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Physiol. Genomics 31: 236-243, 2007. First published June 19, 2007; doi:10.1152/physiolgenomics.00283.2006
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Received 21 December 2006; accepted in final form 18 June 2007.
Physiological Genomics 31:236-243 (2007)
1094-8341/07 $8.00 © 2007 American Physiological Society

Association of CA repeat polymorphism at intron 1 of insulin-like growth factor (IGF-I) gene with circulating IGF-I concentration, growth, and fatness in swine

Joan Estany 1, Marc Tor 1, Daniel Villalba 1, Lluís Bosch 2, David Gallardo 3, Neus Jiménez 3, Laura Altet 3, Jose L. Noguera 4, Josep Reixach 5, Marcel Amills 3 and Armand Sánchez 3

1 Departament de Producció Animal, Universitat de Lleida, Lleida
2 Departament d'Enginyeria Química, Agrària i Tecnologia Agroalimentària, Universitat de Girona, Girona
3 Departament de Ciència Animal i dels Aliments, Universitat Autònoma de Barcelona, Bellaterra
4 Àrea de Producció Animal, Centre Universitat de Lleida-Institut de Recerca i Tecnologia Agroalimentàries, Lleida
5 Selección Batallé, Riudarenes, Spain


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Evidence is accumulating that intronic polymorphic cytosine-adenosine (CA) repeats may play a role in gene expression. In this work, we investigated whether a polymorphic CA short tandem repeat (STR) located at the first intron of the pig insulin-like growth factor I (IGF-I) gene influences plasma IGF-I concentration in pigs as well as phenotypic variation in growth and fatness traits. We measured plasma IGF-I levels at one to four time points from 35 to 215 days of age in 340 performance-tested Landrace and Duroc pigs previously genotyped for the IGF-I STR. Data were analyzed within breed with a linear mixed model with the number of CA repeats as a covariate. At least five alleles were segregating in each breed, differing in one to seven repeats. The results showed that in each breed, circulating IGF-I at 160 days of age increased with the length of the shortest allele, accounting for an average trend of 4.38 ± 1.28 ng/ml of IGF-I per additional repeat (P = 0.001). Longer repeats were associated with early growth in Landrace boars (1.92 ± 0.92 kg per CA at 160 days; P = 0.038) and with back fat thickness (–0.57 ± 0.20 mm per CA; P = 0.005) and lean content (7.52 ± 3.00 g/kg per CA at 105 kg; P = 0.013) adjusted for carcass weight in Duroc barrows, as expected from the effect of circulating IGF-I on these traits. The consistency of the results across populations supports the hypothesis that the length of the CA repeats at intron 1 of the IGF-I gene is associated with circulating IGF-I levels, and that this effect is not neutral with respect to growth and fatness.

microsatellite; live weight; back fat; pigs


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
INSULIN-LIKE GROWTH FACTOR (IGF)-I is a mitogenic polypeptide that is responsible for a wide array of cellular actions (27, 42). Evidence suggests that circulating levels of IGF-I may play a role in several human chronic disorders (40) and in cancer (36) and aging (26). Studies undertaken in domestic animals have shown that serum IGF-I levels are correlated to a vast diversity of traits, such as growth and feed intake (7, 9, 16), body composition and meat quality (14, 15, 49), and reproduction efficiency (57). Quantitative genetic analyses in humans (25), mice (5), pigs (7), and cattle (15) have shown that the levels of circulating IGF-I are under genetic control, with heritability estimates around 30%. This observation has been experimentally confirmed in mice (6), sheep (4), and cattle (35), where divergent selection for IGF-I plasma concentration resulted in genetic divergence between lines.

The existence of genetic variation influencing IGF-I expression in conjunction with the extensive progress made in understanding the molecular biology of this hormone (43) has made the IGF-I gene a very suitable target for genetic manipulation (37) and an attractive candidate gene to search for DNA polymorphisms, both in humans (38) and in domestic species (2, 10, 21). Sequencing of the rat and human IGF-I genes revealed the presence of a cytosine-adenosine (CA)n short tandem repeat (STR) in the promoter region (44). In humans evidence is accumulating that the length of this highly polymorphic (CA)n STR may be associated with circulating IGF-I concentration (41). There are also lines of evidence indicating that this polymorphism is associated with body weight and height characteristics (39, 54) and with human diseases (12, 41, 53), although results were not always coincident (17, 51) and their molecular basis remains to be elucidated.

