Linkage Analysis of Candidate Loci for End-Stage Renal Disease due to Diabetic Nephropathy
Sudha K. Iyengar*,,
Katherine A. Fox*,,
Marlene Schachere*,,
Fauzia Manzoor*,,
Mary E. Slaughter*,,
Adrian M. Covic,,
S. Mohammed Orloff*,,
Patrick S. Hayden,,
Jane M. Olson*,,
Jeffrey R. Schelling, and
John R. Sedor,
Departments of *Epidemiology and Biostatistics, and Medicine, Case Western Reserve University, and Rammelkamp Center for Research and Education, MetroHealth Medical Center, Cleveland, Ohio.
Correspondence to Dr. Sudha Iyengar, Department of Epidemiology and Biostatistics, Case Western Reserve University, R215 Rammelkamp Center for Research, 2500 MetroHealth Drive, Cleveland, OH 44109-4945. Phone: 216-778-8484; Fax: 216-778-3280;
ABSTRACT. Diabetic nephropathy (DN), a major cause of ESRD,is undoubtedly multifactorial and is caused by environmentaland genetic factors. To identify a genetic basis for DN susceptibility,we are collecting multiplex DN families in the Caucasian (CA)and African-American (AA) populations for whole genome scanningand candidate gene analysis. A candidate gene search of diabeticsibs discordantly affected, concordantly affected and concordantlyunaffected for DN was performed with microsatellite markersin genomic regions suspected to harbor nephropathy susceptibilityloci. Regions examined were at human chromosome 10p,10q (orthologousto the rat renal susceptibility Rf-1 locus), and at NPHS1 (nephrin),CD2AP, Wilms tumor (WT1), and NPHS2 (podocin) loci. Linkageanalyses were conducted using model-free methods (SIBPAL, S.A.G.E.)for AA, CA, and the combined sample. Allele frequencies andthe identity by descent sharing were estimated separately forAA and CA, and race was included as a covariate in the finallinkage analysis. To date, we have collected 212 sib pairs from46 CA and 50 AA families. The average age of diabetes onsetwas 46.8 yr versus 36.2 yr for CA and 39.5 yr versus 40.2 yrfor AA, in males versus females respectively. Genotyping datawere available for 106 sib pairs (43 CA, 63 AA) from 27 CA (44%male probands) and 38 AA families (43% male probands). AverageAA and CA sibship size was 2.73. Singlepoint and multipointlinkage analyses indicate that marker D10S1654 on chromosome10p is potentially linked to DN (CA only multipoint P = 4 x10-3). Interestingly, the majority of the linkage evidence derivesfrom the CA sib pairs. We are now adding sib pairs and increasingmarker density on chromosome 10. We have excluded linkage withcandidate regions for nephrin, CD2AP, WT1, and podocin in thissample. In conjunction with previous reports, our data supportevidence for a DN susceptibility locus on chromosome 10. E-mail:ski@po.cwru.edu
ESRD: a Common Complex Disease With a Genetic Basis
ESRD is a multifactorial disease with increasing worldwide incidence,due in part to the aging population (1). Progression of diabeticnephropathy (DN) to ESRD can be effectively slowed by aggressivelytreating hyperglycemia and hypertension, using either angiotensinconverting enzyme inhibitors or angiotensin receptor blockers.Although modifiable risk factors have been identified, epidemiologicdata, primarily from Caucasian and Pima Indian populations,indicate that DN is genetically determined, with multiple genesregulating the phenotype (reviewed in reference 2–5).Several lines of evidence suggest that ESRD pathogenesis ismediated by genes. First, there is significant evidence of familialaggregation for ESRD (6–10). Second, animal models alsosuggest that ESRD pathogenesis is mediated by genes (11–14).Lastly, environmental factors alone cannot adequately explainthe excessive clustering of ESRD in families.
