Temporal changes in the frequencies of HLA genotypes in patients with Type 1 diabetes—indication of an increased environmental pressure?

Hermann, Róbert; Knip, Mikael; Veijola, Riitta; Simell, Olli; Laine, A.-P.; Åkerblom, Hans K.; Groop, Per‐Henrik; Forsblom, Carol; Pettersson-Fernholm, Kim; Ilonen, Jorma

doi:10.1007/s00125-003-1045-4

Cited by 217 publications

(181 citation statements)

References 24 publications

Supporting

Mentioning

153

Contrasting

Unclassified

Order By: Relevance

“…We, and others, have already established that the frequency of HLA class II risk genotypes is decreasing as the incidence of type 1 diabetes increases [22,23]. We therefore examined whether there has been a concomitant change in the overall balance of genetic determinants of NK cell activation.…”

Section: Discussionmentioning

confidence: 99%

“…Genetic interactions between functional KIR genes and their HLA ligands were analysed in well-characterised UK populations of 179 children diagnosed with type 1 diabetes before the age of 5 years, 215 children diagnosed with type 1 diabetes between the ages of 5 and 15 years, and 168 healthy controls. As it is well established that HLA class IImediated genetic susceptibility to type 1 diabetes has decreased over the last half century [22,23], the data obtained in the first part of this study were then compared with KIR-HLA-C1 frequency in a historical cohort of individuals diagnosed in childhood with type 1 diabetes diagnosed early in the 20th century-the 'Golden Years' cohort-to establish whether determinants of NK cell function have changed over a period in which the incidence of type 1 diabetes has been increasing.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

An increased frequency of NK cell receptor and HLA-C group 1 combinations in early-onset type 1 diabetes

Mehers

Long

Slik³

et al. 2011

Diabetologia

View full text Add to dashboard Cite

Aims/hypothesis Natural killer (NK) cells serve as primary immune surveillance and are partially regulated by combinations of killer immunoglobulin-like receptor (KIR) genes and their HLA class I ligands. Alterations in NK cell activity have been associated with type 1 diabetes. The aim of this study was to determine whether KIR-HLA class I gene frequency: (1) is altered in a current population with type 1 diabetes compared with healthy controls; and (2) has changed over the half century in which the incidence of type 1 diabetes has increased rapidly.Methods KIR-HLA class I gene frequencies were compared in 551 individuals diagnosed with type 1 diabetes ≤15 years of age (394 in a current cohort and 157 from the historical 'Golden Years' cohort) and 168 healthy controls. The overall balance of activation and inhibition was analysed using KIR-HLA genotype models. Results Children with type 1 diabetes who were positive for KIR2DS2/KIR2DL2 and KIR2DL3 were more often homozygous for HLA-C group 1 and this effect was strongest in children diagnosed with diabetes before the age of 5 years (p=0.003, corrected p [p corr ]=0.012) and (p=0.001, p corr = 0.004), respectively. Children with type 1 diabetes have fewer inhibitory KIRs with their corresponding ligands compared with healthy controls (p=1.9×10 −4 ). This pattern of NK activation has not changed significantly in individuals with type 1 diabetes over the last half century. Conclusions/interpretation Activating combinations of KIR-HLA genes are more frequent in young children with type 1 diabetes diagnosed in the first 5 years of life, suggesting that NK cell responses may be altered in this group.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An increased frequency of NK cell receptor and HLA-C group 1 combinations in early-onset type 1 diabetes

Mehers

Long

Slik³

et al. 2011

Diabetologia

View full text Add to dashboard Cite

show abstract

“…The assays for autoantibodies and their detection limits have been described earlier [10]. HLA genotyping for the study was performed as described [11]. All statistical analyses were performed using StatView (5.0.1; SAS Institute, Cary, NC, USA).…”

Section: Methodsmentioning

confidence: 99%

Cytomegalovirus infection in early infancy: risk of induction and progression of autoimmunity associated with type 1 diabetes

et al. 2008

Self Cite

View full text Add to dashboard Cite

Aims/hypothesis Type 1 diabetes is an autoimmune disease resulting from a complex interplay between genetic and environmental factors. Cytomegalovirus (CMV) infection is one of the environmental factors implicated in the development of type 1 diabetes, although the association remains unproven. We aimed to clarify the possible correlation between CMV infections and type 1 diabetes-associated autoimmunity at the time point of autoantibody appearance in young children with HLA-conferred disease susceptibility.Methods CMV-specific IgG antibodies were analysed from serum samples of 169 children who had developed the first type 1 diabetes-associated autoantibody by the age of 2 years and who turned positive for multiple autoantibodies during later follow-up. We also studied 791 control children matched for sex, age and HLA genotype. The subsequent progression to clinical diabetes was analysed. The serum specimens used were collected at the time of autoantibody seroconversion or within the next 6 months. Results The frequency of CMVantibodies was similar in both study groups at the time of the first autoantibody appearance. Of the index children, 38 (22.5%) were CMV IgG antibodypositive, while the figure for control children was 206 (26.0%; p=0.38). No association between perinatal CMV infection and progression to type 1 diabetes was observed. Conclusions/interpretation According to these results, perinatal CMV infections are not associated with early serological signs of beta cell autoimmunity or progression to type 1 diabetes in children with diabetes risk-associated HLA genotype.

show abstract

“…The 2 relate inversely to each other so that if the risk rises, the proportion of probability attributable to susceptibility must fall. There is good epidemiological evidence that the genetic contribution to the probability of T1D has fallen over recent years [42,43], implying that the 3-fold rise since the 1980s is related to environmental change. Such evidence does not indicate what environmental change, and has to be interpreted sparingly on that account.…”

Section: Evidencementioning

confidence: 99%

Is Autoimmunity or Insulin Resistance the Primary Driver of Type 1 Diabetes?

Wilkin

2013

Curr Diab Rep

View full text Add to dashboard Cite

Diabetes is usually classified as autoimmune or metabolic but, as difficulties have arisen with the taxonomy of diabetes, it may help to forego the conventional classification for a more inclusive model. Thus, all diabetes can be ascribed to beta cell insufficiency-hyperglycemia occurs only when the insulin supply fails to meet demand. Humans enter the world with a reserve of beta cells, which is eroded variably by apoptosis over the course of a lifetime. For most, the loss is slow and inconsequential but, for others fast enough to be critical within a lifetime. The challenge now is to define the factors that vary the tempo of beta cell loss, because tempo, not type, seems likely to determine whether diabetes occurs at all, in adulthood or in childhood. Insulin resistance is generally believed to underpin T2D, but has been a feature of insulin-dependent diabetes as well for nearly 80 years, though largely ignored until immunotherapy trials to test the autoimmunity hypothesis persistently failed to bring patient benefit. It seems possible that insulin resistance accelerates beta cell loss generally, its impact modulated by an immune response (autoimmunity) to the beta-cell stress whose intensity varies with immunogenotype. If so, the target for prevention of T1D might more logically lie with insulin sensitivity than with immunoregulation.

show abstract

Temporal changes in the frequencies of HLA genotypes in patients with Type 1 diabetes—indication of an increased environmental pressure?

Cited by 217 publications

References 24 publications

An increased frequency of NK cell receptor and HLA-C group 1 combinations in early-onset type 1 diabetes

An increased frequency of NK cell receptor and HLA-C group 1 combinations in early-onset type 1 diabetes

Cytomegalovirus infection in early infancy: risk of induction and progression of autoimmunity associated with type 1 diabetes

Is Autoimmunity or Insulin Resistance the Primary Driver of Type 1 Diabetes?

Contact Info

Product

Resources

About