Linkage Analysis of Candidate Loci for End-Stage Renal Disease Due to Diabetic Nephropathy

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Linkage Analysis of Candidate Loci for End-Stage Renal Disease Due to Diabetic Nephropathy J Am Soc Nephrol 14: S195–S201, 2003 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. Abstract. Diabetic nephropathy (DN), a major cause of ESRD, ate in the final linkage analysis. To date, we have collected 212 is undoubtedly multifactorial and is caused by environmental sib pairs from 46 CA and 50 AA families. The average age of and genetic factors. To identify a genetic basis for DN suscep- diabetes onset was 46.8 yr versus 36.2 yr for CA and 39.5 yr tibility, we are collecting multiplex DN families in the Cauca- versus 40.2 yr for AA, in males versus females respectively. sian (CA) and African-American (AA) populations for whole Genotyping data were available for 106 sib pairs (43 CA, 63 genome scanning and candidate gene analysis. A candidate AA) from 27 CA (44% male probands) and 38 AA families gene search of diabetic sibs discordantly affected, concordantly (43% male probands). Average AA and CA sibship size was affected and concordantly unaffected for DN was performed 2.73. Singlepoint and multipoint linkage analyses indicate that with microsatellite markers in genomic regions suspected to marker D10S1654 on chromosome 10p is potentially linked to harbor nephropathy susceptibility loci. Regions examined were DN (CA only multipoint P ϭ 4 ϫ 10Ϫ3). Interestingly, the at human chromosome 10p,10q (orthologous to the rat renal majority of the linkage evidence derives from the CA sib pairs. susceptibility Rf-1 locus), and at NPHS1 (nephrin), CD2AP, We are now adding sib pairs and increasing marker density on Wilms tumor (WT1), and NPHS2 (podocin) loci. Linkage chromosome 10. We have excluded linkage with candidate analyses were conducted using model-free methods (SIBPAL, regions for nephrin, CD2AP, WT1, and podocin in this sample. S.A.G.E.) for AA, CA, and the combined sample. Allele fre- In conjunction with previous reports, our data support evidence quencies and the identity by descent sharing were estimated for a DN susceptibility locus on chromosome 10. separately for AA and CA, and race was included as a covari- ESRD: a Common Complex Disease With a genesis is mediated by genes (11–14). Lastly, environmental Genetic Basis factors alone cannot adequately explain the excessive cluster- ESRD is a multifactorial disease with increasing worldwide ing of ESRD in families. incidence, due in part to the aging population (1). Progression Complex segregation of families in which DN was clustered, of diabetic nephropathy (DN) to ESRD can be effectively performed independently by two groups of investigators, dem- slowed by aggressively treating hyperglycemia and hyperten- onstrated a major genetic effect on susceptibility to DN. Im- sion, using either angiotensin converting enzyme inhibitors or peratore et al. (15) defined nephropathy as a urine protein to angiotensin receptor blockers. Although modifiable risk factors creatinine ratio Ն500 mg/g in 715 nuclear, Pima Indian fam- have been identified, epidemiologic data, primarily from Cau- ilies, and rejected models for no major gene effect and no casian and Pima Indian populations, indicate that DN is genet- transmission of a major effect (P ϭ 0.00001; P ϭ 0.003). In ically determined, with multiple genes regulating the pheno- contrast, they were unable to reject Mendelian transmission type (reviewed in reference 2–5). Several lines of evidence models (P ϭ 0.85), although the specific mode of inheritance suggest that ESRD pathogenesis is mediated by genes. First, could not be determined. Fogarty et al. (16) examined segre- there is significant evidence of familial aggregation for ESRD gation of a quantitative trait, urine albumin to creatinine ratio, (6–10). Second, animal models also suggest that ESRD patho- 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 Correspondence to Dr. Sudha Iyengar, Department of Epidemiology and segregation analyses support the hypothesis of a major genetic Biostatistics, Case Western Reserve University, R215 Rammelkamp Center for Research, 2500 MetroHealth Drive, Cleveland, OH 44109-4945. Phone: 216- effect on susceptibility to DN. 778-8484; Fax: 216-778-3280; E-mail: [email protected] Strategies that have identified the genes responsible for 1046-6673/1407-0195 monogenic renal diseases such as polycystic kidney disease Journal of the American Society of Nephrology (17–20) and Alport’s syndrome (21,22) are being applied to Copyright © 2003 by the American Society of Nephrology more common causes of progressive renal disease, such as DN, DOI: 10.1097/01.ASN.0000070078.66465.55 hypertensive nephrosclerosis (HN), and glomerulonephritis S196 Journal of the American Society of Nephrology J Am Soc Nephrol 14: S195–S201, 2003 (GN). Classical linkage analysis