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 Table of Contents  
ORIGINAL ARTICLE
Year : 2012  |  Volume : 2  |  Issue : 2  |  Page : 51-55

Association of IL-4 gene polymorphism and age-related macular degeneration in Taiwanese adults


1 Department of Ophthalmology, Kaohsiung Veterans General Hospital, Kaohsiung; School of Medicine, National Yang-Ming University, Taipei, Taiwan
2 Department of Research and Education, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
3 Department of Ophthalmology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

Date of Web Publication19-May-2012

Correspondence Address:
Shwu-Jiuan Sheu
Kaohsiung Veterans General Hospital, Number 386, Ta-Chung First Road, Kaohsiung 813
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.1016/j.tjo.2012.02.002

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  Abstract 

Purpose: The purpose of this study was to determine whether interleukin (IL)-4 genetic variants are associated with age-related macular degeneration (AMD).
Methods: The genotyping of IL-4 -590 and intron 3 variable number of tandem repeats (VNTR) was conducted for 171 patients with AMD and 134 controls by using TagMan and polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assays.
Results: There was no difference in distribution of age, sex, body mass index, and status of systemic disease between AMD patients and healthy controls. Significantly, more patients were current smokers in the AMD group compared with the controls (p = 0.038). The genotypes of IL-4 -590 and intron 3 VNTR were associated with the risk of AMD in our results. In the stratification analysis, both IL-4 -590 allelic type and smoking status were independently associated with AMD. No interactions between allelic type and smoking were found to contribute to risk of AMD. The mean AMD score was significantly higher in carriers with IL-4 -590 T/T or T/C genotypes compared with those with C/C.
Conclusions: Our results support the hypothesis that polymorphisms of IL-4 -590 and intron 3 VNTR might be a genetic marker for the development of AMD.

Keywords: age-related macular degeneration (AMD), interleukin-4 (IL-4), polymorphism, Taiwan


How to cite this article:
Sheu SJ, Ger LP, Kuo NW, Liu NC, Wu TT, Lin MC. Association of IL-4 gene polymorphism and age-related macular degeneration in Taiwanese adults. Taiwan J Ophthalmol 2012;2:51-5

How to cite this URL:
Sheu SJ, Ger LP, Kuo NW, Liu NC, Wu TT, Lin MC. Association of IL-4 gene polymorphism and age-related macular degeneration in Taiwanese adults. Taiwan J Ophthalmol [serial online] 2012 [cited 2020 Jul 2];2:51-5. Available from: http://www.e-tjo.org/text.asp?2012/2/2/51/203722




  1. Introduction Top


Age-related macular degeneration (AMD) is an important cause of loss of vision as people age.[1] The exact pathogenesis of AMD is not known. A number of possible mechanisms have been postulated, including genetic, vascular, Bruch membrane permeability abnormalities, photo-oxidative damage, and increased growth factors or cytokines. Varieties of risk factors for AMD have been incriminated from various epidemiologic studies, suggesting that the condition is multifactorial in etiology involving genetic and environmental factors. The risk factors include age, race/ethnicity, heredity, smoking, sex, socioeconomic status, iris color, macular pigment density, cataract and its surgery, refractive error, cup/disk ratio, cardiovascular disease, hypertension and blood pressure, serum lipid level and dietary fat intake, body mass index hematological factors, reproductive and related factors, dermal elastotic degeneration, antioxidant enzyme, sunlight exposure, micro-nutrients, dietary fish intake, and alcohol consumption.[2]

Although studies regarding the roles of major genes associated with AMD in different populations bloomed recently, there was no conclusion about the exact pathogenesis of AMD.[3],[4] Increasing evidence suggests the role of inflammation in AMD.[5],[6] The relationship between AMD and inflammation further supports genetic studies to identify inflammation-associated single nucleotide polymorphisms (SNPs) that modulate AMD risk. These SNPs focus on gene encoding complement factors, chemokines and chemokine receptors, and toll-like receptors.[7],[8],[9],[10],[11],[12],[13],[14],[15]

Interleukins (ILs) help mediate many of the effector phases of immune and inflammatory response. Several ILs, including IL-6, -8 and -10 have been found to be associated with AMD.[10],[15],[16],[17],[18] IL-4 is a key cytokine in humoral and adaptive immunity. A SNP located at -590 has been reported to affect its transcriptional activity. Previous studies demonstrated that T allele is correlated with higher level of serum IL-4, whereas the C allele is correlated with lower level of serum IL-4.[19],[20] Another polymorphism which is composed of a variable number of tandem repeats (VNTR) of a 70-bp sequence and is located within the third intron of the IL-4 gene may also influence the production of IL-4.[21] Recent studies on the association of IL-4 gene polymorphisms with AMD are limited, although a report has showed that it might be related to the ocular surface inflammatory disorders.[22] In this report, we examine IL-4 -590 T polymorphism with the development of AMD. The influence on the severity of AMD was also analyzed.