Complex segregation of families in which DN was clustered, performedindependently by two groups of investigators, demonstrated amajor genetic effect on susceptibility to DN. Imperatore etal. (15) defined nephropathy as a urine protein to creatinineratio 500 mg/g in 715 nuclear, Pima Indian families,and rejected models for no major gene effect and no transmissionof a major effect (P = 0.00001; P = 0.003). In contrast, theywere unable to reject Mendelian transmission models (P = 0.85),although the specific mode of inheritance could not be determined.Fogarty et al. (16) examined segregation of a quantitative trait,urine albumin to creatinine ratio, in 96 large multigenerationalpedigrees ascertained for type 2 diabetes and found that a multifactorialmode of inheritance best fit the ratio of albumin to creatininelevels. Together, these segregation analyses support the hypothesisof a major genetic effect on susceptibility to DN.
Strategies that have identified the genes responsible for monogenicrenal diseases such as polycystic kidney disease (17–20)and Alport’s syndrome (21,22) are being applied to morecommon causes of progressive renal disease, such as DN, hypertensivenephrosclerosis (HN), and glomerulonephritis (GN). Classicallinkage analysis of extended families has met with moderatesuccess in mapping genes for familial forms of focal segmentalglomerulosclerosis (FSGS) and IgA nephropathy (IgAN). FamilialFSGS has been linked to markers on chromosome 19q13 (23,24),11q21–q22 (25), and 1q25–31 (26). Mutations in thegene encoding -actinin-4, an actin filament cross-linking protein,were identified in three families with an autosomal dominantform of FSGS linked to the 19q13 locus (27), identifying yetanother molecular basis for a common histologic phenotype. Gharaviet al. (28) used genome-wide linkage analysis of 30 multiplexIgAN kindreds and identified a locus for IgAN on 6q22–23,with an autosomal dominant model of transmission with incompletepenetrance. The investigators obtained a lod score of 5.6, andobserved that 60% of kindreds were linked to markers on chromosome6.
Collection of extended family data are problematic for the mostcommon causes of nephropathy, such as DN and HN, because theage of disease in probands is later in life and relatives areoften deceased or unavailable for collection. Furthermore, basicassumptions of traditional linkage analysis for Mendelian traitsoften cannot be applied to multifactorial diseases. The natureof complex diseases precludes the use of specific genetic modelsin the linkage analysis, because the mode of inheritance isoften unknown. Locus heterogeneity, as observed for FSGS above,as well as allelic (mutation) heterogeneity, further constrainsthe usefulness of traditional linkage methods. New linkage methodshave been developed that use nuclear family structures, suchas affected and discordant sibling pairs, which make no assumptionsabout the mode of inheritance of the disease (for reviews seereferences 29 and 30). These novel, model-free methods haveformed the basis of genetic investigations in common forms ofnephropathy. In aggregate, these data suggest that genes mediatingESRD pathogenesis are complex in etiology.
Candidate Loci for Diabetic Nephropathy
In an effort to reduce genetic heterogeneity, our group haslimited recruitment to families with DN. Association analysesof candidate DN pathogenesis genes using case-control designsare common, but results often cannot be replicated. Only twolinkage analyses of families in which DN is clustered have beenreported. Moczulski et al. (31) performed a linkage study using66 type 1 diabetic Caucasian sib pairs who were discordant forDN. Chromosomal regions containing genes for ACE, angiotensinogen,and angiotensin II type 1 receptor (AT1) were examined. Theinvestigators observed significant evidence of linkage at microsatellitesnear AT1. Follow-up analyses demonstrated that DN was linkedwith a major nephropathy susceptibility locus in a 20-cM region,which included AT1 (P = 7.7 x 10-5). Imperatore et al. (32)undertook a more comprehensive genome-wide survey in 98 diabeticsibling pairs concordant for diabetes and nephropathy to identifyDN susceptibility loci among the Pima Indians. They observedsuggestive evidence for linkage on chromosomes 3, 7, 9 and 20.
