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J Appl Physiol 95: 1425-1430, 2003. First published June 13, 2003; doi:10.1152/japplphysiol.00516.2003
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C174T polymorphism in the CNTF receptor gene is associated with fat-free mass in men and women

Stephen M. Roth,1,2 E. Jeffrey Metter,3 Mechele R. Lee,1 Ben F. Hurley,2 and Robert E. Ferrell1

1Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15261; 2Department of Kinesiology, University of Maryland, College Park, 20742; and 3Clinical Research Branch, National Institute on Aging, Gerontology Research Center, Baltimore, Maryland 21224

Submitted 14 May 2003 ; accepted in final form 11 June 2003


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 DISCLOSURES
 ACKNOWLEDGMENTS
 REFERENCES
 
We performed gene screening of the ciliary neurotrophic factor receptor (CNTFR) gene and genotyped three newly identified polymorphisms: C-1703T in the 5' promoter region, T1069A in intron 5, and C174T in exon 9. We studied the association of these CNTFR variants with muscle strength, mass, and body composition in 465 men and women (20-90 yr) from the Baltimore Longitudinal Study of Aging. Only the C174T variant was significantly associated with muscle-related phenotypes. In the entire cohort, when corrected for age, sex, race, physical activity, and height, homozygotes for the common C allele at C174T (CC) exhibited lower total body mass and body mass index than carriers of the rare T allele, which appeared to be due to significant differences in total nonosseous fat-free mass (FFM) (48.0 ± 0.4 vs. 50.0 ± 0.7 kg; P = 0.011) and lower limb FFM (16.5 ± 0.1 vs. 17.2 ± 0.2 kg; P = 0.002). The CC group also exhibited significantly lower quadriceps concentric and eccentric isokinetic strength values at both 30 and 180°/s than the T allele carriers (all P < 0.04), but these differences were no longer significant after adjustment for lower limb FFM. There were no significant sex-by-genotype interactions. The results indicate that the C174T polymorphism in exon 9 of CNTFR is significantly associated with FFM in men and women, with concomitant differences in muscular strength.

genetics; muscle mass; muscle strength; polymorphism; sex; ciliary neurotrophic factor receptor

ALTHOUGH THE SPECIFIC MECHANISMS are unclear, the etiology of sarcopenia appears to be multifactorial, encompassing humoral, neurogenic, genetic, and environmental factors (27, 29). Genetic factors are known to contribute to a significant fraction of the variability in lean body mass and muscle strength (1, 37, 38), as well as grip strength in older adults (10) and the change in strength with age (2), but the identification of specific contributing genes is difficult. A primary strategy is the use of association studies to test genes with encoded proteins that have known physiological relevance to the proposed mechanisms of muscle wasting, with the ultimate goal of reconciling the complex interplay of genetic and nongenetic factors.

Ciliary neurotrophic factor (CNTF) and its receptor (CNTFR) represent an important physiological pathway from which genetic studies can be initiated. In addition to an important role in motoneuron survival (24), CNTF has direct muscle influences. For example, CNTF administration has been shown to increase muscle fiber number in developing rat muscle (25), stimulate myotube formation in regenerating mouse muscle (23), and slow atrophy of denervated (16) and un-weighted (9) rat soleus muscle. Moreover, Guillet et al. (14) showed that CNTF administration to aged (24 mo) rats improved soleus twitch and tetanic tensions to the level of adult (6 mo) rats. A null mutation in the CNTF gene has been identified, and although it is not associated with neurological disease development (34), the null allele has been implicated as a modifier for the onset of amyotrophic lateral sclerosis (12) and multiple sclerosis (13). We have previously shown that men and women heterozygous for the null allele exhibited greater muscle strength than homozygotes for the common allele (28).

