Balkan Journal of Medical Genetics

ASSOCIATION OF RS35006907 POLYMORPHISM WITH RISK OF DILATED ARDIOMYOPATHY IN HAN CHINESE POPULATION
Yang C, Chen F, Li Sh, Zeng X,Wang Sh, Lan J
*Corresponding Author: Jianjun Lan, Panzhihua Central Hospital, Panzhihua 34# Yi kang Ave., Panzhihua 617000, People’s Rep. of China; Email: pzhzxyyxnkljj@sina.com
page: 27

DISCUSSION

In this study, we found that rs35006907 was associated with DCM in both additive and recessive models, with the C allele increasing the risk of DCM. While the association showed no statistical significance in the dominant model. Similarly, the C allele of rs35006907 was found to be related to enlarged left ventricle and reduced cardiac function. A series of functional studies demonstrated that the rs35006907-C allele displayed higher reporter gene activity and increased MTSS1 expression when compared with A allele. DCM is a life-threatening form of heart disease characterized by enlarged ventricle and reduced LVEF. Approximately 30-40% of DCM patients could be attributable to hereditary factors and classified as familial DCM [21]. The majority of DCM-associated genes were identified encoding proteins involved in sarcomere, cytoskeleton, nucleus, the nuclear lamina, and Z-disc [21]. First identified as a metastasis suppressor, MTSS1 has been demonstrated to be a scaffold protein and could regulate actin dynamic [9, 22]. Pieta et al. have demonstrated that overexpression of mouse MTSS1 (same as MIM) in NIH 3T3 cells could facilitate the formation of abnormal actin filament structures by interacting with actin monomers [15]. Similarly, the WH2 domain in the C-terminal of MTSS1 was identified as the actin-monomer binding site [15, 22]. Importantly, many studies have demonstrated the association of MTSS1 with cardiac structure and function using GWAS [17, 23], further proving the vital role of MTSS1 in heart as a scaffold protein and that the overexpression of MTSS1 is harmful. In our study, we first demonstrated higher reporter activity of rs35006907-C allele compared with the A allele. Secondly, the mRNA and protein level of MTSS1 with rs35006907-C allele were proven significantly higher than the A allele using human heart samples and lymphocytes. These results were in line with those from Michael et al. [18]. Besides, we verified the association of rs35006907 with DCM in the Han Chinese population, which is consistent with the results from Michael et al., which show the that rs35006907-C allele represented increased risk of DCM compared with A allele and MTSS1 knockout mice displayed better cardiac function when compared with wild-type mouse [18]. Finally, patients carrying the rs35006907-CC or AC genotype displayed increase LVEDD and reduced LVEF when compared with the AA genotype. In brief, our results validated the genetic association between MTSS1 and DCM in the Han Chinese population, which strongly implies the vital role of MTSS1 in pathological mechanism of DCM. Furthermore, two missense mutations in actin were found related to DCM [24], which implies that MTSS1 are most probably involved in development of DCM as its regulatory role for actin dynamic. However, the exploration of MTSS1 in the pathological mechanism of DCM was lacking, needing further investigation. One limitation of our study is that we only focus on rs35006907. Other genetic loci in strict linkage disequilibrium with rs35006907 could be the causal variants, which needs further exploration. Besides, our DCM population is limited. Although the results were in line with previous reports, additional larger studies would help verify our findings. In conclusion, our study demonstrated that rs35006907- C allele was associated with increased risk of DCM in Han Chinese population. A series of functional investigations revealed that the rs35006907-C allele represented higher activity and increased MTSS1 expression. Further understanding of the pathological mechanism and functional roles of MTSS1 in DCM may promote novel genetic therapeutic interventions involving MTSS1 in the future.

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