HLA class I and genetic susceptibility to type 1 diabetes: results from the Type 1 Diabetes Genetics Consortium.
OBJECTIVE
We report here genotyping data and type 1 diabetes association analyses for HLA class I loci (A, B, and C) on 1,753 multiplex pedigrees from the Type 1 Diabetes Genetics Consortium (T1DGC), a large international collaborative study.


METHODS
Complete eight-locus HLA genotyping data were generated. Expected patient class I (HLA-A, -B, and -C) allele frequencies were calculated, based on linkage disequilibrium (LD) patterns with observed HLA class II DRB1-DQA1-DQB1 haplotype frequencies. Expected frequencies were compared to observed allele frequencies in patients.


RESULTS
Significant type 1 diabetes associations were observed at all class I HLA loci. After accounting for LD with HLA class II, the most significantly type 1 diabetes-associated alleles were B*5701 (odds ratio 0.19; P = 4 × 10(-11)) and B*3906 (10.31; P = 4 × 10(-10)). Other significantly type 1 diabetes-associated alleles included A*2402, A*0201, B*1801, and C*0501 (predisposing) and A*1101, A*3201, A*6601, B*0702, B*4403, B*3502, C*1601, and C*0401 (protective). Some alleles, notably B*3906, appear to modulate the risk of all DRB1-DQA1-DQB1 haplotypes on which they reside, suggesting a class I effect that is independent of class II. Other class I type 1 diabetes associations appear to be specific to individual class II haplotypes. Some apparent associations (e.g., C*1601) could be attributed to strong LD to another class I susceptibility locus (B*4403).


CONCLUSIONS
These data indicate that HLA class I alleles, in addition to and independently from HLA class II alleles, are associated with type 1 diabetes.
Noble
Janelle A
JA
Children's Hospital Oakland Research Institute, Oakland, California, USA. jnoble@chori.org
Valdes
Ana Maria
AM
Varney
Michael D
MD
Carlson
Joyce A
JA
Moonsamy
Priscilla
P
Fear
Anna Lisa
AL
Lane
Julie A
JA
Lavant
Eva
E
Rappner
Rebecca
R
Louey
Anthony
A
Concannon
Patrick
P
Mychaleckyj
Josyf C
JC
Erlich
Henry A
HA
D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology* / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D005091:Exons; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D015234:HLA-A Antigens / Q000235:genetics; D015235:HLA-B Antigens / Q000235:genetics; D015236:HLA-C Antigens / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000473:pathology; D015810:Linkage Disequilibrium; D008297:Male; D011110:Polymorphism, Genetic; D013601:T-Lymphocytes / Q000276:immunology
D015234:HLA-A Antigens; D015235:HLA-B Antigens; D015236:HLA-C Antigens; D015395:Histocompatibility Antigens Class I
Tissue Antigens. 2003 Feb;61(2):146-53
12694582
Nature. 2007 Dec 6;450(7171):887-92
18004301
Genes Immun. 2009 Dec;10(8):673-7
19693088
Diabetes Obes Metab. 2009 Feb;11 Suppl 1:31-45
19143813
Diabetes. 2006 May;55(5):1265-9
16644681
Hum Immunol. 2005 Mar;66(3):301-13
15784469
Diabetes. 2001 May;50(5):1200-5
11334427
Am J Hum Genet. 1995 Aug;57(2):487-98
7668275
Am J Hum Genet. 1984 Nov;36(6):1309-17
6334991
Bratisl Lek Listy. 2006;107(3):73-5
16796127
Diabetes. 2000 Jan;49(1):121-5
10615959
Tissue Antigens. 2002 Jun;59(6):452-69
12445315
Diabetes. 2004 Aug;53(8):2158-63
15277401
Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2709-14
10694578
Genet Epidemiol. 2001 Nov;21(3):212-23
11668578
Genes Immun. 2010 Apr;11(3):209-18
20054343
Hum Immunol. 2002 Aug;63(8):657-64
12121673
J Exp Med. 2003 Sep 1;198(5):679-91
12939341
Tissue Antigens. 1998 Jun;51(6):587-92
9694350
Diabetes. 2008 Apr;57(4):1084-92
18252895