Although our goal is to identify genes that regulate DN, severalepidemiologic studies indicate that inherited susceptibilityto progressive renal failure is independent of the etiologyof ESRD (8,33), suggesting that genes or loci linked to nondiabeticcauses of kidney disease should be assessed as candidate pathogenesisgenes for DN. Whole genome linkage analysis in the fawn-hoodedrat, a model of hypertension and nephrosclerosis, identifiedtwo renal failure susceptibility genes, Rf-1 and Rf-2 (11).The region of human homology for Rf-1 was identified as thedistal portion of chromosome 10q. Yu et al. (34) investigatedif markers on human chromosome 10 were linked with chronic renalfailure in 129 African-American nondiabetic sibling pairs concordantfor ESRD. The investigators observed weak evidence for linkagewith markers on 10p, but not in the Rf-1 region.
In vitro, animal and human data suggest that podocyte dysregulationcan initiate and/or perpetuate progressive glomerular scarring(35). Both transgenic animal models and familial glomerulosclerosishave been linked to mutations in two novel and two previouslyknown genes, which encode podocyte proteins that comprise componentsof the slit diaphragm. Although mesangial expansion is the classiclesion of DN, recent work suggests that podocyte injury occursearly in the course of DN and filtration barrier dysfunctionis a hallmark of the disease. NPHS1 (nephrin) and NPHS2 (podocin)were identified by positional cloning in families with congenitalnephrotic syndrome of the Finnish type (36), and families withsteroid-resistant nephrotic syndrome (37), respectively. Nephrin,an Ig superfamily member, is thought to be a major transmembranecomponent of the slit diaphragm (38–40). Podocin, whichis similar to stomatin family scaffold molecules, has a singlehairpin-like structure with both the N-terminal and C-terminaldomains in the cytosol (37). ACTN4, which encodes the actincross-linking protein -actinin-4 (41), was identified as a candidategene on the 19q13 locus mapped from three families with FSGS.CD2 associated protein (CD2AP) was originally identified asan adapter protein that interacts with the cytoplasmic domainof CD2, a T cell adhesion protein but subsequently was foundto cause progressive glomerulosclerosis in mice lacking CD2AP(42).
Sib Pair Study Design
In our ongoing project we are collecting sibling pairs who areconcordant for diabetes and renal disease (affected sib pairs,ASP), based upon the rationale that genes predisposing to ESRDare more likely to segregate in families with more than oneaffected sibling. To distinguish between diabetes susceptibilityloci and DN loci, we are also collecting sibling pairs who areconcordant for diabetes and discordant for DN (discordant sibpairs, DSP). In diseases such as DN where the recurrence riskfor diabetes among siblings is high, DSP may provide as muchinformation as ASP (43). Our selection criteria for ASP andDSP with type 2 diabetes and DN, and the strategy for data collectionare described in a previously published methods paper (44).Briefly, the clinical characteristics (phenotype) of index casesfrom dialysis clinics and family members (predominantly sibs)are ascertained with a questionnaire, from medical record review,and from measurement of proteinuria, serum creatinine and HgbA1C.The general classification scheme for sib pairs with varyingdegrees of albumin excretion is described in Figure 1. Diabetesis defined by HgbA1C 7.0 mg/dl, fasting serumglucose 126 mg/dl, random glucose 200mg/dl, or prevalent treatment with insulin or oral hypoglycemicagents. DN is defined by diabetes duration 10yr, urine protein 500 mg/g creatinine, and backgroundor proliferative retinopathy is defined by ophthalmology records,or history of laser surgery. Index cases and affected sibs mustmeet diabetes and DN criteria. Discordant sibs must have diabetes10 yr, but no proteinuria (<30 µg albumin/gcreatinine).
Figure 1. Classification of sib pairs for linkage analysis on the basis of albumin excretion. Model-free linkage analysis used three types of sib pairs; concordantly affected, concordantly unaffected, and discordant. Unaffected sibs were long-standing diabetics (diabetes mellitus duration >10 yr) who did not demonstrate evidence of incipient nephropathy. In contrast, affected sibs were individuals who progressed to overt nephropathy.
