An association study of CASQ1 gene polymorphisms and heat stroke.

Although molecular mechanisms of heat stroke under physiological and pathological conditions have not yet been elucidated, a novel disease-associated gene encoding a calcium-binding protein, calsequestrin-1 (CASQ1), was suggested relevant based on results from a transgenic murine model. Here, we show the association between single nucleotide polymorphisms (SNPs) of CASQ1 and physiological parameters for heat stroke from a study involving 150 patients. Pooled DNA from heat stroke patients were subjected to sequencing and 3 SNPs were identified. Genotypes were assigned for all patients according to g. 175A>G, one SNP which leads to a nonsynonymous substitution (N59D) in the first exon of human CASQ1 gene. We analyzed the genotypic data with a linear model based on significance scores between SNP (175A>G) and heat stroke parameters. As a result, we found a significant association between SNP A175G and heat stroke (P<0.05). Further bioinformatics analysis of the 1-Mb flanking sequence revealed the presence of two genes that encode DDB1 and CUL4 associated factor 8 (DCAF8), and peroxisomal biogenesis factor 19 (PEX19), respectively, which might be functionally related to CASQ1. Our results showed that the blood calcium of patients with allele D increased significantly, compared to patients with allele N (P<0.05), which may result from the decreased calcium in muscle, suggesting that N59D in CASQ1 might account for the dysfunction of CASQ1 in calcium regulation during heat stroke.