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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 11 5569-5576
Copyright © 2004 by The Endocrine Society

Late Life Metabolic Syndrome, Early Growth, and Common Polymorphism in the Growth Hormone and Placental Lactogen Gene Cluster

Ian N. M. Day, Xiao-he Chen, Tom R. Gaunt, Tabitha H. T. King, Anca Voropanov, Shu Ye, Santiago Rodriguez, Holly E. Syddall, Avan Aihie Sayer, Elaine M. Dennison, Faiza Tabassum, David J. P. Barker, Cyrus Cooper and David I. W. Phillips

Human Genetics Division (I.N.M.D., X.-H.C., T.R.G., T.H.T.K., A.V., S.Y., S.R.) and Fetal Origins of Adult Disease Division, Medical Research Council Environmental Epidemiology Unit (H.E.S., A.A.S., E.M.D., F.T., D.J.P.B., C.C., D.I.W.P.), School of Medicine, Southampton University Hospital, Southampton, SO16 6YD United Kingdom

Address all correspondence and requests for reprints to: Prof. Ian N. M. Day, Human Genetics Division, Duthie Building Mp808, Tremona Road, School of Medicine, Southampton University Hospital, Southampton, United Kingdom SO16 6YD. E-mail: inmd{at}soton.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Low rates of fetal and infant growth are associated with the metabolic syndrome and cardiovascular disease in later life. We investigated common genetic variation in the GH-CSH gene cluster on chromosome 17q23 encoding GH, placental lactogens [chorionic somatomammotropins (CSH)], and placental GH variant in relation to fetal and infant growth and phenotypic features of the metabolic syndrome in subjects aged 59–72 yr from Hertfordshire, UK. Allele groups T, D1, and D2 of a locus herein designated CSH1.01 were examined in relation to GH-CSH single nucleotide polymorphisms and to specific phenotypes. Average birth weights were similar for all genotype groups. Men with T alleles were significantly lighter at 1 yr of age, shorter as adults, and had higher blood pressures, fasting insulin (T/T 66% higher than D2/D2) and triglyceride concentrations, and insulin and glucose concentrations during a glucose tolerance test. Birth weight and 1-yr weight associations with metabolic syndrome traits were independent of the CSH1.01 effects. Common diversity in GH-CSH correlates with low 1-yr weight and with features of the metabolic syndrome in later life. GH-CSH genotype adds substantially to, but does not account for, the associations between low body weight, at birth and in infancy, and the metabolic syndrome.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
MEN AND WOMEN who were small at birth and who grew slowly during infancy have increased rates of coronary heart disease, metabolic syndrome, and osteoporosis (1). The effect of low weight gain during infancy on coronary heart disease is independent of size at birth and has been shown in studies in Hertfordshire and confirmed in Helsinki (2). Although these observations have been ascribed to nutritional programming in early life, heritable effects could also be contributory. A given genotype or, alternately, two or more different polymorphic genes in linkage disequilibrium acting as allelically associated markers within the same haplotype block (3) could reduce the growth trajectory in early life while predisposing to disease in later life.

The genes that regulate GH are potential candidates, because in addition to the importance of GH in regulating the growth trajectory after birth, abnormalities of the GH/IGF axis have been observed in a number of the chronic adult diseases associated with low birth weight, including cardiovascular disease (4), diabetes (5), and osteoporosis (6). Furthermore, exogenous GH can reverse these disease traits (7, 8). The GH gene GH1 is located on chromosome 17q23 and is in linkage with the cluster of GH-related genes, including the chorionic somatomammotropin-A and -B (CSH-A and -B; human placental lactogen) genes (CSH1 and CSH2), placental GH gene (GH2), and a CSH pseudogene (CSH5). The genes are in the order GH1, CSH5, CSH1, GH2, and CSH2 and span 66.5 kb. The roles of GH in both growth and intermediary metabolism postnatally and in the adult are well known. However, other genes in this cluster may play an important role in the regulation of the glucose supply to the fetus and in fetal growth regulation (9, 10, 11, 12). Placental lactogen, which is synthesized by the syncytiotrophoblast, is structurally and functionally similar to GH. Placental GH differs from GH by 13 amino acids and has a comparable bioactivity. It is highly expressed by the placental syncytiotrophoblastic epithelium during the second half of pregnancy, during which it is the dominant GH moiety in maternal plasma. Complete deficiency of placental lactogen does not necessarily cause a major clinical disorder (13), although it was assayed as a placental functional test before ultrasound technology became available. A deficiency of placental GH seems to lead to severe intrauterine growth retardation (14). The effects of quantitative variation in these hormones are unknown.

