Early Onset of Diabetes in the Proband Is the Major Determinant of Risk in HLA DR3-DQ2/DR4-DQ8 Siblings

Abstract

Islet autoimmunity is initiated in infancy, and primary prevention trials require children at high genetic risk to be identified before autoantibodies appear. To inform screening strategies, we evaluated risks of autoimmunity and diabetes associated with HLA DR3-DQ2/DR4-DQ8 in U.K. families. Extended HLA haplotypes were determined in 2,134 siblings from the Bart's-Oxford Study followed to a median age of 22 years. Risks of diabetes and islet autoimmunity (more than two antibodies) were estimated by survival analysis. Of 138 informative DR3-DQ2/DR4-DQ8 siblings, 63% shared both haplotypes with their diabetic proband, 29% shared one, and 8% shared neither. In HLAidentical DR3-DQ2/DR4-DQ8 siblings, the cumulative risk of diabetes by age 15 was 17% (vs. 6% in those sharing one haplotype or none; P = 0.095). Risk varied, however, with the age at the onset of diabetes in the proband; the cumulative risk of autoimmunity and/or diabetes by age 15 was 61% in siblings of probands diagnosed when younger than 10 years old compared with only 4.7% in those diagnosed after age 10 years (P < 0.001). The age of the proband at diagnosis, but not HLA haplotype sharing, was an independent determinant of sibling risk. This suggests that non-HLA genes or epigenetic/environmental factors that accelerate the progression of type 1 diabetes in the proband strongly affect risk in siblings. Diabetes 2014;63:104163: -104763: | DOI: 10.2337 Type 1 diabetes results from the autoimmune destruction of insulin-producing b-cells, a process that begins early in life. Islet autoantibodies are detectable by the age of 5 years-often by the age of 2 years-in children who go on to develop diabetes, and autoantibodies to insulin (generally the first to appear) have been detected as early as 6-12 months (1,2). Established islet autoimmunity is difficult to modulate, and therefore strategies aimed at primary prevention before the initiation of autoimmunity are needed. Trials of potential interventions at this stage will have to recruit children on the basis of genetic risk alone.Recent whole-genome studies have resulted in an explosion of information regarding genetic susceptibility to type 1 diabetes, but the HLA region remains the most important genetic determinant. More than 90% of children with type 1 diabetes carry the HLA class II haplotypes DRB1*03-DQB1*02:01 (DR3-DQ2) and/or DRB1*04-DQB1*03:02 (DR4-DQ8), and the highest risk DR3-DQ2/DR4-DQ8 diplotype is present in 50% of cases of very early-onset diabetes (3). We and others have previously shown that the age of diagnosis of children with type 1 diabetes and the number of HLA haplotypes they share are determinants of risk of diabetes in their siblings (3,4). HLA class II determined risk can also be modulated by other factors close to or within the HLA region as well as by non-HLA genes (5).Current trials to prevent the initiation of islet autoimmunity use HLA-based risk assessment to identify individuals eligible for inclusion, but they use different Other primary prevention trials are seeking to ...

ISPAD Clinical Practice Consensus Guidelines 2018: Definition, epidemiology, and classification of diabetes in children and adolescents

“…The lifelong risk of diabetes to an identical twin of a patient with type 1 diabetes is <40%; for a sibling the risk is approximately 4% by age 20 years and 9.6% by age 60 years; compared with 0.5% for the general population. The cumulative risk of diabetes by age 15 is greater in HLA‐identical DR3‐DQ2/DR4‐DQ8 siblings (17% vs 6% in those sharing one haplotype or none) . The risk is also higher in siblings of probands diagnosed at younger age, paternal young‐onset diabetes, male sex, and older parental age …”

Diabetes mellitus in childhood: an emerging condition in the 21st century

“…[14][15][16] The global prevalence of DM1 is estimated at around 0.3 to 0.4%. 17 The IDF has carried out estimates of the prevalence of DM in the world since 2000, noting a large increase in these figures, with significant regional variations. 18 The IDF's Diabetes Atlas -2015 estimates that every year around 86,000 children under the age of 15 develop DM1 worldwide, with a total of around 542,000 children with the disease; among the ten countries with the highest number of children with DM1, Brazil would occupy the third position, with 30,900 cases.…”

“…The causes of this phenomenon are still unknown, and it is possible that the youngest group presents a higher proportion of HLA susceptibility genes or that there has been an increase in the penetrance of these genes at younger ages due to harmful changes in the environment. 17,[26][27][28] The mode of transmission of DM1 is complex and around 80 to 85% of new cases of the disease occur sporadically, without familial aggregation. 29 However, there is a higher prevalence of the disease among patients' first--degree relatives, primarily in populations with a high incidence of DM.…”

Type 1 Diabetes: Disease Stratification

“…Only approximately 10-15% of individuals newly diagnosed with T1D have a family history, but family history increases risk of disease ∼ 10-100-fold higher than background population [24,35] . Risk is higher for identical twins or with sharing of HLA genotype with the proband, is higher in offspring of fathers with T1D compared to offspring of mothers with T1D, and is ∼ 14-fold higher in DR3/DR4-positive siblings if the proband develops symptomatic diabetes before age 10 years [35,36] . As noted above, HLA genotype accounts for half of the genetic risk, and specific HLA alleles are associated with higher risk of disease and have been used to stratify a high versus moderate risk population [35,37] , or protection or resistance from developing disease, such as occurs with HLA class II DRB1 * 1501 and DQA1 * 0102-DQB1 * 0602 [38] .…”

“…HLA [25] and especially non-HLA genes [36,[79][80][81] are associated with a faster rate of progression from stage 1. There are differences in age and genetic predisposition for specificity of antibodies -insulin antibodies occur at an earlier peak age incidence (9-24 months) than GAD antibodies ( ∼ 36 months), with IA-2 and ZnT8 tending to occur later and rarely as the first autoantibody.…”