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Genome-Wide Linkage Scan of a Large Family with IgA Nephropathy Localizes a Novel Susceptibility Locus to Chromosome 2q36

Andrew D. Paterson^*,, Xiao-Qing Liu^*, Kairong Wang^,, Riccardo Magistroni^,||, Xuewen Song^,, Joanne Kappel^¶, Judith Klassen^¶, Daniel Cattran, Peter St. George-Hyslop and York Pei^,

^* Program in Genetics and Genome Biology, Hospital for Sick Children, Department of Public Health Sciences and Divisions of Nephrology and Genomic Medicine, University of Toronto, Toronto, Ontario, Canada; ^|| Division of Nephrology, University of Modena and Reggio Emilia, Modena, Italy; and ^¶ Division of Nephrology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

Correspondence: Dr. York Pei, Division of Nephrology, University Health Network, 8N838, 585 University Avenue, Toronto, Ontario, Canada M5G 2N2. Phone: 416-340-4257; Fax: 416-340-4999; E-mail: york.pei{at}uhn.on.ca

Received for publication February 26, 2007. Accepted for publication April 30, 2007.

	Abstract

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IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide and an important cause of ESRD. Familial clustering of cases suggests genetic predisposition to this disease. Two recent genome-wide studies in IgAN have identified a major susceptibility locus on chromosome 6q22 (IGAN1) and two additional loci with suggestive linkage signals on chromosomes 4q26–31 and 17q12–22. A large four-generation family with 14 affected individuals has been clinically ascertained and excluded from linkage to these loci. A genome-wide linkage scan was performed on this family with GeneChip Mapping 10K 2.0 Arrays using an "affected-only" strategy. By nonparametric analysis, two regions of suggestive linkage (multipoint logarithm of odds [LOD] scores >2) were identified on chromosomes 2q36 and 13p12.3. By parametric analysis (assuming an autosomal dominant inheritance, a disease allele frequency of 0.001, phenocopy rate of 0.01, and penetrance of 75%), a significant linkage to chromosome 2q36 (maximum multipoint LOD score 3.47) was found. Nine simple sequence repeat markers then were genotyped in 21 members (included all of the affected individuals), and significant linkage to chromosome 2q36 over a region of 12.2 cM (maximum multipoint LOD score 3.46) was confirmed. Recombination events in two affected individuals, as detected by haplotype analysis, delineated a critical interval of approximately 9 cM (equivalent to approximately 7 Mb) between D2S1323 and D2S362. Taken together, these data provide strong evidence for a novel disease susceptibility locus for familial IgAN.

	Introduction

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IgA nephropathy (IgAN; MIM 161950; http://www.ncbi.nim.gov/Omim) is the most common primary glomerulonephritis worldwide and an important cause of ESRD in developed countries.^1–7 Typically, it presents in young adults with persistent microscopic hematuria and low-grade proteinuria. Although episodic gross hematuria ("coca-cola" color urine) may occur in some patients shortly after a viral infection, most remain clinically asymptomatic until they have developed chronic kidney failure.^1,2 IgAN is generally a slowly progressive disease: Between 10 to 15% and 20 to 35% of patients will develop ESRD at 10 and 20 yr from the time of diagnosis, respectively.⁸ Risk factors associated with disease progression include male gender, renal insufficiency, high-grade proteinuria, and severe hypertension.^2,8 In patients who had ESRD and underwent renal transplantation, IgAN recurred in approximately 50% of allografts.^1,9,10 Conversely, disappearance of IgA deposits had been documented in donor kidneys with IgAN within weeks after they were inadvertently transplanted into recipients with other renal diseases.¹⁰ Although IgAN is thought to be a systemic disorder of mucosal immunity, its pathobiology remains largely unknown. Nonspecific measures such as BP control with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and fish oil treatment are recommended as therapeutic options to delay the progression of this disease.^1,2

Familial clustering of IgAN has been well documented.^11–15 In a recent family study of patients with biopsy-proven IgAN, a recurrence risk () of approximately 16 (95% confidence interval [CI] 6 to 48) was noted in the first-degree relatives and of 2.4 (95% CI 0.7 to 7.9) in the second-degree relatives.^13,14 In addition, two genome scans of familial IgAN have identified a major susceptibility locus on chromosome 6q22 (IGAN1) and two additional loci with suggestive linkage signals on chromosomes 4q26–31 and 17q12–22.^16,17 Taken together, these data suggest a genetic predisposition to IgAN, albeit with incomplete penetrance.^13,14,16,17 In this study, we report strong evidence of linkage from the genome scan of a large multiplex family with IgAN implicating a novel susceptibility locus on chromosome 2q36.

