A Common Variant of the PAX2 Gene Is Associated with Reduced Newborn Kidney Size
Jacklyn Quinlan*,
Mathieu Lemire,
Thomas Hudson,
Huiqi Qu*,
Alice Benjamin,
Anne Roy,
Elena Pascuet*,
Meigan Goodyer*,
Chandhana Raju*,
Zhao Zhang*,
Fiona Houghton* and
Paul Goodyer*
* Montreal Children’s Hospital Research Institute and Departments of Obstetrics and Gynecology and Radiology, McGill University, and McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada
Address correspondence to: Dr. Paul Goodyer, 4060 Saint Catherine West, PT-413, Montreal, Quebec, Canada H3Z 2Z3. Phone: 514-412-4461; Fax: 514-412-4478; E-mail: paul.goodyer{at}mcgill.ca
Received for publication October 11, 2006.
Accepted for publication March 26, 2007.
Congenital nephron number ranges widely in the human population.Suboptimal nephron number may be associated with increased riskfor essential hypertension and susceptibility to renal injury,but the factors that set nephron number during kidney developmentare unknown. In renal-coloboma syndrome, renal hypoplasia andreduced nephron number are due to heterozygous mutations ofthe PAX2 gene. This study tested for an association betweena common haplotype of the PAX2 gene and subtle renal hypoplasiain normal newborns. A PAX2 haplotype was identified to occurin 18.5% of the newborn cohort, which was significantly associatedwith a 10% reduction in newborn kidney volume adjusted for bodysurface area. This haplotype was also associated with reducedallele-specific PAX2 mRNA level in a human renal cell carcinomacell line. Subtle renal hypoplasia in normal newborns may bepartially due to a common variant of the PAX2 gene that reducesmRNA expression during kidney development.
Between 20 and 30% of North Americans develop hypertension duringthe course of their life, without any obvious cause (1). Afterthe age of 18 yr, the risk for cardiovascular disease risesin parallel with BP >115/75 mmHg (2). Numerous theories havebeen advanced to explain the pathogenesis of essential hypertension,but for more than two decades, Brenner et al. (3) have arguedthat it may be the consequence of suboptimal nephron endowment.Indeed, normal human nephron number ranges widely—from300,000 to >1 million per kidney (4). Although this was oncedismissed as a benign reflection of human diversity, Kelleret al. (5) reported that patients with essential hypertensionhave 46% fewer nephrons than normotensive age-matched controlsubjects. Therefore, individuals who are born into the lowerquartile of the nephron distribution may constitute a largesubgroup that is destined to develop essential hypertensionlater in life (5).
Little is known about how final nephron number is set. Individualnephrons are produced during fetal development through reciprocalinteractions between the arborizing ureteric bud and the metanephricmesenchyme. Mature nephrons are connected, like apples, to thebranches of a tree-like collecting system. Because nephrogenesisends by 36 wk of gestation, the number of nephrons formed bythat time will constitute the individual’s nephron endowmentfor life (6). Environmental factors, such as retinol, can affectbranching morphogenesis in experimental animals (7), but maternalvitamin A deficiency is uncommon in Western countries, wheregenetic factors are presumably the primary determinants of congenitalnephron number (8).
In 1995, Sanyanusin et al. reported that the renal-colobomasyndrome, an autosomal dominant form of renal hypoplasia, iscaused by heterozygous mutations of the gene that encodes adevelopmental transcription factor, PAX2 (9–11). In thissyndrome, nephron structure is relatively intact (except forcompensatory glomerular hypertrophy), but absolute nephron numberis strikingly reduced and patients were given the diagnosis"oligomeganephronia" in cases in which the ocular defect wasnot obvious (12). Studies of the 1Neu mouse strain, which bearsa spontaneous Pax2 gene mutation, have shown that the nephrondeficit is caused by a loss of the antiapoptotic effects ofPax2 during kidney development; heightened levels of programmedcell death in the ureteric bud compromise its arborization (10,13–16).A congenital nephron deficit has also been reported in heterozygousGdnf mutant mice; these mice have a 30% decrease in nephronnumber and develop hypertension in adulthood (17). It is interestingthat the Gdnf gene is regulated by Pax2 (18).
