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236 S.M. Roth analysis revealed a significant association with handgrip strength that was completely explained by the rs1800169 A-allele, such that A/A individuals exhibited lower handgrip strength compared to G-allele carriers. In a follow-up study, Roth et al. (2008) examined multiple polymorphisms in the CNTFR gene in association with strength variables in 465 men and women (20–90 year). For the C174T polymor- phism, T-allele carriers exhibited significantly higher quadriceps and hamstrings concentric and eccentric isokinetic strength at both 30 and 180 deg/s compared to C/C carriers, but these differences were not significant after adjustment for lower limb lean mass. No differences were observed for polymorphisms in the promoter region or elsewhere in the gene. De Mars and coworkers (2007) exam- ined polymorphisms in both the CNTF and the CNTFR genes in 493 middle-aged and older men and women with measures of knee flexor and extensor strength. T-allele carriers of the C-1703T polymorphism in CNTFR exhibited higher strength levels for multiple measures compared to C/C homozygotes, including all knee flexor torque values. In middle-aged women, A-allele carriers at the T1069A locus in CNTFR exhibited lower concentric knee flexor isokinetic and isometric torque compared to T/T homozygotes. The CNTF null allele was not associated with any strength measures, nor were any CNTF*CNTFR interactions observed. These findings indicate the potential for significant influences of CNTF and CNTFR gene variants on skeletal muscle strength, though inconsistencies have been noted for CNTFR. The frequency of the rare A/A genotype in CNTF is so low that, despite some consistent findings of lower muscle strength, public health sig- nificance is uncertain, though clinical importance may be had for those particular individuals. Estrogen Receptor (ESR1) The estrogen receptor alpha is expressed in skeletal muscle, indicating a potential sensitivity to estrogen signaling (Wiik et al. 2009). While several studies have examined genetic variation in the ESR1 gene in relation to muscle strength measures, none have confirmed any association. Salmen et al. (2002) examined 331 early postmenopausal women during a 5-year hormone replacement therapy trial for associations with the ESR1 gene. Neither baseline nor 5-year grip strength values were associated with ESR1 genotype. Vandevyver and colleagues (1999) examined 313 postmenopausal Caucasian women with measures of grip and quadriceps strength and reported no associations with ESR1 genotype. Grundberg et al. (2005) reported no association between a TA-repeat polymor- phism in the ESR1 gene and several muscle strength measures in 175 Swedish women (20–39 year). Ronkainen and co-workers (2008) examined ESR1 genotype in 434 older women (63–76 year) and found no significant association with hand grip or knee extension strength or leg extension power. Insulin-like Growth Factor 2 (IGF2) Two studies have examined the IGF2 gene in relation to strength phenotypes. Sayer et al. (2002) performed grip strength analysis in 693 older men and women and examined association with the IGF2 ApaI polymorphism. IGF2 genotype was associated with grip strength in men but not women, with G/G genotype having lower strength compared to A/A genotype carriers. Interestingly, an independent but additive effect of birth weight on grip strength values was also noted in men. Schrager and colleagues (2004) examined 237Genetic Variation and Skeletal Muscle Traits: Implications for Sarcopenia the same ApaI polymorphism in relation to muscle strength and power phenotypes in 485 men and women. They reported significantly lower arm and leg isokinetic strength measures in A/A women compared to G/G women, differences that were not observed in men. IGF2 is imprinted in mammals such that only the paternal allele is transcribed (Zemel et al. 1992), thus analyses in these studies focused on comparing homozygote groups rather than heterozygotes. The results of these stud- ies stand in direct contrast to each other, and indicate that any influence of IGF2 genotype on strength-related traits is going to be minor or the result of interaction with other yet-to-be identified factors. Myostatin-Related Genes After myostatin’s discovery in the late 1990s, it emerged as a potential target of gene association studies and multiple polymor- phisms were identified in the human gene (MSTN) (Ferrell et al. 1999). Initial investigations reported associations with skeletal