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Published ahead of print on February 15, 2007, doi:10.1164/rccm.200607-992OC
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American Journal of Respiratory and Critical Care Medicine Vol 175. pp. 881-887, (2007)
© 2007 American Thoracic Society
doi: 10.1164/rccm.200607-992OC

Original Article

Ethnicity-specific Gene–Gene Interaction between IL-13 and IL-4R{alpha} among African Americans with Asthma

Natalie C. Battle1,2,*, Shweta Choudhry1,2,*, Hui-Ju Tsai1,2, Celeste Eng1,2, Gunjan Kumar1,2, Kenneth B. Beckman3, Mariam Naqvi1,2, Kelley Meade3, H. George Watson4, Michael LeNoir5 and Esteban González Burchard1,2 on behalf of the SAGE (Study of African Americans, Asthma, Genes, and Environments) Investigators

1 University of California, San Francisco, San Francisco, California; 2 Lung Biology Center, UCSF Mission Bay Campus, San Francisco, California; 3 Children's Hospital Oakland Research Institute (CHORI), Oakland, California; 4 The James A. Watson Wellness Center, Oakland, California; and 5 Bay Area Pediatrics, Oakland, California

Correspondence and requests for reprints should be addressed to Esteban González Burchard, M.D., M.P.H., University of California, San Francisco, San Francisco, CA 94143-2911. E-mail: esteban{at}sfgh.ucsf.edu


   ABSTRACT
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 ABSTRACT
AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Rationale: Genes in the interleukin (IL)-4/IL-13/IL-4R{alpha} pathway have been shown to be associated with asthma and related phenotypes in some populations, but not in others. Furthermore, interaction between these genes has been shown to affect asthma in white and Chinese populations.

Objectives: To determine whether there are IL-4/IL-13 and IL-4R{alpha} gene–gene interactions that are associated with asthma in African Americans.

Methods: Eighteen single-nucleotide polymorphisms (SNPs) in IL-4, IL-13, and IL-4R{alpha} genes were genotyped in 264 African Americans with asthma and 176 healthy control subjects. We tested the SNPs for genetic associations and gene–gene interactions with asthma, baseline lung function, bronchodilator drug response, and total serum IgE levels.

Measurements and Main Results: We identified 94 SNPs in IL-4, IL-13, and IL-4R{alpha} genes by directly sequencing these genes in 24 African-American subjects with asthma. Seventeen SNPs were analyzed for association with asthma and related phenotypes. We found no evidence of association in the IL-4 gene. One SNP in the IL-13 gene (A–646G, rs2069743) and two SNPs in the IL-4R{alpha} gene (A+4679G, rs1805010, and C+22656T, rs1805015) showed association with lung function (both baseline and post-bronchodilator). Although the association between individual SNPs and asthma-related phenotypes differed from previous studies performed in white and Chinese populations, significant gene–gene interaction was found between the IL-13 (A–646G) and IL-4R{alpha} (A+4679G) SNPs for baseline lung function among African-American subjects with asthma.

Conclusions: Gene–gene interaction between the IL-13 and IL-4R{alpha} genes may play an important role in asthma among African Americans.

Key Words: asthma • African Americans • gene–gene interaction



   AT A GLANCE COMMENTARY
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Scientific Knowledge on the Subject
IL-4, IL-13, and IL-4R{alpha} have been associated with asthma-related phenotypes in other populations, but have not been thoroughly studied in African Americans.

What This Study Adds to the Field
Gene–gene interaction between the IL-13 and IL-4R{alpha} genes may play an important role in asthma among African Americans.

 
Asthma is a common yet complex disease caused by a variety of genetic and environmental factors. Symptoms for asthma include wheezing, coughing, bronchial hyperresponsiveness, elevated total serum IgE levels, and allergy. Interleukin (IL)-4 and IL-13 are pleotropic, proinflammatory cytokines produced by activated T cells as part of an immune response to allergen exposure. The genes for IL-4 and IL-13 lie in a cytokine cluster on chromosome 5q31, a locus previously linked to several asthma phenotypes (1–4). The IL-4 and IL-13 cytokines share many structural and functional similarities, as well as a common receptor component, IL-4R{alpha}, located on chromosome 16p11. IL-4 plays important roles in the differentiation of T cells, eosinophilic inflammation, and isotype switching in B cells from IgM to IgE (4–8). IL-13 is a Th2 cytokine found to be overexpressed in the lungs of patients with asthma (4) and in murine models (1).

