Interactive association of heat shock protein 70 genes variants with natural longevity in Xinjiang Hetian Uygur ethnicity

JINXIN LI, WENQUAN NIU, YUE QI, WUFUER MAYILA, PENGCHENG ZHU, MUHUYATI, ZUHENG CHENG, and CHANGCHUN QIU

XINJIANG, SHANGHAI, AND BEIJING, CHINA

Mounting evidence suggests thatall organisms atthe cellularlevel respond to stress by synthesizing heat shock proteins at the expense of other proteins, and the ability of hu- man cells to respond to heat stress decreases with aging. We thus investigate the asso- ciationof3variants(A1267GinHSPA1B,G190CinHSPA1A,andT2437CinHSPA1L)inthe heat shock protein 70 (Hsp70) family with natural longevity in a Xinjiang Hetian Uygur population. A case-control study was conducted in 191 healthy individuals greater than90years of age,and 53naturallydiedpersons 65–70years of age.Promoter activ- ity was evaluated by luciferase reporter assays. The data were analyzed using an EH/ EH1programforhaplotypepredictionandMDRsoftwareforgene–geneinteraction.All studiedvariantssatisfiedtheHardy-Weinbergequilibriumineachgroup.Insingle-locus analysis, no significant differences were found between long-lived people and short- lived people in the genotype/allele distributions of all variants. In contrast, haplotype analysisindicatedthathaplotypesA-G-CandA-C-Tweremoreprevalentinlong-lived people than short-lived people (P 5 0.026 and 0.017), and the analysis conferred a 3.46- and 4.51-fold increased tendency for longevity, respectively (P 5 0.025 and 0.016).Thehaplotyperesultswerestrengthenedbyinteractionanalysis,whichsuggests an optimal model in which G190C and T2437C exert an interacting effect on longevity. No functional significance was observed between 190G and 190C alleles in both con- trol and heat-inducible A549 cells (P . 0.05). Taken together, our findings suggested thatcommongenetic variants inHsp70 familymight contributeinteractively tolongev- ity the Xinjiang Hetian Uygur population. (Translational Research 2009;154:257–264)

Abbreviations: BMI ¼ body mass index; Hsp70 ¼ heat shock protein 70; PCR ¼ polymerase chain reaction

City (W.N.), and Grant

XJ

from the Science Fund of Shanghai Jiaotong University School of Medicine. Submitted for publication March

,

; revision submitted August

,

; accepted for publication August

,

Reprint requests: Wenquan Niu, Ruijin Hospital, Shanghai Institute of Hypertension, Ruijin Second Road

, Shanghai

, China; e-mail: niuwenquan@yahoo.cn, Zuheng Cheng, The First Hospital of Xinjiang Medical University; e-mail: zuheng-cheng@yahoo.com.cn, or Changchun Qiu, Peking Union Medical College, Dong Dan San Tiao

, Beijing,

, China; e-mail: qiucc

@pumc.edu.cn, Tel:

-

/$ – see front matter

Mosby, Inc. All rights reserved. doi:

/j.trsl.

From the Cardiology Department, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China; State Key Laboratory of Medical Genomics; Sino-French Research Center for Life Science and Genomics, Ruijin Hospital, Shanghai Institute of Hypertension, Shanghai Jiaotong University School of Medicine, Shanghai, China; Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. J. Li, W. Niu, and Y. Qi contributed equally. Supported by Grant 2004AA227111 from the Hi-Tech Research and Development Program of China (863 Project) (to Z.C.) as well as by the Shanghai ‘‘Chen Guang’’ Project (to W.N.), Grant 09ZR1426200 from the Natural Science Foundation of Shanghai, two Excellent

Supported by Grant 2004AA227111 from the Hi-Tech Research and Development Program of China (863 Project) (to Z.C.) as well as by the Shanghai ‘‘Chen Guang’’ Project (to W.N.), Grant 09ZR1426200 from the Natural Science Foundation of Shanghai, two Excellent Young Teachers Programs of Ruijin Hospital (W.N.) and Shanghai

the assembly and transport of newly synthesized pro- teins within cells, as well as in the removal of denatured proteins.7,8 The long-term effects of chronic stress could result in many features of mammalian aging, which along with longevity are related to the ability to cope with a variety of stressors. It has been shown in rodents, rhesus monkeys, and humans, as well as in Drosophila and Caenorhabditis elegans, that this ability decreases with age, although the biologic relevance and regulatory mechanisms remain unclear.4,9-11 However, interindi- vidual differences in ability to response to stress can be clarified by studying genetic variants in stress response genes.3

AT A GLANCE COMMENTARY

Background

Translational Significance

We investigate the association of 3 variants (A1267 G in HSPA1B, G190C in HSPA1A, and T2437C in HSPA1L) in heat shock protein 70 (Hsp70) with natural longevity in a Xinjiang Hetian Uygur population. Using a candidate gene approach and the promoter functional assessment, our findings suggested that common genetic vari- ants in Hsp70 family might contribute interactively to longevity in the Xinjiang Hetian Uygur popula- tion.

We therefore focused on a population of Xinjiang Hetian Uygur ethnicity, whose percentage of centenar- ians is significantly greater than the average level of the whole country, to explore association of 3 common genetic variants, including A1267 G (rs1061581, exon 1), G190C (rs1043618, 5’ UTR), and T2437C (rs2227956, exon 2) in 3 polymorphic genes (HSPA1B, HSPA1A, and HSPA1L) of the Hsp70 family with natural longevity. In addition, because the G190C variant is assigned in the promoter region of HSPA1A, a func- tional assessment was conducted to evaluate its potential implications in the current study.