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Association between Angiotensin-Converting Enzyme Gene Polymorphisms and Diabetic Nephropathy: Case-Control, Haplotype, and Family-Based Study in Three European Populations

Samy Hadjadj^*, Lise Tarnow, Carol Forsblom, Gbenga Kazeem, Michel Marre^||, Per-Henrik Groop, Hans-Henrik Parving, François Cambien^¶, David A. Tregouet^¶, Ivo G. Gut^**, Alexandre Théva^¶, Dominique Gauguier, Martin Farrall, Roger Cox, Fumihiko Matsuda^**, Mark Lathrop^**, FinnDiane Study Group, Nathalie Hager-Vionnet^¶ for the EURAGEDIC (European Rational Approach for the Genetics of Diabetic Complications) Study Group

^* CHU de Poitiers, Department of Diabetology, and INSERM ERM 324, Poitiers University Hospital, Poitiers, France; Steno Diabetes Center, Copenhagen, Denmark; Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, and Helsinki University Central Hospital, Department of Medicine, Division of Nephrology, Helsinki, Finland; Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom; ^|| INSERM U695, Xavier Bichat University of Medicine, and Department of Diabetology, Bichat Hospital, Paris, France; ^¶ INSERM and Université Pierre et Marie Curie-Paris 6, UMR S 525, Paris, France; ^** Centre National du Genotypage, Evry, France; and Mammalian Research Council, Oxford, United Kingdom

Address correspondence to: Dr. Samy Hadjadj, Department of Diabetology, Poitiers University Hospital, BP 577, 86021 Poitiers Cedex, France. France: +33-5-49-44-39-00; Fax: +33-5-49-44-40-06; s.hadjadj{at}chu-poitiers.fr

Received for publication October 10, 2006. Accepted for publication February 2, 2007.

	Abstract

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Angiotensin 1-converting enzyme gene (ACE) is a risk factor for diabetic nephropathy (DN) in patients with type 1 diabetes. The selection of this candidate gene is supported by cross-sectional and follow-up studies, but no convincing family-based studies are available. Recruited were 1057 patients (with DN: persistent albuminuria with or without renal failure) and 1127 control subjects (long-standing [15 yr] normoalbuminuric patients with type 1 diabetes) in Denmark, Finland, and France and 532 family trios that were composed of 244 trios with DN probands and 288 trios with non-DN probands. Five ACE polymorphisms were studied. In the case-control analysis, the rs1800764-C, rs4311-T, Insertion/deletion (I/D or rs1799752)-D, rs4366-G, and rs12449782-G alleles were associated with an increased risk for DN, homogeneously across populations, with allelic odds ratios of 1.11 (95% confidence interval 1.00 to 1.22), 1.18 (1.04 to 1.33), 1.13 (1.02 to 1.23), 1.10 (0.99 to 1.20), and 1.12 (1.01 to 1.23), respectively. Haplotype analysis further demonstrated that the haplotype defined by the D, rs4366_G and rs12449782_G alleles was associated with a greater risk for DN. Even though no significant allelic overtransmission to DN or non-DN probands was detected, the family-based study provided consistent results with the case-control analysis. In a large case-control study, it was shown that the ACE polymorphisms were associated with DN; these findings were not confirmed in a family-based association study. This study population is suitable to search for additional candidate genes for DN.

	Introduction

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Diabetic nephropathy (DN) is associated with a risk for end-stage renal failure and accounts for the reduced life expectancy of patients with type 1 diabetes (1). Although almost all patients with type 1 diabetes are affected by diabetic retinopathy over time, only 25 to 35% of these patients develop DN (2–5). Chronic hyperglycemia cannot fully account for the pathogenesis of renal complications. Genetic factors play an important role, as shown by familial studies (6–8).

Angiotensin-converting enzyme gene (ACE) is a risk factor for DN. Its plasma levels have been reported to be associated with DN but not with diabetic retinopathy in type 1 diabetes patients (9). ACE modulates the generation of angiotensin II, which increases intraglomerular hydraulic pressure (10), leading to glomerulopathy. ACE inhibition strongly modifies renal hemodynamics in animals (11), and the course of DN can be considerably improved by treatment with ACE inhibitors, in patients with type 1 diabetes (12,13).