Four patterns of familial isolated adult GH deficiency (IGHD) have been observed (15). Two are transmitted as recessive disorders; form IA displays total absence of GH, and form IB shows low levels of GH. Both forms involve nonsense mutations, complete gene deletions, or splice site mutations of GH1. Form IGHD II displays dominant inheritance and involves protein missense mutations or splice site mutations, which are noted to cluster in the last three exons, exons 3–5. These mutations seem to lead to defective GH protein, which interferes with the transport and storage of protein from the normal allele, but phenotype differs, according to the specific mutation. IGHD III is X chromosome linked, implying interaction in trans between the production of the GH1 gene product and an X-linked locus. Haplotypes of the GH1 promoter have been shown to influence the transcription rate in in vitro reporter assays (16), and a single nucleotide (nt) polymorphism (SNP) in intron 4 of the GH gene (GH1 V004 in our numbering; Fig. 1Go) has been associated with GH levels (17) and stature in highly selective case studies.



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  		FIG. 1. Map of GH, placental lactogen gene cluster, and genotypic markers examined in this study. GH1, Adult GH gene; GH2, placental GH variant gene; CSH1 and CSH2, chorionic somatomammotropin (placental lactogen) genes. Arrows show the direction of transcription. CSH5, Related gene, almost inactive. Each gene has five exons shown as vertical bars. V001–V004 represent polymorphisms included in this study. V003 is a complex microsatellite locus designated CSH1.01; the other loci are SNPs (see text). The base change of the BglII restriction fragment length polymorphism is unknown.

 
Little is known about the impact of common genetic variation across the GH-CSH region on stature, early growth, metabolism, or other diseases in the unselected general population. In this paper we have focused our analysis on lineages (historically related groups of alleles) of a highly polymorphic microsatellite locus (herein designated CSH1.01) which has previously been used as a chromosome 17q23 linkage marker (18, 19, 20), but has never been explored as an association marker. Both SNP-based haplotypes and lineages of length polymorphic tandem repeat loci in or near genes can be used for genetic association studies, although SNP genotypes or haplotypes have been more widely applied. Association studies in diabetes and other disorders of the insulin gene (INS) variable number tandem repeat (VNTR) represent a classic example of the use of a lineage approach; allele groups of this locus mark specific SNP haplotypes (21, 22) as well as type I diabetes risk. We have adopted a similar approach for CSH1.01 in relation to haplotypes of the GH-CSH gene cluster. We have examined the relationship between allele groups of CSH1.01 and SNP haplotypes of GH-CSH (including representation of a marker in GH1 intron 4 (17); of a BglII site studied by Southern blots in diabetics (23), which we have identified to be distal to CSH2; of haplotype-tagging SNPs in the GH1 promoter (16); and of the linked ACE insertion/deletion polymorphism (24). We then undertook genotype-phenotype analyses between inferred allele groups of CSH1.01 and growth traits and traits of the metabolic syndrome.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Participants

Caucasian subjects, aged 59–72 yr, from east and north Hertfordshire were enrolled in studies of late life traits in relation to early life anthropometric measures, subject to ethical approval (north and east Hertfordshire ethical committee) and subject anonymity (25, 26, 27). Five hundred and ninety-four men and 409 women were studied. Their heights, weights, and waist and hip circumferences were measured; birth weight and 1 yr weight were available from historical records. Two hundred and fifteen men and 123 women were included in the analysis of metabolic syndrome traits in relation to CSH1.01. These subjects were selected from among all births in the county of Hertfordshire, UK, between 1911–1930, who were followed forward and found to be alive and still resident there in 1990–1995. The subset selected for detailed evaluation of metabolic syndrome comprised those willing to undergo an oral glucose tolerance test; they did not differ significantly from the larger group with regard to birth weight or socioeconomic status. They underwent metabolic characterization, including measurements of blood pressure; pulse rate; 0, 30, and 120 min glucose and insulin responses to 75-g oral glucose tolerance test; and plasma fasting triglycerides. A subset of 28 subjects had 24-h GH profiling at 20-min intervals (28).

