(Circulation. 1997;96:733-740.)
© 1997 American Heart Association, Inc.
Articles |
Lipoprotein Lipase Variants D9N and N291S Are Associated With Increased Plasma Triglyceride and Lower High-Density Lipoprotein Cholesterol Concentrations
Studies in the Fasting and Postprandial States: The European Atherosclerosis Research Studies
From the Department of Medicine and Cardiology A, Aarhus Amtssygehus University Hospital, Tage Hansensgade 2, DK-8000 C Aarhus, Denmark (C.G., O.F.); Division of Cardiovascular Genetics, University College London Medical School, London, UK (R.M.F., S.E.H., P.J.T.); and INSERM U258, Hôpital Broussais, Paris, France (V.N., J.B.).
Correspondence to Dr C. Gerdes, Department of Medicine and Cardiology A, Aarhus Amtssygehus University Hospital, Tage Hansensgade 2, DK-8000 C Aarhus, Denmark. E-mail c_gerdes{at}post4.tele.dk
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionAppendix 1References |
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Background Variations at the DNA level with moderate effects on biochemical variables may be important for the occurrence of disease at the population level, if they are common. Two mutations in the LPL gene, N9 and S291, are associated with variation in fasting plasma concentrations of HDL cholesterol (HDL-C) and triglycerides (TG). We investigated whether these mutants were more frequent in offspring of cases with premature coronary disease and analyzed the effects on fasting plasma lipids and postprandial TG.
Methods and Results Students with and without paternal history of myocardial infarction (cases and control subjects [controls]) were studied in the European Atherosclerosis Research Studies I and II (EARS-I and -II). Allelic frequencies for the N9 and S291 mutations did not differ between cases and control subjects. The N9 mutation was identified in 4.2% of all subjects in EARS-I, and carriers had higher fasting TG levels (P<.001) than noncarriers. In an oral fat tolerance test, there were no differences in postprandial TG between carriers and noncarriers of the N9 allele. The S291 mutation was identified in 3.1% of all subjects in EARS-I, and carriers had lower fasting HDL-C levels (P<.005) than noncarriers. There was a significant interaction between S291 genotype and body mass index on fasting TG levels (P<.01). In the cases, carriers of the S291 allele had higher TG levels 6 hours postprandially (P<.04) than did noncarriers.
Conclusions The two LPL mutations are common and may predispose to elevated TG and decreased HDL-C concentrations, even in young subjects. In the case of the S291 mutation, this effect appears to be mediated via delayed postprandial TG clearance. Moreover, even moderate obesity potentiates the TG-raising and HDL-lowering effects associated with the S291 allele.
Key Words: genetics • obesity • epidemiology • postprandial lipemia • EARS Group
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Low concentrations of plasma HDL-C are inversely related to atherosclerosis and CHD.1 They are also inversely correlated with fasting TG2 and strongly associated with the activity of LPL, a key enzyme in the metabolism of TG-rich lipoproteins.3 A common lipid phenotype, characterized by both low HDL and high TG levels, substantially increases the risk of CHD.1 It is maintained across generations, suggesting a strong genetic component,2 4 with the LPL gene as an obvious candidate.
Variations at the DNA level in general have moderate-to-weak effects on biochemical variables.5 Nevertheless, they may be important for the occurrence of disease at the population level, if they are common.6 There are two common mutations in the LPL gene. One of these substitutes an asparagine for an aspartic acid at amino acid residue 9 (N9)7 in the mature protein, and the other mutant results in the replacement of asparagine by serine at residue 291 (S291).8
Fasting HDL-C and, to a lesser extent, fasting TG concentrations partially reflect postprandial lipoprotein metabolism.3 9 10 If fat absorption from the gut is normal, the postprandial lipoprotein pattern is largely determined by LPL, and the effects of genetic variation in the LPL gene might therefore be more evident on postprandial than on fasting lipoproteins. The effects of N9 and S291 mutations on postprandial plasma lipids are largely unknown,11 and one of the purposes of this study was to clarify them. We also wanted to test whether subjects with a priori higher risk of CHD had a higher frequency of the variant alleles and to study the effects of the two LPL mutations on fasting plasma lipids in young subjects.