	RESULTS

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Clinical Ascertainment
IgAN6 is a large Canadian family of German-Austrian descent with no history of consanguinity (Figure 1). Two members of this family (ID 2110 and 2168) were previously known to have biopsy-proven IgAN and ESRD. Of the remaining 23 at-risk relatives clinically ascertained, 12 were also considered affected (Table 1). Of interest, episodic gross hematuria occurring shortly after a viral infection, a clinical feature highly suggestive of IgAN, was present in four affected members. There was no history of hearing loss and any disease that may be associated with secondary IgAN (systemic lupus erythematosus, gluten enteropathy, cirrhosis, and HIV infection) in the affected individuals.¹⁰ Consistent with previous reports of familial IgAN, multigeneration and male-to-male transmission in IgAN6 suggest that an autosomal dominant inheritance is most likely. Variable severity is noted in IgAN6, with three of the older members (ID 2113, 2269, and 2138) having milder disease than some of the younger members (ID 2168, 2110, 2109, 2136, and 2111).

View larger version (17K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 1. Pedigree structure of IgAN6. Multigeneration and the presence of male-to-male transmission in IgAN6 suggest an autosomal dominant inheritance. Affected individuals are denoted by filled symbols; unknown and unaffected individuals are denoted by open symbols. The slanted T symbol denotes individuals who have been clinically ascertained. The age at clinical assessment is in parentheses.

The results of our "affected-only" genome-wide linkage scan are shown in Supplementary Figure 1. Multipoint nonparametric linkage analysis identified two loci with suggestive linkage (LOD scores >2) on chromosomes 2q36 and 13q12.3 (Supplementary Figure 1, top). By parametric linkage analysis, the maximal multipoint LOD scores at these loci were 3.47 and 2.97, respectively, under the assumption of autosomal dominant inheritance, disease allele frequency of 0.001, phenocopy rate of 0.01, and penetrance of 75% (Supplementary Figure 1, bottom). The linkage signal detected on chromosome 2q36 was due to 12 single-nucleotide polymorphisms (SNP) spanning approximately 6.5 Mb, all of which yielded significant multipoint LOD scores (>3.3; Figure 2). By contrast, the linkage signal on chromosomes 13q12.3 was due to four SNP spanning approximately 600 kb, which yielded maximal multipoint LOD scores of 2.6 to 2.97.

View larger version (19K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 2. "Affected-only" multipoint parametric linkage plot of chromosome 2 from the GeneChip Mapping 10K 2.0 genome scan. This is an enlarged view of the information content and logarithm of odds (LOD) score plot on chromosome 2 from the bottom panel of Supplementary Figure 1. A maximal LOD score of approximately 3.5 was obtained at chromosome 2q36. The gray lines at –2.0 and 3.0 are classical criteria for exclusion and significant linkage, respectively.

View larger version (18K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 3. Affected-only multipoint parametric analysis of simple sequence repeat (SSR) markers at chromosome 2q36. Markers D2S2228, D2S2390, and D2S1363 yielded a maximal LOD score of 3.46. The "LOD-1" support interval is flanked by markers D2S424 and D2S362, which define a 12.2-cM interval (or 8.4 Mb). The deCode genetic map was used to estimate the genetic interval, and the National Center for Biotechnology Information Human Reference Genome Sequence (Build 36.1) was used to estimate the physical distance between markers.

View larger version (33K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 4. Haplotype analysis of SSR on chromosome 2q36. The putative disease haplotype 5-2-2-5-3-4-1-5-5 co-segregates with all of the affected individuals. Intermarker recombination events are denoted by x. Recombinations within the putative disease haplotype in individuals 2168 and 2108 delineate a critical interval of approximately 9 cM (or approximately 7 Mb) between D2S1323 and D2S362. The deCode genetic map was used to estimate the genetic interval, and the National Center for Biotechnology Information Human Reference Genome Sequence (Build 36.1) was used to estimate the physical distance between markers.

	DISCUSSION

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In our affected-only genome-wide linkage analysis, we detected a significant linkage signal on chromosome 2q36 by parametric analysis, which also modeled for both phenocopies and incomplete penetrance.¹⁶ The maximal multipoint parametric LOD score at chromosome 2q36 was approximately 3.5, which exceeds the genome-wide threshold recommended for significant linkage and matched with the predicted maximal LOD score from our simulation studies.²² These data thus provide strong evidence for a novel locus for familial IgAN (Figure 2). Multipoint parametric analysis with SSR markers was concordant with the SNP-based analysis and shows that the LOD score peaked at markers D2S2228, D2S2390, and D2S1363. The "LOD-1" support interval, flanked by markers D2S424 and D2S362, define a 12.2-cM interval (or 8.4 Mb; Figure 3). Haplotype analysis also supports the localization of this novel locus within the specified interval and further delineates a critical interval of approximately 9 cM (or approximately 7 Mb) between D2S1323 and D2S362 (Figure 4).