Database
All phenotyping information generated from questionnaires, medicalrecord reviews, and laboratory data are entered into a centralizedESRD database. The database design uses client-server architecturewith a Microsoft Access server acting as a graphical front-end,and a high quality UNIX-based SQL server to store data at theback-end. Currently, data can be entered from four differentforms that are linked to each other. To maintain patient confidentiality,all personal information, including the name and address ofeach study subject, is segregated from the rest of the phenotypicinformation in the initial data entry form. After entering asubject’s name and address, a unique identifier and barcode is assigned to all records pertaining to that individual.All subsequent data entry for that patient or relative(s) usesonly the unique identifier, thereby ensuring continued confidentiality,as well as linking family members related to the proband. Allphenotypic data are entered via graphical dialog boxes withdrop-down selection boxes. Each screen has integrated logicto perform internal data encoding and checks to detect commoncoding and consistency errors.
Candidate Gene and Linkage Analyses
A candidate gene search of diabetic sibs discordantly affected,concordantly affected, and concordantly unaffected for DN wasperformed with microsatellite markers in regions suspected toharbor nephropathy susceptibility loci. Regions examined wereat chromosome 10p and 10q, orthologous to the rat renal susceptibilityRf-1 locus, NPHS1 (nephrin, 19q), Wilm’s tumor (WT1),CD2AP, and podocin (NPHS2) loci. Linkage analyses were conductedusing model-free methods (SIBPAL2, S.A.G.E.) for AA, CA, andthe combined sample. Allele frequencies and the identity bydescent sharing were estimated separately for AA and CA. Racewas included as a covariate in the final linkage analysis.
The protocol has been approved by Institutional Review Boardsat MetroHealth Medical Center and University Hospitals of Cleveland.
Data Collection
To date, we have obtained information on 1577 type 2 diabeticindex cases (see Figure 2 and Table 1). Comparison of familyhistory records from subjects with all causes of ESRD (n = 2804)versus DN only (n = 1577) revealed several trends (Table 1).First, there is a significant excess of females with a familyhistory among all-cause ESRD and DN (P = 8.5 x 10-9), althoughthis gender difference is great in DN (P = 3.4 x 10-13). Second,there is no difference in the percentage of African Americans(AA) and Caucasians (CA) with and without a family history forall cause ESRD versus DN (with family history P = 0.968, withoutfamily history P = 0.091). We also compared the DN probandsenrolled in the genetic portion of the study (n = 229) to thosewho participated in the initial questionnaire (n = 964), butdid not meet study criteria (Table 2). There were no significantdifferences in the average ages of the two groups. Comparingindex cases with a living diabetic sib versus the unenrolledpopulation, we did observe an increase in the percentage ofAA compared with CA (P = 0.023). The source of this differenceis likely to be the decrease in the percentage of male CA withliving diabetic sibs.
Table 2. DN probands enrolled in the study versus those not enrolleda
We have completed the administration of questionnaires in 399families and their 287 relatives (see Figure 2). Of these families,96 have questionnaire data confirmed by medical record review,and have provided necessary blood and urine specimens. AverageAA and CA sibship size was 2.73. These families contain 212sibs pairs, of which 59 and 72 meet ASP and DSP criteria, respectively.The remaining sibs pairs (n = 81) fail to meet phenotype requirements,due primarily to sibs with microalbuminuria or diabetes duration<10 yr. Sixty additional families are under evaluation.
We also compared the age-at-diabetes-onset in probands and theirdiabetic sibs (Table 3). When analyzed as a group, ages of diabetesonset are similar in sibs and probands. After stratificationof the sibs by phenotype, DSP sibs are significantly older thanthe probands at the onset of diabetes, despite having diabetesduration as long as the proband.
Table 3. Comparison of DM onset and duration in probands versus sibsa
Candidate Gene Analysis
Genotyping data are available for 106 sib pairs (43 CA, 63 AA)from 25 CA (44% male probands) and 37 AA families (43% maleprobands). Singlepoint and multipoint linkage analyses indicatethat markers on chromosome 10p demonstrate suggestive evidencefor linkage with a putative nephropathy susceptibility locus(Figure 3, P = 0.03 for multipoint analysis) (45). Interestingly,the majority of the linkage evidence derives from the CA sibpairs. A second peak, with weaker evidence for linkage, is identifiedat the Rf-1 locus on 10q D10S1230). In addition, we have excludedlinkage with candidate regions for CD2AP, WT1, podocin, nephrin,and ACTN4 (Table 4).
