CJASN ePress. Published on October 17, 2007 as doi: 10.2215/CJN.02560607
In-Depth Review

Genetic Factors in Diabetic Neph...
Clin J Am Soc Nephrol 2: 1306 –1316, 2007                                                      Diabetic Nephropathy Geneti...
1308       Clinical Journal of the American Society of Nephrology                            Clin J Am Soc Nephrol 2: 1306...
Table 1. Summary of results from genome-wide linkage scans for diabetic nephropathya

Table 2. Candidate genes for DN
         Gene Class                             Gene                   Location   ...
Clin J Am Soc Nephrol 2: 1306 –1316, 2007                                                    Diabetic Nephropathy Genetics...
1312       Clinical Journal of the American Society of Nephrology                               Clin J Am Soc Nephrol 2: 1...
Clin J Am Soc Nephrol 2: 1306 –1316, 2007                                                       Diabetic Nephropathy Genet...
1314          Clinical Journal of the American Society of Nephrology                           Clin J Am Soc Nephrol 2: 13...
Clin J Am Soc Nephrol 2: 1306 –1316, 2007                                                     Diabetic Nephropathy Genetic...
1316          Clinical Journal of the American Society of Nephrology                             Clin J Am Soc Nephrol 2: ...
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Genetic Factors in Diabetic Nephropathy

  1. 1. CJASN ePress. Published on October 17, 2007 as doi: 10.2215/CJN.02560607 In-Depth Review Genetic Factors in Diabetic Nephropathy Barry I. Freedman,* Meredith Bostrom,† Pirouz Daeihagh,* and Donald W. Bowden*†‡ Departments of *Internal Medicine and †Biochemistry, ‡Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina Several genes that predispose to type 2 diabetes have recently been identified. In addition to the recognized and powerful effects of environmental factors, there is abundant evidence in support of genetic susceptibility to the microvascular complication of nephropathy in individuals with both type 1 and type 2 diabetes. Familial aggregation of phenotypes such as end-stage renal disease, albuminuria, and chronic kidney disease have routinely been reported in populations throughout the world, and heritability estimates for albuminuria and glomerular filtration rate demonstrate strong contributions of inherited factors. Recent genome-wide linkage scans have identified several chromosomal regions that likely contain diabetic nephrop- athy susceptibility genes, and association analyses have evaluated positional candidate genes under these linkage peaks. These complimentary approaches have demonstrated that polymorphisms in the carnosinase 1 gene on chromosome 18q, the adiponectin gene on 3q, and the engulfment and cell motility gene on 7p are likely associated with susceptibility to diabetic nephropathy. Additional genes that seem to be of importance in renal phenotypes include manganese superoxide dismutase and angiotensin 1-converting enzyme, with nitric oxide synthase implicated in albuminuria. This article reviews the inherited aspects of diabetic kidney disease with particular emphasis on recently implicated genes and pathways. It seems likely that the risk for diabetes-associated kidney disease is magnified by inheriting risk alleles at several susceptibility loci, in the presence of hyperglycemia. Clin J Am Soc Nephrol 2: 1306 –1316, 2007. doi: 10.2215/CJN.02560607 I t was previously thought that individuals who had diabe- ial clustering of nephropathy could result from shared genes, tes and developed progressive diabetic nephropathy (DN) environmental exposures, or their combination. and/or ESRD were simply exposed to long durations of After repeated demonstrations that DN and diabetic ESRD diabetes with relatively poor glycemic control. In other words, aggregated in families (4) and that this observation was consis- all individuals with diabetes were assumed to be at essentially tent in all ethnic groups evaluated and was to a large extent equivalent risk for developing nephropathy, allowing for dif- independent of blood glucose concentration, the issue of coin- ferences in their ambient serum glucose concentration. In sup- cident familial clustering of an unrecognized environmental port of the concept that exposure to a hyperglycemic environ- risk factor or a lack of access to adequate health care arose. ment led to DN (often with coexisting obesity, metabolic Despite multiple confirmations of familial aggregation of DN syndrome, hypertension, and hyperlipidemia), clinical trials and diabetic ESRD, there was concern that recruitment of bi- have conclusively demonstrated that improving glycemic con- ased samples could have occurred in the predominantly single- trol delays