In the present work, we have analyzed a similar genetic model in a distantly related mammalian species. In pigs, a polymorphic (CA)n sequence repeat is located at the first intron of the IGF-I gene (31, 56), a region that often has an important regulatory role in gene transcription (18, 45). Moreover, there is evidence suggesting that the polymorphism of this STR might be linked to average daily gain (10). The purpose of our work was to examine the genetic variation at the IGF-I gene in commercial pigs and investigate whether the length of the intronic (CA)n sequence repeat is associated with circulating IGF-I and with growth and fatness traits. We have achieved this objective by measuring plasma IGF-I levels in performance-tested individuals with different IGF-I STR genotypes. Two pig breeds with completely different genetic origins and with distinct selective trajectories were used for assessing the consistency of the associations found across populations.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
The experimental procedures in this study were approved by the Ethics Committee for Animal Experimentation of the University of Lleida, and all animal procedures and care were performed in accordance with authorizations AE1170 (Landrace) and AE2374 (Duroc) issued by the Catalan Agency of Agriculture, Livestock, and Fishing, Spain.

Design of experiments and protocols.
The study consisted of two experiments, each with 170 halothane gene-free pigs, that were performed independently to validate the results across populations. Population characteristics and total number of records used in the analyses are given in Table 1. Experiment 1 was based on three purebred Landrace (LN) dam lines of similar characteristics, all selected for litter size and growth rate and against back fat depth. Lines A and B were from separate origins, whereas line C was a synthetic line derived from lines A and B. Piglets used in the experiment were randomly chosen within line (42, 62, and 66 for lines A, B, and C, respectively) from 92 litters sired by 25 boars. All pigs sampled from lines A and B were boars, while those from line C were mostly gilts (52 gilts and 14 boars). Pigs from lines A and B were allocated randomly into four batches and raised until the age of 170 days, as were those from line C in a subsequent fifth batch. Experiment 2 used Duroc (DU) barrows from a closed dam line selected for the same traits as in the lines used in experiment 1 plus intramuscular fat content. Pigs were randomly sampled from 104 litters sired by 36 boars, neutered during the first week of age, and raised in three batches until ~225 days. Throughout the experiment, from 30 days to age of slaughter, pigs were monitored between one and four times (at ~35, 160, 185, and 215 days of age) and always at the reference age of 160 days (Table 1). In each sampling time ~10 ml of blood was obtained with a syringe and kept in tubes containing EDTA. Plasma was collected by centrifugation (3,000 g for 10 min) and stored at –40°C until required for assay. Moreover, pigs were weighed, and from 90 kg onward their subcutaneous back fat depth was ultrasonically measured at 5 cm off the midline between the third and fourth last ribs (A-mode equipment; Renco, Minneapolis, MN). In experiment 2, at the same location where back fat depth was taken, loin depth was also measured (Piglog A-mode equipment, SFK, Herlev, Denmark) and a biopsy of ~160 mg of dry matter of the longissimus muscle, which was immediately stored at –80°C, was taken with spring-loaded biopsy equipment (Biotech PPB-U, Nitra, Slovakia). During the test period pigs from both breeds had ad libitum access to commercial diets. At the end of each experiment, pigs were slaughtered in commercial slaughterhouses, where the subcutaneous back fat and loin thickness at 6 cm off the midline between the third and fourth last ribs were obtained with the SFK Fat-O-Meter (FOM) optical probe (experiment 1) or SFK AutoFOM ultrasound automatic scanning (experiment 2). The carcass lean content was estimated either from these two measurements (FOM) or on the basis of 35 measurement points (AutoFOM) by using the official approved equations (13, 23). After chilling for 24 h at 2°C, each carcass was divided into primal cuts and the weight of untrimmed hams was registered. To determine the intramuscular fat content, slices of ~50 g from the semimembranosus (experiment 1) or gluteus medius (experiment 2) muscles were taken. Muscle samples were vacuum packaged in different bags and stored in a deep freeze. Intramuscular fat content was determined in duplicate by ether extraction in a Soxhlet apparatus (3) or by quantitative determination of the fatty acids by gas chromatography with capillary column (biopsy). In the latter case, fatty acid methyl esters were obtained with a solution of 20% boron trifluoride in methanol (46) and total fat was calculated as the sum of individual fatty acids expressed as triglyceride equivalents (3).