A problem in the study of genetic determinants of risk of CHD is that the study variable (eg, biochemical trait) may itself be affected by the disease, age, environmental factors, and/or by treatment of the disease. A way to circumvent this problem is to study young offspring of patients with and without CHD (cases and control subjects [controls], respectively). The design of an offspring study makes data interpretation complex, and comparison of, for example, allele frequencies between cases and control subjects has less power and cannot be interpreted as in a classic case-control study.12
The EARS-I and -II are case-control offspring studies of European university students with and without a paternal history of myocardial infarction before the age of 55 years. In EARS-I, we screened a large number of subjects for the two LPL mutations and studied the effects on fasting lipids associated with the variant alleles. In EARS-II, we tested the stability of the effects observed in EARS-I and studied the impact of the two LPL mutations on postprandial TG responses.
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Methods |
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Subjects
EARS-I has been described previously.13 Briefly, male and female university students between 18 and 26 years with a paternal history of myocardial infarction before age 55 (cases) were recruited in 1990 from 14 university student populations from 11 European countries: Austria, Belgium, Denmark, Finland, France, Germany, Italy, Spain, Sweden, Switzerland, and the United Kingdom. Two age- and sex-matched control subjects per case were randomly selected from the same university populations. Details of lifestyle, medical history, and physiological measurements were established using standardized protocols. Venous blood was collected after a 14-hour fast.
EARS-II was carried out in 1993. Male students aged 18 to 28 years were recruited from 14 university student populations from 11 European countries: Estonia, Finland, Belgium, Denmark, Germany, Switzerland, the United Kingdom, Spain, Italy, Portugal, and Greece. Subjects were recruited and data were collected using the same protocol as described above with the exception that cases and control subjects were matched 1:1. EARS-II also included an OGTT and an OFTT.
OGTT and OFTT
Subjects were given a standard (75 g) OGTT. One week later, they
were given an oral liquid lipid load containing 66 g fat (42 g
saturated), 22 g protein, 56 g carbohydrate, and 417 mg
cholesterol. The formula contained 6186 kJ. Blood was drawn
at baseline and at 2, 3, 4, and 6 hours. Biochemical analyses
were performed as previously described.14 15
DNA Analysis
DNA was extracted as previously described.7 LPL
exon 2 was amplified by the polymerase chain reaction7
using DNA predried onto microtiter plates.16 Screening for
the N9 allele was by allele-specific
oligonucleotides. Oligonucleotides used
for the allele-specific oligonucleotides had the following sequence:
homologous to D9 sequence 5'-GAT TTT ATC GAC ATC G-3' and homologous to
N9 sequence 5'-GAT TTT ATC AAC ATC GA-3'. Positive samples were
confirmed using a restriction enzyme cleavage assay.7
Screening for the S291 allele was performed as previously
described17 using DNA predried onto microtiter plates.
Statistical Analysis
The recruitment centers in EARS-I were grouped into five regions
on the basis of published age-standardized mortality rates, geography,
and language.14 In EARS-II, we defined the four regions of
Baltic (Finland and Estonia), United Kingdom, Middle Europe (Denmark,
Germany, Belgium, and Switzerland), and Southern Europe (Portugal,
Italy, Spain, and Greece).
We excluded from analyses subjects with both mutations and subjects from whom measurements of TG, cholesterol, or HDL-C were not available. In analyses of N9 carriers, subjects with the S291 mutation were excluded from the noncarrier group and vice versa. Allele frequencies were compared between cases and control subjects with a Mantel-Haenszel test adjusted for region.
In analyses of lipid levels by genotype, means were compared with ANOVA (GLM procedure) after adjustment of matching and stratification criteria (age, region, sex, and case/control subject status) and covariates (oral contraception, tobacco and alcohol consumption, and physical activity assessed as one of three levels [minimal, moderate, and heavy]). TG and insulin levels were log-transformed for analyses, but arithmetic mean values are shown. The homogeneity of the genotype effect in cases and control subjects, in men and women, and by region was systematically tested by introducing the corresponding interaction term in all stages of the analyses. Further analyses were performed in center and gender tertiles of BMI, TG, and HDL-C.
