gene polymorphisms for diabetes mellitus, disease and cancer are associated in Koreans

Abstract

Long-lived people may have a unique genetic makeup that makes them more resistant than the general pop- ulation to prevalent age-related diseases; however, not much is known about genes involved in the longevity. To identify susceptibility variants control- ling longevity, we performed a high-throughput candi- date gene study using 137 Koreans over 90 yr old and 213 young healthy Koreans. We evaluated 463 in- formative markers located in 176 candidate genes mostly for diabetes mellitus, cardiovascular disease and cancer under five genetic models. We estimated the odds ratios for each allele, genotype, haplotype, and gene-gene interaction using logistic regression analysis. Associations between 13 genes and lon- gevity were detected at a P-value less than 0.01. Particularly, the rs671 (A) allele of the aldehyde de- hydrogenase 2 family (mitochondrial) (ALDH2) gene was associated with longevity only in men (OR 2.11, P = 0.008). Four genes, proprotein convertase sub- tilisin/kexin type 1 (PCSK1, P = 0.008), epidermal growth factor receptor (EGFR, P = 0.003), paired box 4 (PAX4, P = 0.008), and V-yes-1 Yamaguchi sarcoma viral related oncogene homolog (LYN, P = 0.002) con- sistently yielded statistical evidence for association with longevity. The findings of the current study may provide a starting point for future studies to unravel ge-

Department of Medical Genetics Hallym University College of Medicine Chuncheon

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, Korea

Center for Genome Research Samsung Biomedical Research Institute

Department of Internal Medicine

Department of Psychiatry

Department of Molecular Cell Biology Sungkyunkwan University School of Medicine Seoul

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, Korea

Aging and Apoptosis Research Center Seoul National University Institute on Aging Seoul

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, Korea

Corresponding authors: Tel,

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; Fax,

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; E-mail, jbpark@med.skku.ac.kr (J.B. Tel,

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; Fax,

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; E-mail, scpark@snu.ac.kr (S.C. Park) *These authors contributed equally to this work. DOI

/emm.

Accepted 22 June 2009

Abbreviations: ABCC8, ATP-binding cassette, sub-family C (CFTR/ MRP), member 8; ACE, angiotensin I converting enzyme (peptidyl- dipeptidase A) 1; ADCY2, adenylate cyclase 2 (brain); ALDH2, aldehyde dehydrogenase 2 family (mitochondrial); APOE, apolipo- protein E; CDK10, cyclin-dependent kinase 10; CETP, cholesteryl ester transfer protein, plasma; CI, confidence interval; CR, call rate; CVD, cardiovascular disease; DM, diabetes mellitus; HWE, Hardy-Weinberg equilibrium; IL12RB2, interleukin 12 receptor, beta 2; LD, linkage disequilibrium; LRM, logistic regression model; LYN, V-yes-1 Yamaguchi sarcoma viral related oncogene homolog; MAF, minor allele frequency; MGP, matrix Gla protein; MTTP, microsomal triglyceride transfer protein; OR, odds ratio; PAX4, paired box 4; PCSK1, convertase subtilisin/kexin type 1; PON1, paraoxonase 1; PPP1R14C, protein phosphatase 1, regulatory (inhibitor) subunit 14C; PPP1R1A, protein phosphatase 1, regulatory (inhibitor) subunit 1A; SNP, single nucleotide polymorphism; TNFSF11, tumor necrosis factor (ligand) superfamily, member 11

Keywords: case-control studies; genome- wide sociation study; longevity; polymorphism, single cleotide

Introduction

In the past 50 yr, the mean life expectancy in most developed countries has increased from around 50 yr to 80 yr. This change suggests that envi- ronmental changes may influence on extending the human lifespan. At the same time, variation in maximum lifespan among species and genetic variations in lifespan across human populations clearly points toward a genetic basis for lifespan (Christensen et al., 2006; Bergman et al., 2007).

According to a birth cohort study from north-east America, having a centenarian sibling increased the chance of survival beyond ninety years old by four times, indicating a strong familial aggregation to longevity (Perls et al., 1998). The heritability of lifespan was around 33% and did not vary by gender in Danish twins (McGue et al., 1993). Linkage study is often considered inappropriate for complex traits; however, a region of chromosome 4 was shown to be linked with exceptional longevity (Puca et al., 2001). Gene-environment interactions (e.g. ACE, angiotensin I converting enzyme (pep- tidyl-dipeptidase A) 1 and exercise; IL6, interleukin 6 (interferon, beta 2) and zinc) also contribute to the development of aging-related phenotypes (e.g. physical decline and inflammation, respectively) (Capri et al., 2006).

syndrome (i.e. WRN), and telomere length have been considered with respect to both age-related diseases and longevity (Atzmon et al., 2006; Capri et al., 2006; Christensen et al., 2006; Salvioli et al., 2006).

Genes involved in increased lifespan may play protective roles in the development of age-related diseases. The presence of deleterious genotypes of age-related diseases may be a surrogate indi- cator of aging. Genes associated with aging-related diseases often have pleiotropic effects, while epistatic interactions affect human longevity (Christensen et al., 2006). For instance, significant decreases of paraoxonase (i.e. PON1) activity on the surface of HDL have been observed in both diabetes mellitus (DM) and cardiovascular disease (CVD) (Mackness et al., 2004). Although asso- ciation between DM and cancer remains contro- versial, an increased risk of lung cancer has been observed among diabetic Korean women (hazard ratio 1.39, 95% confidence interval 1.10-1.76) (Jee et al., 2005) and such experimental evidence has suggested that both insulin and insulin-like growth factors (IGFs) can stimulate tumor cell proliferation (Rousseau et al., 2006).