JAMDA 16 (2015) 365e370
JAMDA journal homepage: www.jamda.com
Original Study
Insulinlike Growth Factor-1 and Its Binding Protein-3 Polymorphisms Predict Circulating IGF-1 Level and Appendicular Skeletal Muscle Mass in Chinese Elderly Chuan-Wei Yang MPH a, b, Tsai-Chung Li PhD c, d, Chia-Ing Li PhD b, Chiu-Shong Liu MD, MPH b, e, f, Chih-Hsueh Lin MD, PhD e, f, Wen-Yuan Lin MD, PhD e, f, Cheng-Chieh Lin MD, PhD a, b, e, f, * a
PhD Program for Aging, College of Medicine, China Medical University, Taichung, Taiwan Department of Medical Research, China Medical University Hospital, Taichung, Taiwan Graduate Institute of Biostatistics, College of Public Health, China Medical University, Taichung, Taiwan d Department of Healthcare Administration, College of Health Science, Asia University, Taichung, Taiwan e Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan f School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan b c
a b s t r a c t Keywords: Appendicular skeletal muscle mass IGF-1 IGFBP3 elderly
Background: Previous studies have demonstrated the polymorphisms of insulinlike growth factor-1 (IGF1) and its binding protein-3 (IGFBP3) genes could affect the circulating IGF-1 level. Moreover, the serum IGF-1 level was correlated with muscle size. Objectives: This study aimed to explore the effect of polymorphisms of IGF1, IGFBP3, and IGFBP5 genes on appendicular skeletal muscle mass in Taiwanese older adults in a metropolitan area. Design: A community-based cross-sectional study. Setting and subjects: A random sample of 472 elders with complete information of dual energy X-ray absorptiometry examination, genotyping analysis, and serum IGF-1 level from Taichung Community Health Study for Elders (TCHS-E) was included. Measurements: Low appendicular skeletal muscle mass index (ASMI) was defined as 2 SDs below the mean of young adults from our TCHS study (n ¼ 471). Seven polymorphisms of IGF1, IGFBP3, and IGFBP5 were analyzed by using Illumina GoldenGate Genotyping Assay. The c2 test, Student t test, and multiple logistic regression were applied for statistical analysis. Results: The prevalence of low ASMI was 7.1%, 8.8%, and 23.0% in those aged 70 or younger, 71 to 75, and older than 75 years, respectively. We found that serum IGF-1 level (natural logarithmic transformation) was significantly lower in the low ASMI group compared with the normal ASMI group and the SNP rs2854744 near IGFBP3 gene was significantly associated with low ASMI. Moreover, we discovered the SNP rs6214 on the IGF1 gene would significantly affect the serum IGF-1 level. Therefore, the joint effect of rs6214 and rs2854744 was analyzed. Elders with GG genotype of rs6214 and AC or CC genotypes of rs2854744 had a 3.18-fold (95% CI 1.02e9.89) risk of having low ASMI compared with those with the AA and AA genotype, after adjusting for age, gender, smoking, exercise, hyperlipidemia, and albumin level. Conclusions: Our results suggest that rs6214 on the IGF1 gene and rs2854744 near the IGFBP3 gene potentially play an important role with ASMI in Taiwanese older adults in a metropolitan area. Ó 2015 AMDA e The Society for Post-Acute and Long-Term Care Medicine.
The authors declare no conflicts of interest. This study was funded by grants from Taiwan National Health Research Institutes (NHRI-EX100-9838PI), Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW103-TDU-B-212-113002), and China Medical University Hospital (DMR-102-064). * Address correspondence to Cheng-Chieh Lin, MD, PhD, China Medical University Hospital, No. 2, Yuh-Der Road, Taichung, Taiwan 404, ROC. E-mail address: [email protected] (C.-C. Lin). http://dx.doi.org/10.1016/j.jamda.2014.11.015 1525-8610/Ó 2015 AMDA e The Society for Post-Acute and Long-Term Care Medicine.