Investigations of the 5q31 locus have resulted in the discovery of significant associations between genetic variants in IL-4 and IL-13 genes and asthma or asthma-related phenotypes in some populations, but not in others (5, 9–13). We have previously identified an association between the IL-4 C–589T allele and asthma severity in whites but not in African Americans (9). Similarly, Basehore and colleagues reported nine SNPs in the IL-4 gene that were significantly associated with asthma or total serum IgE in whites (5). Only one of these SNPs, an intronic SNP (G+3017T), was marginally associated with IgE levels in African Americans and Hispanics (5). However, this SNP was not associated with asthma or IgE levels in other populations (5, 6, 9, 10, 12).

Because asthma is a complex disease, it may be useful to examine gene–gene interactions, particularly between the ligands IL-4 and IL-13 and their shared receptor component, IL-4R{alpha}. Howard and coworkers studied the effects of polymorphisms in IL-13 and IL-4R{alpha} genes in a white Dutch population (11, 14). They found associations between asthma-related phenotypes and polymorphisms in both the IL-13 and IL-4R{alpha} genes, as well as evidence of gene–gene interaction between IL-13 C–1112T and IL-4R{alpha} C+22656T (S478P) SNPs as a contributor to asthma susceptibility (11, 14). In another study, Chan and associates reported significant gene–gene interactions between the IL-13 R130Q and IL-4R{alpha} Ile50Val (A+4679G) polymorphisms for asthma risk in a Chinese population (15).

Although African Americans experience higher rates of asthma prevalence and mortality than whites (16), few genetic association studies for asthma have focused specifically on the roles of the IL-4, IL-13, and IL-4R{alpha} genes in this population (5, 10, 17). Of these studies, none have examined the effects on asthma of interactions between these genes. This is important because populations may be influenced by ethnicity- or race-specific genetic or environmental modifiers, which could influence genetic effects (18). Our study attempts to determine whether there are gene–gene interactions between genetic variants in the IL-4, IL-13, or IL-4R{alpha} genes that influence asthma or related phenotypes in African Americans, as have been described previously in whites (14).


   METHODS
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 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Participants
Recruitment and patient characteristics are described elsewhere and in detail in the online supplement (19). Briefly, as part of the Study of African Americans, Asthma, Genes, and Environments (SAGE), investigators recruited cases and control subjects from community clinics within San Francisco and Oakland, California. Ethnicity was self-reported, and subjects were only enrolled if both biological parents and all grandparents were of African-American ethnicity. Local institutional review boards and clinics approved the study, and age-appropriate written consent was obtained from all study participants. Table 1 lists clinical characteristics of patients with asthma and healthy control subjects.


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  		TABLE 1. DEMOGRAPHIC AND CLINICAL CHARACTERISTICS OF THE 264 SUBJECTS WITH ASTHMA AND 176 CONTROL SUBJECTS IN THE SAGE STUDY

 
Asthma and Medical Questionnaire and Spirometry
All subjects with asthma completed a modified version of the 1987 American Thoracic Society Division of Lung Disease Epidemiology Questionnaire to collect information on asthma and allergy symptoms (20). Results from spirometric tests were expressed as a percentage of the predicted normal value, as calculated by age- and race-adjusted Hankinson equations (21). FEV1 was used as a quantitative measure of baseline lung function (pre-FEV1). FEV1 was measured again after the administration of albuterol (post-FEV1). Bronchodilator responsiveness ({Delta}FEV1) was reported as the percentage of change in baseline FEV1 after the administration of albuterol. Pulmonary function tests are described further in the online supplement. Total plasma IgE for subjects with asthma was measured in duplicate using Uni-Cap technology (Pharmacia, Kalamazoo, MI).

