title: Genetic prediction of type 1 diabetes in a population with low frequency of HLA risk genotypes and low incidence of the disease (the DIABFIN study).
abstract: BACKGROUND
  To develop a sensitive, specific screening strategy for predicting genetic risk for type 1 diabetes mellitus (T1DM) in the low-incidence continental Italian population, and to define with this tool, a cohort of high-to-moderate risk infants for an immunological follow-up study aimed at identifying environmental risk factors for T1DM.
  
  
  METHODS
  4855 newborns in three regions of continental Italy were screened for T1DM HLA-DRB1-DQB1 risk genotypes using a reverse line blot typing method. Risk classification was based on odds ratios (OR) found in a preliminary case-control study (356 T1DM patients, 412 controls). Screening efficiency was optimized by allele subtyping.
  
  
  RESULTS
  Screening for well-known T1DM susceptibility genotypes [DRB1*03/*04-DQB1*0302; DRB1*03/*03; DRB1*04/*04-DQB1*0302; DRB1*04-DQB1*0302/X where X is not equal to DRB1*03, DRB1*04-DQB1*0302, DQB1*0602 or DQB1*0603] was associated with <60% sensitivity due to their low frequencies in the general Italian population. Inclusion of an additional genotype from which protective DRB1 and DQB1 alleles had been excluded [DRB1*03/X degrees where DQB1 is not equal to *0301, *0503, *0602, or *0603 and X degrees not equal DRB1*03, DRB1*04-DQB1*0302 or DRB1*07] increased screening sensitivity to 75% (specificity: 85%). Among 4855 newborns, we have found the high-risk genotype [DRB1*03/*04-DQB1*0302; estimated absolute risk (AR) 1/23] to be present in only 0.9%. The moderate-risk genotypes were found in 13.8% of newborns (estimated AR 1/177).
  
  
  CONCLUSIONS
  Risk classification must be tailored to the characteristics of the individual population, in particular, the allelic frequencies in the background population and T1DM prevalence. We have developed a screening strategy with good levels of sensitivity that should prove effective for use throughout the Italian peninsula.
authors.affiliation: Endocrinology, Department of Clinical Sciences, La Sapienza University, Rome, Italy. raffaella.buzzetti@uniroma1.it
authors.forename: R
authors.initials: R
authors.lastname: Buzzetti
authors.forename: A
authors.initials: A
authors.lastname: Galgani
authors.forename: A
authors.initials: A
authors.lastname: Petrone
authors.forename: M L
authors.initials: ML
authors.lastname: Del Buono
authors.forename: H A
authors.initials: HA
authors.lastname: Erlich
authors.forename: T L
authors.initials: TL
authors.lastname: Bugawan
authors.forename: R
authors.initials: R
authors.lastname: Lorini
authors.forename: F
authors.initials: F
authors.lastname: Meschi
authors.forename: G
authors.initials: G
authors.lastname: Multari
authors.forename: P
authors.initials: P
authors.lastname: Pozzilli
authors.forename: M
authors.initials: M
authors.lastname: Locatelli
authors.forename: G
authors.initials: G
authors.lastname: Bottazzo
authors.forename: U
authors.initials: U
authors.lastname: Di Mario
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D005820:Genetic Testing; D006683:HLA-DQ Antigens / Q000235:genetics*; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006650:Histocompatibility Testing; D006801:Humans; D015994:Incidence; D007231:Infant, Newborn; D007558:Italy / Q000453:epidemiology; D008297:Male; D012307:Risk Factors; D018709:Statistics, Nonparametric
chemical_list: D005819:Genetic Markers; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains