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Absence of Association between SNPs in the Promoter Region of the Insulin-Like Growth Factor 1 (IGF-1) Gene and Longevity in the Han Chinese Population

Liang Xie a,b,c,1, Yuan-ying Gong a,c,1, Shi-gang Lian d, Juan Yang d, Ya Yang e, Shou-jun Gao f, Liang-you Xu f, Ya-ping Zhang a,b,* 

aState Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China 
bLaboratory for Conservation and Utilization of Bio-Resource, Yunnan University, Kunming 650091, China 
cGraduate School of the Chinese Academy of Sciences, Beijing 100049, China 
dPeoples Hospital of Dujiangyan City, Dujiangyan 611830, China 
eKey Laboratory of Animal Models and Human Disease Mechanisms and Learning and Memory, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223 
fDujiangyan Longevity Research Centre, Dujiangyan 611830, China 

Previous studies have indicated that genetic variations in factors of insulin/insulin-like growth factor 1 (IGF-1) signaling pathway could influence human lifespan by affecting IGF-1 levels. The promoter region of the IGF-1 gene is an obvious candidate but has not been studied clearly. To explore the potential role of promoter region variation in the IGF-1 gene in longevity, we investigated 485 longevity subjects and 392 younger individuals from Dujiangyan, China. By sequencing about 2.5 kb upstream from the transcription start site of exon 1 of the IGF-1 gene in 30 individuals from both groups, we acquired three previously described SNPs (rs2288377, rs5742612, and rs35767). We examined the association between these three SNPs and longevity by comparing the distribution of genotypes, alleles, and haplotypes in both the longevity and control groups. None of these variants were found to be associated with longevity. Our results suggest that there is no association between SNPs in the promoter region of the IGF-1 gene and longevity in the Han Chinese population.

2008 Elsevier Inc. All rights reserved.

Introduction

Factors in the insulin/IGF-1 signaling pathway may contribute to longevity by affecting IGF-1 levels. Bonafe et al. suggested that rs2229765 in the IGF-1 receptor (IGF-1R) is associated with the production of IGF-1 (Bonafe et al., 2003). Another study reported that rs2854744 located in insulin-like growth factor binding protein 3 (IGFBP3) promoter region could affect circulating levels of IGFBP3, which might influence circulating levels of IGF-1 accordingly (Deal et al., 2001). Recently, one study in centenarians suggested that variations of IGF-1R may contribute to longevity gender-specifically by increasing IGF-1 levels in female centenarians (Suh et al., 2008). Meanwhile, another study supported that specific SNPs in the IGF-1 gene can influence circulating levels of IGF-1 significantly (Patel et al., 2008). Unfortunately, as far as we know, there is still no research on the association between polymorphisms of the IGF-1 promoter region and longevity, although the promoter region is important to the expression of the IGF-1 gene and serum IGF-1 levels. To explore the potential role of promoter region variation in the IGF-1 gene in longevity, we performed an association study on the SNPs of the promoter region of IGF-1 and longevity in the Han Chinese population.

Ageing is a complex physical process with a variety of changes occurring in many aspects of bodily functions such as physiology and endocrinology. In this process, genetic and environmental factors interact with each other and greatly contribute to the aging process. In 2001, Mitchell et al. estimated a heritability of 25% of lifespan in an Amish population in Lancaster County, Pennsylvania (Mitchell et al., 2001), which implied a relatively strong genetic background in human lifespan. Meanwhile, in invertebrate (Kenyon, 2001) and mice (Holzenberger et al., 2003) studies, a conserved insulin/IGF-1 signaling pathway was speculated to be involved in the regulation of longevity (Bartke, 2008; Tatar et al., 2003). IGF-1 is one of the major factors in the insulin/IGF-1 signaling pathway. In humans,the SNP sites was directly sequenced for the two regions. Any ambiguous results were confirmed by another PCR and sequencing. In the early 1990s, research was conducted on the functional mechanism of the promoter region of IGF-1 (Jansen et al., 1992; Kim et al., 1991), but the results did not provide adequate information to understand the regulation mechanism of IGF-1. There are two promoters located in either exon 1 (P1) or exon 2 (P2) in the IGF-1 gene, and exon 1 50-UTR is considered a potential region for regulatory elements (Rodriguez et al., 2007), which is why we chose this segment. Considering the important role of IGF-1 in life processes, it is necessary to elucidate the association between the regulation of IGF-1 expression and the aging process distinctly. To our knowledge, it is the first time an association study has been conducted between the SNPs in the 50 flanking region of IGF-1 and longevity in the Han Chinese population. In our research, the longevity and control populations were recruited from the same area. They shared a similar living environment and common diet habits, which excluded non-genetic factors to a great extent. Our investigation indicated that individuals in both populations were native Han inhabitants in this research, thus avoiding population stratification to a certain extent in our study (Marchini et al., 2004).