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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 60:1525-1529 (2005)
© 2005 The Gerontological Society of America

Association of Interleukin-10 Promoter Single Nucleotide Polymorphisms –819 T/C and –592 A/C With Aging

Naoko Okayama1,2, Yuichiro Hamanaka1, Yutaka Suehiro1, Yoshinori Hasui3, Junji Nakamura2 and Yuji Hinoda1,2,

1 Department of Clinical Laboratory Science, 2 Division of Laboratory, Yamaguchi University Hospital, Yamaguchi University School of Medicine, Japan.
3 Department of Oral and Maxillofacial Surgery, Yamaguchi University School of Medicine, Japan.

Address correspondence to Yuji Hinoda, MD, PhD, Department of Clinical Laboratory Science, Yamaguchi University School of Medicine, 1-1-1, Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan. E-mail: hinoda{at}yamaguchi-u.ac.jp


   Abstract
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 Abstract
Participants
 Results
 Discussion
 References
 
Increased inflammatory activity is known to accompany aging. Single nucleotide polymorphisms of inflammatory mediator genes might therefore affect the aging process. Relation of eight SNPs (tumor necrosis factor-{alpha} [TNF-{alpha}] –1031 T/C, interleukin-10 [IL-10] –819 T/C, IL-1ß –511 C/T, IL-6 –634 C/G, IL-18 –607 A/C, transforming growth factor-ß [TGF-ß] +869 C/T, matrix metalloproteinase-1 [MMP-1] –1607 1G/2G, and MMP-3 –1171 5A/6A) with age or gender was evaluated in 500 Japanese persons (mean age: 56.7 years old, range: 19–100) by the chi-square test. There was a significant association of IL-10 –819 T/C with age (p =.0026). The association remained significant after multivariate logistic regression analysis (odds ratio for an age interval for 1 year, 1.009; 95% CI, 1.002–1.016). Furthermore, the genotype distribution of IL-10 –819 T/C was completely consistent with that of –592 A/C. These data suggest that IL-10 –819 T/C and –592 A/C may be a promising candidate for an aging-related gene in a Japanese population.

NOWADAYS, a gene–longevity association study of unrelated individuals is one of the most popular study designs used to clarify the molecular basis of inherited components in human longevity (1). A variety of genes involved in DNA repair, drug or lipid metabolism, immune response, tumor suppression, and blood coagulation, have been investigated (1). Among these, inflammatory mediators have gained increasing attention because there is accumulating evidence that: (a) low-grade increases in plasma levels of tumor necrosis factor-{alpha} (TNF-{alpha}) and interleukin-6 (IL-6) are strong predictors of all-cause mortality risk independent of other known risk factors in elderly cohorts (2) and (b) anti-inflammatory drugs reduce the risk of vascular events, and possibly Alzheimer's disease and cancer (3,4). Inflammatory mediators are also involved in glucose and lipid metabolism (5). TNF-{alpha} inhibits insulin-receptor signaling in adipocytes, hepatocytes, and skeletal muscle, and is implicated in the insulin resistance of aging. IL-6 stimulates hepatic glucose release, leading to hyperglycemia. Of interest, caloric restriction strongly inhibits inflammatory responses of aging (5).

Single nucleotide polymorphisms (SNPs) in the following inflammatory mediator genes have been reported to be associated with longevity or aging: IL-6 (2), TNF-{alpha} (6), IL-1 (7), IL-10 (8,9), interferon-{gamma} (IFN-{gamma}) (10), transforming growth factor-ß (TGF-ß) (11), and matrix metalloproteinase (MMP)-3 (12). Although it is highly possible that these genes are important candidates, conflicting data have been obtained for IL-6 (2), TNF-{alpha} (13–15), IL-1 (14,16), IL-10 (14,15,17), and IFN-{gamma} (15,17). One possible explanation for these discrepancies is the complex interaction between lifestyle and genetic factors together with cultural and genetic differences across countries (2). The discrepancies also might be derived from a case–control design by which frequency of genotypes is compared between cases (elderly people) and controls (younger people). To reduce such statistical problems, Tan and colleagues (18,19) recently reported a logistic regression model for measuring gene–longevity associations that enables us to estimate the probability of observing one genotype as a function of age, assuming that frequency of the genotype that affects individual survival should change in the genotypic pool with advancing age (18). In the present study, we evaluated the relationship of cytokine and MMP gene SNPs with age in a randomly selected population by using a multivariate logistic regression analysis.