CNTF can signal through a receptor complex comprised of a CNTF-specific {alpha}-receptor subunit (CNTFR) and two additional subunits, gp130 and leukemia inhibitory factor receptor (4, 5, 30). CNTFR is expressed in skeletal muscle, with expression being upregulated in response to muscle damage (19) and hindlimb un-weighting (15) in rats, and denervation in human skeletal muscle (44). Surprisingly, mice lacking CNTF are viable with no overt abnormalities, yet mice lacking CNTFR die perinatally, although mice heterozygous for a CNTFR null mutation appear normal and are fertile (6). The CNTFR null mice exhibited significantly lower numbers of motoneurons in a number of motoneuron populations. CNTFR also acts as a ligand for cardiotrophin-like cytokine (CLC), which has been shown to support survival of motor and sympathetic neurons in vitro (31), although little else is known about its function. Thus CNTFR appears to act as a receptor for multiple ligands associated with motor nerve survival, and it is expressed in skeletal muscle. Only limited analysis of sequence variation in CNTFR has been previously reported in a Japanese cohort (17).

Given the importance of the CNTFR to multiple ligands, these observations provide support for our hypothesis that genetic variants in the CNTFR gene may be associated with muscle phenotypes, such as mass and strength. Thus the purpose of the present investigation was to study the potential role of sequence variation in the CNTFR gene in influencing nonosseous fat-free mass (FFM) and muscle strength. To address this purpose, we performed direct DNA sequence analysis of CNTFR and identified several novel polymorphisms, then investigated a number of those sequence variants for association with body composition and muscle strength phenotypes in men and women from the Baltimore Longitudinal Study of Aging (BLSA).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 DISCLOSURES
 ACKNOWLEDGMENTS
 REFERENCES
 
Subjects. Four hundred and sixty-five volunteers (234 men and 231 women, age range 20-91 yr) from the BLSA (32) participated in the study. Four hundred and four of the subjects were Caucasian. All subjects received a complete medical history and physical examination. Subjects with clinical cardiovascular or musculoskeletal disorders that could be adversely affected by exercise testing were excluded. Detailed exclusionary criteria are outlined elsewhere (21, 22). The results of a physical activity questionnaire indicated that only a small proportion of the subjects (<1%) participated in regular resistive exercise training, with no differences in participation by age or sex (21). All subjects gave their written, informed consent; the experimental protocols were approved by the Institutional Review Boards for Human Subjects at Johns Hopkins Bayview Medical Center (Baltimore, MD), the University of Maryland (College Park, MD), and the University of Pittsburgh (Pittsburgh, PA).

Total body mass and nonosseous FFM. Body mass and height were measured for each subject to the nearest 0.1 kg and 0.5 cm, respectively, by using a Detecto medical beam scale. A majority of the participating subjects was assessed for total and lower limb FFM (n = 316; 130 men and 186 women). In these subjects, a total body scan was performed by using dual-energy X-ray absorptiometry (DEXA) as described previously (21, 22). On the basis of the total body DEXA scan, nonosseous total FFM and lower limb FFM were determined (21). Limb FFM, as measured by DEXA, is highly correlated with muscle mass in humans (43).

Strength and muscle quality. Peak torque (strength) was measured by using the Kinetic Communicator isokinetic dynamometer (Kin-Com model 125E, Chattanooga Group, Chattanooga, TN). Concentric (Con) and eccentric (Ecc) peak torque were measured at angular velocities of 0.52 rad/s (30°/s) and 3.14 rad/s (180°/s) for the dominant knee extensors. Maximal voluntary isometric torque was measured for the knee extensors at 2.09 rad (120°). For each test, subjects performed three maximal efforts, separated by 30-s rest intervals, from which the highest value of the three trials was accepted as the peak torque. Detailed procedures regarding subject positioning and stabilization, warm-up, testing order, gravity correction, and Kin-Com calibration are described elsewhere (21, 22). Correlation coefficients for test-retest reliability ranged from 0.96 to 0.99 (21). Muscle quality was estimated for the knee extensors by calculating the ratio of Con peak torque at both 0.52 and 3.14 rad/s to the dominant leg estimated muscle mass.

Physical activity. Physical activity was estimated for each of the BLSA participants by using self-reported time spent in 97 activities, as previously reported (35, 41). Physical activity was quantified into MET-minutes based on the metabolic equivalent of each particular activity and the time spent in that activity, normalized to 24 h.