Figure 3. Significant evidence of linkage to ESRD with markers on chromosome 10p in the CA population. The asymptotic P values corresponding to the linkage results obtained using the SIBPAL2 program in the Statistical Analysis for Genetic Epidemiology (S.A.G.E.) linkage package were plotted for Caucasian American (CA), African American (AA), and both races combined. Distance in cM on chromosome 10 was plotted along the x axis. A function of P values obtained from the linkage analysis [-log10 (P value)], was plotted along the yaxis.
The linkage results demonstrate strong evidence for a DN susceptibilitylocus on chromosome 10p in CA families. Yu et al. (34) alsoshowed linkage of two adjacent markers on 10p, D10S1435 andD10S249, to ESRD in sibling pairs with nondiabetic causes ofESRD (P = 0.035 pairwise, P = 0.082 multipoint for D10S1435;P = 0.074 pairwise, P = 0.063 multipoint for D10S249). In contrastto Yu et al. (34), we also observed a second smaller linkagepeak at the Rf-1 locus. Our results indicate the existence ofone DN susceptibility locus of strong effect and a second locusof weak/moderate effect on chromosome 10, consistent with emergingevidence from genetic linkage studies performed in other populations(46,47).
We have previously demonstrated that the sibling recurrencerisk and sibling recurrence risk ratio are greater in CA versusAA (SK Iyengar et al., submitted). The results of our linkageanalyses confirm that CA sib pairs are a powerful tool to mapsusceptibility genes for DN. We anticipate that fine mappingof chromosome 10p and 10q in a CA subpopulation that includesadditional sibs may yield specific candidate genes, which regulatesusceptibility for the development of DN and progression toESRD.
Acknowledgments
This work was supported by grants from the National Institutesof Health (DK54644, DK54178, DK38558, DK51472, DK02281, DK57329),Northeast Ohio chapter of the American Heart Association, CentralOhio Diabetes Association, Kidney Foundation of Ohio, LeonardRosenberg Foundation, Juvenile Diabetes Foundation, and BaxterExtramural Grant Program.
Cooper L: USRDS 2001 Annual data report. Nephrol News Issues 15: 31, 34–35, 38, 2001
Iyengar SK, Schelling JR, Sedor JR: Approaches to understanding susceptibility to nephropathy: From genetics to genomics. Kidney Int 61 [Suppl 1]: 61–67, 2002[Medline]
Krolewski AS, Ng DP, Canani LH, Warram JH: Genetics of diabetic nephropathy: How far are we from finding susceptibility genes? Adv Nephrol Necker Hosp 31: 295–315, 2001[Medline]
Freedman BI, Bowden DW, Rich SS, Appel RG: Genetic initiation of hypertensive and diabetic nephropathy. Am J Hypertens 11: 251–257, 1998[CrossRef][Medline]
Buckalew VMJ, Freedman BI: Candidate gene analysis in African-Americans with renal failure. Ren Fail 21: 403–407, 1999[Medline]
Ferguson R, Grim CE, Opgenorth TJ: A familial risk of chronic renal failure among blacks on dialysis? J Clin Epidemiol 41: 1189–1196, 1988[CrossRef][Medline]
Freedman BI, Soucie JM, Stone SM, Pegram S: Familial clustering of end-stage renal disease in blacks with HIV-associated nephropathy. Am J Kidney Dis 34: 254–258, 1999[Medline]
Freedman BI: Familial aggregation of end-stage renal failure: aetiological implications. Nephrol Dial Transplant 14: 295–297, 1999[Free Full Text]
Seaquist ER, Goetz FC, Rich S, Barbosa J: Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med 320: 1161–1165, 1989[Abstract]