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  		Table 1. Landrace and Duroc pig population characteristics for age of reference and total number of records used in analyses

 
Genotyping of IGF-I intron 1 STR.
Total DNA was isolated from 300-mg muscle samples by incubating them in 5 ml of lysis buffer (50 mM Tris pH 8, 20 mM EDTA, and 5% SDS) and 50 µl of proteinase K (10 mg/ml) at 37°C overnight. Approximately 0.5 ml of the lysate was phenol-chloroform extracted and ethanol precipitated. The resulting DNA pellet was resuspended in 50 µl of ultrapure water and 2 µl of RNase (10 mg/ml). The purification of genomic DNA from blood samples was performed as described previously (55). A microsatellite located in the first intron of the IGF-I gene was used to type the IGF-I gene (56). The PCR mixture contained 2.5 mM MgCl2, each dNTP at 200 µM, each primer at 0.2 µM, 100 ng of genomic DNA, and 0.5 U of AmpliTaq Gold (Roche) in a 10-µl final volume. Primer sequences were 5'-GCT TGG ATG GAC CAT GTT G-3' (forward) (Tet labeled at 5') and 5'-CAT ATT TTT CTG CAT AAC TTG AAC CT-3' (reverse). The thermal profile was 94°C for 10 min, 27 cycles of 94°C for 15 s, 52°C for 30 s, and 72°C for 1 min, and a final extension step of 72°C for 30 min. Samples were analyzed in an ABI Perkin Elmer 3100 capillary electrophoresis device.

Plasma IGF-I determination.
Plasma IGF-I concentration was measured with a commercially available self-extraction ELISA kit by using an antibody raised against human IGF-I (Immunodiagnostic Systems, Boldon, UK). Plasma IGF-I was determined in both LN and DU pigs from blood samples taken at sampling ages. Each sample was evaluated in a double assay. The inclusion of a serum control run in each assay indicated that the intra-assay and interassay coefficients of variation were lower than 5.3% and 18.8%, respectively. The lower limit of detection was 15.9 ng/ml.

Statistics.
Plasma IGF-I concentration, live weight, and back fat thickness were analyzed within breed with a linear mixed model, in which fixed effects included the testing group and the IGF-I genotype with age as a covariate centered at the age of reference. The effect of age was modeled as a first-order polynomial except for complete repeated measurement analyses in DU pigs, where a second-order polynomial was used. The covariance structure of the data was modeled by adding the sire and, if repeated measurements were available, the pig as random effects. Pigs of the same sex and line tested at the same time were considered as a testing group. The IGF-I genotype was defined according to the number of intronic (CA)n sequence repeats in each of the alleles of the IGF-I gene. The additive effect of each of the IGF-I alleles was based on a gene substitution model in which the effects of the different alleles were estimated by multiple regression analyses. The effect of the length of the polymorphism was estimated by substituting the genotype by either a covariate on the number of sequence repeats or length genotype classes. The same approach was used for the analyses of plasma IGF-I concentration as a function of live weight or back fat thickness. Data for carcass traits were fitted to a model including the testing group and the genotype as fixed effects and sire as the only random effect, with carcass weight as a covariate in substitution for age. The association between plasma IGF-I concentration and performance and carcass traits was analyzed with the same models but substituting the plasma IGF-I concentration at control ages for the IGF-I genotype. Within-line and within-sex estimates, as well as pooled estimates between breeds, were also obtained. Estimates are presented as coefficients of regression ± SE and least-square means ± SE. Significance testing between genotypes was done by a t-test pairwise comparison of the respective least-square means and set at P < 0.05. No transformation on dependent variables was performed because no consistent departures from normality according to the Shapiro-Wilk test were found. Data were analyzed with SAS (SAS Institute, Cary, NC) using MIXED procedures.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
IGF-I STR allele frequencies and genotypes.
The studied IGF-I STR at intron 1 displayed a remarkable degree of polymorphism, with at least five alleles segregating in both LN and DU populations (Table 2). However, a different pattern of allele distribution was observed in each breed. Allele 199, which was the predominant allele in LN pigs (frequency of 61.2%), was poorly represented in DU pigs (frequency of 11.0%), and, vice versa, allele 197, the most common in DU pigs (frequency of 56.5%), only reached a frequency of 7.1% in LN pigs. Alleles 195 and 203 were only found in LN pigs, while alleles 191 and 205 were specific to DU pigs. No deviation from Hardy-Weinberg equilibrium was observed either in LN or DU pigs (P > 0.05), and no difference in allele distribution was found among LN lines A, B, and C (P > 0.05). Allele 199 was the predominant allele in the three LN lines and, with the exception of allele 197, which was not present in pigs sampled from line A, all other alleles were found in each line. The average genotype was longer in LN than in DU pigs (+0.54 CA repeats; P = 0.004), the difference being mainly due to the length of the shortest allele in the genotype (+0.39 CA repeats; P = 0.007). No significant difference for the length of the STR among LN lines was observed.