muscle strength, but the sample sizes were very small owing in part to low allele frequencies of the common poly- morphisms. Seibert et al. (2001) reported lower strength in older African American women (70–79 year) with the R-allele compared to K/K genotype at the MSTN K153R polymorphism, but the sample size was quite low (n = 55). Corsi et al. (2002) reported lower isometric muscle strength (averaged across eight muscle groups) in R-allele carriers of the K153R polymorphism in 450 older men and women. Though consistent with the findings of Seibert (2001), the sample size of R-allele carriers was only seven making the findings inconclusive. Because the common polymorphisms have rare allele frequencies, the clinical significance of MSTN genetic variation is unlikely. Two groups have recently examined genes within the myostatin signaling pathway, including the myostatin receptor (activin- type II receptor B; ACVR2B) and follistatin (FST), a myostatin inhibitor. Walsh et al. (2007) examined the genetic association of ACVR2B and FST with muscle strength in 593 men and women across the adult age span. In women but not men, ACVR2B haplotype was significantly associated with knee extensor concentric peak torque. FST haplotype was not associated with muscle strength. Kostek et al. (2005) reported significant associations with the MSTN gene in 23 African Americans for biceps isometric strength. The FST gene was also associated with baseline one- repetition maximum strength levels. Again, the sample sizes of the genotype groups with significant findings were small making the clinical relevance of these findings uncertain but generally not compelling. Vitamin D Receptor (VDR) Vitamin D deficiency has been consistently associated with lower muscle strength (Ceglia 2008) and has been discussed as a potential mechanism of sarcopenia (Montero-Odasso and Duque 2005). In one of the first gene associations for skeletal muscle traits, Geusens et al. (1997) demonstrated a significant relationship between the VDR BsmI polymorphism and both isometric quadriceps and hand grip strength in 501 elderly, healthy women, with 23% higher quadriceps strength and 7% higher grip strength in the b/b compared to B/B genotype carriers. These findings were subsequently sup- ported in a subgroup of these same women (Vandevyver et al. 1999). In contrast, Grundberg et al. (2005) examined two polymorphisms (poly A repeat and BsmI) within VDR in relation to muscle strength in 175 women aged 20–39 year. 238 S.M. Roth They found greater hamstrings isokinetic muscle strength in women homozygous for the shorter poly A repeat (ss) compared to women homozygous for the long poly A repeat (LL). No associations were reported with quadriceps or grip strength. Similar findings were reported for the BsmI variant (b and B alleles) given the significant linkage disequilibrium between the s and B alleles. Thus, the B/B genotype group exhibited higher hamstrings strength in contrast to the Geusens et al. findings. Roth and colleagues (2008) reported significant associa- tions with the VDR FokI polymorphism (f and F alleles) and knee extensor iso- metric strength in 302 older Caucasian men (f/f higher than F/F), but these associations were no longer significant once leg FFM was accounted for in the models, suggesting that the genotype-strength associations were explained by differences in muscle mass. Wang et al. (2006) examined the ApaI, BsmI, and TaqI VDR polymorphisms in 109 young Chinese women in relation to knee and elbow torque measures. At the ApaI locus, A/A women exhibited lower elbow flexor concentric peak torque and lower knee extensor eccentric peak torque compared to either A/a or a/a carriers. For the BsmI locus, the b/b carriers dem- onstrated lower knee flexor concentric peak torque than the B-allele carriers. No associations were observed for the TaqI locus. Windelinckx and colleagues (2007) examined the BsmI, TaqI, and FokI VDR polymorphisms in 493 middle- aged and older men and women for association with various muscle strength phenotypes, with BsmI and TaqI combined in a haplotype analysis. In women, the FokI polymorphism was associated with quadriceps isometric and concentric strength, with higher levels in f/f homozygotes compared to F-allele carriers. In men, the BsmI/TaqI haplotype was associated with quadriceps isometric strength with Bt/Bt homozygotes exhibiting greater strength than bT haplotype carriers. In a study involving 107 COPD patients and 104 healthy controls, Hopkinson et al. (2006) reported Fok1 F/F carriers had