Brown DM, Provoost AP, Daly MJ, Lander ES, Jacob HJ: Renal disease susceptibility and hypertension are under independent genetic control in the fawn-hooded rat. Nat Genet 12: 44–51, 1996[CrossRef][Medline]
Provoost AP, Shiozawa M, Van Dokkum RP, Jacob HJ: Transfer of the Rf-1 region from FHH onto the ACI background increases susceptibility to renal impairment. Physiol Genomics 8: 123–129, 2002[Abstract/Free Full Text]
Zalups RK: The Os/+ mouse: A genetic animal model of reduced renal mass. Am J Physiol 264: F53–F60, 1993
Zheng F, Striker GE, Esposito C, Lupia E, Striker LJ: Strain differences rather than hyperglycemia determine the severity of glomerulosclerosis in mice. Kidney Int 54: 1999–2007, 1998[CrossRef][Medline]
Imperatore G, Knowler WC, Pettitt DJ, Kobes S, Bennett PH, Hanson RL: Segregation analysis of diabetic nephropathy in Pima Indians. Diabetes 49: 1049–1056, 2000[Abstract]
Fogarty DG, Hanna LS, Wantman M, Warram JH, Krolewski AS, Rich SS: Segregation analysis of urinary albumin excretion in families with type 2 diabetes. Diabetes 49: 1057–1063, 2000[Abstract]
Ariza M, Alvarez V, Marin R, Aguado S, Lopez-Larrea C, Alvarez J, Menendez MJ, Coto E: A family with a milder form of adult dominant polycystic kidney disease not linked to the PKD1 (16p) or PKD2 (4q) genes. J Med Genet 34: 587–589, 1997[Abstract/Free Full Text]
Connors TD, Van Raay TJ, Petry LR, Klinger KW, Landes GM, Burn TC: The cloning of a human ABC gene (ABC3) mapping to chromosome 16p13.3. Genomics 39: 231–234, 1997[CrossRef][Medline]
Mochizuki T, Wu G, Hayashi T, Xenophontos SL, Veldhuisen B, Saris JJ, Reynolds DM, Cai Y, Gabow PA, Pierides A, Kimberling WJ, Breuning MH, Deltas CC, Peters DJ, Somlo S: PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 272: 1339–1342, 1996[Abstract]
Germino GG, Weinstat-Saslow D, Himmelbauer H, Gillespie GA, Somlo S, Wirth B, Barton N, Harris KL, Frischauf AM, Reeders ST: The gene for autosomal dominant polycystic kidney disease lies in a 750- kb CpG-rich region. Genomics 13: 144–151, 1992[CrossRef][Medline]
Martin P, Heiskari N, Pajari H, Gronhagen-Riska C, Kaariainen H, Koskimies O, Tryggvason K: Spectrum of COL4A5 mutations in Finnish Alport syndrome patients. Hum Mutat 15: 579, 2000[Medline]
Barker DF, Hostikka SL, Zhou J, Chow LT, Oliphant AR, Gerken SC, Gregory MC, Skolnick MH, Atkin CL, Tryggvason K: Identification of mutations in the COL4A5 collagen gene in Alport syndrome. Science 248: 1224–1227, 1990[Abstract/Free Full Text]
Mathis BJ, Kim SH, Calabrese K, Haas M, Seidman JG, Seidman CE, Pollak MR: A locus for inherited focal segmental glomerulosclerosis maps to chromosome 19q13. Kidney Int 53: 282–286, 1998[CrossRef][Medline]
Vats A, Nayak A, Ellis D, Randhawa PS, Finegold DN, Levinson KL, Ferrell RE: Familial nephrotic syndrome: clinical spectrum and linkage to chromosome 19q13. Kidney Int 57: 875–881, 2000[CrossRef][Medline]
Winn MP, Conlon PJ, Lynn KL, Howell DN, Gross DA, Rogala AR, Smith AH, Graham FL, Bembe M, Quarles LD, Pericak-Vance MA, Vance JM: Clinical and genetic heterogeneity in familial focal segmental glomerulosclerosis. International Collaborative Group for the Study of Familial Focal Segmental Glomerulosclerosis. Kidney Int 55: 1241–1246, 1999[CrossRef][Medline]
Fuchshuber A, Jean G, Gribouval O, Gubler MC, Broyer M, Beckmann JS, Niaudet P, Antignac C: Mapping a gene (SRN1) to chromosome 1q25-q31 in idiopathic nephrotic syndrome confirms a distinct entity of autosomal recessive nephrosis. Hum Mol Genet 4: 2155–2158, 1995[Abstract/Free Full Text]