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  		Table 2. Allele distribution of IGF-I gene polymorphism in Landrace and Duroc populations

 
Plasma IGF-I concentration, growth, and fatness.
Plasma IGF-I concentrations were within the expected range (7, 9, 49), with boars exhibiting 1.6-fold higher values than gilts (Table 1). However, plasma IGF-I level displayed a marked age-related pattern (Fig. 1), showing a consistent increase from 35 to 160 days and a declining trend at older ages. Results in LN boars indicated that plasma IGF-I concentration at 160 days was more than threefold higher than at 35 days, while results in DU barrows showed that from 160 to 185 days plasma IGF-I levels decreased by ~15%. Plasma IGF-I concentration at 35 days was uncorrelated with plasma IGF-I levels at older ages, which, on the contrary, were moderately correlated with each other. The correlation between IGF-I plasma levels at 35 and 160 days was –0.08 (P = 0.571) and –0.03 (P = 0.761) in LN boars and DU barrows, respectively, while the pooled intra-animal correlation between measurements taken at 160, 185, and 215 days in DU barrows was 0.35 (P < 0.001).


Figure 1
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  		Fig. 1. Plasma insulin-like growth factor I (IGF-I) concentration adjusted at 35 (IGF1-35), 160 (IGF1-160), and 185 (IGF1-185) days of age in Landrace (LN) boars and Duroc (DU) barrows. Values are expressed as means ± SE per genetic type. Statistical significance was determined by t-test. Means lacking a common superscript within a breed differ. Plasma IGF-I concentration increased from 35 to 160 days (P < 0.001) in the 2 breeds. In DU barrows plasma IGF-I concentration decreased from 160 to 185 days (P < 0.001).