Because Pax2 haploinsufficiency causes a severe congenital nephrondeficit, we hypothesized that mild, common polymorphisms inthe PAX2 gene might account for subtler reductions in nephronnumber that are seen among normal individuals. We used the HapMapproject data (19) to identify common haplotype-tagging single-nucleotidepolymorphisms (htSNP) in the PAX2 gene and examined their associationwith congenital kidney volume in a cohort of healthy white newbornsin Montreal.
Study Subjects
Healthy white infants who were born to women with uncomplicatedpregnancies were recruited with informed parental consent atthe final prenatal clinical visit (n = 168) to the Royal VictoriaHospital (Montreal, QU, Canada). The study (PED-04-016) wasapproved by the Montreal Children’s Hospital ResearchEthics Board. Mothers with twins, diabetes, intrauterine growthrestriction, genetic abnormalities, renal malformations or hydronephrosis,or delivery <36 wk and who had newborns with low serum albuminwere excluded. In a separate obstetric cohort from the samehospital, we previously found that vitamin A deficiency occursin <5% of Montreal pregnancies (unpublished data). Newbornswith low birth weight (<2500 g) or combined kidney volume<2.5th percentile for published norms in healthy newborns(20) were excluded.
Cord Blood Analyses
At birth, cord blood was obtained for isolation of leukocyteDNA (in EDTA) and serum cystatin C determination. Genomic DNAwas isolated with the FlexiGene DNA kit (Qiagen, Mississauga,ON, Canada) according to the manufacturer’s protocol.DNA was quantified using the Quant-iT PicoGreen dsDNA AssayKit *2000 (Invitrogen, Carlsbad, CA). Cystatin C was measuredby nephelometry (21) in serum that was separated from 5 ml ofcord blood and stored at –70°C before assay.
Renal Volume
Left and right kidney volumes were measured by ultrasonographyin newborns during the first 3 d of life with the followingequation: [volume = 4/3 ï (length/2)(height/2)(width/2)](22). Body surface area (BSA) was estimated from newborn lengthand weight according to Mosteller (23).
Choice of htSNP in the PAX2 Gene Region
htSNP were chosen from a region that spanned the PAX2 gene (80kb) plus 10 kb at both the 5' and 3' flanking segments (totalchromosome location Chr10:102,160,274-102,260,517), using theHapMap human genome database (www.hapmap.org, NCBI_35, dbSNP_b135).All known SNP (n = 248) from the Centre d’Etude du PolymorphismeHumain (CEPH) population (white individuals from Western Europewho settled in Utah) for the PAX2 gene region were downloadedinto Haploview (version 3.32) (24), and a plot of linkage disequilibrium(LD) between SNP was obtained. Using Haploview’s pairwise"Tagger" program (25), we chose 23 htSNP (r2 > 0.8) thatoccurred in at least 5% of the population, which spanned theentire gene plus 10 kb of the flanking DNA to either side.
PAX2 htSNP Genotypes
For each subject, 15 ng of genomic DNA was used for multiplexgenotyping, using Sequenom iPLEX PCR technology (Sequenom, SanDiego CA). This system involves extension of the PCR ampliconwith modified nucleotides to distinguish SNP alleles by matrix-assistedlaser desorption ionization–time of flight technology.Primers for SNP detection were designed using MassARRAY AssayDesignsoftware (Sequenom). Multiplex PCR conditions are outlined inSupplement 1.
Statistical Analyses
Data were analyzed with SPSS for Windows (version 11.0; SPSS,Chicago, IL). The distribution of each clinical end point wastested for skewness. Genotype frequencies for each htSNP wereexamined for divergence from Hardy-Weinberg equilibrium. A totalof 168 subjects were genotyped for 23 htSNP. In preliminaryanalyses, the relationship between mean total renal volume andBSA or cord cystatin C was examined by linear regression. Associationbetween htSNP genotype and each outcome variable was assessedby one-way ANOVA with post hoc t test (independent samples).Among the 168 subjects, it was possible to assign PAX2 haplotypesfor a subset of 161, using the three tightly linked htSNP. Associationbetween PAX2 haplotypes and total renal volume normalized forBSA was assessed by ANOVA followed by post hoc t test as described.