Plasma ACE concentrations are stable in individuals (14) and are partly under genetic control (15). The ACE gene is located on chromosome 17, at q23, and contains 26 exons that span a total of 21 kb, and ACE levels are controlled primarily by the ACE region that maps to an 18-kb interval that is flanked by two intragenic ancestral recombination breakpoints (16). An insertion/deletion (I/D; rs1799752) polymorphism in intron 16 of ACE accounts for a large proportion of interindividual variation for ACE serum concentrations (17).

Several case-control studies have examined the association between the ACE I/D polymorphism and DN. As shown in a recent meta-analysis, a deleterious effect of the D allele was evidenced (18). Longitudinal follow-up studies recently provided further evidence for the deleterious effect of the D allele (19–21). However, one family-based study discordantly showed that the I allele was overtransmitted in cases of DN (22).

We aimed to investigate the role of ACE in DN, using two complementary approaches—a case-control study and a family-based study—on a large population that was recruited from three European countries. In addition to the I/D variant, which is widely investigated in studies of the genetics of DN, we chose to study four single-nucleotide polymorphisms (SNP; rs1800764, rs4311 T, rs4366, and rs1244978) because they were shown to characterize the haplotypic structure of ACE (Supplementary Figure 1) in European populations (16). Indeed, the genetic structure of ACE is made up of three ancestral regions. The chosen SNP were selected in these three regions because they tagged the haplotypic structure of European individuals, according to a previous quantitative trait locus study (16).

	Materials and Methods

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Patient Populations
Three European coordinating centers in Denmark, Finland, and France contributed to the case-control and trio studies. The recruitment characteristics and the general research strategy are described elsewhere (EURAGEDIC 1; Tarnow et al., submitted for publication).

The patients participated in a case-control study (1057 case patients and 1127 control subjects). A complementary family-based study included 244 case patients and 288 control subjects as probands (532 family-based patients) with both parents recruited or, if missing, at least one parent and a sibling to infer probabilities for the missing parental genotype. In the Finnish and Danish populations, both parents were recruited in the studied pedigrees. The majority of pedigrees from the French population are made of trios with both parents recruited. We had the opportunity to infer the genotype of the missing parent in 16 pedigrees (three with missing mothers and 13 with missing fathers).

Case patients had established DN—defined as persistent albuminuria (>300 mg/24 h or >200 µg/min or >200 mg/L) in two of three consecutive measurements on sterile urine samples—with or without renal failure (serum creatinine >150 µmol/L). Control subjects with type 1 diabetes had long-standing diabetes (disease duration 15 yr) and persistently normal albumin excretion rate (<30 mg/24 h or <20 µg/min or <20 mg/L) in two of three consecutive sterile urine samples) and were not treated with ACE inhibitors or angiotensin receptor blockers. Microalbuminuric patients were not retained because they could not be surely classified as case patients or control subjects.

Genotyping
Genomic DNA was isolated from human leukocytes by standard methods. Genotyping was carried out with various automated high-throughput methods (see Supplementary Table 1). Each polymorphism was determined in the same way for all of the populations studied. The ID polymorphism in ACE was determined by PCR with the ACE45 (PF) and ACE46 (PR) primers (16), with subsequent separation of the fragments by electrophoresis on 2% agarose gels. The rs4311 and rs4366 SNP were determined by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry of the primer extension products that were generated by PCR, as described previously (23). The rs12449782 and rs1800764 SNP were determined by the TaqMan method, using the Applied Biosystems protocol with end-point reading with an ABI 7009HT. The genomic control markers were characterized using the SNPlex genotyping technology (Applied Biosystems, Courtaboeuf, France). Quality control for genotyping was ensured by testing for Hardy Weinberg (HW) equilibrium on every 384-well plate and by genotyping 192 replicates.