 
The association of plasma IGF-I concentration with live and carcass traits is presented in Table 3. Plasma IGF-I concentration was shown to be associated with live weight, although the strength of the relationship varied by genetic type and age. In DU barrows a positive association between circulating IGF-I and live weight was observed shortly after weaning (32 ± 5 g per ng/ml at 35 days; P < 0.001), whereas in LN it was not significantly demonstrated until commercial market weights (103 ± 39 g per ng/ml in boars at 160 days; P = 0.009). On the contrary, no relationship was found between circulating IGF-I and live weight at 35 days in LN boars (2 ± 8 g per ng/ml; P = 0.850) or between circulating IGF-I and live weight at 160 days in LN gilts (4 ± 44 g per ng/ml; P = 0.924) or in DU barrows (30 ± 25 g per ng/ml; P = 0.231). Circulating IGF-I was not associated with back fat thickness (Table 3), which may be indicative that increased levels of circulating IGF-I improved growth performance by selectively altering body composition in favor of lean growth. To test the hypothesis that plasma IGF-I concentration affects body composition, the effect of circulating IGF-I on back fat and loin thickness at fixed live weight was determined. Circulating IGF-I did not affect back fat thickness adjusted for live weight at 160 days in LN boars, but results in DU barrows were consistent in showing that high levels of plasma IGF-I at ages approaching puberty were associated with higher lean content. Thus back fat thickness adjusted for live weight decreased with plasma IGF-I level [–15 ± 8 µm per ng/ml at 160 days (P = 0.057) and –22 ± 10 µm per ng/ml at 185 days (P = 0.022)], while loin thickness adjusted for carcass weight (64 ± 31 µm per ng/ml; P = 0.039) and estimated lean content (34 ± 15 mg/kg per ng/ml; P = 0.026) increased. Moreover, intramuscular fat content was also affected by circulating IGF-I concentration. The IGF-I concentration at 185 days was negatively related to intramuscular fat content in both longissimus muscle adjusted for live weight at 185 days (–327 ± 160 µg/g muscle per ng/ml; P = 0.043) and in gluteus medius adjusted for carcass weight at slaughter (–544 ± 184 µg/g muscle per ng/ml; P = 0.004).


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  		Table 3. Association between plasma IGF-I concentration and performance and carcass traits by genetic type and age

 
IGF-I STR genotypes and plasma IGF-I concentration.
The multiple regression analyses revealed significant substitution effects between extreme alleles. Thus in LN pigs, allele 203 showed a positive substitution effect for plasma IGF-I concentration at 160 days compared with both allele 195 (23.1 ± 8.2 ng/ml; P = 0.006) and allele 197 (20.7 ± 9.3 ng/ml; P = 0.028). On the other hand, we found in DU barrows a positive additive effect when substituting allele 201 by allele 197 (10.0 ± 4.8 ng/ml; P = 0.043) on plasma IGF-I level at 35 days, as well as a negative effect of allele 199 on circulating IGF-I level at 160 days and older (–8.6 ± 4.2 ng/ml; P = 0.040). The same effects were also seen after adjusting circulating IGF-I for live weight or back fat thickness. These results suggest that, at least in LN pigs, there might be a positive relationship between the length of the IGF-I STR and circulating IGF-I. To test this hypothesis specifically, plasma IGF-I concentration was modeled on the number of STR repeats with a repeatability model. The results of this analysis showed that circulating IGF-I at 160 days increased with the length of the shortest allele within each breed (Table 4), accounting for an average trend of 4.3 ± 1.28 ng/ml of IGF-I per additional STR (P = 0.001). This result was consistent with the observed trend in each of the LN lines [line A 9.34 ± 2.79 (P = 0.002), line B 7.04 ± 3.11 (P = 0.027), and line C 3.35 ± 3.63 (P = 0.359) ng/ml of IGF-I per additional STR]. The positive effect that longer STR exerted on the plasma IGF-I level was more apparent in boars than in gilts, where it was not significantly demonstrated, in accordance with the fact that LN gilts, like DU barrows, exhibited lower plasma IGF-I levels at 160 days (Table 1). A high (H)- and a low (L)-length genotype class with respect to the length of the STR in the shortest allele were defined and compared with all available IGF-I measurements (Fig. 2). The genotypes with both alleles displaying a number of STRs equal or greater than allele 201 were allocated to the H class, and the rest were assigned to the L class. In LN pigs there were only three pigs with this genotype so that the H class was extended to include pigs with the shortest allele being equal or greater than allele 199. The H class displayed higher levels of plasma IGF-I at 160 days compared with the L class [12.9 ± 5.2 (P = 0.013) and 11.6 ± 4.8 (P = 0.016) ng/ml for LN boars and DU barrows, respectively].