Kaplan JM, Kim SH, North KN, Rennke H, Correia LA, Tong HQ, Mathis BJ, Rodriguez-Perez JC, Allen PG, Beggs AH, Pollak MR: Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet 24: 251–256, 2000[CrossRef][Medline]
Gharavi AG, Yan Y, Scolari F, Schena FP, Frasca GM, Ghiggeri GM, Cooper K, Amoroso A, Viola BF, Battini G, Caridi G, Canova C, Farhi A, Subramanian V, Nelson-Williams C, Woodford S, Julian BA, Wyatt RJ, Lifton RP: IgA nephropathy, the most common cause of glomerulonephritis, is linked to 6q22–23. Nat Genet 26: 354–357, 2000[CrossRef][Medline]
Lander ES, Schork NJ: Genetic dissection of complex traits [published erratum appears in Science 1994 266(5184):353]. Science 265: 2037–2048, 1994[Abstract/Free Full Text]
Elston RC: The genetic dissection of multifactorial traits. Clin Exp Allergy 25 [Suppl 2]: 103–106, 1995
Moczulski DK, Rogus JJ, Antonellis A, Warram JH, Krolewski AS: Major susceptibility locus for nephropathy in type 1 diabetes on chromosome 3q: Results of novel discordant sib-pair analysis. Diabetes 47: 1164–1169, 1998[Abstract]
Imperatore G, Hanson RL, Pettitt DJ, Kobes S, Bennett PH, Knowler WC: Sib-pair linkage analysis for susceptibility genes for microvascular complications among Pima Indians with type 2 diabetes. Pima Diabetes Genes Group. Diabetes 47: 821–830, 1998[Abstract]
Freedman BI, Wilson CH, Spray BJ, Tuttle AB, Olorenshaw IM, Kammer GM: Familial clustering of end-stage renal disease in blacks with lupus nephritis. Am J Kidney Dis 29: 729–732, 1997[Medline]
Yu H, Sale M, Rich SS, Spray BJ, Roh BH, Bowden DW, Freedman BI: Evaluation of markers on human chromosome 10, including the homologue of the rodent Rf-1 gene, for linkage to ESRD in black patients. Am J Kidney Dis 33: 294–300, 1999[Medline]
Kriz W: Podocyte is the major culprit accounting for the progression of chronic renal disease. Microsc Res Tech 57: 189, 195., 2002
Kestila M, Lenkkeri U, Mannikko M, Lamerdin J, McCready P, Putaala H, Ruotsalainen V, Morita T, Nissinen M, Herva R, Kashtan CE, Peltonen L, Holmberg C, Olsen A, Tryggvason K: Positionally cloned gene for a novel glomerular protein–nephrin–is mutated in congenital nephrotic syndrome. Mol Cell 1: 575–582, 1998[CrossRef][Medline]
Boute N, Gribouval O, Roselli S, Benessy F, Lee H, Fuchshuber A, Dahan K, Gubler MC, Niaudet P, Antignac C: NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome [published erratum appears in Nat Genet 25: 125, 2000]. Nat Genet 24: 349–354, 2000[CrossRef][Medline]
Tryggvason K: Unraveling the mechanisms of glomerular ultrafiltration: Nephrin, a key component of the slit diaphragm. J Am Soc Nephrol 10: 2440–2445, 1999[Free Full Text]
Holthofer H, Ahola H, Solin ML, Wang S, Palmen T, Luimula P, Miettinen A, Kerjaschki D: Nephrin localizes at the podocyte filtration slit area and is characteristically spliced in the human kidney. Am J Pathol 155: 1681–1687, 1999[Abstract/Free Full Text]
Holzman LB, St. John PL, Kovari IA, Verma R, Holthofer H, Abrahamson DR: Nephrin localizes to the slit pore of the glomerular epithelial cell. Kidney Int 56: 1481–1491, 1999[CrossRef][Medline]
Kaplan JM, Kim SH, North KN, Rennke H, Correia LA, Tong HQ, Mathis BJ, Rodriguez-Perez JC, Allen PG, Beggs AH, Pollak MR: Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet 24: 251–256, 2000