The elderly population in the world continues to increase and has become a very important issue of public health. In Taiwan, according to Ministry of the Interior statistics, 11.5% of the total population was older than 65 years in 2013.1 The Council for Economic Planning and Development estimates that the elderly population in 2018 will reach 14% and in 2025 will reach 20%,2 which means that there will be 1 elderly individual of every 5 people. There are many factors affecting
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C.-W. Yang et al. / JAMDA 16 (2015) 365e370
the quality of life of the elderly; the most important is the loss of skeletal muscle mass. Sarcopenia is a syndrome characterized by muscle loss in the elderly.3,4 According to European Working Group on Sarcopenia in Older People (EWGSOP) criteria, sarcopenia is defined as age-related deterioration of skeletal muscle mass and function, which includes loss of skeletal muscle mass combined with low handgrip strength and slow usual gait speed.5 However, low muscle strength has many adverse consequences, such as falls, poor quality of life, and even death.6e8 Moreover, the prevalence of sarcopenia in Taiwan (14.4%)9 and other countries, such as the United States (24.3%),10 Mexico (33.6%),11 and Korea (12.4% for men),12 was quite higher. However, the molecular mechanism of sarcopenia is still unclear. Walston et al13 hypothesized the molecular, physiological, and clinical pathway to frailty. Inflammation and neuroendocrine dysregulation including the insulinlike growth factor-1 (IGF-1) would induce anorexia, sarcopenia, and osteopenia. The main function of IGF-1 on skeletal muscle is to promote or inhibit protein synthesis or degradation and then to regulate skeletal muscle growth or recession.14,15 The growth hormone secreted by the pituitary gland can stimulate the liver and muscle cells to synthesize IGF-1. When IGF-1 binds with the IGF-binding proteins (IGFBPs), that can help IGF-1 to reach the target tissue and then induce protein synthesis. Previous study showed that increasing the IGF-1 level in muscle cells can induce muscle cell growth, but the circulating IGF-1 does not affect the muscle mass. However, when IGF-1 was deficient in the circulation or muscle cells, muscle mass was reduced.16 Moreover, the IGF-1 level gradually reduced with age.17 IGF-1 declines with age at the rate of 1.7 ng/mL per year in those older than 50.18 Therefore, it is necessary to determine what kinds of genetic factors are associated with variation of serum IGF-1 levels in elderly individuals. Twin- or family-based hereditary studies indicate the interindividual variation of plasma IGF-1 levels may be affected by genetic factors up to 50%, and the variation of plasma IGFBP-3 levels also may be affected by genetic factors up to 60%.19e21 There are many singlenucleotide polymorphisms (SNPs) on the IGF1 and IGFBP3 genes that can affect serum levels. A previous study22 showed that higher IGF-1 level was associated with the rs6214 TT genotype. Patel et al23 reported the genetic variation of the IGF1 gene (rs35767) could affect the circulating IGF-1 level. The variation of rs3110697 on the IGFBP3 gene was associated with serum IGF-122 and IGFBP-323,24 levels. Some studies found an association between the variation of rs2854744 and rs11977526 near the IGFBP3 gene and serum IGFBP-3 level.22,23,25 Moreover, the genome-wide association study showed that the variation of rs12474719 on the IGFBP5 gene was related to lean body mass,26 and the variation of rs1978346 on the IGFBP5 promoter region exhibited a significantly lower IGFBP5 gene expression level.27 But the knowledge of the pathophysiology of sarcopenia-related genetic factors is limited, not to mention assessment of the contributions of polymorphisms on the IGF1, IGFBP3, and IGFBP5 genes. Therefore, the aim of this study was to explore the effect of polymorphisms of IGF1, IGFBP3, and IGFBP5 genes on low appendicular skeletal muscle mass in Taiwanese older adults in a metropolitan area. Methods Study Population and Sampling Method The Taichung Community Health Study for Elders (TCHS-E) is a community-based study. The study population included all people aged 65 years or older who were registered in June 2009 as residents of the 8 administrative neighborhoods (“Li”) of North District, Taichung City, Taiwan. Taichung is a city located in west-central Taiwan with a population of more than 1 million residents. The population
