title: Family-based association analysis confirms the role of the chromosome 9q21.32 locus in the susceptibility of diabetic nephropathy.
abstract: A genome-wide association scan of type 1 diabetic patients from the GoKinD collections previously identified four novel diabetic nephropathy susceptibility loci that have subsequently been shown to be associated with diabetic nephropathy in unrelated patients with type 2 diabetes. To expand these findings, we examined whether single nucleotide polymorphisms (SNPs) at these susceptibility loci were associated with diabetic nephropathy in patients from the Joslin Study of Genetics of Nephropathy in Type 2 Diabetes Family Collection. Six SNPs across the four loci identified in the GoKinD collections and 7 haplotype tagging SNPs, were genotyped in 66 extended families of European ancestry. Pedigrees from this collection contained an average of 18.5 members, including 2 to 14 members with type 2 diabetes. Among diabetic family members, the 9q21.32 locus approached statistical significance with advanced diabetic nephropathy (P = 0.037 [adjusted P = 0.222]). When we expanded our definition of diabetic nephropathy to include individuals with high microalbuminuria, the strength of this association improved significantly (P = 1.42×10(-3) [adjusted P = 0.009]). This same locus also trended toward statistical significance with variation in urinary albumin excretion in family members with type 2 diabetes (P = 0.032 [adjusted P = 0.192]) and in analyses expanded to include all relatives (P = 0.019 [adjusted P = 0.114]). These data increase support that SNPs identified in the GoKinD collections on chromosome 9q21.32 are true diabetic nephropathy susceptibility loci.
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA, USA. marcus.pezzolesi@joslin.harvard.edu
authors.forename: Marcus G
authors.initials: MG
authors.lastname: Pezzolesi
authors.forename: Jackson
authors.initials: J
authors.lastname: Jeong
authors.forename: Adam M
authors.initials: AM
authors.lastname: Smiles
authors.forename: Jan
authors.initials: J
authors.lastname: Skupien
authors.forename: Josyf C
authors.initials: JC
authors.lastname: Mychaleckyj
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.forename: James H
authors.initials: JH
authors.lastname: Warram
authors.forename: Andrzej S
authors.initials: AS
authors.lastname: Krolewski
mesh_terms: D000328:Adult; D000368:Aged; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
references.citation: Am J Kidney Dis. 2004 May;43(5):796-800
references.pmid: 15112169
references.citation: Kidney Int. 2011 Jul;80(1):105-11
references.pmid: 21412220
references.citation: N Engl J Med. 1989 May 4;320(18):1161-5
references.pmid: 2710189
references.citation: Kidney Int. 2006 Jan;69(1):129-36
references.pmid: 16374433
references.citation: Diabetes. 2009 Nov;58(11):2698-702
references.pmid: 19651817
references.citation: Mol Genet Metab. 2010 Dec;101(4):383-90
references.pmid: 20826100
references.citation: Am J Physiol Renal Physiol. 2007 Nov;293(5):F1649-56
references.pmid: 17804484
references.citation: Diabetes. 2000 Jun;49(6):1057-63
references.pmid: 10866060
references.citation: Diabetes. 1999 Apr;48(4):909-13
references.pmid: 10102711
references.citation: Kidney Int. 2000 Jan;57(1):250-7
references.pmid: 10620206
references.citation: Genet Epidemiol. 2000;19 Suppl 1:S36-42
references.pmid: 11055368
references.citation: J Am Soc Nephrol. 1996 Jun;7(6):930-7
references.pmid: 8793803
references.citation: Ann Hum Genet. 2009 Mar;73(2):152-9
references.pmid: 19183347
references.citation: PLoS Genet. 2011 Jun;7(6):e1002150
references.pmid: 21698141
references.citation: Diabetes. 2012 Aug;61(8):2187-94
references.pmid: 22721967
references.citation: Diabetologia. 1999 Nov;42(11):1359-66
references.pmid: 10550421
references.citation: Diabetes Care. 2002 Dec;25(12):2292-301
references.pmid: 12453976
references.citation: Pediatr Nephrol. 2003 Feb;18(2):75-84
references.pmid: 12579392
references.citation: Diabetologia. 1997 Jul;40(7):816-23
references.pmid: 9243103
references.citation: Adv Chronic Kidney Dis. 2005 Apr;12(2):155-69
references.pmid: 15822051
references.citation: Diabetes. 2010 Aug;59(8):2075-9
references.pmid: 20460425
references.citation: Diabetes. 2007 Dec;56(12):3027-32
references.pmid: 17881614
references.citation: Diabetes. 2005 Apr;54(4):1171-8
references.pmid: 15793258
references.citation: Diabetologia. 1996 Aug;39(8):940-5
references.pmid: 8858216
references.citation: Bioinformatics. 2005 Jan 15;21(2):263-5
references.pmid: 15297300
references.citation: Diabetes. 2007 Apr;56(4):975-83
references.pmid: 17395743
references.citation: Diabetes. 2009 Jun;58(6):1403-10
references.pmid: 19252134
references.citation: Diabetes. 2013 Jul;62(7):2605-12
references.pmid: 23434934
references.citation: PLoS Biol. 2010 Jan 26;8(1):e1000294
references.pmid: 20126254