title: Strong parent-of-origin effects in the association of KCNQ1 variants with type 2 diabetes in American Indians.
abstract: Parent-of-origin effects were observed in an Icelandic population for several genetic variants associated with type 2 diabetes, including those in KLF14 (rs4731702), MOB2 (rs2334499), and KCNQ1 (rs2237892, rs231362). We analyzed parent-of-origin effects for these variants, along with two others in KCNQ1 identified in previous genome-wide association studies (rs2237895, rs2299620), in 7,351 Pima Indians from 4,549 nuclear families; 34% of participants had diabetes. In a subset of 287 normoglycemic individuals, acute insulin secretion was measured by an intravenous glucose tolerance test. Statistically significant (P < 0.05) parent-of-origin effects were seen for association with type 2 diabetes for all variants. The strongest effect was seen at rs2299620 in KCNQ1; the C allele was associated with increased diabetes when maternally derived (odds ratio [OR], 1.92; P = 4.1 × 10(-12)), but not when paternally derived (OR, 0.93; P = 0.47; P = 9.9 × 10(-6) for difference in maternal and paternal effects). A maternally derived C allele also was associated with a 28% decrease in insulin secretion (P = 0.002). This study confirms parent-of-origin effects in the association with type 2 diabetes for variants in KLF14, MOB2, and KCNQ1. In Pima Indians, the effect of maternally derived KCNQ1 variants appears to be mediated through decreased insulin secretion and is particularly strong, accounting for 4% of the variance in liability to diabetes.
authors: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona, USA. rhanson@phx.niddk.nih.gov
authors: Robert L
authors: RL
authors: Hanson
authors: Tingwei
authors: T
authors: Guo
authors: Yunhua L
authors: YL
authors: Muller
authors: Jamie
authors: J
authors: Fleming
authors: William C
authors: WC
authors: Knowler
authors: Sayuko
authors: S
authors: Kobes
authors: Clifton
authors: C
authors: Bogardus
authors: Leslie J
authors: LJ
authors: Baier
mesh_terms: D000328:Adult; D000483:Alleles; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005951:Glucose Tolerance Test; D006239:Haplotypes; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D051741:Kruppel-Like Transcription Factors; D008137:Longitudinal Studies; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics; D010290:Parents; D020641:Polymorphism, Single Nucleotide; D051703:Sp Transcription Factors / Q000235:genetics
chemical_list: D007328:Insulin; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; C417549:KLF14 protein, human; D051741:Kruppel-Like Transcription Factors; C431903:MOB2 protein, human; D009419:Nerve Tissue Proteins; D051703:Sp Transcription Factors
references: Am J Hum Genet. 2007 Jun;80(6):1014-23
references: 17557415
references: Hum Hered. 2002;54(2):99-110
references: 12566741
references: PLoS One. 2009 Jun 11;4(6):e5872
references: 19516902
references: Nature. 2009 Dec 17;462(7275):868-74
references: 20016592
references: Ann Hum Genet. 2006 May;70(Pt 3):332-49
references: 16674556
references: Clin Endocrinol (Oxf). 2012 Mar;76(3):365-72
references: 21767287
references: Am J Hum Genet. 1984 Mar;36(2):460-5
references: 6585139
references: PLoS One. 2012;7(3):e32148
references: 22403629
references: Nat Genet. 2010 Jul;42(7):579-89
references: 20581827
references: Am J Phys Anthropol. 1986 Aug;70(4):433-41
references: 3766713
references: Diabetologia. 2009 Jul;52(7):1322-5
references: 19308350
references: Am J Epidemiol. 1978 Dec;108(6):497-505
references: 736028
references: Diabetes. 2007 Dec;56(12):3082-8
references: 17909099
references: Nat Genet. 2008 Sep;40(9):1092-7
references: 18711367
references: Diabetes Metab Rev. 1988 Aug;4(5):517-40
references: 3061759
references: Nat Genet. 2012 Sep;44(9):981-90
references: 22885922
references: Diabetes. 2009 Jul;58(7):1715-20
references: 19366866
references: Diabetes Metab Res Rev. 2007 May;23(4):304-10
references: 17001619
references: Nat Genet. 2008 Sep;40(9):1098-102
references: 18711366
references: Diabetes Care. 1997 Jul;20(7):1183-97
references: 9203460
references: Diabetes. 2000 Dec;49(12):2208-11
references: 11118027
references: Nat Genet. 2011 Jun;43(6):561-4
references: 21572415
references: Nat Genet. 1997 Feb;15(2):181-5
references: 9020845
references: Genome Res. 2007 Dec;17(12):1723-30
references: 18055845
references: Birth Defects Res A Clin Mol Teratol. 2011 Aug;91(8):682-92
references: 21648055
references: N Engl J Med. 1993 Dec 30;329(27):1988-92
references: 8247074
references: Diabetes. 2009 Jun;58(6):1445-9
references: 19252135
references: J Evol Biol. 2005 Sep;18(5):1368-73
references: 16135132
references: Am J Hum Genet. 1999 Jul;65(1):229-35
references: 10364536
references: Diabetes. 2009 Oct;58(10):2409-13
references: 19584308