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Candidate Gene Polymorphisms for Diabetes Mellitus, Cardiovascular Disease and Cancer Are Associated with Longevity in Koreans

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Candidate Gene Polymorphisms for Diabetes Mellitus, Cardiovascular Disease and Cancer Are Associated with Longevity in Koreans EXPERIMENTAL and MOLECULAR MEDICINE, Vol. 41, No. 11, 772-781, November 2009 Candidate gene polymorphisms for diabetes mellitus, cardiovascular disease and cancer are associated with longevity in Koreans Ji Wan Park1*, Yong Ick Ji2*, Yoon-Ho Choi3, Abstract Mi-Yeon Kang2, Eunhyun Jung2, Se Young Cho2, Hee-Youn Cho2, Byung Kyu Kang2, Long-lived people may have a unique genetic makeup 4 2,5 that makes them more resistant than the general pop- Yoo Sook Joung , Duk-Hwan Kim , 6,7 2,5,7 ulation to prevalent age-related diseases; however, Sang Chul Park and Joobae Park not much is known about genes involved in the longevity. To identify susceptibility variants control- 1 Department of Medical Genetics ling longevity, we performed a high-throughput candi- Hallym University College of Medicine date gene study using 137 Koreans over 90 yr old and Chuncheon 200-702, Korea 2 213 young healthy Koreans. We evaluated 463 in- Center for Genome Research formative markers located in 176 candidate genes Samsung Biomedical Research Institute mostly for diabetes mellitus, cardiovascular disease 3Department of Internal Medicine 4 and cancer under five genetic models. We estimated Department of Psychiatry the odds ratios for each allele, genotype, haplotype, 5Department of Molecular Cell Biology and gene-gene interaction using logistic regression Sungkyunkwan University School of Medicine analysis. Associations between 13 genes and lon- Seoul 135-710, Korea gevity were detected at a P-value less than 0.01. 6Aging and Apoptosis Research Center Particularly, the rs671 (A) allele of the aldehyde de- Seoul National University Institute on Aging hydrogenase 2 family (mitochondrial) (ALDH2) gene Seoul 110-799, Korea 7 was associated with longevity only in men (OR 2.11, P Corresponding authors: Tel, 82-2-3410-3600; Fax, 82-2-3410-3620; E-mail, [email protected] (J.B. Park), = 0.008). Four genes, proprotein convertase sub- Tel, 82-2-740-8244; Fax, 82-2-744-4534; tilisin/kexin type 1 (PCSK1, P = 0.008), epidermal E-mail, [email protected] (S.C. Park) growth factor receptor (EGFR, P = 0.003), paired box *These authors contributed equally to this work. 4 (PAX4, P = 0.008), and V-yes-1 Yamaguchi sarcoma DOI 10.3858/emm.2009.41.11.083 viral related oncogene homolog (LYN, P =0.002) con- sistently yielded statistical evidence for association with longevity. The findings of the current study may Accepted 22 June 2009 provide a starting point for future studies to unravel ge- Abbreviations: ABCC8, ATP-binding cassette, sub-family C (CFTR/ netic factors controlling longevity in Koreans. MRP), member 8; ACE, angiotensin I converting enzyme (peptidyl- dipeptidase A) 1; ADCY2, adenylate cyclase 2 (brain); ALDH2, Keywords: case-control studies; genome- wide as- aldehyde dehydrogenase 2 family (mitochondrial); APOE, apolipo- sociation study; longevity; polymorphism, single nu- protein E; CDK10, cyclin-dependent kinase 10; CETP, cholesteryl cleotide 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 Introduction 2; LD, linkage disequilibrium; LRM, logistic regression model; LYN, V-yes-1 Yamaguchi sarcoma viral related oncogene homolog; MAF, In the past 50 yr, the mean life expectancy in most minor allele frequency; MGP, matrix Gla protein; MTTP, microsomal developed countries has increased from around 50 triglyceride transfer protein; OR, odds ratio; PAX4, paired box 4; yr to 80 yr. This change suggests that envi- PCSK1, convertase subtilisin/kexin type 1; PON1, paraoxonase ronmental changes may influence on extending the 1; PPP1R14C, protein phosphatase 1, regulatory (inhibitor) subunit human lifespan. At the same time, variation in 14C; PPP1R1A, protein phosphatase 1, regulatory (inhibitor) subunit maximum lifespan among species and genetic 1A; SNP, single nucleotide polymorphism; TNFSF11, tumor variations in lifespan across human populations necrosis factor (ligand) superfamily, member 11 clearly points toward a genetic basis for lifespan (Christensen et al., 2006; Bergman et al., 2007). Candidate genes for human longevity 773 According to a birth cohort study from north-east syndrome (i.e. WRN), and telomere length have America, having a centenarian sibling increased been considered with respect to both age-related the chance of survival beyond ninety years old by diseases and longevity (Atzmon et al., 2006; Capri four times, indicating a strong familial aggregation et al., 2006; Christensen et al., 2006; Salvioli et al., to longevity (Perls et al., 1998). The heritability of 2006). lifespan was around 33% and did not vary by Genes involved in increased lifespan may play gender in Danish twins (McGue et al., 1993). Linkage protective roles in the development of age-related study is often considered inappropriate for complex diseases. The presence of deleterious genotypes traits; however, a region of chromosome 4 was of age-related diseases may be a surrogate