Pairwise linkage disequilibrium (LD) between polymorphisms was estimated and expressed in terms of the D' and r² statistics, as implemented in THESIAS software (24). THESIAS software was also used for haplotype analysis of the 5 ACE polymorphisms with respect to DN. In each population, we compared the haplotype frequency distributions of case patients and control subjects by means of a likelihood ratio test (² with m – 1 degrees of freedom for m haplotypes), and haplotype effects (95% confidence interval [CI]) were expressed as haplotypic OR, assuming additive effects on a logistic scale.

For trio data analysis, a family-based test of association (in the presence of linkage) of the pedigree data was carried out for each population to account for possible differences in allele frequencies and associations with DN among the three populations. The transmission of alleles to affected (case patients) or unaffected (control subjects) patients with type 1 diabetes was analyzed using the transmission disequilibrium test (TDT). TRANSMIT software, which incorporates cases of uncertain transmission (25), was used for the analysis. The proportion T of "overtransmitted" or "high-risk" alleles from informative (i.e., heterozygous) parents was estimated by counting informative transmissions. For each polymorphism, the results from the three populations were combined to obtain an overall estimate of the effect that was associated with each polymorphism.

Combination of Results from Case-Control and Trio Studies
For the trio data, the OR for each marker was estimated from the transmission counts (T) that were obtained from TDT analysis, as follows: OR_tdt = T/(1 – T) (26). The SE can be easily obtained because the logarithm of the OR is asymptotically normally distributed (27). These OR were then combined using a weighted analysis method (27). Statistical significance was set at 0.05.

	Results

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Genotyping success rates of between 90 and 98.4% were obtained and no mismatches were detected among the 192 replicate samples. All polymorphisms were in HW equilibrium. Each pair of polymorphisms was in linkage disequilibrium (see Supplementary Table 2). The main clinical and biologic characteristics of the patients with type 1 diabetes are described in Table 1.

In the combined population, the rs4311-T allele, the ACE_ID D allele, and the rs12449782-G allele were significantly associated with the risk for DN (OR 1.18 [95% CI 1.04 to 1.33; P = 0.01], 1.13 [95% CI 1.02 to 1.23; P = 0.024], and 1.12 [95% CI 1.01 to 1.23; P = 0.039], respectively). Some patients (298 Danish and 417 French) were already analyzed in previous reports on ACE (28,29). To limit the impact of already analyzed people, we restricted the study to newly recruited patients. It had no major effect on the statistical significance of the alleles that were associated with DN risk (rs4311, P = 0.023; ACE_ID, P = 0.055; and rs4366, P = 0.086).

The association of the 94 genomic control markers was compatible with expectations of null hypothesis of no association (data not shown), which indicates that stratification within one or more of the populations is unlikely to cause positive association results. Multivariate adjustment for clinical factors showed that the adjusted OR (Table 3) were similar to those for the nonadjusted data presented in Table 2.

Combined Analysis
The combined results of case-control and trio studies are presented in Table 5. No heterogeneity was found between data from the case-control and family-based studies. All of the risk alleles were associated with an increase of approximately 15% in the risk for DN (Table 6).

	Discussion

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In the European Rational Approach for the Genetics of Diabetic Complications (EURAGEDIC) program, we used a research strategy that consists of a candidate gene approach with a case-control design combined with a familial transmission analysis. This strategy to analyze trios with DN probands but also trios with non-DN probands was recently presented as relevant for diabetic kidney disease (30). In the studied populations, the risk for any founder effect is small as a result of the international recruitment of patients. No heterogeneity was found across the three populations, one of which came from Finland, a country that often is considered a genetic isolate. In addition, a genomic control allowed us to rule out stratification bias. The overall results for the ACE genetic variants tested were positive, although some variation between populations was possible. No statistically significant heterogeneity was detected, but it should be noted that most of the positive results were obtained for the French population, with no contribution from the Finnish population.

