A microsatellite polymorphism in IGF1 gene promoter and longevity in a Han Chinese

Liang Xie1,2,3, Yuan-ying Gong1,3, Shi-gang Lian4, Juan Yang4, Shou-jun Gao5, Liang-you Xu5, Ya-ping

Abstract

Background: Previous studies have suggested a probable association between the polymorphism of a microsatellite locus located in the promoter of IGF1 (Insulin-like growth factor 1) gene and the serum level of as well as many age-related diseases. Based on these results, we hypothesized that this polymorphism may influence longevity in humans. We performed an association study in a Han Chinese population to test this hypothesis.

Findings: We recruited 493 elderly Han Chinese individuals (females 94; males 90) and 425 young (controls) from Dujiangyan (Sichuan province, China). The genotype distributions and allele frequencies of the microsatellite site in the elderly and control groups were compared by chi square test. Our results suggested that there was no association between the microsatellite polymorphism and longevity in Han Chinese population. However, there were more male persons with 18/21 genotype in elderly group than in control group (11.11 vs. 5.45%, p = 0.011). As the difference was not significant when corrected by Bonferroni method, we speculate that the 18/21 genotype can not be functional in longevity; however, it may link with the real functional loci as there is a long haplotype block embracing the microsatellite locus.

Conclusions: There was no association between polymorphism of the microsatellite in promoter of IGF1 gene and longevity in our study. Future association studies containing the long haplotype block are deserved and can test our speculation of the potential linkage of 18/21 genotype and functional loci.

Background

risk factor for cardiovascular diseases, premature athero- genesis, and diabetes [5]. Furthermore, Yang et al. sug- gested that in humans, a reduced level of serum IGF1 in early adulthood and an increased level in elderly time might be a predictor of high longevity. Meanwhile, the heritability of individual IGF1 level variation is about 50% [9], which implies that IGF1 regulation is geneti- cally determined. Considering the evidence for heritabil- ity of longevity [10], perhaps there is a hereditable shift in IGF1 regulation in long-lived people [8].

IGF1 (Insulin-like growth factor 1) plays a number of important roles in the human body. It is involved in physiological processes such as growth, development, and metabolism [1], and has been implicated as a factor in the development of common diseases [2]. Meanwhile, a conserved insulin/IGF1 signal pathway which may E.coli affect ageing and longevity is known in , yeast, dro- sophila, mice and humans [3-7]. Elucidating the func- tions of insulin/IGF1 pathway in ageing and longevity is a current hot spot in longevity research [8].

A cytosine-adenine (CA) repeat polymorphism in IGF1 gene promoter region (1 kilo base pairs upstream from the transcription start site) [11] has been asso- ciated with serum IGF1 level [12,13]. At the same time, many studies have related this microsatellite polymorph- ism to age-related diseases such as diabetes, cancers, and cardiovascular diseases [14-19]. These results are disputed by several other studies [9,20-24]. However,

Serum IGF1 levels appear to influence susceptibility to disease, and therefore longevity. For example, people with a high level of circulating IGF1 are more suscepti- ble to cancers, while a low level of circulating IGF1 is a

1State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China

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they suggest that this microsatellite locus might be a potential functional site for serum IGF1 level regulation, and might therefore function in ageing and longevity. Therefore, exploring the association of this microsatel- lite polymorphism and longevity is urgent.

Thermocycling parameters included an initial denatura- tion of 5 min. at 95°C; 35 cycles of: 95°C for 30 s, 62°C for 1 min. and 72°C for 1 min.; and a final extension at 72°C for 10 min. PCR products were denatured and size fractionated on 6% denaturing polyacrylamide gel run on an ABI 3730 automated sequencer (AppliedBiosys- tems, Foster City, CA). Alleles were read and scored by GeneMapper V4.0 software (ABI Perkin Elmer) using Liz500 as size standard. Alleles were verified artificially twice by two different persons. The number of repeats contained in alleles of different length was confirmed by cloning and sequencing two differently sized PCR pro- ducts (ie. two alleles). We replicated PCR amplication and genotyping of 30% of the samples, ensuring that replicates were performed by a different researcher. Ambiguous results were confirmed by another PCR and fragment analysis.

To our knowledge there have been no reports on the association between the microsatellite polymorphism and longevity in the Han Chinese people. In this study, we conducted an association study in a Han Chinese population to investigate the potential function of this microsatellite locus in predicting longevity.

Methods

Subjects