Single-Nucleotide Polymorphism Discovery
Single-nucleotide polymorphism (SNP) discovery for the IL-4, IL-13, and IL-4R{alpha} genes was performed using our SNP discovery panel of 24 unrelated African-American subjects with asthma. All exons, exon–intron boundaries, and the 1-kb promoter region upstream of IL-4, IL-13, and IL-4R{alpha} genes were sequenced. Sequencing was performed using the BigDye Terminator Cycle Sequencing Kit (Applied Biosystems, Foster City, CA) and the ABI Prism 3700 sequencer (Applied Biosystems).

Genotyping
A total of 94 SNPs were identified in IL-4, IL-13, and IL-4R{alpha} genes. SNPs were selected for genotyping based on functional significance, minor allele frequency > 5% in our population, linkage disequilibrium (LD) patterns, and association with asthma and related phenotypes in previous studies. Eighteen SNPs in IL-4, IL-13, and IL-4R{alpha} genes were selected for genotyping. Schematic diagrams for IL-4, IL-13 and IL-4R{alpha} genes with the genotyped SNPs are provided in Figure 1. Additional SNP details are provided in Table 2. Genotyping methods and conditions are described in detail in the online supplement.


Figure 1
Figure 1
Figure 1
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  		Figure 1. Schematic diagrams of (A) IL-4, (B) IL-13, and (C) IL-4R{alpha} genes with the genotyped single-nucleotide polymorphisms.

 

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  		TABLE 2. SINGLE-NUCLEOTIDE POLYMORPHISMS GENOTYPED IN IL-4, IL-13, AND IL-4R{alpha} GENES

 
Population Stratification
To test for confounding due to population stratification, we genotyped a subset of the samples (176 cases and 176 controls) using 31 Ancestry Informative Markers. As previously described, we did not find evidence of genetic confounding due to population stratification for asthma disease status or asthma-related phenotypes (19). Thus, individual genetic admixture was not included as a covariate in subsequent analyses.

Statistical Analysis
Statistical analyses are described in detail in the online supplement. SNPs were analyzed for Hardy-Weinberg equilibrium (HWE) in control subjects using the {chi}2 goodness-of-fit test. Pairwise LD was estimated separately for cases and control subjects using the program LD Plotter (22). Haplotypes were reconstructed using the program PHASE version 2.1 (23).

The difference in allele frequency between subjects with asthma and control subjects was tested using {chi}2 analysis. Tests for association with asthma disease status among cases and control subjects were performed using logistic regression analysis, adjusting for covariates. Tests for association with pre-FEV1, post-FEV1, {Delta}FEV1, and total serum IgE among cases only were performed using linear regression. An additive model was used for all regression analyses. IgE levels were transformed to their log values before analysis for normalization.

To test for the effects of gene–gene interaction, we used the model described by Howard and colleagues (14). SNPs with the strongest evidence for association from our analysis of IL-4 and IL-13 genes were paired with SNPs most strongly associated in IL-4R{alpha}. These SNP pairs were examined for association with asthma, pre-FEV1, post-FEV1, {Delta}FEV1, and log10 IgE. All regression analyses were performed using the statistical software package Stata/SE 9.0 (Stata Corp., College Station, TX). Analyses were not adjusted for multiple testing because we were attempting to replicate previous findings of association between SNPs in these genes and asthma-related phenotypes.


   RESULTS
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 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
A total of 264 African-American subjects with asthma and 176 healthy control subjects were included in this analysis. Table 1 shows the demographic and clinical characteristics of subjects with asthma and control subjects analyzed in the study. Cases and control subjects were well matched with respect to gender, sex proportion, and average socioeconomic status. Control subjects were older than cases on average (p < 0.01). This was purposely done to ensure that control subjects would not develop asthma at an older age.

Table 2 shows the number of cases and control subjects with genotype information for each SNP. For each SNP, the genotype success rate was greater than 96%. All SNPs were tested for HWE using the goodness-of-fit test among control subjects. One SNP was found to be out of HWE with a p value <= 0.01: C+22448T in IL-4R{alpha} (p value = 0.004). This SNP was excluded from further analyses. We did not find any significant differences in allele frequency between subjects with asthma and control subjects for the remaining 17 SNPs tested using {chi}2 test or logistic regression analysis (Table 2).