and, in some cases, may prevent the subsequent center reports. Familial aggregation of DN has since been dem- development of albuminuria, DN, and macrovascular compli- onstrated to be independent from family size, the number of cations such as coronary artery disease (1,2). The concept that relatives affected with diabetes and hypertension, socioeco- select individuals with diabetes were at differential risk for nomic status, and inadequate access to health care (5), strongly developing nephropathy on the basis of familial aggregation of suggesting the existence of DN-susceptibility genes. kidney disease was initially reported in 1989 but has only In the largest analysis to date, nearly 26,000 incident US recently gained broad acceptance among nephrologists and dialysis patients from more than 450 dialysis clinics were diabetologists (3). screened for family history of ESRD (6). Individuals with known genetic disorders (e.g., autosomal dominant polycystic Familial Aggregation of DN kidney disease, hereditary nephritis) and urologic disorders The notion that genetic factors contribute to any complex dis- (surgical nephrectomy) were excluded. Independent risk fac- ease rests on the demonstration of familial aggregation. Famil- tors for a family history of ESRD in first- or second-degree relatives included earlier age at ESRD onset, female gender, black ethnicity, and diabetes-associated nephropathy. Nearly 32% of black women and 27% of black men reported having Published online ahead of print. Publication date available at www.cjasn.org. close relatives with ESRD, compared with 15 and 12% of Eu- Correspondence: Dr. Barry I. Freedman, Section on Nephrology, Wake Forest ropean Americans, respectively. These data were collected University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1053. Phone: 336-716-6192; Fax: 336-716-4318; E-mail: bfreedma@ from a wide geographic area that contained a range of dialysis wfubmc.edu facility types (academic, large chain, independent, for profit, Copyright © 2007 by the American Society of Nephrology ISSN: 1555-9041/206 –1306
  2. 2. Clin J Am Soc Nephrol 2: 1306 –1316, 2007 Diabetic Nephropathy Genetics 1307 and nonprofit), and questionnaires were completed by the local ture disequilibrium (MALD) (21) and whole-genome associa- nursing and social worker staffs. This large study confirmed the tion (WGA) studies (22). results of the single-center reports. An even larger percentage Linkage studies are family based and evaluate coincident of individuals with ESRD likely have relatives who either have inheritance of polymorphic genetic markers that are relatively clinically silent nephropathy that has not yet progressed to uniformly distributed throughout the genome with the pres- need for dialysis or died from cardiovascular causes related to ence or absence of disease among relatives. In DN, families chronic kidney disease before starting dialysis (7). A recent US have often been limited to sibling pairs or two-generation fam- population-based sample (8) detected association between se- ilies because of the late age at onset of DN. Initial linkage rum levels of C-reactive protein and family history of ESRD studies were performed using microsatellite repeat genetic while confirming the effects of ethnicity, gender, and cause of markers; however, single-nucleotide polymorphisms (SNP) are renal disease. now commonly used with equal or better information content Urinary albumin excretion is a hallmark of DN; however, at lower cost. Because we receive one copy or allele of a given albuminuria can fluctuate widely, even fully resolve, and is a gene (or a given polymorphic genetic marker) from each par- stronger predictor of cardiovascular disease (CVD) events than ent, among full siblings, 50% are expected to share one (of two) progressive nephropathy. Heritability estimates for albumin- alleles at a given locus, 25% share both alleles, and 25% share uria (urine albumin:creatinine ratio) and kidney function (GFR) neither allele; overall allele sharing is at 50%. In siblings who allow for the estimation of genetic and environmental contri- are concordant for DN (affected sibling pairs) and are tested for butions to DN. A heritability (h2) 1 suggests the presence of sharing of a polymorphic marker that is in linkage disequilib- a Mendelian disorder (e.g., autosomal dominant polycystic kid- rium with a nearby DN locus, analysis of large numbers of ney disease), whereas h2 0 reveals the contribution of envi- sibling pairs would demonstrate that significantly more than ronmental factors. Heritability estimates for albuminuria were 50% of affected sibling pairs share the linked genetic marker. In significant, ranging from 0.3 to 0.44 in Finnish (9), New En- contrast, siblings who are