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  		Table 4. Plasma IGF-I concentration adjusted at 160 days of age by IGF-I genotype and genetic type

 

Figure 2
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  		Fig. 2. Plasma IGF-I concentration adjusted at 160 days of age by IGF-I genotype class in LN boars and DU barrows. Low and High refer to the number of cytosine-adenosine (CA) repeats in the shortest allele of the IGF-I genotype. High class includes genotypes with the greatest number of repeats in the shortest allele in each breed [no. of repeats ≥allele 199 in LN boars (n = 43 pigs) and ≥allele 201 in DU barrows (n = 16 pigs)]. Low class includes the rest of the genotypes (n = 29 pigs for LN boars and n = 151 for DU barrows). Values are expressed as means ± SE per genetic type. Statistical significance was determined by t-test. Within each breed, means lacking a common superscript differ (P = 0.013 in LN boars; P = 0.016 in DU barrows). In both breeds plasma IGF-I at 160 days increased as the length of the shortest allele increased.

 
IGF-I STR genotypes, growth, and fatness.
In LN pigs a positive substitution effect was observed of allele 203 for allele 195 for live weight (4.6 ± 2.2 kg; P = 0.035) and back fat thickness (0.8 ± 0.4 mm; P = 0.053) at 160 days, a feature that agrees with the positive trend of these traits with the length of the STR in the shortest allele (Table 5). In contrast, the analyses conducted in DU barrows were not able to detect any significant effect of the IGF-I STR genotype on live weight and back fat thickness. The comparison of H and L classes for live weight and back fat thickness in LN boars and DU barrows is depicted in Fig. 3. The association pattern in LN gilts, although not significant, was consistent with that observed in boars. Pigs in the H class were heavier at 160 days than pigs in the L class in LN boars (2.5 ± 1.0 kg; P = 0.015) but not in DU barrows. There was no significant difference between classes for back fat thickness at 160 days in LN boars or in DU barrows. The small increasing trend appearing in LN boars (0.4 ± 0.3 mm; P = 0.117) vanished after adjusting for live weight (0.2 ± 0.3 mm; P = 0.488).


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  		Table 5. Change in performance and carcass traits per additional copy of CA repeat in short allele of IGF-I genotype

 

Figure 3
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  		Fig. 3. Live weight and ultrasonic back fat thickness adjusted at 160 days of age by IGF-I genotype in LN boars and DU barrows. See Fig. 2 for definition of low and high IGF-I class genotypes and statistical procedures used. Within each breed, means lacking a common superscript differ. In LN boars live weight at 160 days increased with the length of the shortest allele (P = 0.015) but not back fat thickness (P = 0.117), whereas in DU barrows both traits were unaffected by the length of the shortest allele (P = 0.406 and P = 0.914 for live weight and back fat thickness, respectively).

 
In LN boars the substitution effect of allele 203 for allele 195 for the weight of hams was –0.47 ± 0.20 kg (P = 0.024), while substituting it for allele 197 led to increase in intramuscular fat content (75.8 ± 22.4 mg/g dry matter; P = 0.001). However, the length of the STR in the shortest allele was related to weight of hams but not to intramuscular fat content (Table 5). In DU barrows a negative substitution effect was observed of allele 201 for allele 191 for carcass back fat thickness (–2.1 ± 0.7 mm; P = 0.005) adjusted for carcass weight, together with a positive effect for carcass loin thickness (4.1 ± 2.4 mm; P = 0.086). In consequence, carcass lean content was higher for allele 201 compared with allele 191 (23.9 ± 11.3 g/kg; P = 0.037). These results led in DU barrows to a negative association of carcass back fat thickness with the length of the STR in the shortest allele, as well as a positive relation with loin thickness and estimated lean content (Table 5). The comparison of the H and L classes for carcass weight and estimated carcass lean content is depicted in Fig. 4. Pigs in the H class showed higher carcass weights than pigs in the L class both in LN boars and in DU barrows [3.6 ± 1.7 (P = 0.036) and 6.5 ± 2.8 (P = 0.020) kg, respectively], but while in LN boars the carcass lean content was unchanged between classes, in DU barrows the H class was leaner at constant carcass weight (+26.5 ± 12.2 g/kg; P = 0.032) than the L class.