density was 6249 per km2 in 2009. Taichung City contains 8 districts, which include the North District. The North District contains 36 administrative neighborhoods. The residents in these 8 administrative neighborhoods had similar distributions of age and gender compared with the population of both Taichung City and Taiwan. There were a total of 3997 older citizens in these 8 administrative neighborhoods and they were invited to participate in the TCHS-E study. Through household visits, we excluded 1247 individuals because of having moved out of the area, institutionalization, errors on their registry, or death. A total of 2750 individuals were eligible, and 1347 individuals agreed to participate in the study. However, there were some who did not complete the dual-energy X-ray absorptiometry (DXA) examination; only 844 individuals completed all measurements. In the genotyping assay, there were 472 individuals successfully genotyped by the Illumina GoldenGate genotyping assay Table 1 Subject Characteristics According to Low ASMI Status Normal ASMI
Low ASMI
c2 test Low ASMI vs Control
Sociodemographic factors Age 75 Gender Men Women Education Illiterate 13 y Health-related practice Smoking Never Current Former Drinking Never Current Former Exercise No Yes Chronic problem/Illness Hypertension No Yes Diabetes mellitus No Yes Heart disease No Yes Hyperlipidemia No Yes Hyperuricemia No Yes Arthritis No Yes Stroke No Yes Fall history No Yes *Fisher’s exact test.
n (%)
n (%)
158 (38.5) 125 (30.5) 127 (31.0)
12 (19.4) 12 (19.4) 38 (61.3)
201 (49.0) 209 (51.0)
50 (80.7) 12 (19.4)
39 92 145 122
7 13 19 22
P Value
JAMDA journal homepage: www.jamda.com
Original Study
Insulinlike Growth Factor-1 and Its Binding Protein-3 Polymorphisms Predict Circulating IGF-1 Level and Appendicular Skeletal Muscle Mass in Chinese Elderly Chuan-Wei Yang MPH a, b, Tsai-Chung Li PhD c, d, Chia-Ing Li PhD b, Chiu-Shong Liu MD, MPH b, e, f, Chih-Hsueh Lin MD, PhD e, f, Wen-Yuan Lin MD, PhD e, f, Cheng-Chieh Lin MD, PhD a, b, e, f, * a
PhD Program for Aging, College of Medicine, China Medical University, Taichung, Taiwan Department of Medical Research, China Medical University Hospital, Taichung, Taiwan Graduate Institute of Biostatistics, College of Public Health, China Medical University, Taichung, Taiwan d Department of Healthcare Administration, College of Health Science, Asia University, Taichung, Taiwan e Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan f School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan b c
a b s t r a c t Keywords: Appendicular skeletal muscle mass IGF-1 IGFBP3 elderly
Background: Previous studies have demonstrated the polymorphisms of insulinlike growth factor-1 (IGF1) and its binding protein-3 (IGFBP3) genes could affect the circulating IGF-1 level. Moreover, the serum IGF-1 level was correlated with muscle size. Objectives: This study aimed to explore the effect of polymorphisms of IGF1, IGFBP3, and IGFBP5 genes on appendicular skeletal muscle mass in Taiwanese older adults in a metropolitan area. Design: A community-based cross-sectional study. Setting and subjects: A random sample of 472 elders with complete information of dual energy X-ray absorptiometry examination, genotyping analysis, and serum IGF-1 level from Taichung Community Health Study for Elders (TCHS-E) was included. Measurements: Low appendicular skeletal muscle mass index (ASMI) was defined as 2 SDs below the mean of young adults from