Nephrology Dialysis Transplantation

NDT Advance Access originally published online on October 18, 2005
Nephrology Dialysis Transplantation 2006 21(1):13-16; doi:10.1093/ndt/gfi220

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Editorial Comment

Genetic determinants of albuminuria and renal disease in diabetes mellitus

Michèle M. Sale^1,2 and Barry I. Freedman²

¹ Center for Human Genomics and ² Department of Internal Medicine/Section on Nephrology, Wake Forest University School of Medicine, Winston-Salem, NC, USA

Correspondence and offprint requests to: Barry I. Freedman, MD, Department of Internal Medicine, Section on Nephrology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1053, USA. Email: bfreedma{at}wfubmc.edu

Keywords: albuminuria; chronic kidney failure; diabetes mellitus; genetics

	Introduction

Top Introduction Dissection of the trait... Genetic factors involved in... Genetic factors involved in... ‘Nephropathy genes’... Conclusions References

 
Type 2 diabetes mellitus (T2DM) is increasing in epidemic proportions. The worldwide prevalence of diabetes was estimated to be 171 million cases in 2000 and is projected to rise to 366 million cases by 2030 [1]. Given current trends, the lifetime risk for developing T2DM is 30% in European Americans born in 2000, contrasted with 40% in African American males and 49% in African American females [2]. This global epidemic will clearly increase the development of diabetic nephropathy (DN) and cardiovascular disease (CVD) for decades to come. The dramatic change in prevalence of T2DM is clearly rooted in environmental shifts, with westernization leading to obesity, metabolic syndrome and hypertension. However, diabetes and its associated nephropathy and CVD strongly aggregate in families [3–5]. Here, we review our current understanding of the impact of genetic factors on the development of DN.

	Dissection of the trait ‘diabetic nephropathy’

Top Introduction Dissection of the trait... Genetic factors involved in... Genetic factors involved in... ‘Nephropathy genes’... Conclusions References

 
Reports evaluating the linkage and/or association of genes or genomic regions with DN have often yielded conflicting results. Discordant findings probably relate to true genetic heterogeneity, coupled with study design flaws such as population stratification between cases and controls, small sample sizes lacking in statistical power, and evaluation of inadequate numbers of polymorphisms in genes to determine their true involvement. However, the definitions of DN in each report typically differ, contributing to the confusion. The genetic bases of albuminuria and progressive DN or end-stage renal failure (ESRF) appear to differ [6]. Albuminuria and glomerular filtration rate (GFR) are both heritable, but GFR to a greater degree [7]. Albuminuria, especially of mild degree, is more strongly predictive of risk for CVD death than for development of progressive nephropathy [8]. The phenotype ‘albuminuria’, whether using timed urine collection or the albumin:creatinine ratio (ACR), is highly variable [9,10]. While it is likely that overt albuminuria (>300 mg/dl) is a useful surrogate for ESRF, the United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that more overtly albuminuric patients will die of CVD events than survive to initiate renal replacement therapy [8]. Therefore, we will attempt to dissect the existing genetic analyses in diabetic subjects into those evaluating predominantly albuminuria (i.e. in cohorts with presumed endothelial dysfunction and at relatively low risk for progressive DN) and those with overt DN/diabetic ESRF. We focus on genes and genomic regions that have demonstrated reproducible results.

	Genetic factors involved in overt diabetic nephropathy and ESRF

Top Introduction Dissection of the trait... Genetic factors involved in... Genetic factors involved in... ‘Nephropathy genes’... Conclusions References

 
Imperatore et al. conducted a genome scan on 98 Pima Indian sibling pairs with type 2 diabetic ESRF or macroalbuminuria and found the strongest evidence for linkage on chromosome 7q35 [11]. Other regions of potential interest included chromosomes 3q26, 9q22 and 20p12. Although originally investigated as a functional candidate, the gene for endothelial nitric oxide synthase (NOS3) falls within the 7q region of linkage detected in the Pima Indian families [11]. Studies in a number of different populations have found evidence for association with either NOS3 T-786C or an intron 4 insertion/deletion polymorphism and persistent proteinuria and ESRD in type 1 diabetes [12]; overt nephropathy (ESRD excluded) in type 2 diabetes [13], non-DN and DN [14]; and increased ACR in families enriched for type 2 diabetes [15]. There have also been negative reports with these and other variants of this gene with chronic renal failure [16] and DN [17]. The gene for aldose reductase (AKR1B1), also located in the vicinity of the 7q linkage peak, has been investigated extensively as a functional candidate for DN (reviewed in [18] and, more recently, see [19–22]).

