title: Comprehensive testing of positionally cloned asthma genes in two populations.
abstract: BACKGROUND
  Replication of gene-disease associations has become a requirement in complex trait genetics.
  
  
  OBJECTIVE
  In studies of childhood asthma from two different ethnic groups, we attempted to replicate associations with five potential asthma susceptibility genes previously identified by positional cloning.
  
  
  METHODS
  We analyzed two family-based samples ascertained through an asthmatic proband: 497 European-American children from the Childhood Asthma Management Program and 439 Hispanic children from the Central Valley of Costa Rica. We genotyped 98 linkage disequilibrium-tagging single-nucleotide polymorphisms (SNPs) in five genes: ADAM33, DPP10, GPR154 (HUGO name: NPSR1), HLA-G, and the PHF11 locus (includes genes SETDB2 and RCBTB1). SNPs were tested for association with asthma and two intermediate phenotypes: airway hyperresponsiveness and total serum immunoglobulin E levels.
  
  
  RESULTS
  Despite differing ancestries, linkage disequilibrium patterns were similar in both cohorts. Of the five evaluated genes, SNP-level replication was found only for GPR154 (NPSR1). In this gene, three SNPs were associated with asthma in both cohorts, although the opposite alleles were associated in either study. Weak evidence for locus-level replication with asthma was found in the PHF11 locus, although there was no overlap in the associated SNP across the two cohorts. No consistent associations were observed for the three other genes.
  
