Novel Susceptibility Locus at 22q11 for Diabetic Nephropathy in Type 1 Diabetes

Background Diabetic nephropathy (DN) affects about 30% of patients with type 1 diabetes (T1D) and contributes to serious morbidity and mortality. So far only the 3q21–q25 region has repeatedly been indicated as a susceptibility region for DN. The aim of this study was to search for new DN susceptibility loci in Finnish, Danish and French T1D families. Methods and Results We performed a genome-wide linkage study using 384 microsatellite markers. A total of 175 T1D families were studied, of which 94 originated from Finland, 46 from Denmark and 35 from France. The whole sample set consisted of 556 individuals including 42 sib-pairs concordant and 84 sib-pairs discordant for DN. Two-point and multi-point non-parametric linkage analyses were performed using the Analyze package and the MERLIN software. A novel DN locus on 22q11 was identified in the joint analysis of the Finnish, Danish and French families by genome-wide multipoint non-parametric linkage analysis using the Kong and Cox linear model (NPLpairs LOD score 3.58). Nominal or suggestive evidence of linkage to this locus was also detected when the three populations were analyzed separately. Suggestive evidence of linkage was found to six additional loci in the Finnish and French sample sets. Conclusions This study identified a novel DN locus at chromosome 22q11 with significant evidence of linkage to DN. Our results suggest that this locus may be of importance in European populations. In addition, this study supports previously indicated DN loci on 3q21–q25 and 19q13.

[1]  E. Brennan,et al.  The Genetics of Diabetic Nephropathy , 2013, Genes.

[2]  J. Navarro-González,et al.  Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy , 2011, Nature Reviews Nephrology.

[3]  S. Akkina,et al.  MicroRNAs in kidney function and disease. , 2011, Translational research : the journal of laboratory and clinical medicine.

[4]  R. Elston,et al.  Genomewide Linkage Scan for Diabetic Renal Failure and Albuminuria: The FIND Study , 2011, American Journal of Nephrology.

[5]  Jasmin Divers,et al.  A genome-wide association study for diabetic nephropathy genes in African Americans. , 2011, Kidney international.

[6]  H. S. Kang,et al.  Gli-similar (Glis) Krüppel-like zinc finger proteins: insights into their physiological functions and critical roles in neonatal diabetes and cystic renal disease. , 2010, Histology and histopathology.

[7]  John A. Todd,et al.  Genetics of Type 1 Diabetes: What's Next? , 2010, Diabetes.

[8]  S. Rosset,et al.  Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene , 2010, Human Genetics.

[9]  S. Gaffen.  The role of interleukin-17 in the pathogenesis of rheumatoid arthritis , 2009, Current rheumatology reports.

[10]  M. Hurles,et al.  Copy number variation in human health, disease, and evolution. , 2009, Annual review of genomics and human genetics.

[11]  Stephen S. Rich,et al.  Genome-Wide Association Scan for Diabetic Nephropathy Susceptibility Genes in Type 1 Diabetes , 2009, Diabetes.

[12]  J. Tuomilehto,et al.  Association of genetic variants at 3q22 with nephropathy in patients with type 1 diabetes mellitus. , 2009, American journal of human genetics.

[13]  A. Paterson,et al.  Genome-wide Association Scan for Diabetic Nephropathy Susceptibility Genes in Type 1 Diabetes Mellitus , 2009 .

[14]  S. Maeda.  Review: Genetics of diabetic nephropathy , 2008, Therapeutic advances in cardiovascular disease.

[15]  D. Vlahov,et al.  MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis , 2008, Nature Genetics.

[16]  D. Reich,et al.  MYH9 is associated with nondiabetic end-stage renal disease in African Americans , 2008, Nature Genetics.

[17]  D. Moczulski,et al.  High-Density Single Nucleotide Polymorphism Genome-Wide Linkage Scan for Susceptibility Genes for Diabetic Nephropathy in Type 1 Diabetes , 2008, Diabetes.

[18]  M. Daly,et al.  Consistently replicating locus linked to migraine on 10q22-q23. , 2008, American journal of human genetics.

[19]  D. Moczulski,et al.  High-density SNP genome wide linkage scan for susceptibility genes for diabetic nephropathy in type 1 diabetes: Discordant sib-pair approach. , 2008 .

[20]  D. Bowden,et al.  Genetic factors in diabetic nephropathy. , 2007, Clinical journal of the American Society of Nephrology : CJASN.

[21]  Kari Stefansson,et al.  A common variant on chromosome 9p21 affects the risk of myocardial infarction. , 2007, Science.

[22]  C. Gieger,et al.  Genomewide association analysis of coronary artery disease. , 2007, The New England journal of medicine.

[23]  M. McCarthy,et al.  Replication of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes , 2007, Science.

[24]  G. Abecasis,et al.  A Genome-Wide Association Study of Type 2 Diabetes in Finns Detects Multiple Susceptibility Variants , 2007, Science.

