Palm dermatoglyphs and interleukin‑4 receptor polymorphisms in asthma
- Authors:
- Published online on: November 7, 2016 https://doi.org/10.3892/br.2016.803
- Pages: 21-26
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Copyright: © Sun et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Since last century, the prevalence of asthma has increased worldwide, which has resulted in substantial morbidity and healthcare costs (1). Patients with different phenotypes have different outcomes and prognoses. The most effective treatment strategy to effectively control asthma, as suggested by the Global Initiative for Asthma (GINA), is to implement personalized treatment according to the different phenotypes of asthma. However, it is difficult to correctly and rapidly identify the phenotype using simple clinical features, without complicated or invasive examinations.
Genetic susceptibility is critical in the development of asthma; therefore, it is often used to identify the phenotypes of asthma. Interleukin-4 receptor (IL-4R) is important in regulating T helper (Th)2 cell development and immunoglobulin E (IgE) production via its response to IL-4 or IL-13 (2). The loci of IL-4R, located on genomic region 16p12, are linked to asthma phenotypes with increased airway mast cells and IgE (+) cells. Numerous single nucleotide polymorphisms (SNPs) in IL-4R gene have been associated with a phenotype of severe asthma (3,4). However, sequencing the IL-4R gene for every patient is not considered a feasible method of differentiating the phenotypes of asthma.
In the past two decades, the value of palm dermatoglyphic or fingerprint patterns has been described in the detection of bronchial asthma by different studies; however, the underlying mechanisms have not been clarified (5–8). In our previous study, a distinctive palm pattern was identified, which was characterized by deep grids in the thenar area that facilitated the diagnosis of asthma, with a close association to two a disintegrin and metalloprotein-33 (ADAM33) gene polymorphisms (9). The palm pattern appears to be a potential biomarker for endotypes of asthma, although the association between distinctive palm patterns and other SNPs associated with asthma have yet to be investigated.
Thus, in the present study, 11 SNPs of the IL-4R gene were analyzed in a population of East Chinese Han adults to clarify the link between a particular palm pattern and IL-4R gene polymorphisms.
Materials and methods
Subjects
A total of 400 asthma patients were recruited from the pulmonary clinics of two teaching hospitals, Qingdao Municipal Hospital (Qingdao, China) and Qingdao Haici Hospital (Qingdao, China) from January 2011 to January 2012 successively. Asthma was diagnosed and evaluated based on symptoms and on spirometry assessments by the criteria of the Global Initiative for Asthma (version: 2010 update) (10). Two-hundred healthy adults were recruited successively from the Health check-up centers of Qingdao Municipal Hospital and Qingdao Haici Hospital to serve as healthy controls. All control subjects were asymptomatic for asthma and devoid of any atopic or pulmonary diseases. Pregnant or lactating female subjects were excluded. The age range for all of the study subjects was 18–70 years old. Smoking status and education history data were collected for all subjects. The study was performed in accordance with the Helsinki Declaration and approved by the Ethics Committee of Qingdao Municipal Hospital and Qingdao Haici Hospital. In addition, all subjects provided written informed consent prior to the study.
Dermatoglyphic palm patterns
The palms of each subject were observed, after washing clean with soap and water, by two researchers under natural light. The palm patterns were determined by the dermatoglyphic variables in the thenar area, including number and shape of the ridges, as described in our previous study (9). A positive palm pattern typically exhibited an increased ridge count (≥10) and deep grid patterns in the thenar area, while a negative palm pattern demonstrated normal ridge count (<10) and light grid patterns in the thenar area. All subjects were sub-categorized into two groups; a positive palm pattern group and a negative palm pattern group according to the above standard.
Polymorphism genotyping
Whole blood (10 ml) was taken in lithium heparin-coated test tubes from each subject and immediately centrifuged at 1,600 × g. Buffy coat (peripheral white cells) was separated and stored at −70°C on the day of enrollment by a nurse. Genomic DNA was isolated from the peripheral blood leukocytes using a DNA extraction kit (Tiangen Biotech Co., Ltd., Beijing, China). The DNA was genotyped for the SNPs of the IL-4R gene at the Center for Human Genetics Research, Shanghai Genesky Bio-Tech Co., Ltd. (Shangai, China). Three SNPs of the IL-4R gene, rs1805010, rs1805012 and rs1801275, were selected according to the published literatures regarding SNP associations with asthma (11,12). Eight tag SNPs, rs3024608, rs1110470, rs3024685, rs3024619, rs2057768, rs3024585, rs12925861, and rs3024613, were then selected according to the frequency information for Chinese populations from two public databases the International HapMap Project (http://www.hapmap.org/) and the NCBI database (http://www.ncbi.nlm.nih.gov/). The PCR primers were designed by the authors and are presented in Table I.