Allele-Specific PAX2 Expression Assay
From a panel of human renal cell carcinoma cell lines, we selectedthe A498 line that was heterozygous for a PAX2 exonic SNP (rs1800898)that was tightly linked (D' = 0.827, r2 = 0.63) to the htSNP(rs1159825, rs1119068, and rs1190702) and used to establishthe PAX2 haplotypes. The cells were grown in minimal essentialmedium supplemented with calf serum (5%)/FBS (5%) and penicillin/streptomycin(1%) at 37°C in humidified 5% CO2. Cells were trypsinized,pelleted, and washed for genomic DNA isolation using the WizardGenomic DNA Purification Kit (Promega, Madison, WI). DNA wasamplified by PCR using specific primers that flanked the rs1800898SNP that spanned exons 8 and 9 as in Supplement 2.
Total cellular RNA was isolated using Qiagen RNeasy Mini Columnextraction kit (Qiagen), reverse-transcribed, and amplifiedin a one-step reverse transcription–PCR (RT-PCR) reactionusing the Qiagen OneStep RT-PCR kit as in Supplement 2. Relativelevels of mRNA expression from each allele were estimated byquantitative HPLC sequencing (Genome Quebec, Montreal, QC, Canada)of the RT-PCR amplicon as described by Pastinen et al. (26).PCR amplicons (six replicates) and RT-PCR amplicons (five replicates)were sequenced in duplicate.
Characteristics of Study Subjects
Characteristics of the newborn cohort (n = 168) are shown inTable 1. Mean gestational age was 39.6 wk (37.1 to 42.2 wk),and approximately half of the study subjects were female (49.1%).Mean (±SD) newborn weight, height, and BSA were 3.58± 0.47 kg, 51.1 ± 2.5 cm, and 0.225 ± 0.018m2, respectively. Unadjusted left, right, and total kidney volumeswere 14.1 ± 3.9, 15.4 ± 3.9, and 29.7 ±7.0 ml, respectively. These values are similar to those of alarge cohort of Danish newborns who were studied within thefirst 5 d of life (20). Total (left + right) kidney volume correctedfor BSA was 132.6 ± 28.9 ml/m2. The mean level of cystatinC in newborn cord serum was 1.92 ± 0.32 mg/L. The distributionof these characteristics in our cohort approached normality(skewness <2 for all parameters).
As seen in Figure 1A, total renal volume was correlated withBSA (r2 = 0.110, P < 0.001). Kidney volume was inverselycorrelated with cord cystatin C (r2 = 0.101, P < 0.001; Figure 1B).
Figure 1. Correlation between total kidney volume and body surface are (BSA) or cord cystatin C. (A) Newborn total kidney volume is significantly correlated with BSA (n = 168; Pearson r2 = 0.110, P < 0.001). (B) Newborn total kidney volume is inversely correlated with cord serum cystatin C (n = 168; Pearson r2 = 0.101, P < 0.001).
Frequencies of PAX2 Variants in Study Subjects and LD between htSNP
To characterize the common variants of the human PAX2 gene,we chose 23 htSNP that captured >93% of alleles in the CEPHpopulation and spanned the PAX2 gene plus 10 kb of DNA on eitherside. All subjects were genotyped at these loci; SNP frequencieswere similar to those of the CEPH population, indicating noappreciable genetic drift in our cohort. Genotype distributionsfor each htSNP locus conformed to the expected Hardy-Weinbergequilibrium. The degree of LD between htSNP in our cohort (Haploviewversion 3.32) is shown in Figure 2.
Figure 2. Linkage disequilibrium (LD) between PAX2 haplotype-tagging single-nucleotide polymorphisms (htSNP) in the study cohort. The PAX2 gene region on chromosome 10 (Chr10:102,160,274-102,260,517) is shown. Twenty-three htSNP were chosen to span the region. The exon 8 SNP (rs1800898) that was used for allelic imbalance studies is also indicated (in green). The extent (D') of LD between htSNP in our cohort is indicated inside each square as the value of pairwise D' measure (D' = 1 when unspecified), according to HapMap convention. Five htSNP were associated with total kidney volume/BSA and are highlighted in gray. Minor allele frequencies for three of the five htSNP were relatively common (18.8 to 19.5% of the population) and were in very tight LD (>95%); these were used to assign haplotypes for each subject.