lower quadriceps isometric strength than f-allele carriers. The b-allele of the Bsm1 polymorphism was associated with greater strength compared to B-allele carriers in COPD patients but not in controls. In summary, VDR genetic variation has been associated with muscle strength variables in numerous studies, though inconsistencies have been noted. Studies having examined the BsmI locus are mixed with regard to their findings and future studies need to incorporate the haplotype of BsmI and TaqI rather than looking at either site independently. The VDR FokI site is considered func- tional (Arai et al. 1997; Jurutka et al. 2000) and two studies reported higher strength in f/f compared to F/F carriers, so this site should be investigated more thoroughly for possible clinical significance. In summary, several genes have been associated with skeletal muscle strength phenotypes in multiple studies. While none of these genes can yet be tagged as conclusively contributing to inter-individual variation in strength phenotypes, their consistency across multiple studies is encouraging. These genes will require additional validation and clarification as to their specific roles in modifying strength-related traits, with the eventual goal to determine their clinical importance to sarcopenia. 239Genetic Variation and Skeletal Muscle Traits: Implications for Sarcopenia 4.2 Genetic Variation and Skeletal Muscle Mass Table 3 summarizes the genes that have been studied in relation to skeletal muscle mass measurements, focusing on genes associated with baseline muscle mass values; genes related to muscle mass adaptation to exercise training are discussed in a later section. Genes that have been studied in only one paper or that have not been replicated in some way and are not discussed here include: MTHFR (Liu et al. 2008b); CNTF and CNTFR (Roth et al. 2000, 2008); COL1A1 (Van Pottelbergh et al. 2001); TNF (Liu et al. 2008a); IL15 and IL15RA (Pistilli et al. 2008); COMT (Ronkainen et al. 2008); ESR1 (Ronkainen et al. 2008); NR3C1 (Peeters et al. 2008); and IGF2 (Schrager et al. 2004). Angiotensin Converting Enzyme (ACE) The majority of papers examining the ACE I/D polymorphism have been focused on muscle strength rather than muscle mass phenotypes, though some studies have examined both. Most have shown no significant association (Thomis et al. 1998a; Pescatello et al. 2006), though Charbonneau et al. (2008) reported higher quadriceps muscle volume in D/D com- pared to I/I carriers in a study of 225 older men and women (50–85 year). Thus, it appears unlikely that ACE genotype contributes significantly to muscle mass phe- notypes, which is similar to the conclusion for muscle strength traits. Alpha Actinin 3 (ACTN3) As discussed above, several studies have examined the potential for the ACTN3 R577X polymorphism to explain variability in muscle strength measures. Many of those same papers have also examined muscle mass variables, though the results are less consistent. Vincent and colleagues (2007) did not observe any genotype difference in FFM determined by bioelectrical imped- ance in their study of 90 young men. Norman et al. (2009) reported no significant genotype associations with FFM determined by skinfold measurements in 120 young men and women. Delmonico et al. (2008) reported no significant genotype associations with DXA-measured FFM in their study of 1,367 older adults (70–79 year). Walsh et al. (2008) examined 848 adult men and women (22–90 year) and found that X/X women displayed lower levels of both total body FFM and lower limb FFM compared with R/X + R/R women. Concomitant differences were noted for muscle strength that were explained by the FFM differences, as discussed in the previous section. No genotype-related differences were observed in men. Thus, only Walsh et al. (2008) have found evidence of an association between muscle mass and the ACTN3 null allele, indicating at best a minor role for this polymor- phism in explaining inter-individual variability in this trait. Androgen Receptor (AR) Walsh and colleagues (2005) examined the associa- tion between the AR CAG-repeat polymorphism with muscle strength and mass variables in two cohorts of older men and women. Though they found no associa- tion between muscle strength and AR genotype, significant genotype associations with FFM were observed in the men of both cohorts. The androgen receptor is a nuclear transcription factor, for which testosterone is an important ligand. The CAG-repeat sequence in exon 1 of the AR gene appears to modulate receptor