our TCHS study (n ¼ 471). Seven polymorphisms of IGF1, IGFBP3, and IGFBP5 were analyzed by using Illumina GoldenGate Genotyping Assay. The c2 test, Student t test, and multiple logistic regression were applied for statistical analysis. Results: The prevalence of low ASMI was 7.1%, 8.8%, and 23.0% in those aged 70 or younger, 71 to 75, and older than 75 years, respectively. We found that serum IGF-1 level (natural logarithmic transformation) was significantly lower in the low ASMI group compared with the normal ASMI group and the SNP rs2854744 near IGFBP3 gene was significantly associated with low ASMI. Moreover, we discovered the SNP rs6214 on the IGF1 gene would significantly affect the serum IGF-1 level. Therefore, the joint effect of rs6214 and rs2854744 was analyzed. Elders with GG genotype of rs6214 and AC or CC genotypes of rs2854744 had a 3.18-fold (95% CI 1.02e9.89) risk of having low ASMI compared with those with the AA and AA genotype, after adjusting for age, gender, smoking, exercise, hyperlipidemia, and albumin level. Conclusions: Our results suggest that rs6214 on the IGF1 gene and rs2854744 near the IGFBP3 gene potentially play an important role with ASMI in Taiwanese older adults in a metropolitan area. Ó 2015 AMDA e The Society for Post-Acute and Long-Term Care Medicine.
The authors declare no conflicts of interest. This study was funded by grants from Taiwan National Health Research Institutes (NHRI-EX100-9838PI), Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW103-TDU-B-212-113002), and China Medical University Hospital (DMR-102-064). * Address correspondence to Cheng-Chieh Lin, MD, PhD, China Medical University Hospital, No. 2, Yuh-Der Road, Taichung, Taiwan 404, ROC. E-mail address: [email protected] (C.-C. Lin). http://dx.doi.org/10.1016/j.jamda.2014.11.015 1525-8610/Ó 2015 AMDA e The Society for Post-Acute and Long-Term Care Medicine.
The elderly population in the world continues to increase and has become a very important issue of public health. In Taiwan, according to Ministry of the Interior statistics, 11.5% of the total population was older than 65 years in 2013.1 The Council for Economic Planning and Development estimates that the elderly population in 2018 will reach 14% and in 2025 will reach 20%,2 which means that there will be 1 elderly individual of every 5 people. There are many factors affecting
366
C.-W. Yang et al. / JAMDA 16 (2015) 365e370
the quality of life of the elderly; the most important is the loss of skeletal muscle mass. Sarcopenia is a syndrome characterized by muscle loss in the elderly.3,4 According to European Working Group on Sarcopenia in Older People (EWGSOP) criteria, sarcopenia is defined as age-related deterioration of skeletal muscle mass and function, which includes loss of skeletal muscle mass combined with low handgrip strength and slow usual gait speed.5 However, low muscle strength has many adverse consequences, such as falls, poor quality of life, and even death.6e8 Moreover, the prevalence of sarcopenia in Taiwan (14.4%)9 and other countries, such as the United States (24.3%),10 Mexico (33.6%),11 and Korea (12.4% for men),12 was quite higher. However, the molecular mechanism of sarcopenia is still unclear. Walston et al13 hypothesized the molecular, physiological, and clinical pathway to frailty. Inflammation and neuroendocrine dysregulation including the insulinlike growth factor-1 (IGF-1) would induce anorexia, sarcopenia, and osteopenia. The main function of IGF-1 on skeletal muscle is to promote or inhibit protein synthesis or degradation and then to regulate skeletal muscle growth or recession.14,15 The growth hormone secreted by the pituitary gland can stimulate the liver and muscle cells to synthesize IGF-1. When IGF-1 binds with the IGF-binding proteins (IGFBPs), that can help IGF-1 to reach the target tissue and then induce protein synthesis. Previous study showed that increasing the IGF-1 level in muscle cells can induce muscle cell