| Backgroud.Inflammation is considered a response set by the tissues in response to injury elicited by trauma or infection.It is a complex network of molecular and cellular interactions that facilitates a return to physiological homeostasis and tissue repair.The individual response against infection and trauma is also determined by gene variability. Ageing is accompanied by chronic low-grade inflammation state clearly showed by 2-4-fold increase in serum levels of inflammatory mediators.A wide range of factors has been claimed to contribute to this state;however,the most important role seems to be played by the chronic antigenic stress,which affects immune system thorough out life with a progressive activation of macrophages and related cells.This pro-inflammatory status,interacting with the genetic background,potentially triggers the onset of age-related inflammatory diseases as atherosclerosis.Thus,the analysis of polymorphisms of the genes that are key nodes of the natural immunity response might clarify the patho-physiology of age-related inflammatory diseases as atherosclerosis.On the other hand,centenarians are characterized by marked delay or escape from age-associated diseases that,on average,cause mortality at earlier ages.In addition,centenarian offspring have increased likelihood of surviving to 100 years and show a reduced prevalence of age-associated diseases,as cardiovascular disease(CVD) and less prevalence of cardiovascular risk factors.So,genes involved in CVD may play an opposite role in human longevity.Thus,the model of centenarians can be used to understand the role of these genes in successful and unsuccessful ageing.The centenarian,who represents the extremity of longevity,was the optimal population of researching the human longevity.The quantity and relative ratio of centenarian in Xinjiang Hetian were over the average level of whole country,so Hetian was classified as one of four longevity regions in the world.Furthermore,because of environment,living characteristics,customs and habits,the Uygur who lived in this region became genetic isolation population and belonged to the natural longevity.Thereby,they were the value resource of gendetic study about longevity.Besides the common methods which compared the genotype distribution of single polymorphism between the longevities and the controls,the genetic methods of longevity study include the linkage disequilibrium and haplotype analysis,which became increasingly the effective methods of studying the life-span that was the complex phenotype controlled by multiple genes and gene-environment interaction.The linkage disequilibrium and haplotype analysis were valuable to association analysis,especially the association study of complex diseases.Objectives:To investigate the association between polymorphisms(A1267G, G190C andT2437C) and their haplotype within heat shock protein(HSP) gene,as well as polymorphisms(+252G/A,-863C/A and-308G/A) and their haplotype within the tumor necrosis factor(TNF) gene,and natural longevity in Xinjiang Uygur population.Methods:191 healthy Uygur individuals over 90 years in Xinjiang Hetian were recruited.And 53 area-,nationality-,gender-matched individuals who had no longevity family history and died in their 75 years were studied as control subjects.Their height, weight,systolic blood pressure(SBP) and diastolic blood pressure(DBP),serum total cholesterol(TC),triglyceride(TG),high density lipoprotein cholesterol(HDL-C),low density lipoprotein cholesterol(LDL-C),apolipoprotein A(ApoA) and blood glucose(BG) were measured.Genome DNA was extracted from white blood cells.Using polymerase chain reaction(PCR),PCR-restriction fragment length polymorphism(PCR-RFLP) and direct sequencing technique,we tested the polymorphisms of the polymorphisms of A1267G,G190C and T2437C within H SP70 gene,the polymorphisms of+252G/A within TNFβand the polymorphisms of -308G/A and-863C/A within TNFαgene,moreover, performed the linkage disequilibrium and haplotype analysis.Results:We investigate the association of three variants(A1267G,G190C and T2437C) in 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 aged above 90 years,and 53 naturally-died persons aged 65-70 years.Promoter activity was evaluated by luciferase reporter assays.Data were analyzed using EH/EH+ program for hypotype prediction and MDR software for gene-gene interaction.All studied variants satisfied Hardy-Weinberg equilibrium in each group.In single-locus analysis,no significant differences were found between longevities and controls in the genotype/allele distributions of all variants.In contrast,haplotype analysis indicated that haplotypes A-C-G(in order of A1267G,T2437C and G190C) and A-T-C were more prevalent in longevities than controls(P=0.026 and 0.017),and conferred a 3.46- and 4.51-fold increased tendency for longevity,respectively.Haplotype results were further strengthened by interaction analysis,suggesting an optimal model with G190C and T2437C exerting an interacting effect on longevity.Taken together,our findings suggested that common genetic variants in Hsp70 family might contribute interactively to longevity in Uygur.The variants(+252G/A,-308G/A and -863C/A) in TNF gene,including alleles, genotype and haplotype show no association with longevity.The gene polymorphism exist not only in ethinity but also in area.Special charactoristics exist in polymorphism of +252G/A,-308G/A and -863C/A with Hetian Uygur.There are 8 haplotypes of the TNF gene,that is,A-G-C,G-G-C,A-G-A,G-A-C,A-A-C,G-G-A,G-A-A and A-A-A.The most common is A-G-C.There is no association with longevity.Conclusions:AA genotype of promoter-2437G/A polymorphism within HSP gene was the advantageous factor of longevity.A-C-G and A-C-T haplotype of A1267G,T2437C和G190C polymorphisms was the beneficial factor of longevity.. Furthermore,there was the extensive linkage among G190C and T2437C,resulted from long-term genetic isolation in Uygur in Xinjiang Hetian.There was no correlation between the alleics,genotypes and haplotypes of polymorphisms within TNF gene,Furthermore,there was no linkage between+252G/A, -308G/A and -863C/A,resulted from long-term genetic isolation in Uygur in Xinjiang Hetian.And the result of-863C/A polymorphism suggested the base sequences of this polymorphism had race specificity... |
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