Pairwise LD was computed between 17 SNPs using the r2 statistic. The LD patterns were computed separately for cases and control subjects and also for cases and control subjects combined (see Table E1 of the online supplement). Overall LD was low with one exception: C–33T and C+8427A of the IL-4 gene had an r2 value of 0.69. In the IL-4R{alpha} gene, linkage between A+4679G in exon 5 and the other three SNPs in exon 11 was very low (r2 < 0.006). No significant LD was observed between SNPs on different genes. This suggests that polymorphisms in the three genes are not transmitted together. There was no significant difference in LD pattern between cases and control subjects.

Association Analysis for Asthma-related Phenotypes
Of the 17 SNPs tested, 2 were significantly associated with asthma-related phenotypes. The IL-13 A–646G allele was associated with post-FEV1 (p = 0.009) and {Delta}FEV1 (p = 0.019) (Table 3). Subjects with the IL-13 –646G allele had lower post-FEV1 and lower bronchodilator drug responsiveness compared with those subjects with the A allele. This SNP also had a trend of association with pre-FEV1 (p = 0.064). The IL-4R{alpha} C+22656T allele was associated with post-FEV1 (p = 0.049). This SNP had a trend for association with pre-FEV1 (p = 0.066). In addition, there was a trend for association between the IL-4R{alpha} A+4679G allele and pre-FEV1 (p = 0.064) and post-FEV1 (p = 0.092). No SNPs in the IL-4 gene were significantly associated with any of the five phenotypes tested (Table 3).


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  		TABLE 3. ASSOCIATION ANALYSES OF IL-4, IL-13, AND IL-4R{alpha} GENOTYPES WITH LUNG FUNCTION, RESPONSE TO ALBUTEROL, AND IgE LEVELS IN SUBJECTS WITH ASTHMA

 
Haplotype Association Analysis
Separate haplotypes were reconstructed for each of the three genes. There were 8, 196, and 14 haplotypes observed for IL-4, IL-13, and IL-4R{alpha} genes, respectively. In addition, 5, 13, and 13 haplotypes observed for the IL-4, IL-13, and IL-4R{alpha} genes, respectively, had frequencies of greater than 2%. No significant associations were found between haplotypes for IL-4, IL-13, or IL-4R{alpha} and asthma disease status, pre-FEV1, post-FEV1, {Delta}FEV1, or log IgE levels (results not shown) except for a borderline association between the major IL-4 haplotype pair (TTAA/CCAC) and higher risk for asthma (p = 0.03).

Gene–Gene Interaction Analysis
In testing for the effects of gene–gene interaction between the IL-4/IL-13 genes and the IL-4R{alpha} gene on asthma in our population, we followed the method described previously (14). Individual SNPs that were significant or that approached significance for association with asthma-related phenotypes were selected from each gene for gene–gene interaction analysis. These SNPs were A–646G in the IL-13 gene, and A+4679G and C+22656T in the IL-4R{alpha} gene.

Results from gene–gene interaction analysis are shown in Table 4. The IL-13 A–646G and the IL-4R{alpha} A+4679G SNPs interacted significantly for pre-FEV1 (p = 0.042) and a trend was observed for log IgE levels (p = 0.09). No other significant associations were found.


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  		TABLE 4. p VALUES FOR GENE–GENE INTERACTION ANALYSIS*

 

   DISCUSSION
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 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
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 DISCUSSION
REFERENCES
 
Genetic variants in IL-4, IL-13, and IL-4R{alpha} genes have been linked to asthma and related phenotypes in various populations. In this study, we analyzed the effects of genetic variants and haplotypes in these genes in an African-American asthmatic cohort. We also examined the effects of gene–gene interaction between SNPs that showed an association with asthma or asthma-related phenotyes. One genetic variant in the IL-13 gene was significantly associated with post-FEV1 and bronchodilator responsiveness. Another variant in the IL-4R{alpha} gene was associated with post-FEV1. Two SNPs, which were modestly correlated with baseline lung function independently of each other, interacted to significantly affect this phenotype. Although our results from the interaction analysis were consistent with our results from the single SNP analysis, neither SNP reached statistical significance in association with pre-FEV1 alone. Both polymorphisms may have modestly contributed to baseline lung function individually, but the effect was more pronounced when the SNPs interacted in our cohort.

