摘要
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 sub- stitution （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.
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 sub- stitution （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.
基金
support from the Department of Emergency of Beijing Electric Power Hospital
the Department of Molecular Biology of Chinese PLA Medical School