discordant for DN (discordant sibling gland (10), and southeastern US (11) families enriched for mem- pairs) are expected to demonstrate significantly less than 50% bers with type 2 diabetes, and the estimate was higher (h2 sharing of the polymorphic marker that is linked to the nearby 0.49) in Hypertension Genetic Epidemiology Network (Hyper- DN disease locus. Chromosomal regions linked with DN in GEN) families enriched for multiple siblings with hypertension families (e.g., linkage peaks) presumably contain DN susceptibility (12). Similarly, GFR was significantly heritable in families with gene(s) or are false-positive results. Genome-wide linkage analy- diabetes and hypertension, ranging from 0.36 to 0.75 (11,13,14). ses provide a model-free screen of the entire genome; however, These results are impressive, considering that albuminuria and linkage is generally regarded as less sensitive compared with GFR change during the course of DN. Thus, familial aggrega- association analyses (see below, Table 2) but does have the capa- tion of these intermediate phenotypes solidifies the concept bility of identifying genomic regions that harbor multiple genes or that DN susceptibility genes exist. Environmental factors multiple variants with small effect sizes, in addition to the simpler seemed to be minor contributors to these relatively high h2 scenario of a single strong contributor to risk. estimates. Two segregation analyses in multiplex families with Because of the need to recruit large numbers of informative members who had type 2 diabetes suggested that major gene families, linkage studies are difficult, expensive, and time-con- effects likely contribute to the development of DN (15,16). suming. Association analyses using unrelated case patients and Quinn et al. (17) reported that an autosomal dominant major control subjects are simpler and often far less expensive. Asso- gene with a common disease allele was likely present. ciation analysis approaches are used for detecting disease genes In addition, familial aggregation of renal histology is ob- (or markers that are in linkage disequilibrium with causative served in siblings with diabetes, independent of diabetes dura- genes) but may be subject to false-positive results because of tion and disease control (18); a greater prevalence of hyperten- population stratification. The important capability of associa- sive parents among children with diabetes and nephropathy tion analyses is the ability to detect relatively modest effect are seen (19); and ethnic differences in susceptibility to DN exist sizes (e.g., good power to detect odds ratios (OR) of 1.3 to 1.5 or (20). Together, these observations support genetic contributions less in 500 case patients and 500 control subjects). It should be to DN. These epidemiologic studies set the stage for genome- noted that even with this approach, success depends on the wide searches to detect chromosomal regions that harbor DN- existence of a relatively common risk allele. Family-based as- susceptibility genes. sociation studies, also called family-based transmission dis- equilibrium testing (TDT), tend to reduce the potential bias of Genetic Approaches to Identifying DN population stratification. Recently, it has become possible to Genes perform association analyses in large numbers of case patients In tandem with advances in the epidemiology of DN, options with DN and control subjects with diabetes and without ne- for gene identification in common complex diseases have rap- phropathy using 500,000 (or more) SNP markers spaced across idly evolved with completion of the Human Genome Project all chromosomes, a WGA analysis. This approach will become and an improved understanding of the haplotype block struc- even more powerful in the near future with technologies using ture of our genome. Broad categories of molecular genetic upward of 1 million SNP markers for association analysis. approaches include linkage and association studies, with recent WGA remains an expensive undertaking, but several groups advances in association analysis including mapping by admix- have DN studies planned or under way.
