evidence for an association between the stud- variants and longevity, the more powerful haplotype suggested a positive one. Haplotype analysis, studies single genetic variants in their combina- simultaneously, has a higher complexity level single-locus analysis and can provide additional with respect to the effect of genetic interac- especially when these alleles have a synergistic Our haplotype analysis indicated that haplo- A-G-C and A-C-T had a genetic predisposition live longer. A previous study by Singh et al4 examin- haplotypes of Hsp70 family and longevity suggested haplotype harboring 1267A and 2437C alleles had worse survival as compared with in cross-sectional and cohort studies, which inconsistent with the current results. Furthermore, noted that the linkage patterns were heterogeneous different ethnic populations. For example, G and T2437C variants were in moderate linkage (D’ 5 0.6–0.8) in Singh et al’s study,4 in weak linkage disequilibrium (D’ . 0.5) in study (data not shown). Given the importance of nat- selection in human evolution, haplotype structure or might be dissimilar among populations of dif- origins. Although haplotype analysis preponder- over single-locus analysis, it may represent a first in uncovering the genetic underpinnings of natural Subsequent validation among different popu- or using different analytical approaches is essen- for explanation and extrapolation of haplotype

Fig 1. The interaction information of the 3 studied variants by the MDR method.In theupperpanel,a red or orangelineconnecting2 var- iants suggests a positive information gain that can be interpreted as a synergistic or nonadditive relationship, whereas a blue or green linesuggestsalossofinformationthatcanbeinterpretedasredundancy or correlation (eg, linkage disequilibrium). A yellow line indicates in- dependence or additivity. The lower panel shows the distribution of cases (left bars) and short-lived people (right bars) for the 2 interacting variants (G190C and T2437C). Boxes were labeled as ‘‘high risk’’ (heavy gray) if the ratio of the number of cases (n 5 191) to short-lived people (n 5 53) met or exceeded the threshold of 191/53z3.60, and boxes were labeled as ‘‘low risk’’ (light gray) if the threshold was not exceeded. (Color version of figure is available online).

The most noteworthy finding of this study was a posi- tive association between the haplotype constructs of 3 studied variants and natural longevity in Uygur ethnic- ity, 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 interact- ing effect on longevity. This is the first study to report the interactive association of Hsp70 genes variants with natural longevity in Chinese.

Since the study relating Hsp70 family variants with longevity was first reported by Altomare et al17 in an Ital- ian population, many studies provide support for the involvement of Hsp70 genes in the long period of surviving.18,19 A study by Ross et al18 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 the significant association of 2437C allele with longevity, which was not in line with the

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 and gene-environment interactions in case-control and discordant-sib-pair studies with relatively small sample.21-23 An application of MDR can, to some extent, strengthen the validity of our results and statistically

pret the interactive association of Hsp70 genes variants with human longevity.

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We wholeheartedly thank the kind assistance and support of the and doctors in the First Affiliated Hospital of Xinjiang Medical and the dedicators for their enthusiastic participation.

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