Association between htSNP and Renal Volume/BSA
Five htSNP variants were individually associated (P < 0.05)with low total kidney volume/BSA. Four of these were clusteredin a region that spanned intron 3 to intron 5 of the PAX2 gene.Three of the four (rs11599825, rs11190688, and rs11190702) wererelatively common (major allele frequency approximately 0.70)and in tight LD with each other (D' = 0.911, r2 = 0.795) bothin our cohort and in the CEPH population. These htSNP were usedto construct PAX2 haplotypes for 161 of 168 subjects (Figure 3A);in seven subjects, haplotypes could not be assigned confidently.A total of 28% of the 161 subjects were heterozygous for theAAA haplotype; an additional 5% of infants were homozygous forthis allele (AAA/AAA). Total renal volume/BSA (123.44 ml/m2)among infants with at least one PAX2 AAA haplotype (32.5% ofthe cohort) was 10% lower than that (137.19 ml/m2) of subjectswho were homozygous for the more common GGG/GGG haplotype (63%of the cohort; P = 0.004).
Figure 3. Effect of PAX2 haplotype on newborn renal volume. (A) PAX2 haplotypes were constructed from three htSNP for each subject (n = 168). A total of 63% of newborns were homozygous for the GGG haplotype. A total of 28% of newborns were heterozygous (GGG/AAA), and 5% were homozygous for the less common AAA haplotype. In seven (4%) individuals, a haplotype could not be confidently assigned. Newborns with one or more AAA alleles had lower total kidney volume/BSA (123.48 ml/m2) compared with GGG/GGG homozygotes (137.19 ml/m2; *P = 0.004). Newborns with an AAA allele had slightly higher cord cystatin C (1.94 mg/L) compared with the GGG homozygotes (1.90 mg/L), but this difference was NS (P > 0.05). (B) The effect of PAX2 haplotype on kidney volume/BSA percentile in our newborn cohort is compared with the effect of BP status on nephron number percentile in the normal adult population. Data from Keller et al. (5) on nephron number in adults with essential hypertension (EHT) versus normotensive control subjects (NT) are plotted according to the nephron number distribution reported by Nyengaard et al. (4). Nephron number percentile in relationship to the overall population mean (µ) were calculated from Keller’s data, assuming that 25% of the normal population has essential hypertension (1). Accordingly, the presence of a PAX2 AAA haplotype decreases total kidney volume/BSA by 10% (versus GGG homozygotes), whereas the presence of EHT decreases nephron number by 46% (versus normotensive control subjects).
PAX2 Allele Expression Imbalance
To determine whether PAX2 haplotype influences the level ofmRNA expression, we screened human renal cell carcinoma celllines for heterozygosity at an exon 8 SNP (rs1800898) in tightLD (D' = 0.827, r2 = 0.63) with all three htSNP used to constructthe PAX2 haplotype (HapMap). One cell line (A498) was shownto be heterozygous for both the exonic SNP and the three htSNPthat were used to construct the PAX2 haplotype. Allele-specificPAX2 expression was examined in this cell line by amplifyingan approximately 250-bp fragment of genomic DNA or the correspondingreverse-transcribed cDNA that contained the rs1800898 locus(Figure 4). The estimated level of transcript that was derivedfrom the more common rs1800898(A) allele (70% of the CEPH population)was 65.3% of the total, whereas the transcript from the lesscommon rs1800898(C) allele (30% of the CEPH population) contributedonly 34.5% of the total (P < 0.001).
Figure 4. Allele-specific expression of PAX2. Allele-specific PAX2 expression in the human A498 renal cell carcinoma cell line was quantified by sequencing an approximately 250-bp amplicon that contained the exon 8 rs1800 (898) SNP from genomic DNA or the corresponding reverse-transcribed cDNA according to the method of Pastinen et al. (26). The transcript level of the more common rs1800898(A) allele was 65.3% of total PAX2 mRNA, whereas the transcript from the less common rs1800898(C) allele contributed only 34.5% of total PAX2 mRNA (P < 0.001).