Genotyping

DNA bank. DNA was extracted from 5 ml K-EDTA venous blood and quantitated by picoGreen assay, and concentrations were equalized. Long-term stock DNA aliquots were laid down, and working 96-well plates of DNA dilutions to 7 ng/µl were prepared. Degenerate oligo primer amplifications (DOP-DNA) were made from dilution plates to conserve stock DNA, and 96- or 384-well PCRs were performed from DOP-DNA representing 0.07 ng original genomic DNA.

Microsatellite markers. CSH1.01 (size range, 220–311 nt) was coamplified with an IGF1 (CA)n microsatellite (size range, 175–199 nt) (29) using primers 5'-ACTGCACTCCAGCCTCGGAG and 5'-ACAAAAGTCCTTTCTCCAGAGCA for CSH1.01 and 5'-GCTAGCCAGCTGGTGTTATT and 5'-ACCACTCTGGGAGAAGGGTA for the IGF1 marker (www.sgel.humgen.soton.ac.uk/data.html). One primer of each pair was labeled with the same fluorescent dye. For some subjects we used 6-carboxyfluorescein, for some we used HEX, and for some we used NED. Post-PCR pooling of three subjects enabled two-size, three-color multiplexing for ABI377 size calling.

SNP markers. Three hundred and eighty-four-well, allele-specific PCR (using flanking primers and internal allele-specific primers) in conjunction with 384-well microplate array diagonal gel electrophoresis, fluorescent image scanning, and PhoretiX gel image analysis, essentially as previously described (30), was used for most SNP analyses. The BglII B site near CSH2 was examined by PCR and BglII digestion. PCR was all on MJ Tetrads, and the specific oligonucleotide, thermal, and biochemical conditions for each marker are listed at www.sgel.humgen.soton.ac.uk/data.html. The locations of the markers examined are shown in Fig. 1Go.

Statistical analyses

SNP heterozygote data were discarded for examination of distribution of SNP allele frequencies relative to the CSH1.01 allele size spectrum. Microsoft Excel was used for counts and histogram plots. Dichotomizations of CSH1.01 to D1/T or D2/T allele categories (see Results) were coded 1 (for either D1 or D2) and 2 (for T) and entered with SNPs coded 1 (more frequent allele) and 2 into analysis programs. The 2LD program (31) was used to calculate the intensity of pairwise disequilibrium by use of the D' coefficient, defined as D/Dmax, where D = f(AB) – pu, f(AB) is the frequency of the AB haplotype, and p and u are the allele frequencies at the two loci. Dmax is min [p(1 – u), (1 – p) u], when D > 0, or min [pu, (1 – p)(1 – u)], when D < 0. D' ranges from –1 to +1. The significance of nonrandom associations was also calculated by the program 2LD according to the formula {chi}2 = N D (2)/p(1 – p) u(1 – u), where N is the gamete sample size.

In STATA version 7.0, data were analyzed by genotype on 2d.f. and regression on allele on 1d.f. against phenotypes, with or without adjustment for age, adult body mass index, social class at birth, and current alcohol consumption and smoking, as appropriate. Prior hypotheses were restricted to a subset of main phenotypes defined by committee. Birth weight, 1 yr weight, adult height, weight, systolic and diastolic blood pressures, pulse rate, and 0, 30, and 120 min glucose and insulin levels during a 75-g oral glucose tolerance test were examined under prior hypothesis. Other variables were considered as post-hoc descriptive tests. On the basis of known physiology of GH, and general sexual dimorphism of growth and metabolic traits, we elected a priori to analyze genotype associations separately for males and females. Interactions between CSH1.01 and birth weight, and weight at one year, as predictors of metabolic syndrome phenotypes were also examined in STATA 7.0.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
All genotypic markers were in Hardy-Weinberg equilibrium. Allele frequencies are given in Table 1Go.


