The most noteworthy finding of this study was a positive association between the haplotype constructs of three studied variants and natural longevity in Uygur ethnicity, although no significance was observed in a single-locus analysis. Furthermore, this positive association was strengthened by interaction analysis, which suggests that G190C and T2437C variants might have an interacting effect on longevity. This is the first study to report the interactive association of Hsp70 gene variants with natural longevity in Chinese.

Since the study relating Hsp70 family variants with longevity was first reported by Altomare et al in an Italian population, many studies provide support for the involvement of Hsp70 genes in the long period of surviving. A study by Ross et al observed an increased frequency of the 2437 T allele (83.3%) of HSPA1L in an aged Irish population, which was almost equal to that (82.2%) in the current study. However, our results failed to find a significant association of 2437C allele with longevity, which was not in line with the results of Ross et al.

The MDR, which is nonparametric and genetic model-free in design, is widely believed to be an analytical data-mining method to facilitate the identification of complex genetic interactions. Moreover, this method has been successfully applied to detect and characterize gene-gene andDrosophila is caused by histone deacetylase inhibitors. J Exp Biol; : Morrow G, Samson M, Michaud S, Tanguay RM. Overexpression of the small mitochondrial Hsp extends Drosophila lifespan and increases resistance to oxidative stress. FASEB J; : Song HO, Lee W, An K, et al. C. elegans STI, the homolog of Sti/Hop, is involved in aging and stress response. J Mol Biol; : Jiang W, Qiu C, Cheng Z, et al. Correlation between haplotype of apolipoprotein B gene and natural longevity persons in Uygur nationality. Sci China C Life Sci; : W R, Wan K, Che M, et al. Analysis of heat-shock protein gene polymorphisms and the risk of Parkinson's disease. Hum Genet; : Putics A, Vegh EM, Csermely P, Soti C. Resveratrol induces the heat-shock response and protects human cells from severe heat stress. Antioxid Redox Signal; : Kletsas D, Pratsinis H, Gioni V, Pilichos K, Yiacoumettis AM, Tsagarakis S. Prior chronic in vivo glucocorticoid excess leads to an anabolic phenotype and an extension of cellular lifespan of skin fibroblasts in vitro. Ann NY Acad Sci; : Vital Statistics Governmental Department of State Statistics Bureau, ed. Annual report forms of China vital statistics. Beijing: China Statistics Publishing Company, : Altomare K, Greco V, Bellizzi D, et al. The allele (A)(-) in the promoter region of the HSP- gene is unfavorable to longevity in women. Biogerontology; : Ross OA, Curran MD, Crum KA, Rea IM, Barnett YA, Middleton D. Increased frequency of the T allele of the heat shock protein -Hom gene in an aged Irish population. Exp Gerontol; : REFERENCES Fig 2. Comparison of the promoter activity of the alleles of G190C polymorphism using HSPA1A 5-flanking 488 bp fragment. The promoter activity was examined using a luciferase reporter system in human lung carcinoma A549 cells. The data are expressed as mean 6 SD of 5 independent experiments. The blank and grid bars indicate the control and heat-inducible levels of luciferase activities expressed as percentages of the activity of G190C alleles. RLA, the ratio of firefly luciferase activity to Renilla luciferase activity. To overcome the small sample size in this study, although some underlying limitations of this method, such as computational intensiveness, indistinct interpretation, lack of sensitivity, and heterogeneity-free assumption as summarized by Manuguerra et al.24 Using MDR, we identified a strong 2-locus interaction between G190C and T2437C variants. In view of both haplotype and interaction results, we refer that the genetic framework within these 2 variants confers a predisposition to longevity in the presence of only 1 minor allele (190 G-2437C and 190C-2437 T) for these 2 variants, whereas the 2 minor allele combination (190C-2437C) is unfavorable for longevity. This might indicate the existence of interaction because the coexistent minor alleles have the opposite role with only 1 minor allele. Unfortunately, in the current study, we failed to find any significance in the promoter activity of HSPA1A for G190C alleles. It is possible that G190C variant can be considered a possible marker in linkage disequilibrium with another functionally relevant variant interacting with T2437C in affecting structure or expression of Hsp70 genes. However, because of the complexity of genetic interaction in human longevity, a decision must not be made until functional studies confirm or refute these findings. In sum, we demonstrated a strong interaction of the 3 studied variants in Hsp70 family with natural longevity in the Xinjiang Hetian Uygur population. Independent replication in other populations and subsequent functional validation are also required to confirm and inter- Singh R, Klvraa S, Bross P, et al. Heat-shock protein genes and human longevity: a view from Denmark. Ann NY Acad Sci; : Qi Y, Niu W, Zhou W, Hou S, Qiu C. Correlation between angiotensinogen gene polymorphisms and essential hypertension in Chinese population. J Hum Hypertens; : Ritchi D, Hah W, Rood, et al. Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Hum Genet; : interactions in hypertension. Ann Med; : Moore JH, Gilbert JC, Tsai