In a genome scan of 18 extended Turkish families, Vardarli et al. localized a type 2 DN gene to 18q22.3–q23 [23] and confirmed this result in a study of 101 Pima Indian sib pairs [23], although the modest evidence for linkage to this locus had not been noted in the original Pima Indian scan [11]. Bowden et al. [24] found evidence to support early-onset ESRF loci at 3q13 (45 cM proximal to the Pima Indian peak [11]) and 18q22 in a genome scan of 206 African American sib pairs with ESRF, chronic renal failure or macroalbuminuria, while the strongest overall evidence for linkage was at chromosome 7p21. After excluding the Kruppel-like zinc-finger gene ZNF236 gene [25] on 18q, Janssen et al. [26] investigated carnosinase genes CNDP1 and CNDP2 as positional candidates. They found that the shortest allele of a trinucleotide repeat coding for leucine in the leader peptide of carnosinase-1 precursor (five leucines) was more common in diabetic patients without overt nephropathy, and individuals homozygous for this allele also possessed the lowest serum carnosinase activity. Carnosine functions as a scavenger of reactive oxygen species and an inhibitor of the formation of advanced glycation end-products. Therefore, lower levels of carnosinase would be expected to increase renal levels of carnosine and protect from the development of nephropathy. Replication of the CNDP1 association in African American and European American patients with T2DM-associated ESRF was unsuccessful [27]. However, the role of the carnosinase gene in DN remains under intense study.

A genome scan of GFR measured by serum cystatin C in 63 extended Caucasian pedigrees (426 individuals with type 2 diabetes, 431 without diabetes) detected linkage peaks on chromosomes 7p and 6q [6], with the latter overlapping with the 7p linkage peak of Bowden et al. [24]. By genotyping >80 000 single nucleotide polymorphisms (SNPs) in a gene-centric genome-wide association approach, Shimazaki et al. [28] identified an association between the engulfment and cell motility 1 gene (ELMO1) and overt nephropathy in patients with type 2 diabetes. They also demonstrated that ELMO1 expression was increased in the kidneys of diabetic mice, compared with controls. This gene is located on chromosome 7p14, 29 cM distal to the peak marker of the 7p locus identified by Bowden et al. [24].

	Genetic factors involved in diabetic albuminuria

Top Introduction Dissection of the trait... Genetic factors involved in... Genetic factors involved in... ‘Nephropathy genes’... Conclusions References

 
Moczulski et al. [29] investigated three candidate regions in a study of type 1 diabetes patients with ESRF, persistent macroalbuminuria and persistent microalbuminuria, and found evidence for linkage around 3q24. This locus was confirmed in a case–control comparison of type 1 diabetes patients from Russia with (300 mg/24 h) or without (200 mg/24 h) persistent proteinuria [30]. Both studies concluded that the angiotensin II type 1 receptor (AT1B) gene was unlikely to be responsible for this signal [29,30].

A scan of the ACR as a quantitative trait in 63 extended Caucasian families with type 2 diabetes [6] detected linkage peaks on chromosomes 7q and 22q, with the 7q linkage peak in the same region as that reported by Imperatore et al. [11].

The Diabetes Heart Study, a family study assessing for genes underlying type 2 diabetic atherosclerosis, found strong association between the P-selectin gene [31] and albuminuria in 565 European American siblings from 227 families (84% had diabetes). P-selectin is involved in leukocyte adhesion to the endothelium during inflammation and has been postulated to play a role in atherosclerosis. Each copy of the 290Asn (S290N) allele was associated with a significant 45% absolute increase in ACR, and a higher risk for the presence of albuminuria (odds ratio 1.71 for each 290Asn allele). The N-N-T haplotype, containing asparagine codons at sites S290N and N562D, was associated with a significantly increased risk of albuminuria (odds ratio 1.77 for each additional copy of the N-N-T haplotype).