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  		TABLE 1. Linkage disequilibrium (D' and P value) between CSH1.01 and haplotype tagging SNPs in GH1, CSH2, and ACE

 
CSH1.01 lineages relative to SNPs and haplotypes

The raw data for allele size estimates, from which allele size binning was undertaken, are shown in Fig. 2Go. Above a size 267 nt, each allele group clusters 4 nt apart, with a mode at 275 nt. Below 267 nt, each allele group clusters 2 nt apart, with a mode at 249 nt. It is also notable that every second group from 249 nt upward in size (i.e. 253, 257, etc.) is much more frequent than the group 2 nt nearer to the mode at 249 nt (i.e. 255, 259, etc.). Alleles 267–311 nt were classified as T (tetranucleotide group); alleles less than 267 nt were classified as D1 (dinucleotide group). Alleles 249, 253, 257, 261, and 265 nt, which seem to largely represent a separate tetranucleotide register within the D1 group, were excluded from the D1 group to define a D2 group. Several different lines of genetic evidence other than the pattern of allele sizes and frequency distribution detailed here confirm the biological rationale (evolutionary relatedness) of the allele groupings made. These data have been placed on our web site (www.sgel.humgen.soton.ac.uk) and were available to the referees. In brief, these aspects included patterns of linkage disequilibrium between CSH1.01 and SNPs in the gene cluster; the sequence repeat motifs in CSH1.01; and the evolutionary relatedness of neighboring size alleles according to dinucleotide and tetranucleotide repeat slippage data. One summary table (Table 1Go) is retained for the convenience of the genetically orientated reader and because it is important in relating this paper both to other literature and to our accompanying paper (41) about the relationships of GH-CSH to osteoporosis.



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  		FIG. 2. CSH1.01 allele frequency distribution and relationship to SNP allele distributions. A, CSH1.01 allele frequency distribution. The x-axis shows allele size (nt); raw data exactly as alleles were sized to the nearest 0.1 nt. The y-axis shows the number observed. An arbitrary numbering of alleles is shown above each cluster. Within experimental error, almost all alleles cluster very precisely, consistent with 2- and 4-base repeat length allelic variation. Note first the group of alleles designated T (tetranucleotide), which are spaced at 4-base intervals; second, the group of alleles designated D (dinucleotide) located at 2-base intervals; and third, that D group (in total designated D1) contains alternating high (marked by arrows) and low frequency allele bins. Exclusion of the arrowed bins formed a subset of D group designated D2. T, D1, and D2 are inferred to represent lineages of CSH1.01, which is supported by their relationship to deduced SNP haplotypes (B and C) and Table 1Go. B, Relative occurrence of CSH1.01 alleles in 11 vs. 22 homozygotes for SNP V001. The strong linkage disequilibrium, with V001 1 in positive association with D alleles and V001 2 in positive association with T alleles, confirms the lineage inference made in A about T vs. D1 groups. C, Relative occurrence of CSH1.01 alleles in 11 vs. 22 homozygotes for SNP V004. V004 confirms the inference of B. In addition, it should be noted that the 1 allele of V004 is in especially strong repulsion with the arrowed bins noted in A, supporting the inference of sublineages within D1, as represented by the D2 coding (A, legend). We also suspect microheterogeneity/lineages of group D, but this has not been pursued in this paper.

 
The total number of subjects characterized for metabolic syndrome traits was 215 men and 123 women. In Table 2GoGo we show the mean and SD, number analyzed, and significance for each main trait of metabolic syndrome or anthropometry examined, for CSH1.01 T/D1 and T/D2 genotype classifications, for both males (Table 2AGo) and females (Table 2BGo). There are considerably fewer subjects in the D2/T analyses, because subjects with one or two alleles of 249, 253, 257, 261, and 265 nt are excluded. However, the magnitude of phenotypic differences is greater in the T/T vs. D2/D2 comparisons, and the T/D2 heterozygotes emerge with clearly intermediate phenotypes. The main positive findings are summarized graphically in Fig. 3Go. Essentially no phenotypic differences were observed for females (Table 2BGo), whereas almost every trait of the metabolic syndrome showed significant differences by genotype in males (Table 2AGo). However, there was no difference in body mass index or waist/hip ratio between any T/D1/D2 allelic combination. There was a trend for lower GH levels in 20-min interval, 24-h GH profile peaks in males (Table 2AGo), but not in females possessing a T allele. It appears that one T allele confers a 0.70-fold difference in peak (95th percentile) GH level, and a similar trend was observed for trough, median, and area under the curve measures (data not shown).