Despite the detection of a positive association in the case-control analysis, we found no association with ACE in the family-based study. Unlike Krolewski (22), we observed no overtransmission of the ACE I allele in patients with type 1 diabetes and nephropathy. The recruitment of the trios must be discussed. As reported elsewhere (EURAGEDIC 1; Tarnow et al., submitted for publication), the probands who had type 1 diabetes and for whom the parents were also recruited differed in clinical characteristics relating to age and diabetes duration from patients who had type 1 diabetes and for whom the parents were not recruited. Because DN in probands was associated with a high risk for premature mortality and cardiovascular disease in both the patients and their parents, the parents of case patients were less likely to be alive than the parents of control subjects. However, although this recruitment bias must be recognized, it is unlikely to have led to spurious results. We recruited more than 500 trios, corresponding to one of the largest family-based studies of DN in patients with type 1 diabetes. However, only informative trios can be considered in transmission analysis, and transmission was analyzed separately in the 244 trios with DN and the 288 trios without DN. In addition, the power calculation, assuming an additive effect, shows that we would need 526 trios to detect with 85% power significant associations (P 0.05) with an OR of 1.3 for a gene with minor allelic frequency of 0.45. The number rises to 3980 for an OR at 1.1.

It is interesting that the combination of cross-sectional and trio analyses gave similar results to the case-control study. However, it must be recognized that the relative sample size of trios compared with case-control samples leads to a relatively small contribution of trios to the combined statistics. The results of our study are not consistent with those for the family-based study reported by Krolewski (22), which supported a deleterious effect of the I allele. No combined analysis of case-control and family-based studies (27) has been reported before regarding ACE. This new statistical tool confirmed the results that were obtained elsewhere (18,19).

Our data for the I/D polymorphism are consistent with the results of cross-sectional studies, analyzed in a recent meta-analysis (18), and with three prospective follow-up studies (19–21). We found that the ACE D allele is a risk factor for DN. This is at variance with one of the first published studies on the relationship between the ACE I/D polymorphism and DN (28). However, in this later report, glycosylated hemoglobin was significantly lower in control subjects than in case patients. In addition, diabetic retinopathy was less frequently encountered in control subjects than in case patients. Altogether, this suggests that the glycemic exposure in control subjects was not sufficient, leading to an unbalanced matching. The inclusion of a large-scale recruitment from different populations allowed us to correct this probable lack of statistical power and recruitment bias.

The ID polymorphism can be considered a "reference" polymorphism because it has been determined in the majority of the studies in this area. The magnitude of the effect of this polymorphism must be interpreted with caution. The relative risk for DN for the ACE I/D polymorphism was approximately 1.30 in the recent meta-analysis (18) and a large-scale long-term prospective study (19). This value is higher than the combined OR of 1.13 reported here. However, we considered transmission of the D allele, whereas most studies compared the genotype of the patients (18,19), with II genotype patients as the reference group.

Because the ACE gene is long, with its 26 exons spanning 21 kb, we restricted our study to five genetic markers near the 18-kb region that are strongly associated with ACE concentration (16). This limitation should be recognized because we concentrated on this region of interest rather than analyze the whole gene. Because genetic variants in the vicinity of the critical 18-kb region have been shown to influence ACE concentrations (16), which determine the progression of DN (20), we compared the effects of the whole haplotype and of the single ACE_ID variant on the risk for DN.

Haplotype analysis showed that –DGG was associated with increased risk for DN, compared with the –ICA reference haplotype. However, even if the D allele was associated with DN in many publications, our data did not allow us to identify it clearly as the putative risk allele. Because of the strong LD, the association could also be due to the G alleles of the rs4366 and rs 12449782 polymorphism. Accordingly, we speculate that the polymorphisms in the 5' region are unlikely to be responsible for the predisposition to DN. In the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort, the rs 1800764 polymorphism was also analyzed (19). In the genotype analysis, CT patients had a higher risk for developing microalbuminuria, compared with TT patients. In the haplotype analysis, patients who carried the T allele were at lower risk for persistent microalbuminuria or severe nephropathy. We were not able to replicate this result, because we found no effect of the polymorphism in the 5' region. However, in the univariate analysis, only heterozygous patients with a CT genotype had a higher risk for severe nephropathy, suggesting a genotype rather than an allele effect. This discordant result might be due to the different geographic origin of the two study populations and also to the design (case-control in our study and longitudinal prospective study for the DCCT/EDIC).

