title: ELMO1 variants and susceptibility to diabetic nephropathy in American Indians.
abstract: Variants in the engulfment and cell motility 1 gene, ELMO1, have previously been associated with kidney disease attributed to type 2 diabetes. The Pima Indians of Arizona have high rates of diabetic nephropathy, which is strongly dependent on genetic determinants; thus, we sought to investigate the role of ELMO1 polymorphisms in mediating susceptibility to this disease in this population. Genotype distributions were compared among 141 individuals with nephropathy and 416 individuals without heavy proteinuria in a family study of 257 sibships, and 107 cases with diabetic ESRD and 108 controls with long duration diabetes and no nephropathy. We sequenced 17.4 kb of ELMO1 and identified 19 variants. We genotyped 12 markers, excluding those in 100% genotypic concordance with other variants or with a minor allele frequency <0.05, plus 21 additional markers showing association with ESRD in earlier studies. In the family study, the strongest evidence for association was with rs1345365 (odds ratio [OR]=2.42 per copy of A allele [1.35-4.32]; P=0.001) and rs10951509 (OR=2.42 per copy of A allele [1.31-4.48]; P=0.002), both of which are located in intron 13 and are in strong pairwise linkage disequilibrium (r(2)=0.97). These associations were in the opposite direction from those observed in African Americans, which suggests that the relationship between diabetic kidney disease and ELMO1 variation may involve as yet undiscovered functional variants or complex interactions with other biological variables.
authors.affiliation: Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 1550 East Indian School Road, Phoenix, AZ 85014, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hanson
authors.forename: Meredith P
authors.initials: MP
authors.lastname: Millis
authors.forename: Naomi J
authors.initials: NJ
authors.lastname: Young
authors.forename: Sayuko
authors.initials: S
authors.lastname: Kobes
authors.forename: Robert G
authors.initials: RG
authors.lastname: Nelson
authors.forename: William C
authors.initials: WC
authors.lastname: Knowler
authors.forename: Johanna K
authors.initials: JK
authors.lastname: DiStefano
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D003928:Diabetic Nephropathies / Q000208:ethnology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D007676:Kidney Failure, Chronic / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C465214:ELMO1 protein, human
references.citation: Curr Diab Rep. 2001 Dec;1(3):275-81
references.pmid: 12643210
references.citation: Diabetologia. 1990 Jul;33(7):438-43
references.pmid: 2401399
references.citation: Diabetologia. 1989 Dec;32(12):870-6
references.pmid: 2612758
references.citation: Diabetes. 2009 Nov;58(11):2698-702
references.pmid: 19651817
references.citation: Ann Hum Genet. 2006 May;70(Pt 3):332-49
references.pmid: 16674556
references.citation: Diabet Med. 2006 Apr;23(4):367-76
references.pmid: 16620264
references.citation: BMC Genomics. 2008 Oct 31;9:516
references.pmid: 18976480
references.citation: Diabetologia. 1993 Oct;36(10):1094-8
references.pmid: 8243860
references.citation: N Engl J Med. 1989 May 4;320(18):1161-5
references.pmid: 2710189
references.citation: Diabetes. 2005 Jan;54(1):284-9
references.pmid: 15616040
references.citation: Hum Mol Genet. 2004 Mar 15;13(6):577-88
references.pmid: 14734624
references.citation: Diabetes. 2000 Jun;49(6):1049-56
references.pmid: 10866059
references.citation: Adv Chronic Kidney Dis. 2005 Apr;12(2):155-69
references.pmid: 15822051
references.citation: Am J Hum Genet. 2007 Mar;80(3):531-8
references.pmid: 17273975
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: Ann Hum Genet. 2009 Mar;73(2):152-9
references.pmid: 19183347
references.citation: Arch Intern Med. 1998 May 11;158(9):998-1004
references.pmid: 9588433
references.citation: Diabetes Care. 1995 Feb;18(2):182-7
references.pmid: 7729295
references.citation: Diabetologia. 1988 Oct;31(10):730-6
references.pmid: 3240833
references.citation: Am J Epidemiol. 1978 Dec;108(6):497-505
references.pmid: 736028
references.citation: Diabetologia. 1991 Sep;34(9):655-61
references.pmid: 1955098
references.citation: Diabet Med. 2009 Nov;26(11):1090-8
references.pmid: 19929986
references.citation: Clin J Am Soc Nephrol. 2010 Jun;5(6):1072-8
references.pmid: 20299368