DNA sequencing/screening. The 9 exons, corresponding exon-intron boundaries, and ~2,500 bases of 5' flanking sequence of CNTFR were screened for variation in randomly selected subjects by using standard DNA sequencing techniques in a cohort of 24 men and women of mixed race, but predominantly Caucasian. Intronic regions were not targeted for sequencing. Amplimers of selected regions were sequenced in both directions directly by using the BigDye Terminators reaction kit (Applied Biosystems) and analyzed on an ABI PRISM 3700 fluorescence sequencer (Applied Biosystems). Sequences were aligned for comparison by using Sequencher version 4.1 (GeneCodes). As polymorphic loci were identified (Fig. 1), allelic frequencies were determined through genotype analysis in racially homogeneous groups.



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  		Fig. 1. Genetic structure of ciliary neurotrophic factor receptor (CNTFR), including locations of identified polymorphisms in the 5' promoter, 9 exonic, 8 intronic, and the 3' untranslated (UTR) regions. Sites shown above the gene were selected for genotyping; rare allele frequencies are shown for variable sites not genotyped in the Baltimore Longitudinal Study of Aging (BLSA; represented below the gene). Note: drawing is not to exact scale. Polymerase chain reaction primers (forward and reverse) and annealing temperatures for the 3 CNTFR polymorphisms selected for genotyping in the BLSA cohort are as follows: C-1703T, forward: 5'-GCATCTGGAGGTCAAGTCCGT and reverse: 5'-GCAGACCGGGATTAGACTGTG (anneal = 57°C); T1069A, forward: 5'-GAAGAGGCACGCTGACTATGAT and reverse: 5'-AAGACTCACGGTCAGGCCAGG (anneal = 56°C); C174T, forward: 5'-CTGCAGACCCCGGTTTCTAT and reverse: 5'-AGTCGCTGGCATTGGAGGGT (anneal = 52°C).

 

Genotyping. Polymorphisms were selected for genotyping based on allele frequency and available populations. Genomic DNA was extracted from peripheral lymphocytes by using standard methods, and the following single-nucleotide polymorphisms were genotyped: C-1703T, T1069A, and C174T. PCR primers and annealing temperatures used for the PCR are shown in the caption for Fig. 1. Genotyping was performed for T1069A by using fluorescence polarization (3) and for C-1703T and C174T by direct DNA sequencing.

Statistics. A {chi}2 analysis was used to determine deviations of genotype distribution from expected Hardy-Weinberg equilibrium. Haplotype frequencies were estimated as previously described (36), and D' was calculated to estimate linkage disequilibrium (7). Body composition variables were compared in relation to CNTFR genotype and sex by using analysis of covariance (ANCOVA), with age, race, physical activity, and height covaried (height was not included for the analysis of body mass index). Measures of peak torque were also analyzed by using ANCOVA both with and without lower limb FFM included as a covariate along with age, race, physical activity, and height. The physical characteristics of those subjects with no measures of FFM did not differ significantly from the subjects with those measures. Analyses were also performed within each sex group. Data are reported as adjusted means ± SE. Statistical significance was accepted at P <= 0.05.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 DISCLOSURES
 ACKNOWLEDGMENTS
 REFERENCES
 
DNA sequencing. Direct sequencing of the coding and 5'-flanking regions of CNTFR revealed several rare and common polymorphisms, as shown in Fig. 1, including four variants in the 5' promoter region, an intron 5 variant 37 bases upstream of exon 6, a rare silent mutation in exon 8, and a variant in exon 9, which is untranslated. In our screening cohort, which was predominantly Caucasian, the majority of these variants had rare allele frequencies <0.06. The polymorphisms with common variant alleles C-1703T, T1069A, and C174T were genotyped in the BLSA cohort. Genotype and allele frequencies are shown in Table 1. The genotype frequencies of only the T1069A polymorphism differed significantly from expected Hardy-Weinberg equilibrium (Table 1; P < 0.01), and direct sequencing confirmed that our genotyping methods were accurate. No evidence of linkage disequilibrium was observed among any of the three variable sites (D' = 0.02-0.20).