Figure 4
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  		Fig. 4. Carcass weight adjusted for age and estimated carcass lean content adjusted for carcass weight by IGF-I genotype in LN boars and DU barrows. LN boars were slaughtered at 170 days (82 kg carcass weight) and DU barrows at 225 days (105 kg carcass weight). See Fig. 2 for definition of low and high IGF-I class genotypes and statistical procedures used. Within each breed, means lacking a common superscript differ. Carcass weight increased with the length of the shortest allele both in LN boars (P = 0.036) and in DU barrows (P = 0.020), while estimated carcass lean content at constant carcass weight increased in DU barrows (P = 0.032) but not in LN boars (P = 0.587).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Several lines of evidence from this study support the hypothesis that pigs bearing longer CA repeats at intron 1 of the IGF-I gene, specifically in the shortest allele, have greater circulating IGF-I levels at peripuberty. A plausible explanation of this genetic pattern is to assume that longer alleles have a much greater effect than shorter alleles, or that there is a nonlinear increase of allelic effects with the length of the STR. Under this model, the slope of the regression of circulating IGF-I on STR number is expected to be more marked when calculated on the basis of the number of repeats in the shortest allele in a genotype than in the longest, as is the case here. However, because regression estimates may be greatly influenced by sampling errors associated with extreme genotypes (usually less numerous), it is advisable to validate the results across populations. Our results were consistent across genetic groups in showing that the longer the short allele is the higher the concentration of circulating IGF-I. However, the effect of the IGF-I genotypes on circulating IGF-I was only significantly demonstrated at 160 days, with the differences more marked in boars than in gilts or barrows. This result can be explained in light of the ontogeny of IGF-I and its differential pattern between sexes. After weaning, circulating IGF-I concentration increases up to a peak at ~100–120 days before decreasing smoothly (8), with a higher and 2–3 wk later peak in boars than in gilts or barrows (11, 34). Maximum variability in plasma IGF-I concentration is expected to occur in boars at ages around the peak, so the measurement taken in boars at 160 days is where differences between genotypes, if they exist, should more likely be detected.

Some authors have reported a relationship between the number of STRs and plasma IGF-I levels in humans. The highly polymorphic (CA)n STR 1 kb upstream of the transcription site of IGF-I, lying within the promoter region of IGF-I, has been associated with serum IGF-I levels, although with conflicting results. While some authors observed a positive relationship with the length of the STR (19, 41), others found that the relationship was negative (32, 53), null (1), or group dependent (29, 30). Our findings are in line with seminal investigations reporting that the common allele, one of the shortest in the analyzed populations, was found to be associated with decreased IGF-I levels (19, 41) and not with investigations that suggest that there exists a ceiling effect of IGF-I levels according to genotype or that a functional significance is limited to shorter repeats (12). Other authors have attempted to reconcile previous conflicting results suggesting that there is a broader optimum for IGF-I gene-regulated transcriptional activity, with both shorter and longer alleles having lower circulating IGF-I levels (39). To the best of our knowledge, no similar results have been reported in pigs. The polymorphism we studied is located in another region, at intron 1, which has also been shown to have an important regulatory role in gene transcription (18, 45). On the other hand, there is increasing evidence that the number of intronic STRs can cause quantitative changes in gene expression (22) or splicing efficiency (28), acting either as enhancers or repressors according to environmental challenges (48, 50). We can anticipate that the length of CA repeats at intron 1 of the IGF-I gene may have a functional significance, resulting in variable levels of IGF-I expression, although alternative explanations cannot be ruled out. Because circulating IGF-I levels are regulated by complex interactions among multiple loci (24), the existence of other DNA sequences in linkage disequilibrium with the IGF-I STR or affecting circulating IGF-I half-life cannot be discarded.