of extended families has met bility to progressive renal failure is independent of the etiology with moderate success in mapping genes for familial forms of of ESRD (8,33), suggesting that genes or loci linked to non- focal segmental glomerulosclerosis (FSGS) and IgA nephrop- diabetic causes of kidney disease should be assessed as candi- athy (IgAN). Familial FSGS has been linked to markers on date pathogenesis genes for DN. Whole genome linkage anal- chromosome 19q13 (23,24), 11q21–q22 (25), and 1q25–31 ysis in the fawn-hooded rat, a model of hypertension and (26). Mutations in the gene encoding ␣-actinin-4, an actin nephrosclerosis, identified two renal failure susceptibility filament cross-linking protein, were identified in three families genes, Rf-1 and Rf-2 (11). The region of human homology for with an autosomal dominant form of FSGS linked to the 19q13 Rf-1 was identified as the distal portion of chromosome 10q. locus (27), identifying yet another molecular basis for a com- Yu et al. (34) investigated if markers on human chromosome mon histologic phenotype. Gharavi et al. (28) used genome- 10 were linked with chronic renal failure in 129 African- wide linkage analysis of 30 multiplex IgAN kindreds and American nondiabetic sibling pairs concordant for ESRD. The identified a locus for IgAN on 6q22–23, with an autosomal investigators observed weak evidence for linkage with markers dominant model of transmission with incomplete penetrance. on 10p, but not in the Rf-1 region. The investigators obtained a lod score of 5.6, and observed that In vitro, animal and human data suggest that podocyte 60% of kindreds were linked to markers on chromosome 6. dysregulation can initiate and/or perpetuate progressive glo- Collection of extended family data are problematic for the merular scarring (35). Both transgenic animal models and most common causes of nephropathy, such as DN and HN, familial glomerulosclerosis have been linked to mutations in because the age of disease in probands is later in life and two novel and two previously known genes, which encode relatives are often deceased or unavailable for collection. Fur- podocyte proteins that comprise components of the slit dia- thermore, basic assumptions of traditional linkage analysis for phragm. Although mesangial expansion is the classic lesion of Mendelian traits often cannot be applied to multifactorial dis- DN, recent work suggests that podocyte injury occurs early in eases. The nature of complex diseases precludes the use of the course of DN and filtration barrier dysfunction is a hall- specific genetic models in the linkage analysis, because the mark of the disease. NPHS1 (nephrin) and NPHS2 (podocin) mode of inheritance is often unknown. Locus heterogeneity, as were identified by positional cloning in families with congen- observed for FSGS above, as well as allelic (mutation) heter- ital nephrotic syndrome of the Finnish type (36), and families ogeneity, further constrains the usefulness of traditional link- with steroid-resistant nephrotic syndrome (37), respectively. age methods. New linkage methods have been developed that Nephrin, an Ig superfamily member, is thought to be a major use nuclear family structures, such as affected and discordant transmembrane component of the slit diaphragm (38–40). sibling pairs, which make no assumptions about the mode of Podocin, which is similar to stomatin family scaffold mole- inheritance of the disease (for reviews see references 29 and cules, has a single hairpin-like structure with both the N- 30). These novel, model-free methods have formed the basis of terminal and C-terminal domains in the cytosol (37). ACTN4, genetic investigations in common forms of nephropathy. In which encodes the actin cross-linking protein ␣-actinin-4 (41), aggregate, these data suggest that genes mediating ESRD was identified as a candidate gene on the 19q13 locus mapped pathogenesis are complex in etiology. from three families with FSGS. CD2 associated protein (CD2AP) was originally identified as an adapter protein that Candidate Loci for Diabetic Nephropathy interacts with the cytoplasmic domain of CD2, a T cell adhe- In an effort to reduce genetic heterogeneity, our group has sion protein but subsequently was found to cause progressive limited recruitment to families with DN. Association analyses glomerulosclerosis in mice lacking CD2AP (42). of candidate DN pathogenesis genes using case-control designs are common, but results often cannot be replicated. Only two Materials and Methods linkage analyses of families in which DN is clustered have Sib Pair Study Design been reported. Moczulski et al. (31) performed a linkage study In our ongoing project we are collecting sibling pairs who are using 66 type 1 diabetic Caucasian sib pairs who were discor- concordant for diabetes and renal disease (affected sib pairs, ASP), dant for DN.
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