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Physical Function and Its Response to Exercise: Associations With Cytokine Gene Variation in Older Adults With Knee Osteoarthritis

¹ Sticht Center on Aging, Section on Gerontology and Geriatric Medicine, Department of Internal Medicine, ² Center for Human Genomics, and ³ Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
⁴ Department of Health and Exercise Sciences, Wake Forest University, Winston-Salem, North Carolina.

Address correspondence to Barbara J. Nicklas, PhD, J. Paul Sticht Center on Aging, Wake Forest University School of Medicine, Winston-Salem, NC 27157. E-mail: bnicklas{at}wfubmc.edu

	Abstract

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Background. We determined whether physical function and its response to exercise training are associated with polymorphisms in cytokine genes (interleukin-6 [IL-6] –174 G/C; tumor necrosis factor alpha [TNF] –308 G/A and –238 G/A; and TNF receptors [TNFR]1 +36 A/G, TNFR2 +676 T/G, and TNFR2 +1663 A/G), in 214 older (60 years), overweight (body mass index 28 kg/m²) individuals with knee osteoarthritis.

Methods. Physical function (walking distance, stair-climb time, self-reported disability) was measured before and after an 18-month randomized, controlled exercise trial involving walking and weight lifting 3 days/week.

Results. In cross-sectional analyses, baseline walking distance was greater in individuals homozygous for the major G allele at IL-6 –174 compared to individuals with at least one C allele (p =.05). Both walking distance (p =.02) and stair-climb time (p =.003) were better in individuals homozygous for the major G allele of the TNF –308 polymorphism compared to those with at least one A allele. Walking distance was better (p =.02), and stair-climb time tended to be better (p =.06), in individuals homozygous for the major T allele of the TNFR2 +676 polymorphism. No associations were seen with self-reported physical disability nor with the other polymorphisms. In response to exercise, there was a significant interaction between TNF –308 genotype and exercise treatment on 6-month changes in stair-climb time (p =.007), and on 18-month changes in self-reported physical disability (p =.01), such that individuals with an A allele showed greater improvement in response to exercise.

Conclusions. Walking distance and stair climbing speed are partly influenced by genetic variation in the IL-6 and TNF genes in older individuals with knee osteoarthritis.

Chronic activation of inflammation is emerging as a biological mechanism underlying aging-related decline in physical function. Poorer physical function is associated with elevated concentrations of inflammatory markers (10,11), and inflammation predicts the loss of function and onset of disability (12–15). Moreover, chronic inflammation may play a pathophysiological role in the progression of osteoarthritis (16–20). Thus, we hypothesized that genes involved in regulation of inflammation are likely candidates for association with individual variation in physical function of older osteoarthritis patients. In the current study, we determined whether objective and self-reported measures of physical function are associated with polymorphisms in several cytokine-related genes (interleukin-6 [IL-6], tumor necrosis factor alpha [TNF], and the TNF receptors TNFR1 and TNFR2) in older osteoarthritis patients who were recruited for a large, randomized, controlled clinical trial involving diet and exercise. In addition, because there was wide variability in physical function responses to the exercise training intervention (21), we also hypothesized that changes in physical function in response to exercise would be related to genetic variation in these genes.

	METHODS

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Study Population
The study population consisted of older (60 years), overweight and obese (body mass index [BMI] 28 kg/m²), sedentary men and women who had been enrolled in the Arthritis, Diet and Activity Promotion Trial (ADAPT), a randomized, controlled trial to determine the effects of exercise- and diet-induced weight loss, alone and in combination, on physical function (22). All participants provided written, informed consent to participate in the study according to the Wake Forest University School of Medicine's Institutional Review Board. The screening protocol for study eligibility was published previously (21,22). In brief, participants were excluded if they: (a) did not have radiographic evidence of tibiofemoral osteoarthritis; (b) did not have knee pain; (c) had contraindications for participation in an exercise program, severe hypertension, recent stroke, chronic obstructive pulmonary disease, insulin-dependent diabetes, psychiatric disease, renal disease, liver disease, active cancer other than skin cancer, or anemia; (d) were not sedentary (>20 minutes of formal exercise per week); (e) had cognitive impairment (Mini-Mental State Examination score < 24); or (f) consumed 14 alcoholic drinks per week. Severity of tibiofemoral osteoarthritis was measured using the Kellgren–Lawrence grading scale (23).

A total of 316 individuals met the study criteria and were assigned to one of four treatments (exercise, dietary weight loss, exercise and dietary weight loss, or control). The trial was completed in early 2001, after which all participants were called back in 2001–2002 and asked to donate a blood sample for extraction of DNA for genetic analyses for the present study. The primary study results were recently published (21). The current study reports our findings of retrospective analyses of associations between genetic variation in selected cytokine genes and physical function, at baseline and in response to the exercise intervention.

Interventions
The goal of the dietary weight loss intervention was to produce and maintain an average weight loss of 5% for the duration of the 18-month intervention. During the first 6 months of the study, individuals in the diet groups attended weekly behavior counseling sessions (three group sessions and one individual session per month) with a registered dietitian. The diet groups met monthly for the final 12 months of the study.

The 3 days/week exercise program consisted of an aerobic phase (15 minutes), a resistance-training phase (15 minutes), a second aerobic phase (15 minutes), and a cool-down phase (15 minutes). The first 4 months of the 18-month intervention was facility-based. After the first 4 months, participants who wished to exercise at home underwent a 2-month transition phase in which they alternated between the facility and the home. Participants were provided with an aerobic exercise prescription that included walking within a heart rate range of 50%–75% of heart rate reserve. The resistance-training portion of the program consisted of two sets of 12 repetitions of the following exercises: (a) leg extension, (b) leg curl, (c) heel raise, and (d) step up. Cuff weights and weighted vests were used to provide resistance. Following two orientation sessions, participants began with the lowest possible resistance. Weight was increased after the participant performed two sets of 12 repetitions for two consecutive days. Exercise and attendance logs were used to gather data and monitor progress.

The control group met monthly for 1 hour for the first 3 months during which topics concerning osteoarthritis, obesity, and exercise were discussed. Monthly phone contact was maintained during months 4–6 and bi-monthly contact during months 7–18.

Clinical Procedures
Information concerning comorbid conditions was obtained from a medical history, determination of medication use, and a physical examination at baseline. Objective and self-reported measures of physical function, along with body weight and height, were obtained at baseline, and 6 and 18 months after randomization. All staff involved in data collection were masked to the treatment assignment of the participants.

Physical disability.-- Physical disability was measured by the self-reported Fitness Arthritis and Seniors Trial (FAST) functional performance inventory (24). This measure uses 23 questions to assess perceived difficulty with a number of activities including basic activities of daily living (ADLs), instrumental ADLs, ambulation, transferring, and upper extremity strength. The scale for each question ranges from 1 (no difficulty) to 5 (unable to do), and the score of each question is averaged to create a composite score. The composite index has an alpha reliability of 0.79.

Walking distance and stair-climbing speed.-- Two physical performance tasks with high test–retest reliability (>0.85) for patients with knee osteoarthritis were used to objectively measure physical function (25). These tasks included the distance walked in 6 minutes and a timed stair-climb task. General instructions, a demonstration (including a question and answer period), and a habituation period preceded the testing.

DNA Extraction and Genotyping
DNA was isolated from whole-blood samples using the AutoPure LS automated workstation (Gentra Systems, Inc., Minneapolis, MN). The DNA concentration and purity (Abs260/Abs280) were determined by an ultraviolet spectrophotometer, and all samples were adjusted to 250 µg/ml final concentration. All polymorphisms were genotyped using the MassARRAY system (SEQUENOM, Inc., San Diego, CA). Polymerase chain reactions (PCRs) were performed in a total volume of 5 µl with 5 ng of genomic DNA, 10X PCR buffer (Qiagen, Valencia, CA), 2.5 mM MgCl₂ (Qiagen), 0.1 U of Hot StarTaq polymerase (Qiagen), 200 µM deoxynucleotide phosphate (dNTP; Invitrogen, Carlsbad, CA), and 200 nM each primer (Integrated DNA Technologies, Coralville, IA). The extension reactions were performed in a total volume of 9 µl with 50 µM dNTP/dideoxynucleotide phosphate (ddNTP) each, 0.063 U/µl Thermo Sequenase (both obtained from SEQUENOM, Inc.), and 600 nM extension primers. After cleaning up the extension reaction products with SpectroCLEAN, the products were transferred to SpectroCHIP using SpectroPOINT, and then scanned through SpectroREADER (SEQUENOM, Inc.). Genotyping was done using SpectroTYPER (SEQUENOM, Inc.).

Statistical Analyses
SAS statistical software (SAS Institute, Cary, NC) was used for all statistical analyses. Each single nucleotide polymorphism was first tested for consistency with Hardy–Weinberg proportions using chi-square tests. Outcomes were assessed for approximate conformity to model assumptions (i.e., normally distributed, constant variance). Analysis of covariance (ANCOVA) models were used to test for associations between genotype and the outcomes. Genotype was tested for association with baseline values under a two degrees of freedom (df) general model (no mode of inheritance assumption) and under a 1 df dominant model for the minor allele. Tests of association between genotype and 6- and 18-month change in physical function were also performed. Tests of genotype effects were adjusted for sex, age, race, and BMI.