Polymerase chain reaction (PCR) amplification of the corresponding genomic region surrounding each SNP locus was performed in a Takara PCR thermal cycler (Takara TP600; Takara Biotechnology Co., Ltd., Dalian, China). The reaction was performed in a final volume of 10 µl, including 3.0 mM Mg2+, 0.3 mM dNTP, 1 unit HotStarTaq polymerase (Qiagen Inc., Valencia, CA, USA), 1 µl of each primer, and 1 µl (10 ng) of genomic DNA. The cycling conditions were as follows: 1 Cycle at 95°C for 2 min, 11 cycles at 94°C for 20 sec, 65–0.5°C for 40 sec and 72°C for 1.5 min, and 24 cycles at 94°C for 20 sec, 59°C for 30 sec and 72°C for 1.5 min, and a final extension at 72°C for 2 min. The PCR products were purified using a PCR purification kit containing 1unit Shrimp Alkaline Phosphatase (SAP) and 1 unit Exonuclease I (Qiagen GmbH, Hilden, Germany) and were used as DNA templates for the cycle sequencing. Direct DNA sequencing was performed using 5 µl SNaPshot Multiplex kit (Applied Biosystems; Thermo Fisher Scientific, Inc., Waltham, MA, USA) in 10-µl volumes containing 2 µl primer and 2 µl DNA template, and were subjected to 1 cycle at 96°C for 1 min, 28 cycles of denaturation at 96°C for 10 sec, annealing at 52°C for 5 sec, and extension at 60°C for 30 sec. Sequencing products were purified using 1 unit SAP at 37°C for 1 h and annealing at 75°C for 15 min. All SNPs were detected with an ABI 3130xl, and the data were analyzed with GeneMapper 4.0 (Applied Biosystems; Thermo Fisher Scientific, Inc.). The association analysis between a single SNP and phenotype were conducted under five different genetic models (inheritance patterns) as follows: Codominant, dominant, recessive, overdominant and log-additive.
Statistical analysis
The differences in age, gender, body mass index (BMI), smoking status and education history between patients and control subjects were compared using the χ2 test or a t-test accordingly. The correlation between palm patterns and asthma severity was evaluated by Spearman analysis. The odds ratios (ORs) and 95% confidence interval (CI) of asthma risk of individuals with various genetic polymorphisms were calculated using logistic regression analysis adjusting for differences in gender. Hardy-Weinberg equilibrium and linkage disequilibrium was estimated using SNPAnalyzer version 2.0 (Istech Corp., Korea; http://istech21.com/). Statistical analyses were conducted using the SPSS for Windows version 17.5, statistical package (SPSS, Inc, Chicago, IL, USA) and P<0.05 was considered to indicate a statistically significant difference.
Results
Demographics
The demographics of the asthma group and the control group are presented in Table II. No significant differences were identified between the age, gender, BMI, smoking status, and education history of the asthma and control groups (all P>0.05).
 | Table II.Demographics of asthma patients and healthy control subjects (presented as means ± standard deviation). |
Polymorphisms with asthma
All genotype frequencies were consistent with Hardy-Weinberg equilibrium (P>0.05). The genotype distributions of all 11 IL-4R SNPs in the asthma and control groups are listed in Table III. There are two SNPs, rs1805012 and rs3024608, which are associated with asthma in different models as follows: rs1805012, dominant model (P=0.03) and rs3024608, codominant model (P=0.029).