Our results show that genetic variants in IL-13 and IL-4R{alpha} genes may interact to affect baseline lung function in African-American subjects with asthma. Interaction between genetic variants in these genes has previously been shown to influence asthma susceptibility in several populations. In a study by Chan and colleagues, the IL-4R{alpha} (A+4679G) allele was shown to interact with the IL-13 (R130Q) allele to influence asthma risk in a Chinese cohort (15). Similarly, Howard and associates' report on Dutch subjects with asthma demonstrated an interaction between the IL-13 (C–1112T) and IL-4R{alpha} (C+22656T) alleles for asthma susceptibility (14). Although the SNPs that interacted in our cohort differed from those of Chan and colleagues or Howard and coworkers, our results suggest that interaction between IL-13 and IL-4R{alpha} genes may play a role in lung function in our population as well. It has been suggested that replication of complex genetic associations may be more informative on a genewide level as opposed to the individual SNP level, especially among different populations (24). To our knowledge, this study is the first to test the effects of gene–gene interaction between IL-4, IL-13, and IL-4R{alpha} genes and asthma in an African-American population.

Gene–gene interaction between IL-4 and IL-4R{alpha} and asthma has been demonstrated in several populations (25, 26). Because no significant or moderately significant associations were found for IL-4 SNPs in our population, we did not test for interaction between this gene and IL-4R{alpha}. It is still possible, however, that there was an interaction between these two genes, but the effects were not detectable via single SNP analysis. Although we may have been underpowered due to sample size, our sample size of 264 cases and 176 control subjects is comparable to other genetic association studies for these genes. Finally, the interaction with IL-4R{alpha} could be with alternative SNPs in the IL-4 gene, which were not analyzed in our study.

Although our results were globally consistent with previous studies of gene–gene interactions, our results were not entirely consistent with studies of individual SNPs. For example, polymorphisms in the IL-4 gene, in particular the C–589T and C–33T alleles, have been linked to asthma and related phenotypes in some studies (5, 6, 9, 10, 12), but not in others (26, 27). One or both of these promoter SNPs has been linked to asthma, total serum IgE levels, or allergy in white (5, 6, 10, 12) and Japanese (28) populations. In contrast, we did not find any associations between IL-4 SNPs and asthma (pre- or post-FEV1), drug responsiveness, or total serum IgE. However, our results were fairly consistent with Basehore and colleagues' study of 168 African-American subjects with asthma and 269 African-American control subjects (5). Basehore and coworkers genotyped 11 IL-4 SNPs (including C–589T, C–33T, and A+8427A) in white, African-American, and Hispanic populations; 9 of the 11 SNPs were significantly associated with an asthma-related phenotype in whites. However, only one of these SNPs (G+3017T), which was not genotyped in our population, was associated with an asthma-related phenotype in African Americans or Hispanics. Likewise, Donfack and colleagues (10) found associations between C–589T and/or C–33T and asthma-related phenotypes in Europeans and Hutterites, but not in African Americans. We have previously reported an association between the IL-4 C–589T allele and baseline FEV1 in whites but not in African Americans (9). These studies may suggest that, although polymorphisms in the IL-4 gene may be significant contributors to asthma in whites, their effects may be attenuated in African Americans. Alternatively, SNPs in the IL-4 gene may not themselves be biological contributors to asthma but may be in LD with other SNPs that are biological contributors to asthma in whites, but not in African Americans. Furthermore, Basehore and colleagues noted that IL-4 G+3017T SNP was in LD with at least three other SNPs.