  
  CONCLUSIONS
  These results provide some further support for the role of genetic variation in GPR154 (NPSR1) and PHF11 in asthma susceptibility and also highlight the challenges of replicating genetic associations in complex traits such as asthma, even for genes identified by linkage analysis.
authors: Channing Laboratory and Center for Genomic Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. craig.hersh@channing.harvard.edu
authors: Craig P
authors: CP
authors: Hersh
authors: Benjamin A
authors: BA
authors: Raby
authors: Manuel E
authors: ME
authors: Soto-Quirós
authors: Amy J
authors: AJ
authors: Murphy
authors: Lydiana
authors: L
authors: Avila
authors: Jessica
authors: J
authors: Lasky-Su
authors: Jody S
authors: JS
authors: Sylvia
authors: Barbara J
authors: BJ
authors: Klanderman
authors: Christoph
authors: C
authors: Lange
authors: Scott T
authors: ST
authors: Weiss
authors: Juan C
authors: JC
authors: Celedón
mesh_terms: D051722:ADAM Proteins / Q000235:genetics; D000293:Adolescent; D001249:Asthma / Q000208:ethnology* / Q000235:genetics*; D002648:Child; D003001:Cloning, Molecular; D003364:Costa Rica; D004268:DNA-Binding Proteins / Q000235:genetics*; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics; D005260:Female; D023061:Gene Order; D006680:HLA Antigens / Q000235:genetics; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D007197:Indians, Central American / Q000235:genetics*; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D009656:North America; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D044465:White People / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; C484532:NPSR1 protein, human; C493258:PHF11 protein, human; D043562:Receptors, G-Protein-Coupled; D014157:Transcription Factors; C476879:DPP10 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D051722:ADAM Proteins; C450441:ADAM33 protein, human
references: Clin Exp Allergy. 2006 Jul;36(7):884-91
references: 16839403
references: Nat Genet. 2003 Nov;35(3):258-63
references: 14566338
references: Nat Genet. 2003 Jun;34(2):181-6
references: 12754510
references: Genet Med. 2002 Mar-Apr;4(2):45-61
references: 11882781
references: Vital Health Stat 10. 2006 Feb;(227):1-85
references: 16532761
references: Am J Respir Crit Care Med. 2005 Jul 1;172(1):55-60
references: 15805180
references: Genome Res. 2006 Mar;16(3):323-30
references: 16467560
references: J Allergy Clin Immunol. 2003 Oct;112(4):717-22
references: 14564349
references: J Allergy Clin Immunol. 2007 Mar;119(3):654-61
references: 17336615
references: Am J Respir Crit Care Med. 2003 Dec 1;168(11):1312-6
references: 12958057
references: Hum Genet. 2006 Feb;118(6):669-79
references: 16323010
references: J Allergy Clin Immunol. 2007 Jul;120(1):84-90
references: 17561245
references: Science. 2002 Jun 21;296(5576):2225-9
references: 12029063
references: Int J Immunogenet. 2006 Aug;33(4):303-6
references: 16893396
references: Nat Genet. 2001 Nov;29(3):306-9
references: 11600885
references: Clin Exp Allergy. 2007 Jan;37(1):83-9
references: 17210045
references: J Allergy Clin Immunol. 2004 Nov;114(5):1226-7
references: 15536436
references: Thorax. 2005 Apr;60(4):274-6
references: 15790980
references: Am J Hum Genet. 2004 Feb;74(2):367-9
references: 14740322
references: Am J Hum Genet. 2003 Oct;73(4):711-9
references: 13680525
references: J Allergy Clin Immunol. 2006 Mar;117(3):612-7
references: 16522461
references: J Clin Endocrinol Metab. 2002 Oct;87(10):4438-41
references: 12364414
references: Nat Rev Genet. 2006 Oct;7(10):781-91
references: 16983374
references: Am J Respir Crit Care Med. 2005 Jun 15;171(12):1358-62
references: 15764725
references: Nature. 2002 Jul 25;418(6896):426-30
references: 12110844
references: N Engl J Med. 2000 Oct 12;343(15):1054-63
references: 11027739
references: Am J Respir Crit Care Med. 2005 May 15;171(10):1089-95
references: 15710598
references: Nat Genet. 2006 Nov;38(11):1298-303
references: 17057720
references: JAMA. 1997 Dec 10;278(22):1855-73
references: 9396647
references: Hum Genet. 2003 May;112(5-6):534-41
references: 12601469
references: Science. 2004 Apr 9;304(5668):300-4
references: 15073379
references: Am J Hum Genet. 2005 Feb;76(2):349-57
references: 15611928
references: Eur Respir J. 1999 Nov;14(5):1210-27
references: 10596715
references: Am J Hum Genet. 2007 Mar;80(3):531-8
references: 17273975
references: Nat Genet. 2005 Nov;37(11):1217-23
references: 16244653
references: Bioinformatics. 2005 Jan 15;21(2):263-5
references: 15297300
references: Am J Hum Genet. 2006 Feb;78(2):243-52
references: 16400608
references: Clin Exp Allergy. 2004 Jan;34(1):26-31
references: 14720258
references: Pharmacogenomics. 2003 Mar;4(2):201-7
references: 12605554
references: Clin Exp Allergy. 2004 Jun;34(6):860-5
references: 15196271
references: J Allergy Clin Immunol. 2004 Jun;113(6):1071-8
references: 15208587
references: Am Rev Respir Dis. 1987 Dec;136(6):1412-7
references: 3318599
references: Am J Hum Genet. 1998 Jul;63(1):259-66
references: 9634505
references: Nat Genet. 2006 May;38(5):556-60
references: 16582909
references: Am J Respir Crit Care Med. 2005 Jul 15;172(2):183-8
references: 15879417
references: Nat Genet. 1999 May;22(1):1-2
references: 10319845
references: Lancet. 2003 Mar 8;361(9360):865-72
references: 12642066
references: J Allergy Clin Immunol. 1981 Aug;68(2):106-11
references: 7251998
references: Nature. 2007 Feb 22;445(7130):881-5
references: 17293876
references: Nature. 1996 Sep 19;383(6597):247-50
references: 8805698
references: Respir Res. 2006 Jun 19;7:91
references: 16784537
references: Clin Exp Allergy. 2006 May;36(5):602-8
references: 16650044
references: Am J Respir Crit Care Med. 2007 Nov 1;176(9):849-57
references: 17702965
references: Eur J Hum Genet. 2006 Sep;14(9):1027-36
references: 16773130
references: Nature. 2003 Dec 18;426(6968):789-96
references: 14685227
references: Control Clin Trials. 1999 Feb;20(1):91-120
references: 10027502