The postprandial response studied in EARS-II was characterized by three different methods in which we adjusted for age, region, case/control subject status, and covariates: (1) two-way ANOVA for repeated measures to test the overall significance of postprandial measurements over time and between genotypes and the parallelism of the two curves (GLM procedure); (2) the AUC above the fasting concentration, calculated by the trapezoidal rule; and (3) the peak, calculated as the highest value minus the fasting value.
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Results |
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For technical reasons, DNA samples from Italy in EARS-I could not be analyzed. Because of a low yield of DNA from some other samples and exclusion due to missing data, final analysis was based on 84% and 74% of 1994 subjects for the N9 and S291 genotypes, respectively. In EARS-II, all data were obtained on 90% of 822 subjects for both genotypes.
LPL: N9
The overall frequency of the N9 allele for pooled cases and
control subjects was 2.1% in EARS-I (Table 1
) and 1.7% in EARS-II (legend to Table 3). Allele frequencies varied statistically significantly between
regions in EARS-I, and the EARS-II data suggested the same pattern.
Allelic frequencies did not differ significantly between cases and
control subjects in either of the studies. One subject was homozygous
for the N9 allele, and three subjects (who were excluded from
analysis) were heterozygous for both the N9 and S291
alleles. Plasma lipid and apolipoprotein concentrations as well as
body mass indices were within the normal range for these four subjects
(data not shown). There were more smokers in the N9 carrier group in
EARS-I than in the noncarrier group (42% versus 26%,
P=.003), whereas the proportion of smokers was the same in
carriers and noncarriers in EARS-II (26% versus 23%).
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Biochemical and anthropometric data for carriers and noncarriers of the
N9 allele are given for all subjects (pooled regardless of gender
or case/control subject status) in Table 2 (EARS-I) and Table 3
(EARS-II). Pooling of the data was
justified by the homogeneity of the observed effects of the N9
allele on the variables (data not shown).
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In EARS-I, carriers of the N9 allele had statistically
significantly higher fasting TG concentrations than noncarriers (Table 2), and a similar trend was found in EARS-II (Table 3), although the
difference in TG was smaller and not statistically significant. In
EARS-I, HDL-C concentrations were lower in N9 carriers than in
noncarriers (P=.05, Table 2). No significant differences in
BMI, waist-to-hip ratio, or other biochemical traits were observed
between N9 carriers and noncarriers in either the subgroups (data not
shown) or pooled groups (Tables 2 and 3) in either of the studies.
Possible interaction between N9 carrier status and BMI, as previously
reported,7 was investigated. As shown in Fig 1a, carriers of the N9 allele in
EARS-I had a graded increase in plasma TG with increasing BMI. Although
N9 carriers in the upper tertile showed a more marked increase in TG
concentrations than did noncarriers, the test for interaction between
BMI and N9 carrier status on TG was not statistically significant. The
EARS-II data showed a similar pattern (data not shown).
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N9 allele carriers and noncarriers in EARS-II did not differ in
postprandial TG responses after the OFTT (Fig 2a and 2b) before or after correction for
baseline values. There were no differences in glucose or insulin
responses after OFTT or OGTT in either cases or control subjects (data
not shown).
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LPL: S291
The overall frequency of the S291 allele was 1.6% and 1.9%
in EARS-I (Table 1) and EARS-II (legend to Table 3), respectively.
There were no significant differences in allele frequencies between
cases and control subjects in either of the studies. One female subject
in EARS-I was homozygous for the S291 allele. She had a normal BMI
and had lipid and apolipoprotein concentrations within the normal range
(data not shown). There was the same proportion of smokers in carriers
and noncarriers in both studies (data not shown).
In the pooled data in each of the studies, carriers of the S291
allele had statistically significantly lower HDL-C concentrations
than did noncarriers (Tables 2 and 3), and this effect associated with
the S291 allele was homogeneous in men and women and
cases and control subjects in both populations (data not shown). In
EARS-II the HDL-C–lowering effect associated with the S291 allele
was stronger in cases than in control subjects. In cases mean HDL-C
concentration±SEM was 0.93±0.06 and 1.17±0.02 mmol/L
(P=.0001) for carriers and noncarriers, respectively, and in
the control group, mean HDL-C concentration±SEM was 1.10±0.07 and
1.16±0.02 mmol/L (P=NS) in carriers and
noncarriers, respectively. In the pooled data in each of the studies,
carriers of the S291 allele had higher fasting TG concentrations
than did noncarriers (Tables 2 and 3), and this effect associated with
the S291 allele was homogeneous in men and women and
cases and control subjects in both populations (data not shown).