tran- scriptional activity (Chamberlain et al. 1994). Subjects were grouped according to 240 S.M. Roth Table 3 Genes and gene sequence variants associated with skeletal muscle mass phenotypes in multiple studies Gene References Variants Examined Subjects Skeletal Muscle Mass Measurements AR Walsh et al. (2005) CAG repeat 295 men (cohort 1) and 202 men and women (cohort 2) FFM (DXA) in men in both cohorts FST Walsh et al. (2007) Haplotype analysis 593 men and women FFM (DXA) in men Kostek et al. (2009) A-5003T 23 young African American Biceps cross-sectional area TRHR Liu et al. (2009) rs16892496, rs7832552 1,000 men women (cohort 1); 1,488 men and women (cohort 2); 2,955 Chinese men and women (cohort 3); 1,972 men and women from 593 families (cohort 4) LBM (DXA) in all four cohorts VDR Van Pottelbergh et al. (2002) TaqI, ApaI, FokI 271 older men FFM (DXA) Roth et al. (2004) FokI, BsmI 302 older men FFM (DXA) FFM, fat-free mass; LBM, lean body mass; DXA, dual-energy X-ray absorptiometry. Gene abbreviations are defined in the text. 241Genetic Variation and Skeletal Muscle Traits: Implications for Sarcopenia the length of the CAG repeat, with subjects grouped for short and long fragments. Men in both cohorts with the long fragment lengths demonstrated significantly greater appendicular skeletal muscle mass and higher relative total lean mass. The results could not be explained by genotype-based differences in either bioavailable or total testosterone. Additional work is required to determine the extent to which the AR CAG-repeat polymorphism contributes to muscle mass variation, though these consistent findings in two cohorts is encouraging. Myostatin-Related Genes Despite the strong physiological evidence behind myostatin as a candidate gene for muscle mass traits, genetic variation in the MSTN gene has not been associated with muscle mass (Ivey et al. 2000; Kostek et al. 2005). Kostek et al. (2009) did report strength differences for MSTN in a small number of African American subjects, as noted above. Two studies have examined myostatin-related genes in relation to muscle mass phenotypes. In 593 men and women across the adult age span, Walsh et al. (2007) reported significant associa- tions between follistatin (FST) haplotype and leg FFM in men but not women, but no association with FFM and haplotype structure in the myostatin receptor, ACVR2B. Strength differences were discussed in the previous section. Kostek et al. (2005) also examined the FST gene and found that African Americans carriers of the FST T-allele had greater biceps CSA than A/A genotype carriers for the A-5003T polymorphism, but sample sizes were small. There is little compelling evidence that MSTN or myostatin-related genes are major contributors to skeletal muscle mass, though minor contributions are indicated. Thyrotropin-Releasing Hormone Receptor (TRHR) As described above, Liu and colleagues (2008a) identified TRHR as a potential candidate gene for skel- etal muscle mass from the first genome-wide association study for this trait. After the initial genome-wide analysis that identified two polymorphisms in the TRHR locus, the authors performed separate replication studies in three cohorts consisting of over 6,000 total white and Chinese subjects and consistent signifi- cant associations with LBM were observed in those analyses. Importantly, inter- actions between TRHR and genes in the growth hormone/insulin-like growth factor (GH/IGF1) pathway were explored and tentative connections were indi- cated. Though only a single paper, the multiple replications pointing to TRHR provide strength for this as a potentially important candidate gene for muscle mass variation. Vitamin D Receptor (VDR) VDR genetic variation has been studied fairly extensively for muscle strength phenotypes, as described above, but fewer studies have focused on skeletal muscle mass. Van Pottelbergh and colleagues (2001) reported associations between the TaqI (T and t alleles)/ApaI (A and a alleles) haplotypes and lean mass in 271 older men (>70 year). The highest lean mass was observed in the At-At haplotype group, which differed most from haplotypes con- taining T-allele homozygosity (e.g., aT-aT, AT-aT, and AT-AT haplotypes). This relationship was not observed, however, in a group of younger men from the same study. Roth et al. (2008) reported significant associations with the VDR FokI poly- morphism (f and F alleles) and leg FFM in 302 older Caucasian men, with con- comitant differences in muscle strength as noted above. No significant differences 