title: Association analysis of dyslipidemia-related genes in diabetic nephropathy.
abstract: Type 1 diabetes (T1D) increases risk of the development of microvascular complications and cardiovascular disease (CVD). Dyslipidemia is a common risk factor in the pathogenesis of both CVD and diabetic nephropathy (DN), with CVD identified as the primary cause of death in patients with DN. In light of this commonality, we assessed single nucleotide polymorphisms (SNPs) in thirty-seven key genetic loci previously associated with dyslipidemia in a T1D cohort using a case-control design. SNPs (n = 53) were genotyped using Sequenom in 1467 individuals with T1D (718 cases with proteinuric nephropathy and 749 controls without nephropathy i.e. normal albumin excretion). Cases and controls were white and recruited from the UK and Ireland. Association analyses were performed using PLINK to compare allele frequencies in cases and controls. In a sensitivity analysis, samples from control individuals with reduced renal function (estimated glomerular filtration rate<60 ml/min/1.73 m(2)) were excluded. Correction for multiple testing was performed by permutation testing. A total of 1394 samples passed quality control filters. Following regression analysis adjusted by collection center, gender, duration of diabetes, and average HbA1c, two SNPs were significantly associated with DN. rs4420638 in the APOC1 region (odds ratio [OR] = 1.51; confidence intervals [CI]: 1.19-1.91; P = 0.001) and rs1532624 in CETP (OR = 0.82; CI: 0.69-0.99; P = 0.034); rs4420638 was also significantly associated in a sensitivity analysis (P = 0.016) together with rs7679 (P = 0.027). However, no association was significant following correction for multiple testing. Subgroup analysis of end-stage renal disease status failed to reveal any association. Our results suggest common variants associated with dyslipidemia are not strongly associated with DN in T1D among white individuals. Our findings, cannot entirely exclude these key genes which are central to the process of dyslipidemia, from involvement in DN pathogenesis as our study had limited power to detect variants of small effect size. Analysis in larger independent cohorts is required.
authors.affiliation: Nephrology Research Group, Centre for Public Health, Queen's University Belfast, Belfast, United Kingdom. g.j.mckay@qub.ac.uk
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: McKay
authors.forename: David A
authors.initials: DA
authors.lastname: Savage
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Patterson
authors.forename: Gareth
authors.initials: G
authors.lastname: Lewis
authors.forename: Amy Jayne
authors.initials: AJ
authors.lastname: McKnight
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Maxwell
mesh_terms: D000293:Adolescent; D000328:Adult; D053302:Apolipoprotein C-I / Q000097:blood / Q000235:genetics*; D002648:Child; D053480:Cholesterol Ester Transfer Proteins / Q000097:blood / Q000235:genetics*; D015331:Cohort Studies; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000097:blood / Q000235:genetics*; D050171:Dyslipidemias / Q000097:blood / Q000235:genetics*; D005260:Female; D006442:Glycated Hemoglobin / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007494:Ireland; D007676:Kidney Failure, Chronic / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D006113:United Kingdom
chemical_list: D053302:Apolipoprotein C-I; D053480:Cholesterol Ester Transfer Proteins; D006442:Glycated Hemoglobin; C505803:APOC1 protein, human; C506642:CETP protein, human; C517652:hemoglobin A1c protein, human
references.citation: PLoS Genet. 2010 Jan;6(1):e1000798
references.pmid: 20066028
references.citation: Diabetes Care. 2009 Apr;32(4):658-63
references.pmid: 19171721
references.citation: Atherosclerosis. 2008 Jan;196(1):455-460
references.pmid: 17196207
references.citation: Am J Kidney Dis. 1997 Jun;29(6):919-30
references.pmid: 9186079
references.citation: Curr Opin Nephrol Hypertens. 2002 May;11(3):287-93
references.pmid: 11981258
references.citation: Diabetologia. 1998 Jul;41(7):784-90
references.pmid: 9686919