Using the UCSC Human Genome Browser (March 2006 Assembly), we identified at least 22 annotated and 17 nonannotated genes in this region (see Table 3). Among the annotated genes, CCL20 seems to be the only obvious biologic candidate gene for immunologic disorders.^23–27 CCL20 (also called macrophage inflammatory protein 3-) is a -chemokine expressed by keratinocytes and pulmonary and intestinal epithelial cells.^23,24 It is a specific ligand for the chemokine receptor CCR6, which is expressed on most B cells, effector/memory T cells, and dendritic cells.^23,24 CCR6 signaling is responsible for chemoattraction of these cells under homeostatic and inflammatory conditions. Of interest, CCR6 signaling also regulates intestinal mucosal immunity. Specifically, CCR6^–/– knockout mice exhibited underdeveloped gut associated lymphoid tissue, altered composition of T cells and dendritic cells in the intestinal submucosal region, and impaired IgA production in response to oral antigen challenge and to the enteropathic rotavirus infection.^25–27 These animals also exhibited altered dermal contact hypersensitivity and alteration of disease severity in two models of experimental inflammatory bowel disease.^26,28 These findings therefore implicate a potential role for CCL20 in IgAN as well. However, we did not find any potentially pathogenic mutation in the promoter region, coding sequence, and splice junctions of this gene. COL4A3 and COL4A4, two other genes in the critical region, are also of interest because mutations of either gene cause an autosomal recessive form of Alport syndrome.²⁹ More recent studies suggest that heterozygous carriers of COL4A3 or COL4A4 mutations may develop thin basement membrane nephropathy, which can segregate as a dominant trait.³⁰ However, thin basement membrane disease is a benign nonprogressive disorder associated with low-grade hematuria and is not compatible with the phenotype observed in our family. As seen in most inherited kidney diseases, the pathogenic mutation of our study family may not reside in an obvious biologic candidate gene. Therefore, future studies with additional chromosome 2q36-linked families will be needed to identify informative recombinant individuals to narrow further the critical interval. Ultimately, the identification of the disease susceptibility gene may require gene-by-gene screening for potentially pathogenic mutations within the critical interval, segregation analysis, and possibly functional analysis of the putative pathogenic variants.

We have presented strong genetic evidence implicating a novel disease susceptibility locus for IgAN on chromosome 2q36. Additional linkage studies with multiplex families with IgAN are needed to define the relative contribution of this gene locus in familial forms of IgAN and, possibly, to refine further the critical interval. The ultimate identification of the causative gene may provide important insights into the molecular pathobiology of IgAN. Such knowledge is essential for improving the diagnostic and therapeutic approaches to this disease.

	CONCISE METHODS

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Clinical Ascertainment
Several members of pedigree IgAN6 previously received a diagnosis of IgAN either clinically or by renal biopsy. We ascertained the complete pedigree structure of IGAN6 over four generations and clinically evaluated 22 at-risk or affected individuals and three spouses. All study participants provided their medical records for review and were screened for hematuria, proteinuria, and renal function. Serum creatinine was measured with an autoanalyzer. Estimated GFR, adjusted for age, gender, and body weight, was calculated using the formula of Cockcroft and Gault.³¹ We used the clinical criteria described by Gharavi et al.¹⁶ to assign affection status. At-risk individuals were classified as affected when they had renal biopsy findings diagnostic of IgAN, which was defined pathologically as dominant or co-dominant glomerular staining for IgA and histologic evidence of mesangial proliferation or expansion.¹⁰ In addition, at-risk individuals who had hematuria (more than five red blood cells per high-power field) or proteinuria (3+ on urine dipstick) on at least three separate occasions or ESRD without other identifiable causes were also considered as affected. In turn, the severity of chronic kidney disease in the affected individuals was staged according to their estimated GFR.³² The affection status of all other at-risk individuals was coded as unknown. All study participants gave informed consent, and in the case of minors, parental consent was obtained. The Human Subject Review Board at the University of Toronto approved the research protocol used in this study.