In contrast to our results for the IL-4 gene, we found evidence of association between a promoter SNP (A–646G) in the IL-13 gene and post-FEV1 and drug response, and a trend for association with baseline lung function. SNPs in the promoter region of the IL-13 gene have been associated with various asthma-related phenotypes in other studies. Donfack and colleagues described an association between a two-SNP haplotype containing IL-13 (C–1112T) and IL-4 (G+3017T), and allergic sensitization to molds in an African-American population (10). This result confirmed the results of a study by van der pouw Kraan and colleagues, who found an association between IL-13 (C–1112T) and allergic asthma in another population (referred to as –1055 in van der pouw Kraan and colleagues' study) (13).

It has been shown that soluble IL-4R protein levels are found in higher concentrations in patients with asthma than in healthy control subjects, lending support to a possible role in the pathogenesis of asthma (29). Genetic variants in IL-4R{alpha} have been examined several times in association studies for asthma (14, 29) and other related phenotypes (6, 30), although findings were not consistent (31). In our population, two SNPs in the IL-4R{alpha} gene (A+4679G and C+22656T) showed a trend of association with pre-FEV1. Patients with asthma with the minor allele at IL-4R{alpha} (A+4679G) or the major allele at IL-4R{alpha} (C+22656T) had lower baseline lung function.

We have previously demonstrated that genetic and pharmacogenetic associations for asthma vary among different racial and ethnic groups (18, 19). This has been confirmed for other diseases as well (18). For example, a meta-analysis has shown that the impact of apolipoprotein (APO)-E4 on Alzheimer's disease varies by race (32). Although there are many potential explanations for these observations, one possibility is that there are unique racial and ethnicity-specific modifiers (genetic and environmental) that attenuate or accentuate genetic risk factors.

In this study, we were able to replicate findings of gene–gene interaction between IL-13 and IL-4R{alpha} and asthma-related phenotypes, which has been shown in other populations. However, we were unable to replicate previous single SNP associations with these phenotypes. One possible explanation is that genetic associations may be affected by differing LD patterns between ethnic groups (e.g., Africans typically have less LD when compared with other populations). The differences in LD between racial groups can be exploited to identify putative disease-causing genetic variants. Specifically, examination of SNP associations across multiple ethnic groups may reveal precisely which SNPs are consistently observed to be associated in the different populations, regardless of LD pattern. For example, in cloning the phenylthiocarbamide (PTC) bitter-taste gene, three different amino acid substitutions were observed to be associated with taste blindness (33). Although there was strong to complete LD among these SNPs in most populations, it was also observed that studies of Africans could disentangle the effects of individual SNPs because of reduced LD in this group. Similar such examples have been provided in the association study of adult macular degeneration (34, 35). Such findings underscore the importance of studying multiple ethnic and racial groups in genetic association studies.


   FOOTNOTES
 
Supported by the National Institutes of Health (K23 HL04464, HL078885, HL07185, GM61390), the American Lung Association of California, RWJ Amos Medical Faculty Development Award, NCMHD Health Disparities Scholar, Extramural Clinical Research Loan Repayment Program for Individuals from Disadvantaged Backgrounds, 2001–2003 (E.G.B.), the American Thoracic Society "Breakthrough Opportunities in Lung Disease" (BOLD) Award and Tobacco-Related Disease Research Program New Investigator Award (15KT-0008) (S.C.), NCMHD grant 1P60MD000222-01 (K.B.B.), UCSF–Children's Hospital of Oakland Pediatric Clinical Research Center (M01 RR01271), Oakland, California, the Sandler Center for Basic Research in Asthma, and the Sandler Family Supporting Foundation.

* These authors contributed equally to this article. Back

This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Originally Published in Press as DOI: 10.1164/rccm.200607-992OC on February 15, 2007

Conflict of Interest Statement: N.C.B. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.C. has no financial relationship with a commerical entity that has an interest in the subject of this manuscript. H.T. has no financial relationship with commercial entity that has an interest in the subject of this manuscript. C.E. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. G.K. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. K.B. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.N. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. K.M. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. H.G.W. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.L. has been reimbursed as a consultant on a community grant dealing with asthma in the African American community; he has received $155,000 from GlaxoSmithKline directly over 3 years plus a grant. E.G.B. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form July 20, 2006; accepted in final form February 15, 2007


   REFERENCES
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 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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