	‘Nephropathy genes’ underlying diabetic and non-diabetic nephropathy

Top Introduction Dissection of the trait... Genetic factors involved in... Genetic factors involved in... ‘Nephropathy genes’... Conclusions References

 
Apart from evidence for linkage to creatinine clearance/serum creatinine concentration on chromosomes 3q [32] and 18q [33], there are few overlapping peaks for DN and non-DN or albuminuria [33–37]. This suggests that susceptibility to chronic renal failure may differ in diabetic and non-diabetic settings, despite the fact that both often cluster in the same families [5]. Although GFR and urinary albumin excretion are known to be heritable [7,38], the only known scans to date for these quantitative traits in diabetic populations are in press [6]. Lastly, given the clear association between microalbuminuria and CVD [39], the identification of genes contributing to albuminuria and calcified vascular plaque are urgently required.

	Conclusions

Top Introduction Dissection of the trait... Genetic factors involved in... Genetic factors involved in... ‘Nephropathy genes’... Conclusions References

 
The genes underlying susceptibility to DN/ESRF and albuminuria have, thus far, been elusive. It appears likely that multiple genes, each having an intermediate effect and in an appropriate hyperglycaemic environment, are required for full disease expression. Large studies searching for DN susceptibility are underway. For example, the Genetics of Kidneys in Diabetes (GoKinD) Study has recruited large numbers of cases with type 1 DN and their parents (DN-affected trios), as well as large numbers of controls with longstanding type 1 diabetes and no evidence for nephropathy and their parents (control trios). This study will have DNA available for the performance of association analyses and transmission disequilibrium testing (TDT) (http://www.gokind.org/access). Similarly, the Family Investigation of Nephropathy and Diabetes (FIND) Study has collected renal phenotype data, DNA and cell lines from large numbers of European American, African American, Native American and Hispanic American families [40]. All families consist of at least one diabetic sibling pair that is either concordant or discordant for DN. Mapping by admixture disequilibrium (MALD) studies will also be performed in Mexican American and African American DN cases and diabetic, non-nephropathy controls. It is hoped that the combination of existing genome-wide scans and candidate gene analyses in DN, coupled with the larger FIND and GoKinD studies, will identify the genes underlying susceptibility to DN and provide novel pathways for the prevention and treatment of diabetic kidney disease.

Conflict of interest statement. None declared.

	References

Top Introduction Dissection of the trait... Genetic factors involved in... Genetic factors involved in... ‘Nephropathy genes’... Conclusions References

 

1. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004; 27: 1047–1053[Abstract/Free Full Text]
2. Narayan KM, Boyle JP, Thompson TJ, Sorensen SW, Williamson DF. Lifetime risk for diabetes mellitus in the United States. J AM Med Assoc 2003; 290: 1884–1890[Abstract/Free Full Text]
3. Rotimi C, Cooper R, Cao G, Sundarum C, McGee D. Familial aggregation of cardiovascular diseases in African-American pedigrees. Genet Epidemiol 1994; 11: 397–407[CrossRef][Medline]
4. Hanson RL, Elston RC, Pettitt DJ, Bennett PH, Knowler WC. Segregation analysis of non-insulin-dependent diabetes mellitus in Pima Indians: evidence for a major-gene effect. Am J Hum Genet 1995; 57: 160–170[Web of Science][Medline]
5. Freedman BI. End-stage renal failure in African Americans: insights in kidney disease susceptibility. Nephrol Dial Transplant 2002; 17: 198–200[Free Full Text]
6. Placha G, Canani LH, Warram JH, Krolewski AS. Evidence for different susceptibility genes for proteinuria and ESRD in type 2 diabetes. Adv Chronic Kidney Dis 2005; 12: 155–169[CrossRef][Web of Science][Medline]
7. Langefeld CD, Beck SR, Bowden DW, Rich SS, Wagenknecht LE, Freedman BI. Heritability of GFR and albuminuria in Caucasians with type 2 diabetes mellitus. Am J Kidney Dis 2004; 43: 796–800[CrossRef][Web of Science][Medline]
8. Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int 2003; 63: 225–232[CrossRef][Web of Science][Medline]
9. Mogensen CE, Vestbo E, Poulsen PL et al. Microalbuminuria and potential confounders. A review and some observations on variability of urinary albumin excretion. Diabetes Care 1995; 18: 572–581[Web of Science][Medline]
10. Perkins BA, Ficociello LH, Silva KH, Finkelstein DM, Warram JH, Krolewski AS. Regression of microalbuminuria in type 1 diabetes. N Engl J Med 2003; 348: 2285–2293[Abstract/Free Full Text]
11. 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 1998; 47: 821–830[Abstract]
12. Zanchi A, Moczulski DK, Hanna LS, Wantman M, Warram JH, Krolewski AS. Risk of advanced diabetic nephropathy in type 1 diabetes is associated with endothelial nitric oxide synthase ge polymorphism. Kidney Int 2000; 57: 405–413[Web of Science][Medline]
13. Neugebauer S, Baba T, Watanabe T. Association of the nitric oxide synthase gene polymorphism with an increased risk for progression to diabetic nephropathy in type 2 diabetes. Diabetes 2000; 49: 500–503[Abstract]
14. Asakimori Y, Yorioka N, Taniguchi Y et al. T(-786)C polymorphism of the endothelial nitric oxide synthase gene influences the progression of renal disease. Nephron 2002; 91: 747–751[CrossRef][Web of Science][Medline]
15. Liu Y, Burdon KP, Langefeld CD et al. T-786C polymorphism of the endothelial nitric oxide synthase gene is associated with albuminuria in the diabetes heart study. J Am Soc Nephrol 2005; 16: 1085–1090[Abstract/Free Full Text]
16. Zychma MJ, Gumprecht J, Rutkowski P et al. Nitric oxide synthase gene polymorphisms and diabetic nephropathy. (correspondence) Diabetologia 2003; 46: 1707–1708[Medline]
17. Rippin JD, Patel A, Belyaev ND, Gill GV, Barnett AH, Bain SC. Nitric oxide synthase gene polymorphisms and diabetic nephropathy. Diabetologia 2003; 46: 426–428[Web of Science][Medline]
18. Demaine AG. Polymorphisms of the aldose reductase gene and susceptibility to diabetic microvascular complications. Curr Med Chem 2003; 10: 1389–1398[CrossRef][Web of Science][Medline]
19. Makiishi T, Araki S, Koya D, Maeda S, Kashiwagi A, Haneda M. C-106T polymorphism of AKR1B1 is associated with diabetic nephropathy and erythrocyte aldose reductase content in Japanese subjects with type 2 diabetes mellitus. Am J Kidney Dis 2003; 42: 943–951[Web of Science][Medline]
20. Wang Y, Ng MC, Lee SC et al. Phenotypic heterogeneity and associations of two aldose reductase gene polymorphisms with nephropathy and retinopathy in type 2 diabetes. Diabetes Care 2003; 26: 2410–2415[Abstract/Free Full Text]