242 S.M. Roth were associated with the VDR BsmI site. This study is described in more detail in the section on genes specifically associated with sarcopenia. Thus, only two studies have examined VDR genotype in relation to skeletal muscle mass phenotypes, but the results provide some evidence for positive association. In summary, remarkably few studies have provided evidence of genetic associa- tion of specific candidate genes with muscle mass phenotypes despite the strong heritability of the trait. The strongest findings are perhaps those with the least evi- dence, as TRHR and AR have at least been replicated, but only one research group has contributed to each of those studies. Presumably the advent of genome-wide association studies will provide a greater push for identifying potential candidate genes with relevance to skeletal muscle mass. 4.3 Genetic Variation and Sarcopenia While a number of studies have addressed specific genes and genetic variants in relation to skeletal muscle strength and mass phenotypes, only one study to date has specifically targeted a measure of sarcopenia per se. Roth and colleagues (2004) analyzed the influence of the VDR BsmI and FokI variants on muscle strength and mass in a cohort of 302 older (58–93 year) Caucasian men with measures of FFM by DXA. VDR FokI genotype was significantly associated with total lean mass, appendicular lean mass, and normalized appendicular lean mass (all P < 0.05), with the F/F group demonstrating significantly lower mass than the F/f and f/f groups. In addition, the group categorized the men as normal or sarcopenic based on the definition of Baumgartner et al. (1998), which relies on a cutoff value based on appendicular FFM relative to body weight (kg/m 2 ). Logistic regression revealed a significant 2-fold higher risk for sarcopenia in VDR Fok I F/F homozygotes than carriers of the f-allele (OR = 2.17; 95%CI = 1.19–3.85; P = 0.03). Quadriceps mus- cle strength was also significantly lower in the F/F group compared to the F/f and f/f groups, but this association was eliminated when the analysis controlled for dif- ferences in total body lean mass. No significant differences were associated with the VDR BsmI site. Thus, VDR FokI genotype was significantly associated with lean mass and sarcopenia in this cohort of older Caucasian men, with concomitant differences in muscle strength. Vitamin D deficiency has been consistently associ- ated with lower muscle strength (Ceglia 2008), and appears to be related to type II fiber atrophy (Pfeifer et al. 2002), thus making it an important potential mechanism in the etiology of sarcopenia in some individuals (Montero-Odasso and Duque 2005). The FokI polymorphism in the VDR gene affects the translational start site of the gene (Arai et al. 1997; Jurutka et al. 2000) thus making it a potentially func- tional polymorphism, though other variants in the VDR gene may interact in a more complex haplotype (Uitterlinden et al. 2004). Obviously, considerable work remains to be done to take the many genes outlined above and address the clinical relevance of sarcopenia in particular. 243Genetic Variation and Skeletal Muscle Traits: Implications for Sarcopenia 4.4 Genetic Variation and Skeletal Muscle Adaptation to Training Though not an emphasis of this chapter, several studies have examined the role of genetic variation in the adaptation of skeletal muscle to exercise training, especially strength or resistance training. The adaptation of skeletal muscle to strength train- ing is a heritable trait in itself (Thomis et al. 1998b) and linkage studies have been successfully performed using such traits as outcome variables, as described above (Chagnon et al. 2000; Sun et al. 1999). Moreover, specific genes have been studied and specific gene variants identified as being potentially important to skeletal muscle adaptation. The bulk of these studies have been described most recently in the updated Human Gene Map for Performance and Health-Related Fitness Phenotypes (Bray et al. 2009). Genetic variation important to skeletal muscle adaptation has relevance for sar- copenia in multiple contexts. First, the identification of particular genes that con- tribute to inter-individual variation in skeletal muscle adaptation provide insights into the basic biology of skeletal muscle, which could be exploited in multiple ways to facilitate new or improved intervention techniques for muscle disorders and sar- copenia in particular. Second, the possibility exists that the same gene variants important to skeletal muscle