	RESULTS

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Baseline Characteristics and Genotype Frequencies
Of the 316 randomized participants, a total of 214 provided a blood sample for DNA analyses and are included in the present study. The baseline physical characteristics, comorbidity, and severity of knee osteoarthritis of the sample are shown in Table 1. Cross-sectional associations between baseline physical function and cytokine gene polymorphisms were analyzed for those participants with available genotype data for IL-6 –174G/C (n = 198), TNF –238G/A (n = 190), TNF –308G/A (n = 209), TNFR1 +36A/G (n = 201), TNFR2 +676T/G (n = 201), and TNFR2 +1663A/G (n = 208). All genotype frequencies (shown in Table 2 by race) were in expected Hardy–Weinberg equilibrium, except for TNF –308G/A, which resulted in a slight excess of rare homozygotes (chi-square p <.05). There was a significant race difference in the allele frequencies for IL-6 –174 G/C and TNFR2 +1663A/G (p <.001).

View larger version (18K): [in this window] [in a new window]   Figure 1. Cross-sectional relationships of walking distance and stair-climb time to the interleukin-6 (IL-6) –174, tumor necrosis factor alpha (TNF) –308, and TNF receptor 2 (TNFR2) +676 polymorphisms. Analyses were adjusted for age, race, sex, and body mass index

We next analyzed whether there was a genotype effect on 6- and 18-month changes in physical performance and disability among exercisers and whether there was a Genotype x Treatment (exercise vs no exercise) interaction on responses to exercise. There were no effects of the IL-6 –174, TNF –238, or the TNFR1 and TNFR2 polymorphisms on responses to exercise for any of the outcomes. However, there was a significant interaction between TNF –308 genotype and exercise treatment on 6-month changes in stair-climb time (p =.007; adjusted for age, race, sex, and diet intervention assignment; Figure 2), and a marginally significant interaction on 18-month changes in stair-climb time (p =.07), in individuals with an A allele, decreasing their stair-climb time more than those homozygous for the G allele in response to exercise (Figure 2). In addition, there was a significant interaction between TNF –308 genotype and exercise treatment on 18-month changes in self-reported physical disability (p =.01), again with individuals with at least one A allele showing greater improvement in function in response to exercise than those homozygous for the G allele (AA + AG = –0.41 ± 0.12 U vs GG = –0.12 ± 0.08 U; p =.03). No association was seen between changes in walking distance and TNF –308 genotype.

View larger version (17K): [in this window] [in a new window]   Figure 2. Interaction between exercise intervention and tumor necrosis factor alpha (TNF) –308 genotype on 6-month and 18-month changes in stair-climb time. Analyses were adjusted for age, race, sex, and diet intervention assignment

	DISCUSSION

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Our results showed that individuals homozygous for the G allele at position –174 in the promoter region of the IL-6 gene had greater walking distance than those with at least one copy of the C allele. Although there are no prior studies assessing the effects of this polymorphism on physical function specifically in older individuals with osteoarthritis, a study in middle-aged men showed that muscle mass was greater in those homozygous for the G allele (27). This association was not found in women, which prompted us to assess whether our data showed an interaction between sex and genotype for walking distance. This interaction was not significant (data not shown), indicating no effect of sex on the association between walking distance and the IL-6 –174 G/C polymorphism in our study sample. Functional studies of this polymorphism are inconsistent with regard to which allele results in greater IL-6 gene expression and higher basal or stimulated circulating IL-6 concentrations. Some studies report that the CC genotype confers less transcription, an inhibitory response to known stimuli, and lower plasma IL-6 (28–31), whereas other studies report an opposite association (32–34). Two studies showed that IL-6 production increased with age only in individuals with a C allele (30,31). These disparate findings have been explained by the possibility of a localized or tissue-specific genotype effect or by data suggesting that IL-6 polymorphisms interact to affect protein function (35). Thus, the biological mechanism underlying the genotype and walking distance association demonstrated in these older osteoarthritis patients remains to be elucidated.

TNF is a multifunctional, proinflammatory cytokine implicated in the muscle catabolism present in a number of conditions, including aging (36,37). TNF also contributes to the pathophysiology of osteoarthritis via catabolism of cartilage (38,39). Likewise, there is evidence that soluble TNF receptor levels predict the onset of disability in elderly persons (15) and that these receptors may have a mediating effect on disease progression of osteoarthritis (40,41). Thus, it is plausible that variation in the genes encoding for TNF and its two known receptors (TNFR1 or TNFR p55 and TNFR2 or TNFR p75) account for some of the genetic variability underlying physical function in older osteoarthritis patients.

