and occur predominantly in nonobese people. These associations may broaden our understanding of the mechanism underlying T-box family gene activity and related cardiovascular pathologies.

Keywords

Gene association study; Haplotype; Interaction; Matrix metalloproteinase 9; TBX5 gene