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  		Table 1. Genotype and allele frequencies for polymorphisms in CNTFR genotyped in the BLSA cohort

 

Associations with body composition phenotypes. Subject characteristics are shown in Table 2 both for the entire cohort and for men and women separately for the C174T polymorphism. The results revealed significant genotype differences for body composition phenotypes for the CNTFR C174T polymorphism in exon 9. In the entire BLSA cohort, homozygotes for the common C allele at C174T exhibited significantly lower body mass (P = 0.040) and BMI (P = 0.052) than carriers of the rare T allele (CT + TT; Table 2). These differences were due to significant differences in total FFM (P = 0.011) and lower limb FFM (P = 0.002; Table 2). When analyses were performed within each sex group separately by using the same covariates, similar results were observed for both total and lower limb FFM, but not for total body mass and BMI (Table 2), because of smaller sample sizes. No significant sex-by-genotype interactions were observed in any analysis within the entire cohort.


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  		Table 2. Subject characteristics and body composition measures by CNTFR C174T genotype in the BLSA

 

Associations with muscle strength phenotypes. The CC group also exhibited significantly lower knee extensor Con and Ecc isokinetic peak torque measures compared with the T allele carriers in the entire cohort. When covarying for age, height, physical activity, and race, the CC group compared with the T allele carriers exhibited significantly lower knee extensor Con peak torque at 30°/s (158.2 ± 3.5 vs. 149.7 ± 1.9; P = 0.035) and 180°/s (106.0 ± 2.4 vs. 99.7 ± 1.3; P = 0.023). Similar results were observed between the CC group vs. the CT + TT group for knee extensor Ecc peak torque at 30°/s (210.0 ± 5.0 vs. 190.9 ± 2.8; P = 0.001) and 180°/s (219.6 ± 5.1 vs. 195.3 ± 2.8; P < 0.001). The group differences in all of these strength measures were no longer statistically significant, however, after adjustment for lower limb FFM. Similar results were observed in men and women when analyzed separately, as shown in Table 3, with P values shown for analyses with and without adjustment for FFM. No significant sex-by-genotype interactions were observed in any analyses. Muscle quality measures did not differ between the two C174T genotype groups (data not shown).


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  		Table 3. Knee extensor peak torque values by CNTFR C174T genotype group in BLSA men and women

 

The C-1703T and T1069A polymorphisms were not associated with any body composition or muscle strength measure (data not shown). Sample sizes were not large enough to allow the assessment of multiple alleles simultaneously (i.e., multilocus genotypes).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
DISCLOSURES
 ACKNOWLEDGMENTS
 REFERENCES
 
We performed screening of the genetic sequence of CNTFR and identified single-nucleotide polymorphisms. Of these, three single-nucleotide polymorphisms were genotyped in the BLSA cohort and examined in relation to muscle mass and strength phenotypes. The results reveal an association between the C174T polymorphism in exon 9 of CNTFR and FFM in men and women from the BLSA. Carriers of the rare T allele (CT + TT) exhibited significantly greater total and lower limb FFM than C allele homozygotes, with concomitantly greater quadriceps Con and Ecc strength. The significant association between the C174T polymorphism and muscle strength was eliminated after the influence of FFM was accounted for.

Our results suggest a role for CNTFR C174T genotype in FFM, although the potential mechanisms of such a role are uncertain. In the present study, total body mass and BMI were significantly higher in carriers with the T allele compared with C allele homozygotes. Because significant group differences were eliminated after they were adjusted for lower limb FFM, we concluded that no direct association exists between CNTFR genotype and muscle strength. Only the C174T genotype was observed as significantly associated with any muscle mass or strength measure; neither the C-1703T nor T1069A polymorphisms were associated with muscle phenotypes.