Nephron number seems to correlate fairly well with renal sizeat birth, because placental clearance of fetal solutes bufferssuboptimal renal function in the antenatal period. In a limitedstudy of spontaneously aborted normal human fetuses, Hinchcliffeet al. (6) demonstrated a tight correlation between renal volumeand glomerular number up to 40 wk of gestation Other small studiesof humans who were autopsied in the perinatal period consistentlyshowed an association between renal size and glomerular number(27–29). Similarly, in heterozygous Pax21Neu mice, kidneymass and nephron number were reduced in parallel (60 and 65%,respectively, in comparison with wild-type littermates) whenmeasurements were made at 1 wk of age (15). We recently showedthat newborn kidney volume correlates with serum creatinineat 1 mo of age (30), but long-term prospective studies of congenitalnephron deficit have been difficult to perform because compensatoryhypertrophy continues throughout the first few months of life,erasing the initial correlation between renal size and nephronnumber. Keller et al. (5) documented a 46% reduction in nephronnumber among subjects with essential hypertension by extensiveglomerular counts in autopsy specimens, but glomerular volumewas double that of age-matched control subjects and renal masswas equivalent in the two groups. Similarly, adult heterozygousPax21Neu mice show glomerular hypertrophy, resulting in kidneymass equivalent to wild-type littermates by 1 yr of age (15).
In this study, we used total kidney volume at birth (measuredby ultrasonography) as a surrogate for congenital nephron number.Total newborn kidney volume (left + right kidney volume) correlatedinversely with umbilical cord cystatin C level, a low molecularweight protein that is used as a marker of GFR in infants (31)and that does not seem to cross the placental barrier (32).To eliminate the confounding effect of body size (BSA) on newbornkidney volume, we tested for htSNP association with total kidneyvolume/BSA.
Like other complex traits (33,34), congenital nephron numberis normally distributed in human populations (4) and is likelyto have multiple genetic determinants. We focused on the PAX2gene as a candidate determinant of human nephron number because,in the autosomal dominant renal-coloboma syndrome, there isno compensation for the loss of one PAX2 allele (35) and PAX2protein levels are reduced to approximately 50% of normal, inaccordance with gene dosage. We identified a cluster of htSNPthat defined a relatively common (18.5% of the population) PAX2haplotype (AAA) associated with a 10% reduction in mean newborntotal kidney volume/BSA compared with the most common haplotype(GGG/GGG). The AAA haplotype was widely distributed in our population;combined renal volume in infants with an AAA haplotype rangedfrom 17.06 to 44.06 versus 17.71 to 50.33 ml in infants whowere homozygous for the more common GGG haplotype. Therefore,the association between AAA haplotype and renal volume cannotbe attributed to a few infants with very small kidneys.
The observed decrease in renal volume associated with the PAX2AAA haplotype is approximately one fifth of the 46% decreasein nephron number that was observed in individuals with essentialhypertension (5) (Figure 3B). Therefore, the PAX2 AAA haplotypeis presumably only one of several variables in a multifactorialmodel that accounts for low nephron number and seems to shiftmean renal volume downward across the whole population.
No common polymorphisms affect the amino acid sequence of humanPAX2. However, our allele-specific expression studies in a humanrenal cell carcinoma cell line showed that an allele that bearsa PAX2 exonic SNP that is tightly linked to the AAA haplotypegenerates only one third of the total PAX2 transcript (versustwo thirds from the more common allele). Because this methodcompares expression of one allele versus the other within thesame cell, the allelic expression ratio is independent of anyunique features of the cell line. In a recent study, similaranalyses of allele-specific expression showed that the majorityof genes from the CEPH population exhibit allelic balance (26);individual measurements of allele-specific transcripts variedby no more than 10%, 95% of the time. Using independent replicatemeasurements (n = 5), our finding of allelic imbalance (65%GGG versus 35% AAA) cannot be attributed to variability in theassay.
We hypothesize that the AAA haplotype identifies a fairly commonancestral allele that bears an intronic mutation that reducesthe level of PAX2 expression during fetal kidney development.Reduced PAX2 expression from the AAA allele presumably thencompromises branching of the ureteric bud and reduces congenitalnephron number by 10%. Our study provides the first evidenceof a common gene variant that contributes to subtle renal hypoplasiain normal newborns and, possibly, to the risk for essentialhypertension or susceptibility to renal injury later in life.
This study was supported by an operating grant from the CanadianInstitutes of Health Research (MOP 12954) and by a Pilot ProjectGrant from the McGill University Health Centre Research Institute.P.G. is the recipient of a James McGill (Canadian Institutesof Health Research) Research Chair.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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Abstract
Introduction
