P172HSPA1A phenotypes and risk of cardiovascular disease

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Abstract

Purpose

HSPA1A is a serum and intracellular heat shock protein with antiapoptotic / antithrombotic properties. Possible polymorphisms of the regulatory region of HSPA1A could affect HSPA1A protein synthesis, determining diminished, normal or increased HSPA1A-producing phenotypes. The hypo-producing phenotype would entail a greater risk of developing atherosclerotic disease. The present study was made to identify SNPs in the HSPA1A regulatory region and evaluate whether any of them could affect HSPA1A synthesis in a randomly selected population which was later stratified into different groups according to the degree of vascular risk.

Methods

Serum and intragranulocytic HSPA1A was quantified by ELISA and direct Sanger sequencing performed in all subjects. An analysis was made of the association of two SNP (db rs1008438 -110A/C and db rs1043618 + 190G/C) with circulating and intragranulocytic HSPA1A and the risk of atherosclerosis. Data were analyzed using a nonparametric Mann-Whitney rank sum test or a Kruskal-Wallis test. A Chi-square test or a Fisher's exact test was used to assess the goodness-of-fit between the observed allele frequencies and the expected counterparts by Hardy-Weinberg equilibrium, and to evaluate differences in allele distributions between groups.

Results

The study population consisted of 452 randomly selected subjects, 234 females (49.95 ± 6.89 years), and 218 males (48.86 ± 7.27 years). They were stratified into three groups according to Task Force Chart Criteria: no vascular risk or risk < 5%, n=239; moderate vascular risk (10-20%) without clinical atherosclerosis, n=161; and overt atherosclerosis n=52. The greatest percentage of intragranulocytic HSPA1A hypo-producers corresponded to the subjects with the CC genotypes of -110A/C and + 190G/C SNPs. The assignment to a given vascular risk group revealed differences in the percentages of hyper-, normal or hypo-producing individuals. The CC genotype entails a risk of being a low intracytoplasmic HSPA1A producer with respect to normal production of 1.673 (95% CI 1.191-2.351, p=0.004) versus the AC genotype, and of 1.419 (95% CI 1.034-1.947, p=0.033) versus the AA genotype.

Conclusions

Based on our results, -110A/C and + 190G/C homozygous carrier status entails a risk of presenting moderate vascular risk or declared atherosclerosis – probably as a result of diminished intracellular HSPA1A synthesis and a consequent partial loss of its antiinflammatory and antithrombotic properties. In coincidence with other authors, this leads us to postulate the -110 A and + 190 G alleles as possible genetic markers of less severe clinical phenotypes

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