However, the differences were not statistically significant. No
significant differences in BMI or other biochemical traits were
observed between S291 carriers and noncarriers in either the pooled
data (Tables 2 and 3) or in subgroups (data not shown) in either of the
populations.
Possible interaction between S291 carrier status and BMI as previously
reported17 was tested. As shown in Fig 1b, S291 carriers
in EARS-I showed a more marked increase in plasma TG with increasing
BMI than noncarriers. The EARS-II data showed a similar pattern (data
not shown), and the test for interaction between S291 carrier status
and BMI on plasma TG concentrations was statistically significant in
both studies (P<.01). Moreover, S291 carriers showed a more
marked decrease in HDL-C concentrations with increasing BMI than did
noncarriers (data not shown).
In the OFTT, plasma TG concentrations in cases were significantly
higher in S291 carriers than noncarriers (P<.03) at
baseline and 3, 4, and 6 hours (Fig 2). The overall significance of
carriers being above noncarriers was P=.007, and the test
for parallelism of the two curves was of borderline statistical
significance (P=.057). After correction for baseline value,
the 6-hour TG concentration remained significantly higher in S291
carriers (P=.04). In control subjects, only baseline TG
concentrations were higher in S291 carriers, although they did not
reach statistical significance. There were no differences in other
postprandial parameters between carriers and noncarriers in
either cases or control subjects.
There were no differences in postprandial insulin responses in either cases or control subjects (data not shown) to either the OFTT or OGTT. In cases, S291 carriers had higher glucose at 2 hours after OFTT than noncarriers (data not shown; repeated-measures ANOVA, P=.03), whereas no differences in glucose responses after the OGTT were observed between S291 carriers and noncarriers in the control group (data not shown).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Patients at high risk of developing CHD benefit from lipid-lowering treatment, and early identification is therefore important. If an atherogenic biochemical phenotype is characterized at the DNA level, it is possible to identify cases before their clinical phenotype becomes evident. This approach has been used successfully in FH.18 However, with an occurrence of 0.1% to 0.2% in the general population, FH is a relatively rare disease,18 and variation in other genes involved in lipoprotein metabolism must be considered.19
In general, variations at the DNA level have moderate-to-weak effects on biochemical variables.5 Nevertheless, they may be important for the occurrence of disease at the population level, if they are common.6 This was recently demonstrated in a study showing that the LPL N9 variation was significantly associated with progression of coronary atherosclerosis, despite having only subtle effects on plasma lipids.20 Here, we report on two common mutations (variants) resulting in amino acid changes in the mature LPL protein (ie, N9 and S291) with effects on plasma lipids in two offspring studies, EARS-I and -II.
The N9 mutation was identified in 4.2% of all subjects in EARS-I, confirming that this mutation is common in Western populations.20 21 Carrier frequencies differed markedly between European regions, but the frequency of the N9 allele was not higher in subjects with a paternal history of MI (cases) than in control subjects. This accords with another study in which N9 carrier frequencies were insignificantly higher in myocardial infarction survivors than in control subjects.21 In contrast, Jukema et al20 found that the N9 allele was associated with a family history of CHD.
In accordance with previous studies,7 20 21 carriers of the N9 allele in EARS-I had higher plasma TG and lower HDL-C levels. To a lesser extent, these associations were also present in EARS-II. In vitro studies22 indicate that the N9 mutation reduces hydrolytic activity by reducing the amounts of LPL protein secreted by the cell LPL protein by 15% to 20%. We therefore expected the effects of the N9 mutant on fasting lipids to be evident in an OFTT, but there was no difference in postprandial TG responses between carriers and noncarriers. We propose the following: Inactive intracellular deposits of LPL are activated when TG-rich lipoproteins bind to the luminal surface of the endothelium.23 Before the OFTT, our study subjects had fasted for 14 hours, and maximal LPL deposition had therefore probably occurred. The partial catalytic defect in N9 carriers does not prevent activation of sufficient LPL protein from the intracellular deposits to meet the demand during the OFTT. Instead of a single OFTT, successive OFTTs might have unmasked the moderate decrease in catalytic capacity in N9 carriers.
