The septic shock associated HSPA1B1267 polymorphism influences production of HSPA1A and HSPA1B

Objective: To identify a functional polymorphic site(s) within HSPA1A and/or HSPA1B which is in linkage disequilibrium with the silent mutation HSPA1B1267A>G and explains its association with septic shock. Subjects: The promoter region of HSPA1A and HSPA1B was sequenced in 100 healthy whites. Stimulation experiments were performed on 36 healthy subjects. Measurements and results: Sequencing the HSPA1A and HSPA1B promoter regions (approx. 500 bp upstream of the translation start site) identified ten novel and three known polymorphisms. Mononuclear cells were stimulated with lipopolysaccharide (10 mug/ml) for 4 and 8 h, and mRNA levels measured by reverse transcriptase polymerase chain reaction. Two polymorphisms, HSPA1A27G>C and HSPA1A-327A>C, were found to be in strong linkage with HSPA1B1267A>G but, as with HSPA1B1267A>G, were not associated with stimulated mRNA levels. However, HSPA1B-179C>T, which is also in linkage with HSPA1B1267, was associated with stimulated HSPA1A and HSPA1B mRNA levels. Individuals homozygous for the C allele of HSPA1B-179C>T were associated with lower HSPA1A and HSPA1B mRNA levels than HSPA1B-179CT after 8 h lipopolysaccharide stimulation. Conclusions: HSPA1B-179C>T is in linkage disequilibrium with HSPA1B1267A>G and is associated with variable production of HSPA1B and HSPA1A production. This suggests that HSPA1B-179C>T affects HSP70 production and is a key determinant of individual susceptibility to a variety of infectious and inflammatory diseases.