Our finding is at variance with a recently published study in which a risk haplotype in ACE was identified, even though the risk haplotype also carried the ID_ D allele (31). However, even when studying polymorphisms located in the same key regions of ACE, we did not select the same SNP. In addition, the authors studied American patients with type 2 diabetes, with control subjects having a relatively short diabetes duration, whereas we studied European patients with long-term type 1 diabetes. These points can possibly account for the discrepant findings.

	Conclusion

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Our data, obtained using two complementary approaches, confirm the role of ACE in DN risk. This large-scale study produced interesting results with very narrow CI. These results for the EURAGEDIC study may increase interest in future candidate gene analyses for DN.

	Disclosures

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None.

	Acknowledgments

 
The EURAGEDIC study was made possible through funding from the European Commission through contract QLG2-CT-2001-01669.

All type 1 diabetes patients and their family are sincerely acknowledged.

The Danish Diabetes Association and the Sehested Hansen Foundation are thanked for their continued support to this study.

The French Diabetes Association is thanked for its support to this study (bourse AFD recherche 2000). The list of participating centers in France and Belgium is available in references (29,32). A. Boland and A. Lemainque (CNG) are acknowledged for handling DNA bank and for microsatellite and Taqman genotyping; V. Laneuze and C. Demer are thanked for secretarial assistance.

Oluf Pedersen (Steno Diabetes Center, Gentofte, Denmark) and Ludovic Drouet (Hôpital Lariboisière, Paris, France) are kindly acknowledged for providing nondiabetic individuals from population-based studies.