  3. 3. 1308 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 2: 1306 –1316, 2007 Ethnic differences in disease course, such as occur in DN, can (34). Circulating levels of adiponectin are reduced in individu- suggest the presence of causative genetic factors. Genetic ad- als who are obese and have diabetes, and levels rise after mixture between two populations results from the sharing of weight loss. Positive correlations have been reported between alleles that were initially far more common in one ethnic group. circulating high molecular weight adiponectin level and HDL For example, black and European American admixture has cholesterol, with negative correlations among circulating in- resulted in approximately 20% admixture of “European alleles” flammatory markers, triglycerides, and homeostasis model as- in the black population. A novel technique to detect association, sessment of insulin resistance. Adiponectin gene polymor- MALD, tests for association of ethnic-specific genetic markers phisms reportedly play a protective role in susceptibility to that were more common in one ethnic group (either the one coronary heart disease (35). It is thought to have antiathero- with the higher or the lower disease prevalence) and are then genic properties via downregulation of expression of adhesion disproportionately transmitted into affected members in the molecules on endothelial cells through inhibition of NF- B other ethnic group (21). MALD is potentially useful in situa- activation, reduction of endothelial oxidative stress and prolif- tions in which ethnic differences in disease incidence exist eration while stimulating nitric oxide synthase activity, and between recently admixed populations. Examples of each of reduction of vascular smooth muscle cell proliferation by in- these techniques as applied to DN are described next. hibiting the effects of a number of growth factors (34). With clear relationships between atherosclerosis and DN, adiponec- Genome-Wide Linkage Scans for DN tin is likely a gene that may play a role in both vascular Six complete genome-wide linkage scans have been published processes. in type 2 DN, with one in type 1 DN (and another partial genome scan in type 1 DN) (14,23–29). Although most of these TDT and Microsatellite Association Analysis analyses evaluated small numbers of families from different in Type 1 DN ethnic groups, several consistent regions of linkage have been Ewens et al. (30) tested 115 candidate genes for association with detected (Table 1). In type 1 DN, two reports identified linkage type 1 DN using TDT. This was a comprehensive analysis of a to markers on chromosome 3q in white families (27,28), and this large number of potential candidate genes that previously were location was subsequently replicated in a family-based TDT implicated in the pathogenesis of DN. The power of this study analysis (30). A 3q peak was also observed in a type 2 DN was limited by the inclusion of only 72 trio families. Several genome scan in black families (23), in the same region but distal genes were nominally associated with type 1 DN, including to the white peak. Several regions of linkage have been repli- genes in the broad categories of extracellular matrix material cated among the various groups with type 2 DN, as well. The (COL4A1, LAMA4, and LAMC1), matrix metabolism (TIMP3 18q22–23 linkage region was replicated in four populations and MMP9), transcription factors/signaling molecules (23,26,29), the 7q35–36 peak in three reports (25,26,31), and the (HNF1B1/TCF2, NRP1, PRKCB1, SMAD3, and USF1), growth 7p15 and 10q26 peaks in two each (14,23,32). Positional candi- factors/growth factor receptors (IGF1, TGFBR2, and TGFBR3), date genes for DN in these regions are now being sought and and those that are believed to be important in the regulation of identified (Table 2). kidney function (AGTR1, AQP1, BCL2, CAT, GPX1, LPL, and p22phox). Chromosome 3q Linkage Peak in Type 1 DN McKnight et al. (36) performed a novel genome-wide fluores- Intensive efforts have been undertaken to identify the causative cence-based DNA microsatellite association screen in 400 Irish gene under the 3q linkage peak in type 1 DN. The nearby individuals with diabetes (200 case patients with type 1 DN and angiotensin II type 1 receptor gene was quickly excluded from 200 control subjects without nephropathy). This “low-resolu- involvement (27). Vionnet et al. (33) subsequently evaluated 14 tion” WGA study used 6000 microsatellite markers and pooled candidate genes for type 1 DN on chromosome 3q in an asso- DNA samples from case patients and control subjects. The top ciation analysis using a combined population of 1057 unrelated 50 most consistently associated marker pools were identified, Danish, Finnish, and French case patients with type 1 DN, 1127 and the samples that composed the pools were individually control subjects with diabetes and without nephropathy, and genotyped. Two markers on chromosome 10q (D10S558 and 532 trio families. In an initial association analysis, polymor- D10S1435) were significantly associated with type 1 DN, and phisms in three genes— glucose transporter 2, kininogen, and four additional markers demonstrated trends toward associa- adiponectin—were nominally associated with DN. Attempts at tion (D6S281, D4S293, D2S291, and D17S515). Of note, the 10q replication using TDT testing in trios confirmed