The IGF-I STR polymorphism has been found to be associated with live weight and carcass lean content, with longer STRs showing higher live and carcass weights in LN boars and higher carcass weight and lean content in DU barrows. This result is in accordance with the effect that circulating IGF-I had on live weight and lean content. We have seen that at early phases of growth circulating levels of IGF-I were primarily related to growth, but as pigs approach mature weight the strongest associations were found with compositional traits. It is known that the relationship of circulating IGF-I with live weight decreases with age (52), as pigs become fatter. In consequence, a precocious fat deposition can lead to shortening of the period in which the association of circulating IGF-I with live weight is more evident. DU barrows have less potential for protein deposition than LN boars, so it is not surprising that the STR IGF-I polymorphism is preferentially related to lean content in DU barrows and to live weight in LN boars. In DU barrows, the effect of the polymorphism on body weight was only significantly demonstrated in the carcass, once the abdominal fat had been removed. Results in field trials carried out in pigs observed that juvenile blood IGF-I concentration was positively correlated with back fat thickness but not with daily gain at the end of the performance test (7). This would suggest, in correspondence with our results, that high early circulating IGF-I may be indicative of pigs with precocious fat deposition. On the other hand, maintaining high levels of circulating IGF-I after puberty may help, as expected from the anabolic function of IGF-I, in promoting protein synthesis, with the desired consequence of increasing fat-free mass while inhibiting fat accretion. In line with this, it has been shown that in pigs expressing an IGF-I transgene small elevations of circulating IGF-I increased lean content as pigs became older but did not have any major effect on growth performance (37). The effects of IGF-I on glucose uptake are different in skeletal muscle and adipose tissue. Prolonged treatment with IGF-I stimulates glycogen synthesis in the skeletal muscle, whereas lipogenesis is reduced in the adipose tissue via inhibition of insulin secretion (20).

There are some limitations to this study. The size of the experiments was sufficient for detecting relevant effects, but a higher number of pigs would have given more validity to the research. Large samples are required to estimate the effect of rare individuals carrying extreme genotypes with precision. This was partially amended by using repeated measurements of IGF-I and compensated by looking for consistency across populations with different genetic backgrounds and selection trajectories, which are known to affect the relationship among circulating IGF-I, live weight, and lean content at a given age (7, 9). Circulating IGF-I displayed a marked nonlinear trend from shortly after weaning to peripuberty, and it is easily influenced by recent feeding events (9, 52). It would have been desirable to have additional measurements to determine the IGF-I pattern, particularly around the peak and after enforced fasting. However, it was impossible to obtain these extra measurements because pigs belonged to commercial lines subjected to conventional management. Finally, not only endocrine but also autocrine effects play a relevant role in growth regulation. Circulating IGF-I is modulated by several blood binding proteins, while differential expression of autocrine IGF-I may differ across muscles (33, 47). A proteomic approach involving more than one muscle would have provided a more complete picture of lean and adipose tissue growth regulation.

Two questions were addressed in this study, first, whether variation in the length of the intronic (CA)n STR in the IGF-I gene influences circulating IGF-I in pigs and second, whether this polymorphism is associated with growth and fat traits. In summary, the consistency of the results across populations gives credit to the hypothesis that the STR polymorphism at intron 1 of the IGF-I gene is associated with growth and fatness and that this effect is exerted through a modification of IGF-I expression. Increased plasma IGF-I levels were demonstrated in pigs displaying longer STRs of the IGF-I gene, and longer STRs were associated with early growth and lean content at peripuberal ages. Lean content and intramuscular fat content are two important economic traits in pork production. Blood juvenile IGF-I level has been proposed as a biomarker for lean (7) or intramuscular fat (49) content in pigs. Our results indicate that age at measurement, especially with measurement at early ages, is critical for using plasma IGF-I concentration as a method for biomarking pigs. The IGF-I STR polymorphism may be a valuable alternative. However, further studies are needed to determine whether circulating IGF-I could be useful for altering specifically either lean content or intramuscular fat, as the industry demands. In any case, the identification and follow-up of extreme allelic variants may help to gain insight into the physiological mechanisms by which IGF-I regulates growth and fatness.


   GRANTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This research was funded by the Spanish Ministry of Education and Culture (CICYT AGF99-1221 and AGL2001-0648).


   ACKNOWLEDGMENTS
 
The authors are indebted to Teresa Giró and Anna Ñaco for assistance in the laboratory analyses and to the staff of Nova Genètica and Selección Batallé for cooperating in the experimental protocol.


   FOOTNOTES
 
Address for reprint requests and other correspondence: J. Estany, Departament de Producció Animal, Universitat de Lleida, Rovira Roure 191, 25198 Lleida, Spain (e-mail: jestany{at}prodan.udl.es).

Article published online before print. See web site for date of publication (http://physiolgenomics.physiology.org).


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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