indi- shown to be linked with exceptional longevity cator of aging. Genes associated with aging-related (Puca et al., 2001). Gene-environment interactions diseases often have pleiotropic effects, while (e.g. ACE, angiotensin I converting enzyme (pep- epistatic interactions affect human longevity tidyl-dipeptidase A) 1 and exercise; IL6, interleukin (Christensen et al., 2006). For instance, significant 6 (interferon, beta 2) and zinc) also contribute to decreases of paraoxonase (i.e. PON1) activity on the development of aging-related phenotypes (e.g. the surface of HDL have been observed in both physical decline and inflammation, respectively) diabetes mellitus (DM) and cardiovascular disease (Capri et al., 2006). (CVD) (Mackness et al., 2004). Although asso- The frequency of centenarians is approximately ciation between DM and cancer remains contro- 1/100,000 people worldwide. According to the versial, an increased risk of lung cancer has been Korea National Statistical Office (KNSO) Report in observed among diabetic Korean women (hazard 2005 (http://www.kosis.kr.), the frequencies of nona- ratio 1.39, 95% confidence interval 1.10-1.76) (Jee genarians and centenarians were 131 and 2/100,000 et al., 2005) and such experimental evidence has Koreans, respectively (KNSO, 2005). Centenarians suggested that both insulin and insulin-like growth may not be free of disease, but manage to survive factors (IGFs) can stimulate tumor cell proliferation with or without treatment owing to their resistance to (Rousseau et al., 2006). disease (Franceschi et al., 2000). The incidences of Because the difficulty in finding centenarians or major common diseases slow down or even decline nonagenarians limits the replication of genome-wide around age 85-90 yr (Bergman. et al., 2007). Gender association (GWA) studies using an extremely also accounts for important differences in longevity large number of randomly spaced markers, we as well as in the occurrence of a variety of adopted a high-throughput candidate gene approach age-related disease. The male/female ratios were to identify susceptibility variants controlling lifespan about 1:4 in nonagenarians and 1:8.2 in centena- in Koreans. rians in Korea (KNSO, 2005). Such data raise the possibility of gender-specific genetic determinants of human longevity. Results Approximately 30 candidate genes for longevity have been reported in previous studies since Among 565 polymorphic SNPs analyzed, 102 SNPs Herman (1956) proposed the free radical theory of (18%) with MAF ＜ 2%, HWE P ＜ 10-4, or CR ＜ aging, where oxidative stress causes aging 95% in the young age group did not passed the (Salvioli et al., 2006). Genes involved in inflamma- threshold of our quality test for genotypes. Thus, a tion and the immune response (e.g. IL6; LMP2, low total of 463 informative markers located in 176 molecular mass protein 2; TNFA, tumor necrosis genes were included in the subsequent analyses. factor (TNF superfamily, member 2); TGFB1, trans- For the comparison of the individuals above age forming growth factor, beta 1; and PPARγ, pero- 90 versus the young healthy controls, our study xisome proliferator-activated receptor gamma), had a sample size adequate to reach a power of genome maintenance and repair (e.g. P53), lipid 80% to significantly detect a genotypic OR over metabolism (e.g. APOE, apolipoprotein E; CETP, 1.7/2.4 (heterozygote/ homozygote) under the cholesteryl ester transfer protein, plasma; MTTP, assumptions shown above (see the Methods). The microsomal triglyceride transfer protein, and PON1, result obtained from centenarian women was paraoxonase 1), glucose metabolism (e.g. IGF1, shown in Supplemental Data Tables. insulin-like growth factor 1 (somatomedin C); and HFE, hemochromatosis), oxidative stress (e.g. SOD1, superoxide dismutase 1, soluble; PARP, poly Allelic- and genotypic association (ADP-ribose) polymerase 1; and GSTT1, gluta- A total of 43 SNPs located in 33 genes (18.8% of thione S-transferase theta 1), mitochondrial muta- 176 candidate genes) had a nominally significant tion, premature aging syndromes such as Werner association with lifespan (P ＜ 0.05) in the allelic χ2 774 Exp. Mol. Med. Vol. 41(11), 772-781, 2009 tests (data not shown). Among these, 34 SNPs of ryotic translation initiation factor 4 gamma, 1 28 genes showed a significant allelic OR and 7 (EIF4G1), ATP-binding cassette, sub-family C genes had a P value less than 0.01 in at least one (CFTR/MRP), member 8 (ABCC8), ALDH2, and age/gender group (i.e. IL12RB2, interleukin 12 telomerase-associated protein 1 (TEP1) showed receptor, beta 2; PPP1R14C, protein phosphatase evidence for genotypic association and 9 genes 1, regulatory (inhibitor) subunit 14C; EGFR, epider- yielded P values less than 0.01 (Table 1B). By way mal growth factor receptor; PAX4, paired box 4; of example, a male with an A allele of the rs671 MMP1, matrix metallopeptidase 1 (interstitial colla- (Lys504Glue) located in the ALDH2 increased the genase); PPP1R1A, protein phosphatase 1, regu- chance of living longer than 90 yr by 2.11 times latory (inhibitor) subunit 1A; and ALDH2, aldehyde compared to men having a G allele (P = 0.009) and dehydrogenase 2 family (mitochondrial)).
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