   PARTICIPANTS
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 Abstract
 Participants
Results
 Discussion
 References
 
Peripheral blood samples were obtained from 500 unrelated Japanese individuals (252 males, 248 females; mean age, 56.7 years; range, 19–100 years) after obtaining written informed consents. Number and sex ratio (male/female) of the 500 participants in each decade age were as follows: 5 (0/5) in 10s, 133 (70/63) in 20s, 39 (23/16) in 30s, 43 (22/21) in 40s, 30 (11/19) in 50s, 28 (22/6) in 60s, 79 (57/22) in 70s, 100 (35/65) in 80s, 42 (12/30) in 90s, and 1 (0/1) in 100s. Among these individuals, 337 were healthy volunteers including students, hospital staff members, and elderly people who visited the Yamaguchi University Hospital for regular physical examinations (187 males, 150 females; mean age, 44.3 years; range, 19–98 years), and 163 were patients treated in that hospital for a variety of chronic disorders including ischemic heart disease, essential hypertension, diabetes mellitus, peptic ulcer, and liver disease (65 males, 98 females; mean age, 82.3 years; range, 64–100 years) from January 2001 through October 2004. Patients with malignancy or with severe organ failure were not enrolled in this study. Participants were drawn from Yamaguchi Prefecture and the surrounding prefectures (assuming similar environmental and social factors), and all were native Japanese. The experimental protocol was approved by the Institutional Ethics Committee of the Yamaguchi University School of Medicine.

Genotyping
Using a conventional NaI method, we extracted genomic DNA from peripheral blood anti-coagulated with EDTA-2Na (20). For genotyping of IL-10 –819 T/C, TNF-{alpha} –1031 T/C, IL-1ß –511 C/T, IL-6 –634 C/G, and MMP-3 –1171 5A/6A, tetra-primer amplification refractory mutation system (ARMC) polymerase chain reaction (PCR) was performed with validation by PCR-restriction fragment length polymorphism (RFLP) as described previously (21). MMP-1 –1607 1G/2G, IL-18 –607 A/C, and IL-10 –592 A/C were genotyped using a TaqMan assay, and TGF-ß +869 C/T and IL-10 –1082 A/G were genotyped using PCR-RFLP. Primers, probes, and restriction enzymes used in this study are shown in Table 1.


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  		Table 1. Primers, Probes, and Restriction Enzymes Used for Genotyping.

 
Each PCR was carried out in a total volume of 10 µl containing template DNA at 80 ng/µl, 10 pmol primers, 200 µM deoxyribonucleotide triphosphates (dNTPs), 20 mM MgCl2, 20 mM Tris-HCl (pH 8), 100 mM KCl, and 1 U Taq polymerase (TaKaRa Ex Taq; TAKARA, Tokyo, Japan). The solution was overlaid with 10 µl of mineral oil. Standard conditions of the RoboCycler (Gene Amp PCR System 9600; Perkin Elmer, Tokyo, Japan) used in this study were as follows: initial denaturation at 95°C for 2 minutes, followed by 30 cycles of 30-second denaturation (95°C), 20-second annealing (60°C), and 30-second extension (72°C). PCR products were separated by electrophoresis on a 2% agarose gel, and subsequently stained with ethidium bromide.

TaqMan assay of PCR products was performed according to the manufacturer's protocol. Reaction components for a single 5-µl reaction (for each well of a 384-well plate) were: template DNA at 5 ng/µl, 2.5 µl of TaqMan universal PCR master mix, 0.125 µl of 40 X assay mix, and 2.375 µl of dH2O. Specific forward/reverse PCR primers and TaqMan minor groove binding DNA oligonucleotide (MGB) probes for MMP-1 and IL-18 SNPs were designed with Primer Express version 1.5 software (Applied Biosystems, Foster City, CA), and were custom-synthesized by Applied Biosystems. Sequences of primers for IL-10 –592 A/C are not shown in Table 1 because they were obtained as commercial Assays-on-Demand (Applied Biosystems). Reaction mixtures were loaded into 384-well plates and placed in an ABI Prism 7900HT Sequence Detection System (Applied Biosystems). PCR amplifications were performed as follows: initial denaturation at 95°C for 10 minutes, followed by 40 cycles of PCR with a denaturation at 95°C for 15 seconds and one step annealing and extension for 1 minute at 60°C.

Statistical Analysis
SNPs tested in this study did not show departure from Hardy–Weinberg equilibrium when samples used for this study (n = 500) were examined before analysis (p >.05). Association of the genotypes with age and gender was evaluated by the chi-square test. Multivariate logistic regression analysis was then carried out to obtain odds ratios (OR) and 95% confidence intervals (CI). Presence or absence of a given SNP genotype was used as a dependent variable, and age and gender were used as independent variables. A p value of <.05 was considered statistically significant. The StatView statistical software system (version 5; SAS Institute Inc., Cary, NC) was used for analyses.


   RESULTS
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Discussion
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We genotyped eight SNPs including IL-10 –819 T/C, TNF-{alpha} –1031 T/C, IL-1ß –511 C/T, IL-6 –634 C/G, IL-18 –607 A/C, TGF-ß +869 C/T, MMP-1 –1607 1G/2G, and MMP-3 –1171 5A/6A, and evaluated the relation of age or gender with the genotype distribution of each SNP by a conventional chi-square test. As shown in Table 2, IL-10 –819 T/C showed a significant association with age (p =.0026). In addition, there was a weak association between gender and IL-18 –607 A/C (p =.0456) or MMP-3 –1171 5A/6A (p =.0373), and a tendency of association between age and TNF-{alpha} –1031 T/C (p =.0611).


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  		Table 2. Comparison of Genotype Distribution of Eight SNPs Between Higher and Lower Age Groups.

 
The association of IL-10 –819 T/T, IL-18 –607 A/C, and MMP-3 –1171 6A6A with age or gender remained significant after multivariate logistic regression analysis. The analysis also showed a significant association of TNF-{alpha} –1031 T/T with age. OR and 95% CI are shown in Table 3. Consistent with the results in Table 2, the association of IL-10 –819 T/T with age showed the highest level of statistical significance (OR for an age interval for 1 year, 1.009; 95% CI, 1.002–1.016).


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  		Table 3. Logistic Regression Analysis.

 
To further evaluate the association of IL-10 –819 T/T with age, we divided our population into four groups (two decades each) as follows: 19–40 years, 41–60 years, 61–80 years, and 81–100 years, and the frequency of IL-10 –819 T/T was compared among these 4 groups. As shown in Table 4, it was apparently increased in higher age groups (61–80 and 81–100) compared to lower age groups (19–40 and 41–60).


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  		Table 4. Frequencies of Interleukin 10 (IL-10) –819 T/T in Each Two Decades of 500 Participants Aged 19–100 Years.

 
To investigate the relation of a previously reported IL-10 haplotype (22) consisting of –1082 A/G, –819 T/C, and –592 A/C with age, we then genotyped IL-10 –1082 A/G and –592 A/C. As shown in Table 5, genotype distribution was completely consistent between IL-10 –819 T/C and –592 A/C, but –1082 A/G showed a quite different distribution. There was no significant association of IL-10 –1082 A/G with age (data not shown).


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  		Table 5. Comparison of Genotype Distribution of Interleukin 10 (IL-10) Promoter Single Nucleotide Polymorphisms.

 
The relation of the combination of IL-10 –819 T/T and TNF-{alpha} –1031 T/T with age was also evaluated by the chi-square test. A significant association of the combination of these two genotypes with age was observed (p =.0145), but the association seemed to be weaker compared to the association of IL-10 –819 T/T with age, suggesting that there was no additional advantage of the combination with TNF-{alpha} –1031 T/T (data not shown).


   DISCUSSION
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 Participants
 Results
 Discussion
References
 
In this study, we demonstrated that IL-10 –819 T/C and –592 A/C polymorphisms could be associated with aging in a Japanese population. Our present data also suggested a possible association of TNF-{alpha} –1031 T/C with age and of IL-18 –607 A/C and MMP-3 –1171 5A/6A with gender. However, multiple testing may cause a false-positive result. When our data in Table 2 were evaluated by Bonferroni correction, only an association of IL-10 –819 T/T with age attained statistical significance. However, it may be possible that the Bonferroni correction overcorrects for the inflated false-positive rate and thereby throws away valid information in the sample (23). A weak association should be regarded as a borderline statistical association at the present time and subjected to further investigations. Although the association of TNF-{alpha} –1031 T/C with age and that of IL-18 –607 A/C with gender are our new findings, the association of MMP-3 –1171 5A/6A with gender was previously pointed out in coronary heart disease (24,25).