references.citation: Nat Clin Pract Endocrinol Metab. 2009 Mar;5(3):150-9
references.pmid: 19229235
references.citation: Med Clin North Am. 2004 Jul;88(4):897-909, x
references.pmid: 15308384
references.citation: Cardiol Rev. 2006 May-Jun;14(3):125-35
references.pmid: 16628021
references.citation: N Engl J Med. 1993 Nov 11;329(20):1456-62
references.pmid: 8413456
references.citation: Baillieres Best Pract Res Clin Endocrinol Metab. 1999 Jul;13(2):265-78
references.pmid: 10761866
references.citation: Am J Kidney Dis. 1993 Jul;22(1):196-201
references.pmid: 8322783
references.citation: Nephrol Dial Transplant. 2009 Aug;24(8):2473-6
references.pmid: 19336575
references.citation: Nat Genet. 2008 Feb;40(2):149-51
references.pmid: 18193046
references.citation: J Lipid Res. 2010 Apr;51(4):843-8
references.pmid: 19812053
references.citation: BMJ. 1989 Feb 25;298(6672):487-90
references.pmid: 2495077
references.citation: Circulation. 2005 Jun 28;111(25):3489-93
references.pmid: 15983263
references.citation: BMJ. 1989 Jul 22;299(6693):230-3
references.pmid: 2504376
references.citation: Diabet Med. 2001 Jan;18(1):59-67
references.pmid: 11168343
references.citation: N Engl J Med. 2001 Sep 20;345(12):851-60
references.pmid: 11565517
references.citation: Arterioscler Thromb Vasc Biol. 2010 Nov;30(11):2264-76
references.pmid: 20864672
references.citation: Nat Genet. 2009 Jan;41(1):56-65
references.pmid: 19060906
references.citation: Diabetologia. 2008 Jan;51(1):12-20
references.pmid: 17994214
references.citation: Diabetes. 1996 Jul;45(7):974-9
references.pmid: 8666151
references.citation: Biomed Pharmacother. 2004 Dec;58(10):619-27
references.pmid: 15589073
references.citation: N Engl J Med. 2001 Sep 20;345(12):861-9
references.pmid: 11565518
references.citation: Diabetologia. 2003 Jun;46(6):733-49
references.pmid: 12774165
references.citation: FASEB J. 2004 May;18(7):805-15
references.pmid: 15117885
references.citation: Diabetes Care. 2010 Jul;33(7):1536-43
references.pmid: 20413518
references.citation: Nature. 2010 Aug 5;466(7307):707-13
references.pmid: 20686565
references.citation: Diabetologia. 2011 Feb;54(2):334-8
references.pmid: 21103979
references.citation: Mayo Clin Proc. 1998 Oct;73(10):969-76
references.pmid: 9787748
references.citation: Histol Histopathol. 1998 Jan;13(1):169-79
references.pmid: 9476647
references.citation: Kidney Int Suppl. 2000 Apr;75:S27-31
references.pmid: 10828758
references.citation: Endocrinol Metab Clin North Am. 2006 Sep;35(3):491-510, vii-viii
references.pmid: 16959582
references.citation: Nat Genet. 2009 Jan;41(1):47-55
references.pmid: 19060911
references.citation: Diabet Med. 1989 Jan-Feb;6(1):25-30
references.pmid: 2522370
references.citation: Nat Genet. 2008 Feb;40(2):189-97
references.pmid: 18193044
references.citation: J Clin Endocrinol Metab. 2006 Feb;91(2):383-92
references.pmid: 16291700
references.citation: Kidney Int. 1995 Jun;47(6):1703-20
references.pmid: 7643540
references.citation: Diabetes Care. 1994 Feb;17(2):126-31
references.pmid: 8137682
references.citation: Diabetes Care. 2006 Feb;29(2):317-22
references.pmid: 16443880
references.citation: Hum Mol Genet. 2012 Mar 15;21(6):1444-55
references.pmid: 22156771
references.citation: Diabet Med. 1999 Jun;16(6):466-71
references.pmid: 10391393
references.citation: Diabetologia. 1983 Dec;25(6):496-501
references.pmid: 6363177
references.citation: Nat Rev Genet. 2001 Feb;2(2):91-9
references.pmid: 11253062
references.citation: Diabetes. 2009 Jun;58(6):1403-10
references.pmid: 19252134
references.citation: N Engl J Med. 2003 Jun 5;348(23):2285-93
references.pmid: 12788992
references.citation: Clin J Am Soc Nephrol. 2006 Sep;1(5):1090-9
references.pmid: 17699330
references.citation: JAMA. 1999 Apr 14;281(14):1291-7
references.pmid: 10208144
references.citation: Nat Genet. 2008 Feb;40(2):161-9
references.pmid: 18193043
references.citation: Pharmacogenomics. 2008 Jun;9(6):747-63
references.pmid: 18518852
references.citation: Nat Genet. 2010 Aug;42(8):684-7
references.pmid: 20657596
references.citation: Arterioscler Thromb. 1993 Jun;13(6):815-25
references.pmid: 8499401