significant association with D10S1435 was previously observed in nondi- association in the adiponectin gene (ADIPOQ) with excess abetic ESRD in black individuals (37). transmission of the A allele in the promoter to individuals with DN and of the G allele to those without DN (P 0.011). This Type 2 DN suggests that polymorphisms in ADIPOQ may be involved in To date, six complete genome-wide scans (GWS) have been DN susceptibility. The pooled odd ratio for the ADIPOQ_Prom published in type 2 DN. The largest are the interim and final 2GA allele was 1.46 (95% confidence interval 1.11 to 1.93; P reports from the National Institute of Diabetes and Digestive 0.006), with results driven predominantly from the Danish (P and Kidney Diseases–sponsored Family Investigation of Ne- 0.011) and French (P 0.071) cohorts. phropathy and Diabetes (FIND) (26,38,39). Although these Adiponectin is an adipocytokine that is produced by fat cells GWS were performed in different ethnic groups, most con-
  4. 4. Table 1. Summary of results from genome-wide linkage scans for diabetic nephropathya Maximum Chromosome Regionb Population Study Phenotype Characteristics Reference LOD 3q 13 4.55 Black Sibling pairs Type 2 DN Age at ESRD onset (23) 21.3 2.67 Finnish Discordant sibling Type 1 DN (28) pairs 25.1 3.1 White Discordant sibling Type 1 DN (27) Clin J Am Soc Nephrol 2: 1306 –1316, 2007 pairs 7q 12.3 1.84 West African Sibling pairs Type 2 DN CC (24) 21.1 (6.0 10 4) White 90% sibling pairs Predominantly type ACR (26) 2 DN 21.3 (6.0 10 5) Black 90% sibling pairs Predominantly type Nephropathy (26) 2 DN 33 2.04 to 2.73 Pima Indian Sibling pairs Type 2 DN Nephropathy and (25) retinopathy 36.2 3.1 94% white Families Type 2 DN ACR (31) (99 cM) (1.1 10 4) White 90% sibling pairs Predominantly type Nephropathy (38) 2 DN 7p 21.3 4 94% white Sibling pairs Type 2 DN CC-GFR (14) 32.1 3.59 Black Sibling pairs Type 2 DN Age at diabetes onset (23) (12 cM) (1.6 10 4) American Indian 90% sibling pairs Predominantly type ACR (38) 2 DN (78 cM) (1.0 10 3) Mexican American 90% sibling pairs Predominantly type GFR (39) 2 DN 10q 23.31 3.1 94% white Sibling pairs Type 2 DN Diabetic/nondiabetic; (14) CC-GFR 26 2.47 Black Sibling pairs Type 2 DN Age at ESRD onset (32) 18q 22.1 3.72 Black Sibling pairs Type 2 DN Age at diabetes onset (23) 22.1 (3.15 10 2) White Discordant sibling Predominantly type Nephropathy (26) pairs 2 DN 22.3–23 6.1 Turkish Families Type 2 DN Nephropathy (29) a P values are used where logarithm of odds (LOD) scores were not reported. ACR, albumin-to-creatinine ratio; CC, creatinine clearance; DN, diabetic nephropathy; eGFR, estimated GFR. b Chromosome band (map location). Diabetic Nephropathy Genetics 1309
  5. 5. 1310 Table 2. Candidate genes for DN Gene Class Gene Location Loci Population Phenotype Reference Cytokines and growth Adiponectin 3q ADIPOQ Danish, Finnish, Type 1 DN (33) factors French IGF-1 12q23.2 IGF1 White Type 1 DN (30) IGF-binding protein 1 7p14 IGFBP1 White Type 2 DN (51) TGF- receptor II 3p24.1 TGF R2 White Type 1 DN (30) TGF- receptor III 1p22.1 TGF R3 White Type 1 DN (30) Extracellular matrix Collagen type IV, I 7q32.1 COL4AI White Type 1 DN (30) components Laminin, 4 6q21 LAMA4 White Type 1 DN (30) Laminin, 1 1q25.3 LAMCI White Type 1 DN (30) Matrix metalloproteinases Tissue inhibitor of metalloproteinase 3 22q12.3 TIMP3 White Type 1 DN (30) and dipeptidases Matrix metalloproteinase 9 20q13.12 MMP9 White Type 1 DN (30) Carnosinase 18q22.3 CNDP1 White Type 2 DN (41,42) Transcription factors HNF1B1/transcription factor 2, hepatic 17q12 HNF1B1/TCF2 White Type 1 DN (30) (MODY5) Neuropilin 1 10p11.22 NRPI White Type 1 DN (30) Clinical Journal of the American Society of Nephrology Protein kinase C 1 16p12.1 PRKCBI White Type 1 DN (30) SMAD, mothers against DPP homolog 3 15q22.33 SMAD3 White Type 1 DN (30) Upstream transcription factor 1 1q23.3 USFI White Type 1 DN (30) Renal function and renin Angiotensin II receptor, type 1 3q24 AGTR1 White Type 1 DN (30) angiotensin system Aquaporin 1 7p14.3 AQP1 White Type 1 DN (30) components B-cell leukemia/lymphoma 2 (bcl-2) 18q21.33 BCL2 White Type 1 DN (30) proto-oncogene Catalase 11p13 CAT White Type 1 DN (30) Glutathione peroxidase 1 3p21.3 GPXI White Type 1 DN (30) Lipoprotein lipase 8p21.3 LPL White Type 1 DN (30) Cytochrome b, polypeptide 16q24.3 p22phox White Type 1 DN (30) Angiotensin-converting enzyme 17q23 ACE White Type 1 DN, (60,61,64,65) Type 2 DN Inflammatory factors Engulfment and cell motility factor 7p14 ELMO1 Japanese, Black Type 2 DN (23,46–48) Endothelial function and Nitric oxide synthase 3 7q36.1 NOS3 Japanese, White DN, Type 1 (54–58) oxidative stress DN Superoxide dismutase 2 6q25 SOD2 Caucasian, Korean, Type 1 DN, (66–68) Japanese Type 2 DN Lipid metabolism Apolipoprotein E 19q ApoE White Type 1 DN, (69,70) Type 2 DN Clin J Am Soc Nephrol 2: 1306 –1316, 2007
