Single Nucleotide Polymorphisms in Sarcomeric Protein Genes: Association with Chemotherapy Induced Cardiomyopathy

Seventeen chemotherapy-induced cardiomyopathy (CM) patients and 100 volunteer blood donors (VBD) were analyzed for genetic variability in the following sarcomeric protein genes: cardiac alpha actin (ACTC); myosin light chain 2 (MYL2); myosin light chain 3 (MYL3); myosin heavy chain 7 (MYH7); myosin binding protein C3 (MYBPC3); tropomyosin 1 (TPM1); cardiac troponin I (TNNI3); and cardiac troponin T (TNNT2). No previously published mutations associated with familial CM were found in any of the subjects. No differences in the subjects and the published literature were found in the ACTC, MYL2, or TNNI3 genes. However, eight single nucleotide polymorphisms were identified in the other genes analyzed: a base change in intron 1a of TPM1; a synonymous change in exon 4 of TPM1; a base change in intron 11 of TNNT2; base changes in introns 2 and 4 of MYL3; a base change in introns 8 and 11 of MYH7; and a synonymous change in exon 31 of MYPC3. Both homozygous and heterozygous genotypes for each of these areas were identified among the subjects. Certain genotypes occurred more frequently in the CM patients and were deemed to be “skewed”, with the MYH7I8 (TT) genotype approaching statistical significance (p = 0.052). Eighty-eight percent of the CM patients had one or more “skewed” genotypes, while only 64 percent of the VBD had this genetic pattern (p = 0.032). An increasing number of “skewed” genotypes was significantly associated with cardiomyopathy. Certain genotypes did not occur at all among the CM patients, and theoretically may confer protection against chemotherapy induced toxicity. Only one subject, a woman who developed CM on trastuzumab, had the genotype MYL3I2 (T/T), MYL3I4 (C/C), MYH7I11 (CC). Additional in vitro and clinical studies are warranted to understand the phenotypic, physiologic, and clinical significances of these variabilities in the sarcomeric protein genes.