[25]  J. Tuomilehto,et al.  Genome-wide scan for type 1 diabetic nephropathy in the Finnish population reveals suggestive linkage to a single locus on chromosome 3q. , 2007, Kidney international.

[26]  H. Shin,et al.  SLC12A3 (solute carrier family 12 member [sodium/chloride] 3) polymorphisms are associated with end-stage renal disease in diabetic nephropathy. , 2006, Diabetes.

[27]  S. Sawcer,et al.  A genome-wide DNA microsatellite association screen to identify chromosomal regions harboring candidate genes in diabetic nephropathy. , 2006, Journal of the American Society of Nephrology : JASN.

[28]  K. Merikangas,et al.  Genomewide significant linkage to migrainous headache on chromosome 5q21. , 2005, American journal of human genetics.

[29]  Markus Perola,et al.  AUTOGSCAN: powerful tools for automated genome-wide linkage and linkage disequilibrium analysis. , 2005, Twin research and human genetics : the official journal of the International Society for Twin Studies.

[30]  V. Rigalleau,et al.  Different patterns of insulin resistance in relatives of type 1 diabetic patients with retinopathy or nephropathy: the Genesis France-Belgium Study. , 2004, Diabetes care.

[31]  V. Nosikov,et al.  Confirmation of a susceptibility locus for diabetic nephropathy on chromosome 3q23-q24 by association study in Russian type 1 diabetic patients. , 2004, Diabetes research and clinical practice.

[32]  C. Langefeld,et al.  A genome scan for diabetic nephropathy in African Americans. , 2004, Kidney international.

[33]  J. Tuomilehto,et al.  Population-based assessment of familial clustering of diabetic nephropathy in type 1 diabetes. , 2004, Diabetes.

[34]  Gonçalo R Abecasis,et al.  Genomewide scan in families with schizophrenia from the founder population of Afrikaners reveals evidence for linkage and uniparental disomy on chromosome 1. , 2004, American journal of human genetics.

[35]  Ferdinando Palmieri,et al.  The mitochondrial transporter family (SLC25): physiological and pathological implications , 2004, Pflügers Archiv.

[36]  A. Krolewski,et al.  Familial factors determine the development of diabetic nephropathy in patients with IDDM , 1996, Diabetologia.

[37]  S. Kreiner,et al.  Diabetic nephropathy in type 1 (insulin-dependent) diabetes: An epidemiological study , 1983, Diabetologia.

[38]  Yusuke Nakamura,et al.  Association of solute carrier family 12 (sodium/chloride) member 3 with diabetic nephropathy, identified by genome-wide analyses of single nucleotide polymorphisms. , 2003, Diabetes.

[39]  C. Forsblom,et al.  Diabetic nephropathy is associated with low-grade inflammation in Type 1 diabetic patients , 2003, Diabetologia.

[40]  J. Ilonen,et al.  HLA DR-DQ-encoded genetic determinants of childhood-onset type 1 diabetes in Finland: an analysis of 622 nuclear families. , 2003, Tissue antigens.

[41]  M. McCarthy,et al.  Evaluating the results of genomewide linkage scans of complex traits by locus counting. , 2002, American journal of human genetics.

[42]  B. Morrow,et al.  Genomic disorders on 22q11. , 2002, American journal of human genetics.

[43]  J. Tonn,et al.  Loss of heterozygosity on chromosome 22 in human ependymomas , 2002, Acta Neuropathologica.

[44]  G. Abecasis,et al.  Merlin—rapid analysis of dense genetic maps using sparse gene flow trees , 2002, Nature Genetics.

[45]  J. Tuomilehto,et al.  Record-high incidence of Type I (insulin-dependent) diabetes mellitus in Finnish children , 1999, Diabetologia.

[46]  D. Moczulski,et al.  Major susceptibility locus for nephropathy in type 1 diabetes on chromosome 3q: results of novel discordant sib-pair analysis. , 1998, Diabetes.

[47]  J R O'Connell,et al.  PedCheck: a program for identification of genotype incompatibilities in linkage analysis. , 1998, American journal of human genetics.

[48]  N J Cox,et al.  Allele-sharing models: LOD scores and accurate linkage tests. , 1997, American journal of human genetics.

[49]  L. Tarnow,et al.  Genetics of diabetic nephropathy. , 1996, Journal of the American Society of Nephrology : JASN.

[50]  E. Lander,et al.  Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results , 1995, Nature Genetics.

[51]  E Feingold,et al.  Gaussian models for genetic linkage analysis using complete high-resolution maps of identity by descent. , 1993, American journal of human genetics.

[52]  H. Parving,et al.  Is diabetic nephropathy an inherited complication? , 1992, Kidney international.

[53]  E. Seaquist,et al.  Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy. , 1989, The New England journal of medicine.

[54]  J. Wetzels,et al.  The changing natural history of nephropathy in type I diabetes. , 1986, The American journal of medicine.

[55]  C. Mathew,et al.  Blot hybridisation analysis of genomic DNA. , 1984, Journal of medical genetics.