  6. 6. Clin J Am Soc Nephrol 2: 1306 –1316, 2007 Diabetic Nephropathy Genetics 1311 tained small numbers of families, and each used variable def- patients with definite DN were 5L-5L homozygotes (OR for initions for DN; common linkage peaks on 18q22–23, 7q35–36, definite DN versus type 2 diabetes without nephropathy 1.65; 7p15, and 10q26 were detected across reports. This replication P 0.02). Yard (43) developed reporter assays for the five, six, strongly suggests that causative type 2 DN genes underlie each and seven leucine CNDP1 variants that were expressed in Cos-7 peak and reduces the likelihood that they are false-positive cells and determined the amount of secreted protein. The five results. We describe the linkage reports next, followed by as- leucine-expressing Cos-7 cells secreted significantly less car- sociation analyses that evaluated potentially causative candi- nosinase than the others, demonstrating that the hydrophobic date genes underlying linkage peaks. leucine stretch is of critical importance for targeting this protein into the secretory pathway. Taken together, these studies Chromosome 18q.22–23: The Carnosinase 1 Gene strongly support a role for the carnosinase gene CNDP1 in The chromosome 18q22–23 linkage peak in type 2 DN demon- susceptibility to type 2 DN. Carnosine is a scavenger of oxygen strated a logarithm of odds score 6 (roughly corresponding to free radicals, inhibits formation of advanced glycosylation end P 10 6) in 18 large Turkish families who lived in Germany products, and inhibits TGF- production (44). Individuals who (29). Although not identified in an initial GWS in Pima Indians, are CNDP1 5L-5L homozygotes secrete less carnosinase and are markers in the 18q region were found to be linked in this therefore expected to have higher carnosine levels with protec- population as well. Subsequently, the 18q linkage was con- tion from DN. The role of CNDP1 in DN among black individ- firmed in black sibling pairs with diabetic ESRD and in mem- uals is less clear: There is no evidence of 5L protection; how- bers of the National Institute of Diabetes and Digestive and ever, other CNDP1 alleles may influence risk (45). Kidney Diseases–supported FIND in the first-phase GWS, which contained 1227 individuals in 378 families (linkage in the Chromosome 7p14: The Engulfment and Cell Motility 1 and FIND was predominantly driven by the European American IGF-Binding Protein 1 Genes and American Indian families). This consistent evidence for Shimazaki et al. (46) performed a gene-centric WGA in unre- linkage strongly supported the existence of a type 2 DN gene(s) lated Japanese individuals who had type 2 DN and diabetes in this region (23,26). without nephropathy. A SNP in the 18th intron of engulfment Using association analysis to follow up the linkage peak, and cell motility 1 (ELMO1) on chromosome 7p14 was strongly ZNF236, a glucose-regulated Kruppel-like zinc finger gene on associated with DN, and the region of association extended 100 18q22-q23, was rapidly excluded from involvement (40). Jans- kb upstream and downstream from this SNP. The 7p region sen et al. (41) next reported that the carnosinase 1 gene (CNDP1) was also linked with susceptibility to type 2 diabetes in 638 was associated with type 2 DN in an analysis of 135 case black affected sibling pairs from 247 multiplex families who patients with DN and 107 control subjects with diabetes and had type 2 diabetes and each had a proband with advanced DN without nephropathy from 5000 screened medical charts. Par- (47), in a subset of 266 affected sibling pairs who were concor- ticipants were unrelated white individuals who lived in the dant for diabetic ESRD from 166 of these families (23) and in Czech Republic, Netherlands, Germany, and Qatar. Of 18 vari- FIND families (26). ants tested in CNDP1, the D18S880 polymorphism was associ- Because ELMO1 is a large gene, Shimazaki et al. (46) geno- ated with type 2 DN in a subset of these individuals. The typed an additional 516 polymorphisms in 640 Japanese DN number of leucine residues coded for by numbers of CTG case patients and 426 control subjects. Several of these addi- repeats was the associated variant, with individuals homozy- tional markers were also associated, the strongest being the gous for the 5 leucine–5 leucine (5L-5L) variant protected from 9170 A/G SNP (GG versus AG AA; OR 2.67; P 0.000008). In the development of DN in an autosomal recessive manner. situ hybridization revealed increased gene expression of Overall, 43% (46 of 107) of control subjects were 5L-5L homozy- ELMO1 in diabetic mouse kidney tissue; increased expression gotes, compared with 27% (37 of 135) of