growth, but the circulating IGF-1 does not affect the muscle mass. However, when IGF-1 was deficient in the circulation or muscle cells, muscle mass was reduced.16 Moreover, the IGF-1 level gradually reduced with age.17 IGF-1 declines with age at the rate of 1.7 ng/mL per year in those older than 50.18 Therefore, it is necessary to determine what kinds of genetic factors are associated with variation of serum IGF-1 levels in elderly individuals. Twin- or family-based hereditary studies indicate the interindividual variation of plasma IGF-1 levels may be affected by genetic factors up to 50%, and the variation of plasma IGFBP-3 levels also may be affected by genetic factors up to 60%.19e21 There are many singlenucleotide polymorphisms (SNPs) on the IGF1 and IGFBP3 genes that can affect serum levels. A previous study22 showed that higher IGF-1 level was associated with the rs6214 TT genotype. Patel et al23 reported the genetic variation of the IGF1 gene (rs35767) could affect the circulating IGF-1 level. The variation of rs3110697 on the IGFBP3 gene was associated with serum IGF-122 and IGFBP-323,24 levels. Some studies found an association between the variation of rs2854744 and rs11977526 near the IGFBP3 gene and serum IGFBP-3 level.22,23,25 Moreover, the genome-wide association study showed that the variation of rs12474719 on the IGFBP5 gene was related to lean body mass,26 and the variation of rs1978346 on the IGFBP5 promoter region exhibited a significantly lower IGFBP5 gene expression level.27 But the knowledge of the pathophysiology of sarcopenia-related genetic factors is limited, not to mention assessment of the contributions of polymorphisms on the IGF1, IGFBP3, and IGFBP5 genes. Therefore, the aim of this study was to explore the effect of polymorphisms of IGF1, IGFBP3, and IGFBP5 genes on low appendicular skeletal muscle mass in Taiwanese older adults in a metropolitan area. Methods Study Population and Sampling Method The Taichung Community Health Study for Elders (TCHS-E) is a community-based study. The study population included all people aged 65 years or older who were registered in June 2009 as residents of the 8 administrative neighborhoods (“Li”) of North District, Taichung City, Taiwan. Taichung is a city located in west-central Taiwan with a population of more than 1 million residents. The population
density was 6249 per km2 in 2009. Taichung City contains 8 districts, which include the North District. The North District contains 36 administrative neighborhoods. The residents in these 8 administrative neighborhoods had similar distributions of age and gender compared with the population of both Taichung City and Taiwan. There were a total of 3997 older citizens in these 8 administrative neighborhoods and they were invited to participate in the TCHS-E study. Through household visits, we excluded 1247 individuals because of having moved out of the area, institutionalization, errors on their registry, or death. A total of 2750 individuals were eligible, and 1347 individuals agreed to participate in the study. However, there were some who did not complete the dual-energy X-ray absorptiometry (DXA) examination; only 844 individuals completed all measurements. In the genotyping assay, there were 472 individuals successfully genotyped by the Illumina GoldenGate genotyping assay Table 1 Subject Characteristics According to Low ASMI Status Normal ASMI
Low ASMI
c2 test Low ASMI vs Control
Sociodemographic factors Age 75 Gender Men Women Education Illiterate 13 y Health-related practice Smoking Never Current Former Drinking Never Current Former Exercise No Yes Chronic problem/Illness Hypertension No Yes Diabetes mellitus No Yes Heart disease No Yes Hyperlipidemia No Yes Hyperuricemia No Yes Arthritis No Yes Stroke No Yes Fall history No Yes *Fisher’s exact test.
n (%)
n (%)
158 (38.5) 125 (30.5) 127 (31.0)
12 (19.4) 12 (19.4) 38 (61.3)
201 (49.0) 209 (51.0)
50 (80.7) 12 (19.4)
39 92 145 122
7 13 19 22
P Value