We found that physical function was better in individuals homozygous for the major G allele of the TNF –308 polymorphism and in individuals homozygous for the major T allele of the TNFR2 +676 polymorphism. Both of these polymorphisms exhibit functional consequences in molecular studies. The less common A allele of TNF –308 is a stronger activator of TNF transcription and is associated with higher TNF production, higher circulating TNF concentrations, and greater TNF protein expression in skeletal muscle (42–44). All of these effects may provide a microenvironment in which the TNF –308A genotype could affect skeletal muscle and/or cartilage function resulting in slower walking speed. The TNFR2 +676 T/G is in exon 6 and results in an amino acid substitution (methionine to arginine). The G allele of this polymorphism results in a more effective signal transduction after TNF binding, resulting in an increased IL-6 production compared to that of the T allele (45). It is interesting to note that our data showed a tendency for this polymorphism to interact with the IL-6 –174 variant to affect walking distance. Prior clinical association studies with TNFR2 +676 show that the G allele is more frequent in rheumatoid arthritis patients, and that patients with the G allele have greater functional severity of disease over time and may not respond to anti-TNF agents (46,47). Our data showed no association between traits of physical function, or their response to exercise training, with the TNF –238 G/A polymorphism, the TNFR2 +1663 A/G polymorphism (also referred to as 1466 A/G in some literature) found in exon 10 of the 3' untranslated region of the gene, or with the TNFR1 +36A/G polymorphism, a silent mutation at codon 12 in exon 1 of this gene (48).

We found in a prior study that the diet intervention arm of this trial resulted in greater reductions in circulating concentrations of C-reactive protein, IL-6, and soluble TNFR1 compared to the no-weight-loss treatment, but that there was not a statistically significant effect of exercise training on these inflammatory biomarkers (49). Thus, we hypothesized that cytokine gene polymorphisms may be more predictive of exercise-induced changes in physical function than of changes in systemic markers of inflammation. There is a paucity of information regarding which specific genes interact with physical activity to affect physical function. Our data indicate that the TNF gene may be one of these genetic determinants, because the –308 polymorphism affected changes in stair-climb time and self-reported physical disability in response to the exercise treatment. However, this was a retrospective analysis of the effects of genetic differences on responses to exercise training. A prospective randomized, controlled trial, designed to assess the mediating effects of genetic variation at the TNF –308 locus on changes in physical function with exercise training in individuals with and without osteoarthritis, is needed to confirm our preliminary findings.

Some of the limitations of our study need to be noted. First, because our study population was selected for osteoarthritis, the findings may not apply to all older individuals. The effects of the inflammatory genes on physical function in this select population may be due to differences in inflammatory status that would exacerbate or alleviate pain or mobility directly in joints affected by osteoarthritis. In addition, it would have been advantageous to have had a measure of body composition or cartilage integrity in this study, which would have allowed us to determine whether the association of physical function with these cytokine genes is mediated by differences in muscle mass or cartilage damage. Likewise, although all participants were sedentary for 6 months prior to the assessment of physical function, lifetime physical activity was not accounted for, and may have affected physical function independent of the genes we studied.

Our study describes results from one or two genotyped polymorphisms within each candidate gene. Given our limited gene coverage, clearly our study cannot rule out the possibility that there may be other important polymorphisms in the genes we studied that impact physical function. Furthermore, given our modestly sized sample of older adults, we do not have sufficient statistical power to rule out the possibility that the polymorphisms we have studied actually have weak to modest effects on physical performance. Finally, although we adjusted for race in our analyses, there is a possibility of population stratification concern in the two genes that showed racial differences in allele frequencies. Our sample size was not large enough to conduct ethnicity-specific analyses, which would be useful to validate our results. Independent of these concerns, our findings suggest that genotypes in the IL-6, TNF, and TNFR2 genes are important risk factors for decline in physical function. As with any candidate gene study, confirmation of the positive associations seen between physical function and the IL-6, TNF, and TNFR2 genes is needed before these markers should be used to predict individual loss of physical function.

	Acknowledgments

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This study was supported by the Wake Forest University (WFU) Claude D. Pepper Older Americans Independence Center of the National Institute on Aging (P60 AG10484), by National Institutes of Health grant 1R01 AG18702, and by the WFU General Clinical Research Center (M01-RR07122).

We are grateful to the nursing, research, and laboratory staff of the WFU Geriatric Research Clinic and to the GCRC for their assistance in the conduct of this research. We also thank the individuals who volunteered to participate in this study.

	Footnotes

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Decision Editor: John E. Morley, MB, BCh

Received August 5, 2004

Accepted October 13, 2004

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