case patients (OR 2.56; of ELMO1 was seen in COS cell lines that were exposed to a P 0.0028); some of these participants had type 1 DN. In hyperglycemic environment, and these cells overexpressed ex- associated studies, serum carnosinase concentrations were low- tracellular matrix protein genes (collagen type 1 and fibronec- est among 5L-5L homozygotes; the addition of carnosine to tin) and underexpressed matrix metalloproteinase genes. Our podocyte cell lines that were exposed to high concentrations of analyses confirm a role for this gene in susceptibility to both glucose reduced production of fibronectin and type VI colla- diabetes and ESRD in black individuals (48), although a single gen; exposing mesangial cell lines to a hyperglycemic milieu report in white individuals failed to replicate this association and 20 mmol/L l-carnosine reduced TGF- production; and (49). the kidneys of humans with DN revealed enhanced staining for Previously, ELMO1 was known to play a role in phagocytosis CNDP1. Although this small study replicated results in three of dying cells and is required for cell migration and changes in individual sets of case patients and control subjects, further cell shape. Maeda’s group (50) in Japan subsequently demon- replication was provided in a larger and less selective analysis strated that ELMO1 expression was increased in an animal of 294 European Americans with type 2 DN–associated ESRD, model of chronic glomerulonephritis, resulting in overexpres- 258 patients with type 2 diabetes and without nephropathy, sion of extracellular matrix proteins and loss of cell adhesive and 306 healthy control subjects (42). Similar to the report by properties; hence, ELMO1 could plausibly play a role in the Janssen et al. (41), 38.6% of healthy subjects, 36.8% of patients development of several glomerular disorders, including DN. with type 2 diabetes and without nephropathy, and 26.1% of Another positional candidate gene on 7p14 that has been
  7. 7. 1312 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 2: 1306 –1316, 2007 implicated in susceptibility to type 2 DN is IGF-binding protein markers (A-5466C, T-3892C, and Ins/Del) at the ACE locus for 1 (IGFBP1). Stephens et al. (51) evaluated 732 patients with type disease association with type 2 DN. Although none of these mark- 2 diabetes in the Salford Diabetes Register. Nearly 25% of the ers was associated with DN in isolation, haplotype analysis re- male and 12% of the female participants had DN. Several vealed that nearly twice as many of the DN cases (13.6%) inherited polymorphic SNP were associated with a reduced prevalence the A-5466C, T-3892C, Deletion (ATD) “risk” haplotype, com- of nephropathy, and haplotype analysis revealed that 97% of pared with diabetes non-nephropathy controls (7.5%; P 0.009). the genetic variation for IGFBP1 in the population sample could This report further suggested that haplotypes at the ACE locus be accounted for using two “renoprotective” SNP. One of these may be associated with DN. SNP may affect the tissue delivery of IGF-1 by IGFBP1, because Manganese superoxide dismutase (MnSOD or SOD2) on this SNP is in exon 4 near the integrin-binding RGD motif. The 6q25 has been implicated in risk for type 2 DN on the basis of RGD motif is believed to be important in extracellular matrix the role of oxidative stress on renal cell injury. A valine/alanine interactions mediated by the binding of integrin- 5 1. It is polymorphism in the targeting sequence of the SOD2 gene possible that both of these genes on 7p are involved in suscep- (rs4880) seems to affect the efficiency with which MnSOD is tibility to type 2 DN. transported across the mitochondrial matrix. Association of the Val/Val genotype of SOD2 with type 2 DN was initially re- Chromosome 7q35: Endothelial Nitric Oxide Synthase ported in Korean (66) and Japanese (67) cohorts. This genotype Endothelial nitric oxide synthase (NOS3) is a positional and was then associated with type 1 DN in European cigarette functional candidate gene for DN that is located on chromo- smokers, in whom inheritance of the Val/Val genotype was some 7q. NOS3 regulates systemic endothelial function by associated with a significant 32% increase in overall risk for DN maintaining endothelial-dependent vasodilation, including in (68). In the highest risk group of smokers who inherited the the renal microcirculation. NO is synthesized from l-arginine Val/Val genotype, the risk for DN was 2.5 times greater than by NOS. In rodent models, long-term NO blockade leads to in the low-risk group. In vitro studies demonstrate that the elevated glomerular capillary pressure with proteinuria and valine polymorphism (relative to alanine) results in less effi- glomerulosclerosis (52). The T-786C polymorphism