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  		TABLE 2A. Metabolic syndrome phenotypes in males tabulated for CSH1.01 allele group D1, T genotypes, and for allele group D2, T genotypes

 

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  		TABLE 2B. Metabolic syndrome phenotypes in females tabulated for CSH1.01 allele group D1, T genotypes, and for allele group D2, T genotypes

 


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  		FIG. 3. CSH1.01 genotype, 1-yr weight, and traits of the metabolic syndrome in males. Means for each genotype group (geometric for insulin, glucose, and triglycerides) and P values for trend on allele are shown above the bars. Full details of all phenotypic analyses, numbers tested, etc., and also tests of T/D1 as well as T/D2 allele classifications are given in Table 2AGo.

 
Combined models of CSH1.01 and early anthropometry, as predictors of the metabolic syndrome phenotypes in males in Table 2AGo, are presented in Table 3Go. Based on the above observations, each test used a model of regression on allele (using either D1/T or D2/T coding), in conjunction with either birth weight or 1 yr weight as the other main variable, treated as a continuous variable. These mutually adjusted main variables were tested for interaction under 1 degree of freedom. Models with no adjustments and those containing the adjustments listed in Subjects and Methods, were explored. The respective four models without adjustments are shown in Table 3Go. Essentially no birth weight or 1 yr weight association with any metabolic syndrome trait was dependent on or interacted with CSH1.01 T/D1 or T/D2 allele classification. Birth weight and 1 yr weight showed their main effects in the glucose tolerance test for 2-h glucose and insulin values, whereas CSH1.01 effects in the glucose tolerance test were more prominent for baseline and 30 min insulin and glucose levels.


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  		TABLE 3. Metabolic syndrome phenotypes significantly associated with early life anthropometry or with CSH1.01 alleles in men from Hertfordshire, UK

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We have shown that common genetic variation in the GH-CSH gene cluster correlates with reduced rates of infant weight gain and a higher prevalence of features of the metabolic syndrome in adult life in males. We used a highly polymorphic microsatellite marker (CSH1.01) on chromosome 17 (17q23) to identify an allele category T representing 34% of alleles in the population. Its homozygous form (T/T), compared with D2/D2, was associated with a 5.3% reduction in weight at 1 yr of age, an 11.5% increase in blood pressure, and a 66.5% increase in fasting insulin concentrations. The findings are independent of obesity (see our post hoc analysis of waist/hip ratio as well as our prior test of body mass index) and of possible confounding variables. Effects of GH deficiency on the metabolic syndrome are commonly assumed to be via effects on fat mass, and exogenous GH stimulates insulin secretion; therefore, the relationships observed here seem paradoxical. It is worth noting that concepts of effects of GH deficiency acting through fat mass have been formed primarily from instances of severe GH deficiency, which may not be representative of general population effects. It is also possible that genotype-specific set-points in homeostatic loops operant over a full lifetime could be quite different from outcomes from more transient therapeutic investigations. One possible explanation is that subjects genetically predisposed to high GH levels could exhibit more GH suppression when given a glucose load, which would leave less insulin antagonism, resulting in lower insulin values in a glucose tolerance test. The diverse effects of GH on different organs or systems during development is another possible explanation.

The fetal origins hypothesis proposes that the association of cardiovascular risk and metabolic syndrome with low birth weight is a manifestation of developmental plasticity whereby undernutrition, hypoxia, or stress during development reduces the rate of growth and alters gene expression, leading to disease in later life (32). Increasing evidence suggests that heritable factors may play a part in these associations. This has been demonstrated for rare mutations in glucokinase (33) and possibly for common variation around the insulin gene promoter (34). Other genotypes may interact with birth size. Although low birth weight is associated with 30% higher fasting insulin levels in later life compared with high birth weight, possession of an Ala12 allele of the peroxisome proliferator-activated receptor-{gamma}2 gene seems to neutralize this association (35). In our study the genotype T/T is associated with low 1 yr weight and with the metabolic syndrome. However, the T/T genotype and 1 yr weight affect different time points in the glucose tolerance test. One year weight showed significant association with 120 min glucose level. By contrast, the significant findings for T/T genotype were with fasting insulin and 30 min insulin and glucose levels. The response to a glucose tolerance test hinges on many hormones and organs (peripheral glucose uptake, liver response, etc.). Our findings raise a question about their relative impacts at different glucose tolerance test time points and their relative dependence on GH-CSH genotype and nutritionally determined early growth.

Our data show that the effects of allelic variation of GH-CSH marked by CSH1.01 are gender specific. GH secretion in adult life is sexually dimorphic, with different gender-specific diurnal profiles of secretion in rat and human and different gender-specific induction of gene expression for steroid hydroxylases CYP2C11 and CYP2C12 and for hepatic nuclear factor 6 (36). However, the expression patterns and effects of the other genes in the GH-CSH cluster have not been compared between genders. Previous studies using the marker that we designate CSH1.01 also showed male-specific linkage. In the Framingham Heart Study (1044 siblings; mean age, 56–57 yr) linkage with hypertension was found, but only in males (19), and linkage with hypertension was found in young whites, but only in males in a study of families from Rochester, MN (1488 siblings; mean age, 14.8 yr) (20).

The trend toward low plasma GH levels for CSH1.01 T alleles is consistent with our findings (haplotype analyses tables not shown, but available at www.sgel.humgen.soton.ac.uk) that the T lineage represents a haplotype (or group of haplotypes) containing the GH V004 2 (rarer) allele, the CSH2 BglII B 2 (rarer, noncutting) allele, and the GH V001 2 (rarer) allele, which in case studies have, respectively, been associated with low GH and IGF-I levels (V004) (17), with GH deficit and aspects of the metabolic syndrome (CSH2 BglIIB) (23, 37), and (since submission of this paper) with a partition (V001) of GH1 promoter haplotypes displaying lower activity in in vitro reporter gene assays (16). In our accompanying paper (41), we show a statistically significant relationship between GH promoter SNP V001 and 24-h GH profiles. It is evident that there are multiple different haplotypes (versions) of the GH-CSH cluster of genes, and there are data (focused solely on GH promoter) suggesting graded expression according to haplotype (16). Thus, the study of any single locus or site (gene, SNP, or CSH1.01) is likely to represent only part of the full picture. Nonetheless, our two studies for osteoporosis and metabolic syndrome traits point to the importance of diversity of this gene cluster in affecting disease risk in the general population. It is tempting to assume the hypothesis of a chain of causality through GH expression, corresponding to the effects of exogenous GH in later life (8), but the strong linkage disequilibrium between markers across GH-CSH (i.e. that a particular version of GH may be accompanied by a particular version of one or more of the placentally expressed genes) means that the developmental impact of diversity in the various placental products may be responsible for early canalization toward some or all of the phenotypic traits developing during later life (fetal growth hypothesis). Indeed, the observations we report in this study could explain previously observed associations between ACE genotype and cardiovascular disease traits. More than 700 papers have reported relationships between ACE genotype and several conditions, including myocardial infarction (38, 39), hypertension (19), metabolic traits (40), and birth size and insulin resistance (24). We have observed approximately 20% allelic association between CSH1.01 T alleles and the D allele of the ACE gene, which is also located on chromosome 17q. Some of the many effects ascribed to the ACE genotype may reflect a causality originating in the GH-CSH cluster. The relationship of CSH1.01 T alleles to blood pressure, triglycerides, glucose level (5–10% of trait values), etc., will be weakly marked by the ACE D allele, and it will be of considerable interest to examine whether some ACE D allele phenotypic associations represent weak proxy marking of causal factors located in the GH-CSH gene cluster.


   Footnotes
 
This work was supported by the United Kingdom Medical Research Council, the University of Southampton, and the Wessex Medical Trust (Hope). I.N.M.D. was a Lister Institute Professor, and S.R. is a European Community Marie Curie Research Fellow.

X.-H.C., T.R.G., and S.R. contributed equally to this study.

Abbreviations: CSH, Chorionic somatomammotropin; IGHD, isolated adult GH deficiency; nt, nucleotide; SNP, single nucleotide polymorphism.

Received February 3, 2004.

Accepted August 17, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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