HLA genetics of LADA.pdf — page 1

HLA genetics in LADA
Original article:
An association analysis of the HLA gene region in
latent autoimmune diabetes in adults. Desai M,
Zeggini E, Horton VA, Owen KR, Hattersley AT, Levy JC,
Walker M, Gillespie KM, Bingley PJ, Hitman GA,
Holman RR, McCarthy MI, Clark A. Diabetologia 2007;
50: 68–73.
Summary and Comment:
Vincent Geenen, Liège, Belgium
Key words:
Type 1 diabetes, latent autoimmune diabetes in adults
(LADA), genetic susceptibility, HLA
Summary
The major susceptibility genes for type 1 dia-
betes, HLA-DRB1 and HLA-DQB1, were geno-
typed by sequence-specific polymerase chain
reaction in 387 patients with latent autoimmune
diabetes in adults (LADA) and in 327 non-
diabetic controls.
The main susceptibility haplotypes in LADA
were identical to those in classical type 1 diabetes.
The highest risk genotypes were associated with a
younger age at diagnosis, while genotypes con-
taining protective haplotypes were associated with
an older age at diagnosis. Differential susceptibil-
ity was associated with DR4 subtypes: DRB*0401
conferred susceptibility to LADA, whereas
DRB1*0403 conferred significant protection.
The authors concluded that differences in
HLA-encoded susceptibility could not explain
the differences observed in clinical presentation
between classical type 1 diabetes and LADA.
Differences in HLA-encoded
susceptibility could not explain the
differences observed in clinical
presentation between classical type
1 diabetes and LADA
Comment
Type 1 diabetes is a polygenic chronic disease
that results from the progressive destruction of
insulin-secreting islet β-cells by a cell-specific
autoimmune response. Development of selective
β-cell autoimmunity derives from the absence or
disruption of both central (thymus-dependent)
and peripheral self-tolerance toward islet β-cells.
Genetic and still undefined environmental fac-
tors interact to determine the development and
onset of type 1 diabetes.
Three major autoantigens have been identified
in the disease: the secreted hormone insulin (as
well as its non-secreted precursor proinsulin);
the 65 kDa isoform of glutamic acid decarboxy-
lase, GAD65; and the insulinoma-associated
tyrosine phosphatase, IA-2. Proinsulin is the
most specific β-cell antigen but also the primary
autoantigen tackled by the effector autoreactive
lymphocytes.
Type 1 diabetes represents around 15% of all
cases of diabetes and its peak incidence ranges
between 10 and 14 years of age.The term
LADA was first introduced to describe patients
with a slowly progressive form of autoimmune
diabetes that could be treated initially without
insulin [1].The acronym is also used to distin-
guish LADA from type 1 diabetes with immedi-
ate need for insulin, and from type 2 diabetes
where insulin is not required at all or not for
years after diagnosis.This form of autoimmune
diabetes has also been designated as slowly pro-
gressive insulin-dependent diabetes or as type
1.5 diabetes. Diagnosis of LADA relies on three
criteria: adult age at diagnosis (≥30 years), the
presence of β-cell autoantibodies, and a delay of
several months (at least 6 months) from initial
diagnosis before the need for insulin to control
hyperglycemia. Since islet autoantibodies
against insulin and phosphatase IA-2 are rare in
late-onset diabetes, the diagnosis of LADA is
mainly based upon the detection of GAD
autoantibodies. However, given that GAD
autoantibodies are also detected in classical type
1 diabetes, their use to define LADA lacks
specificity. Consequently, a debate has now
begun with regard to the necessity, as well as the
medical benefit, for designating LADA as a
unique etiological entity [2, 3].
A debate has now begun with regard to
the necessity, as well as the medical
benefit, for designating LADA as a
unique etiological entity
Type 1 diabetes is a polygenic disease, but the
major genetic contribution (±50%) comes from
the histocompatibility HLA region on chromo-
some 6 (IDDM1). Cross-sectional studies have
previously shown that age at diagnosis of type 1
diabetes is inversely correlated to the frequency
of highest risk HLA phenotypes (DR3/DQ2
and/or DR4/DQ8) [4, 5]. Before their present
study, the authors showed that the genetic sus-
144
International Diabetes Monitor
Volume 20, Number 3, 2008
Commentaries