  2. Methods Top


We recruited 171 patients with AMD and 134 controls without any fundus abnormality from the outpatient clinic of the Department of Ophthalmology, Kaohsiung Veterans General Hospital. All types of AMD patients were included. Care was taken to exclude patients who reported any infective or autoimmune diseases, which might interfere with the analysis. The fundus image and fundus fluorescent angiography were performed by using a digital fundus camera (Visupac 450, Zeiss FF450, Germany). The grading of AMD uses a simplified severity scale for AMD.[23] The scale is based on the presence or absence in each eye of two easily identified retinal abnormalities, drusen and pigment abnormalities. The scoring system assigns to each one risk factor for the presence of one or more large drusen and one risk factor for the presence of any pigment abnormality (dry AMD). For persons with neovascular AMD, two risk factors are assigned to that eye (exudative AMD). Risk factors are then summed up across both eyes, yielding a five-step scale (0–4). Recruited patients were older than 55 and have any subtypes of AMD. The healthy controls without any fundus abnormality were from out patient clinic and frequency-matched to case patients on age (± 5 years) and sex. In addition to blood sampling, all patients were asked to complete a questionnaire regarding demographic data and modifiable lifestyle factors. Informed consent was obtained from all participants by way of a consent form approved by the Institutional Review Board for Human Research of Kaohsiung Veterans General Hospital. The procedures used conformed to the tenets of the Declaration of Helsinki.

2.1. Polymorphism genotyping

Genomic DNA was extracted and purified from buffy coat cells using QIAamp DNA blood Midi kit according to the manufacture’s instructions (Qiagen Sciences, Germantown, MD, USA). The detection of genotypes of single nucleotide polymorphisms in IL-4 -590 (rs2243250) were performed by the TagMan real-time polymerase chain reaction (RT-PCR) method (Applied Biosystems, Foster City,

CA, USA), and then analyzed by the ABI PRISM 7500 Sequence Detection System (Applied Biosystems, Foster City, CA, USA) in a 96-well format. PCR reactions were carried out in reaction mixes containing 10 ng DNA, 5 ml 2 × TagMan Universal PCR Master Mix (Applied Biosystems), 0.5 ml 20 × Primer/Probe mixture, and ddH2Otoa final volume of 10 ml. The PCR program was as follows: 95°C for 10 minutes, followed by 40 cycles of 15 seconds at 92°C, and 1 minute at 60° C. One no template control (NTC) in each 96-well format was used for quality-control procedures. The allelic-specific fluorescence data from each plate were analyzed using SDS v1.3.1 software (Applied Biosystems) to automatically determine the genotype of each sample.

The VNTR of IL-4 intron 3 was determined by PCR-based assay with primers already described, 5’-AGGCTGAAAGGGGGAAAGC-3’ and 5’-CTGTTCACCTCAACTGCTCC-3’.[24] The PCR reaction was performed in a 20-μl reaction mixture containing 1 × PCR buffer (10 mM KCl, 2 mM MgSO4, 20 mM Tris-HCl (pH 8.8), 0.1% Triton X-100,10 mM (NH4)2SO4 and 0.1 mg/ml BSA), 0.1 mM dNTPs, 0.1 μM each forward and reverse PCR primers, and 0.5 units Taq polymerase (Yeastern Biotech Co., Ltd, Taipei, Taiwan). The PCR cycling conditions for amplification of polymorphism in intron 3 VNTR was 95° C for 5 minutes, followed by 30 cycles at 95° C for 30 seconds, 58°C for 45 seconds, 72°C for 45 seconds, and a final extension step at 72° C for 10 minutes. Then, the PCR products were separated by 2.5% agarose gels containing ethidium bromide for 15 minutes at 150 V. The separated DNA fragments for VNTR polymorphism were 183 bp (two 70-bp repeats) and 253 bp (three 70-bp repeats) for RP1 and RP2 alleles, respectively.

The quality-control procedures are implemented to ensure high genotyping accuracy in our laboratory. A sample of each genotype assayed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) was randomly selected for DNA sequencing to verify the allele sequence and the results were 100% concordant to the initial analysis. Next, 5% of the random samples of each genotype were repeated for each locus, and the results were 100% concordant to the initial analysis.

2.2. Statistical analysis

All genotype frequencies in each population were tested for deviation from the Hardy-Weinberg equilibrium by the χ2 test. The genotype frequencies for each polymorphism were determined by direct counting, and the allele and allele carriage frequencies were calculated. Differences in genotype frequencies between case and control participants were analyzed with a 2 × 3 unisquare with 2 degrees of freedom. The allele and allele carriage frequency were compared with a 2 × 2χ2 test. Statistical analysis was performed usingχ2 contingency table analysis for all categorical data of clinical phenotypes and laboratory variables, depending on the appropriate number of degrees of freedom. The Fisher exact test was used if any expected frequency was lower than five. The false discovery rate (FDR) was applied for a p value correction for multiple comparisons of all allelic or genotypic types. The calculation of FDR was done following the protocol described previously.[25] Briefly, the procedure runs as following: Starting from the smallest p value p(1), compare each p(i) with h(i) = minute (0.05, 0.05 xm/(m + 1-i)[2]). Reject the hypothesis corresponding to p(i) if it is smaller than or equal to the threshold h(1), and continue to reject the hypothesis as long as p(i) is less than or equal to Stop when p(k) > h(k) for the first time. Reject all of the hypotheses corresponding to the smallest k-1 p values. Student’s t-test was used to compare the means of the continuous variables, such as age. A p value < 0.05 was considered significant.


  3. Results Top


A total of 171 patients with AMD and 134 matched controls were recruited for the polymorphism study. Baseline patient demographics are summarized in [Table 1]. There was no difference in age, age distribution, and sex between patients with AMD and controls. Significantly more patients were current smokers in the AMD group than the control (p = 0.038). Other factors such as body mass index (BMI), hypertension, diabetes mellitus, and cardiovascular disease did not differ significantly between groups. Among controls, the genotype distributions were in Hardy-Weinberg equilibrium. The p values were 0.102 for IL-4 -590 and 0.312 for IL-4 intron 3 VNTR.
Table 1: Basic available demographic characteristics of the study population.

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The allelic and genotypic type frequencies of the IL-4 -590 and intron 3 VNTR in patients with AMD and controls are shown in [Table 2]. At locus -590 T > C, an increased risk was found for T allele [adjusted odds ratio (AOR) = 1.50, 95% confidence intervals (CI): 1.03–2.20], T/C genotype (AOR = 3.19, 95% CI: 1.06–9.59), T/T genotype (AOR = 3.71,95% CI: 1.27–10.83), and combined T/C + C/C genotype (AOR = 3.51, 95% CI: 1.22–10.09); however, only T/C genotype and the combined T/C + T/T genotype reach statistical significances after FDR correction. At locus intron 3 VNTR, no significant association was found between allelic type and risk of AMD. RP1/RP2 genotype (AOR = 5.92,95% CI: 1.21–29.03), RP1/RP1 genotype (AOR = 5.36, 95% CI: 1.12–25.74) and combined RP1/ RP2 + RP1/RP1 genotype (AOR = 5.56, 95% CI: 1.17–26.43) were correlated with the increased risk of AMD, even after FDR correction, except for the RP1/RP2 genotype.
Table 2: Distribution and odds ratios for patients with AMD and controls.

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Modest linkage disequilibrium (LD) was observed between the polymorphisms at locus -590 and locus VNTR in intron 3 (D0 = 0.892). The frequencies of C-RP1, C-RP2, T-RP1, and T-RP2 haplotypes were 2.9%, 17.0 %, 78.1%, and 2.0%, respectively, in AMD cases and 6.0%, 21.6%, 71.3%, and 1.1% in controls, respectively. No associations between the two-locus haplotypes and AMD risk were found (data not shown). In the stratification analysis, we found that people who carried T allele are more susceptible to develop AMD than controls even if they were (AOR = 2.76, 95% CI: 1.62–4.70, pcorrected < 0.001) or were not (AOR = 1.74, 95% CI: 1.13–2.70, pcorrected = 0.013) current smokers [Table 3]. It means that no interactions between allelic type and smoking status were found to contribute to risk of AMD. These result smight suggest that smoking was an important risk factor for AMD, but it cannot modulate the effect of the allelic type of IL-4 -590 on risk of AMD.
Table 3: Odds ratios for AMD according allelic type of IL-4-590 and smoking status.

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We further looked at the influence of the IL-4 -590 genotype on the severity of AMD. In patients with AMD, the mean AMD score of patients with IL-4 –590 T/T or T/C were significantly higher than those with IL-4 –590 C/C (C/C: 3.0 ± 0.7, T/C: 3.7 ± 1.0, T/T: 3.5 ± 1.1; T/C vs. C/C, p = 0.018; T/T vs. C/C, p = 0.010). Patients with AMD and IL-4 -590 C/C were mostly in the less severe group of AMD [Figure 1].
Figure 1: Association of IL-4 -590 genotype and the severity of AMD. Patients with T allele tend to have exudative AMD in at least one eye. AMD = age-related macular degeneration; IL = interleukin.

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  4. Discussion Top


Our study showed that genotypic types of IL-4 -590 and intron 3 VNTR are associated with the risk of AMD in Taiwanese adults. IL-4 -590 T/C genotype and the combined T/C + C/C genotype are associated with the increased risk for AMD. The RP1/RP1 genotype and combined RP1/RP2 + RP1/RP1 genotype were associated with the increased risk of AMD. In addition, the mean AMD score was significantly higher in carriers with IL-4 -590 T/T or T/C genotypes compared with those with C/C. Our results support the hypothesis that inflammation plays an important role in the development and progress of AMD.

IL-4 is a key cytokine that induce the activation and differentiation of B cells as well as the development of the Th2 subset of lymphocytes.[26] IL4 has effects not only on hematopoietic cells, including cells of innate and adaptive immune system, but also on a variety of structural cells. For example, it can potentiate proliferation of vascular endothelium cell.[27],[28] It also up regulates vascular cell adhesion molecule-1, which is a cell surface glycoprotein expressed by cytokine-activated endothelium that mediates the adhesion of monocytes and lymphocytes, which induce vascular inflammation.[29] Therefore, it is found as a mitogen for both microvascular capillary and large vessel.

There are two common polymorphisms in the IL-4 gene, -590 C/T and a 70-bp sequence variable number tandem repeat at intron 3, and many minor polymorphisms, such as -168, -33, 3437, 3557, 4047, 4144, 4271, 4367, and 8427.[30] The IL-4 -590 polymorphism is located upstream of all known control elements of IL-4, such as the negative regulatory element, the Nucleosome-free regions (NF-r) recognition sequence, and the Goldberg-Hogness box (TATA box).[31]

Both the C to T exchange at position -590 and RP1 allele at VNTR have been shown to enhance IL-4 production or activity by T cells.[20],[30] The rare RP2 allele for IL-4 intron 3 is a protective factor for joint destruction in patients with rheumatoid arthritis.[32] AMD is considered to be a complex genetic disease in which there are multiple genetic effects interacting with the environment to modify the susceptibility and severity of this disease. The immune system has been strongly implicated as a contributor to the pathogenesis of AMD. Many of the components of drusen are known immune and inflammatory factors. In our results, IL-4 -590T/T might play a role in AMD development and progress. It supported the association between inflammation and AMD. Recently, some studies have suggested a potential role for chlamydia pneumoniae infection in AMD pathogenesis.[18],[33] It is reported that the presence of risk-conferring CHF a complement factor H (CFH) variant and high C pneumoniae antibody titer significantly increased AMD risk.[34] It is possible that people carry IL-4 -590 T allele might overreact to pathogens or any external stimuli followed by persistent low-grade inflammation, and then predispose to AMD.

Several ILs, including IL-6, -8 and -10 have been found to be associated with AMD.[10],[15],[16],[17],[18] The AA genotype of IL-8 A251 and IL-8 C781T variant had been reported to increase risk of developing AMD. IL-10 was found to suppress or inhibit choroidal neovascularization by regulating macrophage activity in animal model and was proposed to be an attractive therapeutic target for AMD.[16] Our study showed the significant association of IL-4 -590 with AMD, which might help when investigating the pathogenesis and management of AMD. IL-4 -590 might be a genetic marker for the development of AMD.

Despite these findings, there are limitations to this study that are worth noting. This was a single-center cohort investigation of patients in southern Taiwan. The sample size was limited. In genetic study, large sample size is important to prevent false positive results. However, we couldn’t recruit more samples in our study because of our limited resources. Although FDR can not guarantee to prevent false-positive results, it is suggested as a practical method to control false discoveries in genetic study.[35] Our findings about IL-4 may be insufficient to clarify the complex interplays among a number of different genes controlling expression of cytokine in AMD. Therefore, replication studies with independent large cohorts are needed.

Acknowledgments

The study was supported by grant NSC96-2314-B-075B-011 from the National Science Council and Grants VGHKS98-063 and VGHKS 99-059 from the Kaohsiung Veterans General Hospital in Kaohsiung City, Taiwan.



 
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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3]


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