Since the original description of the genetic structure of CNTFR (39), detailed sequencing as part of the Human Genome Project has revealed a total of 9 exons, of which regions in exons 1 and 9 are untranslated. We identified a number of rare and common polymorphisms in CNTFR, including two variants residing in exons (exons 8 and 9). We did not observe two previously identified rare variants (Thr199Thr and A1038T), although those were identified in a Japanese cohort (17). The molecular basis for the observed association between FFM and the C174T polymorphism is unknown and cannot be addressed from the present data. The C174T polymorphism resides in exon 9 of CNTFR in the 3'-untranslated region of the gene and thus is not directly related to protein function. Whether the variant influences mRNA processing or stability is uncertain but is testable. The C174T variant may be acting as a marker for functional variation elsewhere in the CNTFR gene or may be in linkage disequilibrium with functional variation in a nearby gene. Beyond the potential influence of the C174T polymorphism on CNTFR expression, how altered CNTFR protein levels might affect FFM is uncertain. CNTFR is expressed in skeletal muscle, with expression being upregulated in response to muscle damage (19), hindlimb unweighting (15), and denervation (44), and CNTFR null mice exhibit significantly lower numbers of motoneurons (6). Altered expression of CNTFR due to genetic variation could then be expected to influence the response of muscle to CNTF and CLC, both during development and throughout adulthood.

Few studies have begun to identify the specific genetic factors underlying muscle mass and strength phenotypes, especially within the context of aging (e.g., sarcopenia), despite the considerable heritability of these phenotypes (1, 2, 10, 37, 38). Polymorphisms in CNTF (28), myostatin (18), type I collagen-{alpha}1 (40), angiotensin converting enzyme (8, 45), vitamin D receptor (11), and insulin-like growth factor 1 (33) have been tentatively identified to date as being associated with muscle-related phenotypes. The present study provides evidence for an allele in CNTFR acting as a modifier of FFM, with associated differences in muscle strength in men and women across the adult age span.

The CNTFR component regulates signaling for CNTF (4, 5) and CLC (20, 26), and potentially other ligands. Although little is known about CLC, both CLC and CNTF appear important for motoneuron survival (24, 31), and CNTF in particular has been associated with muscle fiber development (25) and muscle regeneration (9, 16, 23). In addition to showing reduced levels of CNTF mRNA and protein with advanced age, Guillet et al. (14) showed that CNTF administration in aged rats improved soleus twitch and tetanic tensions to the level of adult rats. Moreover, Guillet et al. reported increased expression of CNTFR with advancing age in all muscles tested. The authors speculated that the CNTFR overexpression might be compensatory for the reduced expression of CNTF in the aged animals. How CNTF, acting through CNTFR, influences skeletal muscle is uncertain, although direct influences on both protein synthesis and degradation have been reported (42), and both direct and indirect (e.g., through an influence on motoneurons) influences on muscle have been speculated (25).

Limited sample size prevented analysis of multilocus genotypes in the present study, but an analysis of the combination of alleles in CNTFR and in combination with the CNTF null allele (28, 34) would be worthwhile. Our present findings should be verified in an independent sample. Although our research focus is primarily aimed at sarcopenia and muscle-related phenotypes, we anticipate that these newly identified CNTFR polymorphisms will have relevance for neurological phenotypes and related disorders, especially given the importance of the CNTFR to ligands important to motor nerve survival.


   DISCLOSURES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 DISCLOSURES
ACKNOWLEDGMENTS
 REFERENCES
 
This research was conducted as part of the BLSA, a component of the National Institute on Aging Intramural Research Program. Further support was provided by an Obesity/Nutrition Research Center Pilot/Feasibility grant (funded through DK-46204) and AG-05893.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 DISCLOSURES
 ACKNOWLEDGMENTS
REFERENCES
 
We thank the BLSA participants for continued involvement.


   FOOTNOTES
 

Address for reprint requests and other correspondence: S. M. Roth, Dept. Kinesiology, Univ. of Maryland, College Park, MD 20742 (E-mail: sroth1{at}umd.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 DISCUSSION
 DISCLOSURES
 ACKNOWLEDGMENTS
 REFERENCES
 

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