adaptation could also be important to skeletal muscle development and thus baseline phenotypes, though the case can equally be made that different genetic contributions can be expected for these two different traits. Finally, because exercise training in general and strength training in particular are considered some of the most important interventions for the prevention and treat- ment of sarcopenia (Roth et al. 2000), understanding the genetic contributions to muscle adaptation, especially in older men and women, will allow improved appli- cation of such interventions via genetic screening. A number of genes have been identified as potentially important for skeletal muscle adaptation, though arguably none have emerged as clinically meaningful as of this writing. Similar to the situation with baseline skeletal muscle phenotypes, the bulk of these genes remain unreplicated or replicated across different training stimuli or measurement methods, making traditional genetic replication analysis challenging. In fact, the variations on exercise training interventions are arguably more numerous than those related to measurement of skeletal muscle strength, and variations on both of these are often seen across different gene association studies related to muscle strength adaptation. Genes studied in relation to skeletal muscle adaptation include: PPARD with muscle volume response to lifestyle intervention (Thamer et al. 2008); IGF1, IGFBP3, and PPP3R1 (calcineurin) with muscle strength and volume responses to strength training (Kostek et al. 2005, Hand et al. 2007); RST with upper arm muscle strength and muscle CSA responses to strength training (Pistilli et al. 2007); TNF, TNFR1, TNFR2, and IL6 with measures of physical function before and after exercise training (Nicklas et al. 2005); IGF2, ACTN3, and MYLK in different studies with muscle damage in response to a dam- aging exercise protocol (Devaney et al. 2007; Clarkson et al. 2005b); ACE with 244 S.M. Roth muscle strength and mass responses to various exercise training protocols (Folland et al. 2000; Charbonneau et al. 2008; Thomis et al. 1998a; Williams et al. 2005; Pescatello et al. 2006; Frederiksen et al. 2003); IL15 and IL15RA (IL-15 receptor) with muscle strength and size responses to strength training (Riechman et al. 2004, Pistilli et al. 2008); MSTN and FST polymorphisms with muscle strength and size traits in response to strength training (Thomis et al. 1998b; Kostek et al. 2009; Ivey et al. 2000); ACTN3 with muscle strength and size responses to strength training (Clarkson et al. 2005a; Delmonico et al. 2007); and BMP2 with muscle size response to strength training (Devaney et al. 2009). 5 Conclusions and Future Directions Despite remarkably high heritability values, only modest progress has been made in identifying the specific genetic contributors to skeletal muscle strength and mass phenotypes. Only seven genes have been positively associated with strength-related traits in multiple cohorts (Table 2), and the findings are not always consistent within the replication analyses. Similarly, only four such genes have been identified for muscle mass and two of those genes were internally replicated rather than being confirmed in a second paper (Table 3). No genes have been replicated for associa- tion with sarcopenia per se, though VDR has been associated with sarcopenia in one study and associated with muscle mass and strength phenotypes in multiple studies. Not only have few genes been identified, but their contribution to genetic variation is also generally quite small. None of the genes identified in the present chapter have been shown to conclusively contribute more than 5% of the inter- individual variation to their respective traits, and most are on the order of 1–3%. These results mirror what has recently been found for other highly heritable traits: genome-wide association studies are finding genes with relatively small influence that in no way explain the overall genetic influence predicted by heri- tability estimates (Maher 2008). This could reflect the major limitation of genome-wide association studies and most genetic association studies to date in that these have focused almost exclusively on single nucleotide polymorphisms, which though important are not the only DNA-related components that contribute to genetic influence. In addition to typical polymorphisms, copy number variation (CNV; multiple copies of the same gene), epistasis (multiple genes coordinated in a pathway), complex gene*environment interactions, and