Use of class I and class II HLA loci for predicting age at onset of type 1 diabetes in multiple populations.
OBJECTIVE
The study aimed to assess, in multiple populations, the role of HLA alleles on early and late age at onset of type 1 diabetes.


METHODS
Stepwise linear regression models were used to determine which HLA class I and class II risk alleles to include. High-resolution genotyping data for patients from the Type 1 Diabetes Genetics Consortium (T1DGC) collection (n = 2,278) and four independent cohorts from Denmark, Sardinia and the USA (Human Biological Data Interchange [HBDI] and Joslin Diabetes Center) (n = 1,324) (total n = 3,602) were used to assess the role of HLA variation on age of onset and predict early onset (age ≤ 5 years) and late onset (age ≥ 15 years) of type 1 diabetes.


RESULTS
In addition to carriage of HLA class I alleles A*24:02, B*39:06, B*44:03 and B*18:01, HLA class II DRB1-DQB1 loci significantly contributed to age at onset, explaining 3.4% of its variance in the combined data. HLA genotypes, together with sex, were able to predict late onset in all cohorts studied, with AUC values ranging from 0.58 to 0.63. Similar AUC values (0.59-0.70) were obtained for early onset for most cohorts, except in the Sardinian study, in which none of the models tested had significant predictive power.


CONCLUSIONS
HLA associations with age of onset are consistent across most white populations and HLA information can predict some of the risk of early and late onset of type 1 diabetes. Considerable heterogeneity was observed between Sardinian and other populations, particularly with regard to early age of onset.
Department of Twin Research and Genetic Epidemiology, King's College London, St Thomas' Hospital, London SE1 7EH, UK. ana.valdes@kcl.ac.uk
A M
AM
Valdes
H A
HA
Erlich
J
J
Carlson
M
M
Varney
P V
PV
Moonsamy
J A
JA
Noble
D017668:Age of Onset; D002648:Child; D015331:Cohort Studies; D003718:Denmark / Q000453:epidemiology; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology* / Q000235:genetics; D003928:Diabetic Nephropathies / Q000453:epidemiology* / Q000235:genetics; D003930:Diabetic Retinopathy / Q000453:epidemiology* / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006801:Humans; D007558:Italy / Q000453:epidemiology; D007676:Kidney Failure, Chronic / Q000453:epidemiology* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D014481:United States / Q000453:epidemiology
D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II