21. Zhao HL, Tong PC, Lai FM, Tomlinson B, Chan JC. Association of glomerulopathy with the 5'-end polymorphism of the aldose reductase gene and renal insufficiency in type 2 diabetic patients. Diabetes 2004; 53: 2984–2991[Abstract/Free Full Text]
22. Lajer M, Tarnow L, Fleckner J et al. Association of aldose reductase gene Z+2 polymorphism with reduced susceptibility to diabetic nephropathy in Caucasian type 1 diabetic patients. Diabet Med 2004; 21: 867–873[CrossRef][Web of Science][Medline]
23. Vardarli I, Baier LJ, Hanson RL et al. Gene for susceptibility to diabetic nephropathy in type 2 diabetes maps to 18q22.3–23. Kidney Int 2002; 62: 2176–2183[CrossRef][Web of Science][Medline]
24. Bowden DW, Colicigno CJ, Langefeld CD et al. A genome scan for diabetic nephropathy in African Americans. Kidney Int 2004; 66: 1517–1526[CrossRef][Web of Science][Medline]
25. Halama N, Yard-Breedijk A, Vardarli I et al. The Kruppel-like zinc-finger gene ZNF236 is alternatively spliced and excluded as susceptibility gene for diabetic nephropathy. Genomics 2003; 82: 406–411[CrossRef][Web of Science][Medline]
26. Janssen B, Hohenadel D, Brinkkoetter P et al. Carnosine as a protective factor in diabetic nephropathy: association with a leucine repeat of the carnosinase gene CNDP1. Diabetes 2005; 54: 2320–2327[Abstract/Free Full Text]
27. Freedman BI, Hicks PJ, Sale MM, Bowden DW. Association analysis of the carnosinase gene in type 2 diabetic nephropathy [abstract]. J Am Soc Nephrol 2005; in press
28. Shimazaki A, Kawamura Y, Kanazawa A et al. Genetic variations in the gene encoding ELMO1 are associated with susceptibility to diabetic nephropathy. Diabetes 2005; 54: 1171–1178[Abstract/Free Full Text]
29. 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 1998; 47: 1164–1169[Abstract]
30. Chistiakov DA, Savost’anov KV, Shestakova MV et al. Confirmation of a susceptibility locus for diabetic nephropathy on chromosome 3q23–q24 by association study in Russian type 1 diabetic patients. Diabetes Res Clin Pract 2004; 66: 79–86[CrossRef][Web of Science][Medline]
31. Liu Y, Burdon KP, Langefeld CD et al. P-selectin gene haplotype associations with albuminuria in the Diabetes Heart Study. Kidney Int 2005; 68: 741–746[Medline]
32. DeWan AT, Arnett DK, Atwood LD et al. A genome scan for renal function among hypertensives: the HyperGEN study. Am J Hum Genet 2001; 68: 136–144[CrossRef][Web of Science][Medline]
33. Hunt SC, Coon H, Hasstedt SJ et al. Linkage of serum creatinine and glomerular filtration rate to chromosome 2 in Utah pedigrees. Am J Hypertens 2004; 17: 511–515[CrossRef][Web of Science][Medline]
34. Fox CS, Yang Q, Guo CY et al. Genome-wide linkage analysis to urinary microalbuminuria in a community-based sample: the Framingham Heart Study. Kidney Int 2005; 67: 70–74[CrossRef][Web of Science][Medline]
35. Fox CS, Yang Q, Cupples LA et al. Genomewide linkage analysis to serum creatinine, GFR, and creatinine clearance in a community-based population: the Framingham Heart Study. J Am Soc Nephrol 2004; 15: 2457–2461[Abstract/Free Full Text]
36. Freedman BI, Beck SR, Rich SS et al. A genome-wide scan for urinary albumin excretion in hypertensive families. Hypertension 2003; 42: 291–296[Abstract/Free Full Text]
37. Freedman BI, Bowden DW, Rich SS et al. A genome scan for all-cause end-stage renal disease in African Americans. Nephrol Dial Transplant 2005; 20: 712–718[Abstract/Free Full Text]
38. Fogarty DG, Rich SS, Hanna L, Warram JH, Krolewski AS. Urinary albumin excretion in families with type 2 diabetes is heritable and genetically correlated to blood pressure. Kidney Int 2000; 57: 250–257[CrossRef][Web of Science][Medline]
39. Freedman BI, Langefeld CD, Lohman KK et al. Relationship between albuminuria and cardiovascular disease in type 2 diabetes. J Am Soc Nephrol 2005; 16: 2156–2161[Abstract/Free Full Text]
40. Knowler WC, Coresh J, Elston RC et al. The Family Investigation of Nephropathy and Diabetes (FIND): design and methods. J Diabetes Complications 2005; 19: 1–9[Web of Science][Medline]

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