DNA Isolation and Genotyping
Genomic DNA was extracted from peripheral blood using the FlexiGene DNA kit (Qiagen, Mississauga, Ontario, Canada). Genome-wide linkage scan was performed using GeneChip Mapping 10K 2.0 Arrays,³³ in accordance with the manufacturer's recommendation at the Microarray Analysis and Gene Expression Facility, Center for Applied Genomics, Hospital for Sick Children (Toronto, Ontario, Canada). In brief, 250 ng of high-quality genomic DNA was digested with XbaI (20,000 U/ml), and adaptor Xba sequences were ligated using T4 ligase on the digested DNA. After PCR amplification with Xba primers (250 µM dNTP, 2.5 mM MgCl₂, 0.75 µM of each primer, and 0.1 U/µl of AmpliTaq Gold), amplicons were processed via MinElute plate with a QIAvac 96 vacuum manifold and quantified. Twenty micrograms of amplicons was used for the subsequent steps of fragmentation with DNase I, end labeling with biotinylated ddATP, and hybridization to the 10K array. Hybridization was detected by streptavidin-phycoerythrin conjugates. Arrays were processed through Affymetrix microfluidics station with images obtained by use of the Affymetrix GeneArray scanner 2500. Affymetrix Microarray Suite 5.0 software was used to obtain raw microarray feature intensities (raw allele scores), which were further processed to derive SNP genotypes. Quality controls included gel electrophoresis after the PCR (2% agarose) and fragmentation (4% agarose) steps. SSR genotyping was performed with markers selected from the Marshfield and DeCode genetic maps in the regions of interest using an established protocol.³⁴ PCR products were labeled by [³²P]-dCTP and analyzed by PAGE. Genotyping of SSR markers was scored by K.W. without any knowledge of the clinical status of the study subjects, and any ambiguity was resolved by retyping of the markers.

Mutation Screening of CCL20
We amplified by PCR all of the exons (including 5' untranslated region in exon 1, which contains a TATA box, two AP-2 binding sites, and one SV40 T antigen–binding site) and splice junctions of CCL20 using DNA from one affected and one unaffected member of IGAN6. We selected primers using the software Primer3 (http://frodo.wi.mit.edu/) and included in the amplicons 50 to 150 bp of intronic sequences flanking each exon. Bidirectional sequencing of PCR products was used for mutation detection using an ABI PRISM 3730xl DNA Analyzer (Applied Biosystems, Foster City, CA). Primer sequences used for the PCR and the expected size of the amplicons are shown in Supplementary Table 1. PCR was performed on GeneAmp PCR System 9700 (Applied Biosystems) in a 50-µl reaction mixture containing 1x PCR buffer (Qiagen), 200 µM each of dNTP, 0.5 µM each of primer, 50 ng of genomic DNA, and 0.5 U of HotStarTaq (Qiagen) under the conditions of denaturation at 94°C for 15 min; 35 cycles of 94°C for 30 s, 58°C for 30 s, and 72°C for 1 min; and final extension at 72°C for 7 min.

Statistical Analyses
To determine the power of IgAN6 in detecting linkage, we performed simulations of genotypes using SLINK.^18,19 We generated a genetic map for our study by merging the Affymetrix 10K SNP with the Rutgers map (http://compgen.rutgers.edu/maps/) by their physical location (NCBI build 35) and by interval specific interpolation.³⁵ Of the 11,560 Affymetrix SNP, 9756 were placed on the genetic map. Because linkage disequilibrium between markers could cause false-positive results when one or both parents were not genotyped³⁶ and because of the computational limitations for multipoint linkage analysis, selected markers were used in the genome-wide linkage analysis. The SNP were grouped with more than 0.1 cM between the clusters. One SNP with the highest minor allele frequency from the CEU samples of the HapMap database (http://www.hapmap.org/) was chosen from each cluster, resulting in 4541 SNP being selected.³⁷ The mean minor allele frequency of the selected markers was 0.31 (SD = 0.14), and the mean intermarker distance was 0.81 cM (SD = 0.95 cM). PedCheck was used to detect Mendelian errors,³⁸ and Merlin (version 1.0.1; http://www.sph.umich.edu/csg/abecasis/Merlin/) was used to detect non-Mendelian errors.^39,40

Multipoint nonparametric and parametric linkage analyses of SNP were performed by Merlin (version 1.0.1) using an affected-only strategy.^39,40 The allele frequencies were calculated using the genotyped individuals in the family. The nonparametric linkage all statistic method compares the allele sharing among the affected individuals with their expected allele sharing, and the Kong and Cox LOD scores were calculated.⁴¹ For parametric linkage analysis, we applied the same genetic model previously used to map the IGAN1 locus.¹⁶ Pair-wise and multipoint affected-only parametric linkage analysis of SSR markers was performed by GENEHUNTER (version 2.1_r5 beta; http://www.broad.mit.edu/ftp/distribution/software/genehunter/),⁴² using the previously mentioned genetic model. Haplotype analysis was performed via visual inspection and confirmed by using GENEHUNTER to identify critical recombination events. A candidate interval was considered excluded when two affected individuals within the pedigree inherited different haplotypes.

	DISCLOSURES

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None.

	Acknowledgments

 
Supported by a Canada Research Chair in Genetics of Complex Diseases (A.D.P.) and grants from the Canadian Institutes of Health Research (MOP67084) and the Lee and Margaret Lau Family Research Fund (Y.P.).

We thank Dr. Michael West (Division of Nephrology, Dalhousie University, Halifax, NS, Canada) for informing us about the study family. We are indebted to all of the participating members of IgAN6.

	Footnotes

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

Supplemental information for this article is available online at http://www.jasn.org/.

	References

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