The FinnDiane study is supported by grants from the Folkhälsan Research Foundation, Samfundet Folkhälsan, the Wilhelm and Else Stockmann Foundation, the Liv och Hälsa Foundation, and the Finnish Medical Society (Finska Läkaresällskapet). We acknowledge all of the physicians and nurses at each center participating in the collection of patients ( indicates deceased person). Anjalankoski Health Center: S. Koivula, T. Uggeldahl; Central Finland Central Hospital: T. Forslund, A. Halonen, A. Koistinen, P. Koskiaho, M. Laukkanen, J. Saltevo, M. Tiihonen; Central Hospital of Aland Islands: A.-C. Blomqvist, M. Forsen, H. Granlund, B. Nyroos; Central Hospital of Kanta-Hame: P. Kinnunen, A. Orvola, T. Salonen, A. Vähänen; Central Hospital of Kymenlaakso: R. Paldanius, M. Riihelä, L. Ryysy; Central Hospital of Lansi-Pohja: P. Nyländen, A. Sademies; Central Ostrobothnian Hospital District: S. Anderson, B. Asplund, U. Byskata, T. Virkkala; City of Espoo Health Center: (Espoonlahti): A. Nikkola, E. Ritola; (Leppävaara): L. Penttinen, H.-L. Siekkinen; City of Tampere Health Center: P. Alarotu, S. Gummerus, A. Kallio, H. Kirkkopelto-Jokinen, E. Kujansuu, M. Kuortti, T. Maijala, T. Niskanen, T. Saaristo, A. Vadén; City of Vantaa Health Center: (Korso): R. Toivonen, H. Virtanen; (Martinlaakso): M. Laine, T. Pellonpää, R. Puranen; (Myyrmäki): A. Airas, J. Laakso, K. Rautavaara; (Rekola): M. Erola, E. Jatkola; (Tikkurila): R. Lönnblad, A. Malm, J. Mäkelä, E. Rautamo; Helsinki University Central Hospital (Department of Medicine, Division of Nephrology): C.-G. af Björkesten, J. Fagerudd, S. Fröjdö, R. Kilpikari, S. Lindh, M. Parkkonen, K. Pettersson-Fermholm, M. Rosengård-Bärlund, H. Rosvall, M. Rönnback, R. Sallinen, A. Sandelin, M. Saraheimo, L .Sjölind, L. Thorn, T. Vesisenaho, J. Wadyén; Iisalmi Hospital: E. Toivanen; Jokilaakso Hospital, Jyämsyä: A. Parta, I. Pirttiniemi; Jorvi Hospital, Espoo: S. Aranko, S. Ervasti, R. Kauppinen-Myäkelin, A. Kuusisto, T. Leppyälyä, K. Nikkilyä, L. Pekkonen; Kainuu Central Hospital: S. Jokelainen, P. Kemppainen, A.-M. Mankinen, M. Sankari; Kerava Health Center: H. Stuckey, P. Suominen; Kivelyä Hospital, Helsinki: A. Aimolahti, E. Huovinen; Koskela Hospital, Helsinki: V. Ilkka, M. Lehtimyäki; Kouvola Health Center: E. Koskinen, T. Siitonen; Kuopio University Hospital: E. Huttunen, R. Ikyäheimo, P. Karhapyäyä, P. Kekyälyäinen, M. Laakso, T. Lakka, E. Lampainen, L. Mykkyänen, L. Niskanen, U. Tuovinen, I. Vauhkonen, E. Voutilainen; Kuusamo Health Center: E. Isopoussu, H. Suvanto, E. Vierimaa; Kuusankoski Hospital: E. Kilkki, L. Riihelyä; Laakso Hospital, Helsinki: T. Merilyäinen, P. Poukka, R. Savolainen, N. Uhlenius; Lahti City Hospital: A. Myäkelyä, M. Tanner; Lapland Central Hospital: L. Hyvyärinen, S. Severinkangas, T. Tulokas; Lappeenranta Health Center: P. Linkola, I. Pulli; Lohja Hospital: T. Granlund, M. Saari, T. Salonen; Lyänsi-Uusimaa Hospital, Tammisaari: I.-M. Jousmaa, J. Rinne; Malmi Hospital, Helsinki: H. Lanki, S. Moilanen, M. Tilly-Kiesi; Mikkeli Central Hospital: A. Gynther, R. Manninen, P. Nironen, M. Salminen, T. Vyänttinen; North Karelian Hospital: U.-M. Henttula, A. Rissanen, H. Turtola, M. Voutilainen; Oulaskangas Hospital, Oulainen: E. Jokelainen, P.-L. Jylkkyä, E. Kaarlela, J. Vuolaspuro; Oulu Health Center: L. Hiltunen, R. Hyäkkinen, S. Keinyänen-Kiukaanniemi; Pyäijyät-Hyäme Central Hospital: H. Haapamyäki, A. Helanteryä, H. Miettinen; Palokka Health Center: (Palokka): P. Sopanen, L. Welling; (Vaajakoski): K. Myäkinen, P. Sopanen; Pietarsaari Hospital: M.-L. Holmbyäck, B. Isomaa, L. Sarelin; Pori City Hospital: P. Ahonen, P. Merensalo, K. Syävelyä; Porvoo Hospital: M. Kallio, B. Rask, S. Ryämyö; Rauma Hospital: K. Laine, K. Saarinen, T. Salminen; Riihimyäki Hospital: E. Immonen, L. Juurinen; Salo Hospital: A. Alanko, J. Lapinleimu, P. Rautio, M. Virtanen; Satakunta Central Hospital: M. Juhola, P. Kunelius, M.-L. Lahdenmyäki, P. Pyäyäkkyönen, M. Rautavirta; Savonlinna Central Hospital: T. Pulli, P. Sallinen, H. Valtonen, A. Vartia; Seinajoki Central Hospital: E. Korpi-Hyyövyälti, T. Latvala, E. Leijala; South Karelia Hospital District: T. Hotti, R. Hyärkyönen, U. Nyholm, R. Vanamo; Tampere University Hospital: I. Ala-Houhala, T. Kuningas, P. Lampinen, M. Myäyättyä, H. Oksala, T. Oksanen, K. Salonen, H. Tauriainen, S. Tulokas; Turku Health Center: I. Hyämyälyäinen, H. Virtamo, M. Vyähyätalo; Turku University Central Hospital: M. Asola, K. Breitholz, R. Eskola, K. Metsyärinne, U. Pietilyä, P .Saarinen, R. Tuominen, S. yÁyryäpyäyä; Vammala Hospital: I. Isomyäki, R. Kroneld, M. Tapiolinna-Myäkelyä; Vasa Central Hospital: S. Bergkulla, U. Hautamyäki, V.-A. Myllyniemi, I. Rusk.

	Footnotes

 
Published online ahead of print. Publication date available at www.jasn.org.

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