Shih NY, Li J, Karpitskii V, Nguyen A, Dustin ML, Kanagawa O, Miner JH, Shaw AS: Congenital nephrotic syndrome in mice lacking CD2-associated protein. Science 286: 312–315, 1999[Abstract/Free Full Text]
Rogus JJ, Krolewski AS: Using discordant sib pairs to map loci for qualitative traits with high sibling recurrence risk. Am J Hum Genet 59: 1376–1381, 1996[Medline]
Covic AM, Iyengar SK, Olson JM, Sehgal AR, Constantiner M, Jedrey C, Kara M, Sabbagh E, Sedor JR, Schelling JR: A family-based strategy to identify genes for diabetic nephropathy. Am J Kidney Dis 37: 638–647, 2001[Medline]
Lander E, Kruglyak L: Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat. Genet 11: 241–247, 1995[CrossRef][Medline]
Freedman BI, Rich SS, Yu H, Roh BH, Bowden DW: Linkage heterogeneity of end-stage renal disease on human chromosome 10. Kidney Int 62: 770–774, 2002[CrossRef][Medline]
Hunt SC, Hasstedt SJ, Coon H, Camp NJ, Cawthon RM, Wu LL, Hopkins PN: Linkage of creatinine clearance to chromosome 10 in Utah pedigrees replicates a locus for end-stage renal disease in humans and renal failure in the fawn-hooded rat. Kidney Int 62: 1143–1148, 2002[CrossRef][Medline]
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B. Lopez, R. P. Ryan, C. Moreno, A. Sarkis, J. Lazar, A. P. Provoost, H. J. Jacob, and R. J. Roman Identification of a QTL on chromosome 1 for impaired autoregulation of RBF in fawn-hooded hypertensive rats
Am J Physiol Renal Physiol,
May 1, 2006;
290(5):
F1213 - F1221.
[Abstract][Full Text][PDF]
K. G. Ewens, R. A. George, K. Sharma, F. N. Ziyadeh, and R. S. Spielman Assessment of 115 Candidate Genes for Diabetic Nephropathy by Transmission/Disequilibrium Test
Diabetes,
November 1, 2005;
54(11):
3305 - 3318.
[Abstract][Full Text][PDF]
A. Schulz, D. Standke, L. Kovacevic, M. Mostler, P. Kossmehl, M. Stoll, and R. Kreutz A Major Gene Locus Links Early Onset Albuminuria with Renal Interstitial Fibrosis in the MWF Rat with Polygenetic Albuminuria
J. Am. Soc. Nephrol.,
December 1, 2003;
14(12):
3081 - 3089.
[Abstract][Full Text][PDF]
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Abstract
ESRD: a Common Complex...
500 mg/g in 715 nuclear, Pima Indian families, and rejected models for no major gene effect and no transmission of a major effect (P = 0.00001; P = 0.003). In contrast, they were unable to reject Mendelian transmission models (P = 0.85), although the specific mode of inheritance could not be determined. Fogarty et al. (16) examined segregation of a quantitative trait, urine albumin to creatinine ratio, in 96 large multigenerational pedigrees ascertained for type 2 diabetes and found that a multifactorial mode of inheritance best fit the ratio of albumin to creatinine levels. Together, these segregation analyses support the hypothesis of a major genetic effect on susceptibility to DN. 
-actinin-4, an actin filament cross-linking protein, were identified in three families with an autosomal dominant form of FSGS linked to the 19q13 locus (27), identifying yet another molecular basis for a common histologic phenotype. Gharavi et al. (28) used genome-wide linkage analysis of 30 multiplex IgAN kindreds and identified a locus for IgAN on 6q22–23, with an autosomal dominant model of transmission with incomplete penetrance. The investigators obtained a lod score of 5.6, and observed that 60% of kindreds were linked to markers on chromosome 6. 
