Evidence of gene-gene interaction and age-at-diagnosis effects in type 1 diabetes.
The common genetic loci that independently influence the risk of type 1 diabetes have largely been determined. Their interactions with age-at-diagnosis of type 1 diabetes, sex, or the major susceptibility locus, HLA class II, remain mostly unexplored. A large collection of more than 14,866 type 1 diabetes samples (6,750 British diabetic individuals and 8,116 affected family samples of European descent) were genotyped at 38 confirmed type 1 diabetes-associated non-HLA regions and used to test for interaction of association with age-at-diagnosis, sex, and HLA class II genotypes using regression models. The alleles that confer susceptibility to type 1 diabetes at interleukin-2 (IL-2), IL2/4q27 (rs2069763) and renalase, FAD-dependent amine oxidase (RNLS)/10q23.31 (rs10509540), were associated with a lower age-at-diagnosis (P = 4.6 × 10⁻⁶ and 2.5 × 10⁻⁵, respectively). For both loci, individuals carrying the susceptible homozygous genotype were, on average, 7.2 months younger at diagnosis than those carrying the protective homozygous genotypes. In addition to protein tyrosine phosphatase nonreceptor type 22 (PTPN22), evidence of statistical interaction between HLA class II genotypes and rs3087243 at cytotoxic T-lymphocyte antigen 4 (CTLA4)/2q33.2 was obtained (P = 7.90 × 10⁻⁵). No evidence of differential risk by sex was obtained at any loci (P ≥ 0.01). Statistical interaction effects can be detected in type 1 diabetes although they provide a relatively small contribution to our understanding of the familial clustering of the disease.
Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, Department of Medical Genetics, University of Cambridge, Cambridge, UK. joanna.howson@cimr.cam.ac.uk
Joanna M M
JM
Howson
Jason D
JD
Cooper
Deborah J
DJ
Smyth
Neil M
NM
Walker
Helen
H
Stevens
Jin-Xiong
JX
She
George S
GS
Eisenbarth
Marian
M
Rewers
John A
JA
Todd
Beena
B
Akolkar
Patrick
P
Concannon
Henry A
HA
Erlich
Cécile
C
Julier
Grant
G
Morahan
Jørn
J
Nerup
Concepcion
C
Nierras
Flemming
F
Pociot
Stephen S
SS
Rich
D000328:Adult; D017668:Age of Onset; D000483:Alleles; D060908:CTLA-4 Antigen / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D015331:Cohort Studies; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology* / Q000208:ethnology / Q000235:genetics*; D004843:Epistasis, Genetic; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008995:Monoamine Oxidase / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics* / Q000378:metabolism; D012044:Regression Analysis; D044465:White People
D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C508594:IL2 protein, human; D007376:Interleukin-2; D008995:Monoamine Oxidase; C521557:renalase; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22