It has been reported that obesity amplified the effect of the N9 allele on fasting TG concentrations.7 Although we observed the same trend, the effect did not reach statistical significance in these young men and women. It was suggested7 that carriers of the N9 mutation can maintain low plasma TG levels if they are lean, but if the partially impaired LPL function in N9 carriers is additionally strained by the increased VLDL lipoprotein production associated with even moderate obesity,24 the secretion of active LPL protein becomes relatively insufficient and hypertriglyceridemia develops.7 Compared with the subjects studied by Mailly et al,7 mean plasma TG concentrations and BMI ranges were considerably lower in our studies and perhaps within the limits in which N9 carriers can maintain TG homeostasis.
In contrast to N9, the S291 mutant was distributed homogeneously across Europe, with an overall frequency of 3.1% in EARS-I. Again, no differences in carrier frequencies between cases and control subjects were detected, and published case-control studies8 25 have not shown an association between the S291 allele and premature atherosclerosis. These studies did not include deceased cases, however, and offspring studies like the present ones have the power to detect only large effects of fairly common genetic variants on CHD risk12 because the gene pool under investigation is diluted. Currently available data therefore do not rule out an association of the S291 mutant with premature atherosclerosis.
In agreement with one8 but not another25 study, carriers of the S291 allele had significantly lower HDL-C concentrations. In vitro,22 the activity of the S291 mutation is reduced by 30% to 40%. As outlined by Patsch,10 an HDL particle exchanges cholesteryl esters for TG with numerous generations of TG-rich lipoproteins, and HDL can be regarded as "the memory box of TG metabolism." Given the large intraindividual variability of plasma TG concentrations,26 the relatively low number of S291 carriers, and the low mean TG concentration, it was expected that the S291 mutant was associated with variation in HDL-C but not necessarily with fasting TG concentrations.17 The HDL-C–lowering effect of the S291 allele was more pronounced in cases than control subjects in EARS-II, and S291 carriers in the case group accordingly cleared TG more slowly than did noncarrier cases during the OFTT. This difference was not observed in the control group, suggesting that the S291 mutant interacts with one or more genetic or environmental factors present in cases but not in control subjects. Identification of these factors will be of great importance in better developing predictive tests for individuals at risk of becoming severely hypertriglyceridemic.
Despite the low mean TG concentration and narrow BMI range in these healthy young subjects, carriers of the S291 allele could not maintain low plasma TG with increased body weight. We also found that in S291 carriers, obesity amplified the HDL-C–lowering effect more than in noncarriers. These results are in accordance with the reduced catalytic activities of the two LPL mutant proteins (a 15% to 20% and 30% to 40% reduction for the N9 and S291 mutations, respectively) and in accordance with a previous study.17
The remarkable heterogeneity of the N9 carrier frequencies, ranging from 0.2% in Finnish/Baltic populations to 7.7% in British populations in EARS-I, could explain why we could not fully reproduce the results from EARS-I in EARS-II; the two populations were not from the exact same European regions. Although we controlled for environmental factors and region in the statistical analyses, the heterogeneity of the N9 carrier frequencies makes it possible that other region-specific factors might make the results biased. In contrast, data for the S291 mutant were concurrent in EARS-I and -II.
Other LPL gene mutations delay postprandial TG
clearance,27 28 and recently published small studies of
heterozygous carriers of the S291 allele showed that these subjects
also had delayed postprandial TG clearance.11 29 Carriers
of the G188E LPL mutation develop dyslipidemia only after
the age of 40 years,30 whereas carriers of the P201L
mutation have dyslipidemia at a younger age.31
Our subjects were young (mean age, 
23 years), and we could not study
genexenvironment interaction over time. Our results are good estimates
of the effects associated with specific genotypes per se,
however, and increasing age is unlikely to diminish the effects of
these two LPL mutants on plasma lipids. Because even moderate obesity
amplified the atherogenic effects of both mutations on plasma lipids,
carriers are likely to be at increased risk of CHD if certain other
genetic and/or lifestyle factors are present.