The population tested (n = 500) included 163 elderly people (mean age, 82.3 years; range, 64–100 years) with mild chronic disorders except for malignancy; these 163 people made up 65.7% of the 248 participants ≥64 years old. However, when considering that 63.2% of Japanese people aged ≥65 years are receiving regular outpatient treatment due to some disease (based on the data in the Official Web Site of Ministry of Health, Labour and Welfare in Japan, http://www.mhlw.go.jp/), this percentage of patients with chronic disorders in our population could correspond to that in the entire Japanese population. We also compared the genotype distribution of all the SNPs tested between 163 elderly patients from the hospital setting and healthy controls aged ≥64 years (n = 85; mean age, 77.9 years; range, 64–98 years). None of the SNPs showed a significant difference of genotype distribution between these 2 groups (data not shown). Furthermore, there was no significant difference of genotype distribution and allele frequency on IL-10 –819 T/C between our population and other Japanese populations previously reported (26,27), suggesting the absence of remarkable genetic heterogeneity in our population.

Association of IL-10 promoter polymorphisms with longevity was previously shown in two studies. Lio and colleagues (8) first reported that the frequency of the IL-10 –1082 G/G genotype was increased in centenarian men, but not in centenarian women, compared with control participants <60 years old. No difference was found between centenarians and controls for the –819 T/C and –592 A/C genotype distributions. As several functional studies suggested a relation between IL-10 –1082 GG and AG genotypes with a higher production of IL-10 (28), the data indicated that IL-10, a major anti-inflammatory cytokine, could be involved in successful aging. In another study (9), haplotypes (GCC, ACC, ATA) were compared between elderly people in 10 families with longevity members and control participants 25–53 years old, indicating an increased or decreased frequency of the genotype GCC/GCC or ACC/ATA, respectively, in an elderly group. These reports suggested the importance of the G allele of –1082 A/G. However, no significant association of –1082 A/G with longevity was observed in Finnish nonagenarians (14), an aged Irish population (15), or Sardinian centenarians (14). As one possible explanation for such discrepancies, Pes and colleagues (17) suggested that cytokine–longevity associations have a population-specific component, being affected by the population-specific gene pool as well as by gene–environment interactions.

We showed that the genotype distribution of IL-10 –1082 A/G is different from that of –819 T/C or –592 A/C in the Japanese population used in this study. This result was consistent with previous findings in a Japanese population (29), but differed from those in Caucasian populations (8,14), which revealed that these 3 polymorphisms were strongly linked, and only 3 of 8 possible haplotypes (GCC, ACC, ATA) segregated in Caucasian populations (8,22). In our population, IL-10 –819 T/C was in perfect linkage disequilibrium with –592 A/C, whereas it was not with –1031 A/G [linkage disequilibrium was calculated as described previously (30); data not shown]. It was thus considered that there is little significance of this haplotype analysis in our population. The genotype distribution of these 3 polymorphisms was also quite different between our population and a Caucasian population (14). These findings clearly indicate a populational difference of the IL-10 promoter polymorphisms.

The effect of –1082 A/G on IL-10 gene transcription or protein production seems to be controversial at the present time (31). In contrast, Temple and colleagues (32) reported the –819 TT/–592 AA haplotype as a determinant of high IL-10 transcription when peripheral blood mononuclear cells were stimulated with lipopolysaccharide or heat-killed Streptococcus pneumoniae, and IL-10 messenger RNA was measured by reverse transcriptase–PCR, although it is still not clear whether the haplotype affects IL-10 production at the protein level. This finding might be supported by a recent association study showing that the IL-10 –592 A/A genotype was associated with a decreased risk of grade III or IV acute graft-versus-host disease and death in remission in 933 recipients after hematopoietic cell transplantation (33).

Further studies on different populations, and functional analyses of IL-10 –819 and –592 regions, are required to confirm the association of –819 T/C and –592 A/C with aging and to reveal whether the association is population specific.


   Acknowledgments
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 Participants
 Results
 Discussion
 References
 
This work was supported by Grant-in-Aid for Scientific Research (Encouragement of Scientists) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.


   Footnotes
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Decision Editor: James R. Smith, PhD

Received May 24, 2005

Accepted July 27, 2005


   References
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