epigenetic factors are also contributing to the genetic component of inter-individual variability (Altshuler et al. 2008) and these more complex phenomena are just beginning to be studied in large-scale investigations. An important contributor to inter-individual variation in age-related muscle traits will likely be epigenetic factors, which have already been shown to be impor- tant to aging tissues in general (Kahn and Fraga 2009). Epigenetics generally refers 245Genetic Variation and Skeletal Muscle Traits: Implications for Sarcopenia to chemical modifiers to DNA and histone proteins that alter DNA regulation without a direct change to the DNA sequence itself with consequences for normal development and disease risk (Hirst and Marra 2009). DNA methylation has been shown to decline with aging in several species including humans (Bollati et al. 2009) and DNA methylation has important consequences for gene expression. Importantly, modification of epigenetic factors appears to be related to environmen- tal conditions (Foley et al. 2009; Baccarelli et al. 2009). So, both age and environ- ment are likely to contribute to epigenetic changes in skeletal muscle tissue that will alter gene regulation and contribute to age-related losses in strength and mass, thus affecting physical function. How environmental conditions will alter epigenetic factors in a way meaningful for skeletal muscle traits and sarcopenia risk is as yet unclear, but certainly this represents another avenue of exploration for future studies. An underlying theme when considering the genetic aspects of skeletal muscle traits generally and sarcopenia in particular is that of a “threshold” level for these traits below which physical function (e.g., activities of daily living) is impaired. Once a person’s strength falls below a certain threshold, physical function becomes impaired. Such a threshold would surely be defined differently for each individual, but within reason we can expect clinically meaningful thresholds to be established across various physical characteristics, especially sex, age, height, weight, and body composition. This threshold concept has been discussed by a number of groups (Ferrucci et al. 1997; Walston and Fried 1999; Visser et al. 2005; McNeil et al. 2005). Because genetic variation (including epigenetics) will tend to have subtle influences on skeletal muscle and sarcopenia-related traits, the general hypoth- esis is that genetic variation will tend to push trait values closer to or farther away from this threshold, thus altering an individual’s risk for impaired physical function. Thus, identifying individuals with genetic susceptibility to lower levels of skeletal muscle strength or mass who are closer to their likely threshold for physical limitation will allow for early, targeted interventions to help prevent early losses. This is the concept behind personalized or genetic medicine. Early identification for individuals genetically susceptible to sarcopenia could result in a dramatic improvement in health care costs, by introducing interventions prior to the onset of associated infirmities. Of course, finding these genes and developing the individualized interventions will take many years if the last decade provides any clue to future progress. One potential approach to speed discovery will be to examine genes related to bone structure and mass, which may have a pleiotropic influence on skeletal muscle traits (Karasik and Kiel 2008). The development of more sophisticated genome-wide association studies that include copy number variants may also aid in this search. Even if genes of only minor effect are identified that don’t lend themselves to genetic screening and personalized medicine, those genes will point to potential physiological pathways that can be manipulated through more typical means and lend insight into the underlying etiology of sarcopenia in different individuals (Khoury et al. 2007; Burke 2003). . outlined above and address the clinical relevance of sarcopenia in particular. 243Genetic Variation and Skeletal Muscle Traits: Implications for Sarcopenia 4.4 Genetic Variation and Skeletal Muscle. Windelinckx and colleagues (2007) examined the BsmI, TaqI, and FokI VDR polymorphisms in 493 middle- aged and older men and women for association with various muscle strength phenotypes, with BsmI and. men. Schrager and colleagues (2004) examined 237Genetic Variation and Skeletal Muscle Traits: Implications for Sarcopenia the same ApaI polymorphism in relation to muscle strength and power phenotypes