| Table III.Genotype of interleukin-4 receptor SNPs in the asthma and control groups (adjusted for gender and age). |
Polymorphisms with palm patterns
The genotype distribution of all 11 IL-4R SNPs in the negative and positive palm groups are presented in Table IV. Two SNPs, rs1805010 and rs3024608, were associated with the positive palm pattern in different models as follows: rs1805010, log-additive model (P=0.031) and rs3024608, codominant model (P=0.016). Notably, rs3024608 is associated with asthma and the positive palm pattern. The rs1805010, rs1805012 and rs3024608 with different genotypes are presented in Fig. 1.
| Table IV.Genotype of interleukin-4 receptor SNPs in the negative and positive palm pattern groups (adjusted for gender and age). |
Discussion
In the present study, gene segments of 11 SNPs of the IL-4R gene were amplified to identify the genetic basis of the association between a distinctive palm dermatoglyphic pattern and asthma in a Chinese population.
As the results of SNP studies are not always consistent in different populations, the present study evaluated the role of SNPs of IL-4R in asthma development in the Chinese population. Although three SNPs, rs1801275 (−1902G/A), rs1805012 (1291T/C) and rs1805010 (−223G/A) demonstrated associations with asthma in previous studies (11–13), only rs1805012 exhibited an association with asthma (dominant model; P=0.03) in the current study. To further investigate the effect of IL-4R SNPs in asthma, eight tag SNPs of the IL-4R region were investigated for an association with asthma, to the best of our knowledge, for the first time. Of these SNPs, two were associated with asthma in a different model: rs1805010, log-additive model (P=0.031) and rs3024608, codominant model (P=0.016). Thus, polymorphisms of the IL-4R gene may be the genetic basis of asthma in this particular population.
Dermatoglyphs are formed in the 10th to 17th weeks of the embryological phase, when the neurologic and immunity systems are developing. Generally dermatoglyphs remain unchanged throughout an individual's life, except in cases of serious injuries that scar the dermis. Thus, a series of studies have identified the association of dermatoglyphic patterns with certain congenital defects or gene-associated diseases, such as Down's syndrome (14–17). However, few practical associations have been recognized in humans. Palm patterns are affected by many complex factors, for example age-associated changes, gender and ethnic differences. A distinctive palm pattern was identified in asthma patients using theories of Chinese Traditional Medicine (5). However, it is difficult to confirm the clinical significance of these dermatoglyph changes in clinical practice.
As asthma is a disorder associated with multiple genetic factors, establishing the gene polymorphisms associated with asthma is considered to be a convictive method to elucidate the implications of the association between a distinctive palm pattern and asthma. In our previous study, two SNPs of ADAM33, rs44707 and rs2787094, were identified to be associated with a positive palm pattern (6). In the current study, of 11 analyzed SNPs of IL-4R, two SNPs were found to be associated with the distinctive palm pattern in different models (rs1805010: Log-additive model, P=0.031; rs3024608: Codominant model, P=0.016). Notably, rs3024608 was associated with the positive palm pattern and asthma in the same population; thus, IL-4R polymorphisms may be the genetic basis of the association of the distinctive palm pattern and asthma.
Recently Chavarri-Guerra and Soto-Perez-de-Celis (14) described a 65-year-old woman with stage IV breast cancer, who lost her fingerprints following chemotherapy with capecitabine and bevacizumab (18). This indicated that dermatoglyphs may change as a condition of the disease (19,20). The clinical significance of dermatoglyphs requires further clarification using well-designed studies.
In conclusion, the genetic variation in IL-4R may be the basis of the association between asthma and a distinctive palm pattern. Considering the genetic variant, further studies with a prospective design in an unselected population are required to validate the association between a distinctive palm pattern and asthma, in order that a distinctive palm pattern may be considered as a biomarker for asthma development or phenotypes (21).
Acknowledgements
The authors would like to thank all participants of the study, and the Center for Human Genetics Research, Shanghai Genesky Bio-Tech Co., Ltd. for performing the SNP analysis. The current study was supported by a research grant from the National Natural Science Foundation of China (grant nos. 30873315 and 81400024).
Glossary
Abbreviations
Abbreviations:
|
SNP |
single nucleotide polymorphisms |
|
IL-4 |
interleukin-4 |
|
IL-13 |
interleukin-13 |
|
IL-4R |
interleukin-4 receptor |
|
GINA |
Global Initiative for Asthma |
|
ADAM33 |
a disintegrin and metalloprotein-33 |
|
PCR |
polymerase chain reaction |
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