is known to cient transport of SOD, potentially compromising the ability of reduce NOS3 gene promoter activity and has been associated the cell to neutralize superoxide radicals and placing suscepti- with coronary artery disease and DN (53). It is possible that the ble individuals at risk for oxidative stress, albuminuria, and NOS3 association is with albuminuria, in and of itself a potent resulting mesangial expansion and glomerulosclerosis. CVD risk factor, relative to risk for development of progressive The apolipoprotein E gene (APOE) on chromosome 19q has DN (54 –58). also been associated with susceptibility to type 1 DN (69) and type 2 DN (70). ApoE is a polymorphic protein that consists of Additional Candidate Genes of Interest three isoforms, E2, E3, and E4, encoded by the alleles 2, 3, and In addition to the genes described in the previous sections, a 4, which are defined by a single amino acid substitution at two wide range of biologically relevant genes have been assessed sites (reviewed by Mahley and Rall [71]). These substitutions for association with DN. A summary of salient observations is have been shown to alter the affinity of ApoE for its receptors, provided in Table 2. For obvious reasons, there has been long- thereby influencing lipid metabolism. The 4 allele has previ- standing interest in whether genes in the renin-aldosterone- ously been associated with increased risk for both Alzheimer’s angiotensin axis were involved in propensity toward renal disease and CVD. A number of studies have investigated asso- failure or whether gene polymorphisms could provide useful ciations between the ApoE isoforms and DN; however, the markers to predict medical response to therapy (pharmaco- results remain inconclusive. This may be due in part to the genomics). Unfortunately, many such studies were performed small sample size used in all but one study (70). Several studies with inadequate interrogation of the genes (e.g., too few SNP (72–74) concluded that the ApoE4 isoform is associated with evaluated) and contained small numbers of cases and controls. protection from type 2 DN in both white and Japanese individ- The angiotensin-converting enzyme gene (ACE) on chromo- uals. Hsu et al. (70) corroborated this finding, demonstrating some 17q23 has repeatedly been evaluated for a role in DN. that the frequency of the 4 allele is decreased in type 2 diabetes Polymorphisms in this gene are clearly associated with circu- and chronic kidney disease and revealing association between the lating ACE levels (59), and reports suggested association be- 2 allele and chronic kidney disease, a result that is consistent with tween the ACE DD allele and type 1 DN (60 – 62). Although a several older studies of type 1 DN in white individuals (75,76) and large meta-analysis failed to confirm the DN association in one of type 2 DN in Japanese individuals (77). In contrast, an equal white individuals (63), a recent report (64) from the European number of studies (78 – 80) failed to find any association between Rational Approach for the Genetics of Diabetic Complications 2 and type 2 DN or microvascular complications associated with (EURAGEDIC) Study Group detected evidence for association type 2 diabetes. Given the significance of ApoE in lipid metabo- of several ACE polymorphisms (including the “D” deletion lism, the mechanism behind associations between ApoE polymor- allele) in a large case-control study, with somewhat consistent phisms and DN is likely to be complex. findings in a family-based TDT analysis. The results were stron- gest among the French cohort and clearly weaker in the Finnish Conclusions sample, suggesting heterogeneous effects among different eth- There is now a consensus that genes contribute to risk for DN. nic groups. In addition, Ng et al. (65) evaluated three tagging Earlier investigations that focused on genetic mapping and
  8. 8. Clin J Am Soc Nephrol 2: 1306 –1316, 2007 Diabetic Nephropathy Genetics 1313 analysis of specific candidate genes provided the foundation bell RC, Cushman M, Audhya P, Howard G, Warnock DG: for current studies that target linkage peaks and specific genes. Prevalence and characteristics of a family history of end- As our knowledge of DN (and other complex disorders) in- stage renal disease among adults in the United States pop- creases, the sophistication of approaches and size and cost of ulation: Reasons for Geographic and Racial Differences in these studies have also increased. These efforts are beginning to Stroke (REGARDS) Renal Cohort Study. J Am Soc Nephrol identify genes that have increasingly compelling evidence for 18: 1344 –1352, 2007 9. Forsblom CM, Kanninen T, Lehtovirta M, Saloranta C, association. 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