Conclusions
Our results confirm that alleles coding for the two LPL
mutations N9 and S291 are common in the general population, but they do
not show that they are more frequent in subjects with higher a
priori risk of CHD. Both mutants are associated with atherogenic
changes in plasma TG and HDL-C concentrations in young subjects, and
for the S291 mutation, this effect might be mediated by delayed
postprandial TG clearance. Even moderate obesity seems to potentiate
the effects of the two LPL mutants, making it likely that age
aggravates the effects on plasma lipids. Our results suggest that the
LPL gene is a strong candidate as a "high TG/low HDL
gene."2 4
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Selected Abbreviations and Acronyms |
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Appendix 1 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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The EARS-I project leader was J. Shepherd, Glasgow, UK, and the EARS-II project leader was D.StJ. O'Reilley, Glasgow, UK.
The EARS Group, Collaborating Centers, and Associated
Investigators
Austria: H.J. Menzel, C. Sandholzer, C. Duba, H.G.
Kraft (Institute for Medical Biology and Genetics, University of
Innsbruck); Belgium: G. De Backer, S. De Henauw, D. De
Bacquer, A. Bael (Department of Hygiene and Social Medicine, State
University of Ghent); M. Rosseneu, N. Vinaimont (Department of
Clinical Chemistry, University Hospital St Jan, Brügge);
Denmark: C. Gerdes, O. Faergeman, I.C. Klausen, L.U. Gerdes
(Department of Medicine and Cardiology, Aarhus
Amtssygehus University Hospital); Estonia: M. Saava
(Department of Nutrition and Metabolism, Institute of
Cardiology, Tallin); Finland: C. Ehnholm
(National Public Health Institute, Helsinki); A. Kesaniemi (Department
of Internal Medicine, University of Oulu); France: F.
Cambien, L. Tiret, R. Agher, V. Nicaud, R. Rakotovao (INSERM U 258,
Hôpital Broussais, Paris); M.-M. Galteau, S.M. Visvikis (Centre
de Medicine Preventive, Nancy); J.C. Fruchart, J. Dallongeville, J.M.
Bard, P. Lebel (INSERM U235, Institut Pasteur, Lille); L. Bara
(Laboratories de Trombose Expérimentale, Paris); C. Bady, J.
Beylot, A. Lindoulsi (UFR de Sante Publique, Bordeaux);
Greece: G. Tsitouris, N. Papageorgakis (Department of
Medicine/Cardiology, Evangelismos Hospitals, Athens);
Germany: U. Beisiegel, A. Jorge, M. Papanikolaou
(Medizinische Klinik, Universitätskrankenhaus, Hamburg);
Italy: E. Farinaro (Institute of Internal Medicine and
Metabolic Disease, University of Naples); F. De Lorenzo, C.
Cortese, M. Ligouri (Community Medicine, Institute of Hygiene and
Preventive Medicine, University of Naples); The Netherlands:
L.M. Havekes, P. de Knijff (IVVO-TNO Health Research, Gaubius
Institute, Leiden); Portugal: M.J. Halpern (Instituto
Superior de Ciencias da Saude, Lisbon); Spain: S. Sans, T.
Puig, V. Moreno, M. Martin (Programma CRONICAT, Hospital Sant Pau,
Barcelona); P.R. Turner, M. Masana, A. Altadill, M. Castro (Unitat
Recerca Lipids, University Barcelona, Reus); Switzerland: F.
Gutzwiller, B. Martin, M. Knobloch, P. Anliker (Institute of Social and
Preventive Medicine, University of Zürich); United
Kingdom: D. Stansbie, A. Day, S. Plumridge (Department of Chemical
Pathology, Bristol); J. Shepherd, D. St O'Reilly, G.W. Tait, G.M.
Hamilton (Institute of Biochemistry, Royal Infirmary, Glasgow); S.
Humphries, P. Talmud, S. Ye, R.M. Fisher (University College London,
School of Medicine, London); and A. Evans, F. Kee (Department of
Epidemiology and Public Health, The Queens
University of Belfast).
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Acknowledgments |
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This work was supported by grants from the Danish Heart Foundation, Kirsten Anthonius' Mindelegat, British Heart Foundation (grant RG16), and EC Concerted Action MRH-4 COMAC Epidemiology.
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Footnotes |
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1 Members of the EARS Group are listed in the "Appendix."
Received February 6, 1997; accepted March 2, 1997.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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