Fifty years of HLA-associated type 1 diabetes risk: history, current knowledge, and future directions

Abstract

More than 50 years have elapsed since the association of human leukocyte antigens (HLA) with type 1 diabetes (T1D) was first reported. Since then, methods for identification of HLA have progressed from cell based to DNA based, and the number of recognized HLA variants has grown from a few to tens of thousands. Current genotyping methodology allows for exact identification of all HLA-encoding genes in an individual's genome, with statistical analysis methods evolving to digest the enormous amount of data that can be produced at an astonishing rate. The HLA region of the genome has been repeatedly shown to be the most important genetic risk factor for T1D, and the original reported associations have been replicated, refined, and expanded. Even with the remarkable progress through 50 years and over 5,000 reports, a comprehensive understanding of all effects of HLA on T1D remains elusive. This report represents a summary of the field as it evolved and as it stands now, enumerating many past and present challenges, and suggests possible paradigm shifts for moving forward with future studies in hopes of finally understanding all the ways in which HLA influences the pathophysiology of T1D.

Keywords: HLA; Type 1 diabetes; autoimmunity; disease association; diversity,; immune polymorphism.

Figure 1

Schematic representation of chromosomal region encoding HLA-DR antigens; not to scale. Although they are separate loci, DRB3, DRB4, and DRB5 are separate loci but are represented as a single locus for convenience. Expressed loci are represented by solid blocks. Striped blocks represent pseudogenes. Arrows designate direction of transcription for expressed genes. Chromosome groups are designated by the first-field nomenclature, for example, DRB1*01, which represents the corresponding serologic group. Alternate, historical name categories for the groups are given in parentheses.

Figure 2

Representation of individual haplotypes that can be found in a “DR3/DR4” heterozygous individual. (A) Typical DR3/DR4 genotype for a high-risk individual of European descent. Potential allele pairs that could produce trans-encoded DQ molecules are circled. (B) Potential DR3/DR4 haplotype from mixed-population individual with one Asian and one Black parent, composed of two T1D-protective haplotypes.

Figure 3

World map depicting countries from which HLA association with T1D have been reported. Any report from a given country, even if from a small region, results in indication of the country. Countries with reports dating from 2016 to June 2024 are shown in yellow. Citations from those countries are listed in Table 2 and include Albania, Algeria, Argentina, Armenia, Bahrain, Cameroon, Canary Islands (Spain), Chile, Czech Republic, Denmark, Estonia, Fiji, France, Georgia, Georgia, Greece, Hungary, Iraq, Israel, Jamaica, Java (Indonesia), South Korea, La Reunion Island, Latvia, Lebanon, Libya, Lithuania, North Macedonia, Malaysia, Martinique, Morocco, Naura, New Caledonia, Newfoundland (Canada), Nigeria, Philippines, Poland, Puerto Rico, Russia, Russia, Senegal, Serbia, Slovakia, Slovenia, Turkey, Uruguay, Wallis Islands, Zimbabwe. Countries with earlier reported data are shown in blue.

Figure 4

Comparison of data from HLA-DRB1, -DQA1, and -DQB1 association with T1D in Kuwait (K) and Mali (M) (108). (A) Allele level data. Gray: allele was present in the population at sufficiency frequency for association analysis. Black: allele was significantly associated with disease. “Binned” category contains all alleles that were present but at frequencies too low for individual association analysis. (B) Amino Acid position level data. Gray: positions with at least one amino acid residue that shows T1D association not seen in data for the other country. Black: positions in which the same amino acid residues with consistent directions of effect (e.g., predisposing or protective) are seen in both countries. With one exception, each of these positions represents two amino acids, one predisposing and one protective. *Position 125 of DQB1 has only one T1D-associated amino acid residue for each country, but the amino acid and effect direction are consistent. Diagonal lines: positions for which one country shows a greater number of associated amino acids than the other; in all cases, effect direction is consistent for amino acids that appear in both. All but one of these positions shows more associated amino acids for Mali that Kuwait. Only one position, DRB1 position 71, shows more associated amino acids in Kuwait than in Mali. Lines are shown in the opposite diagonal direction to indicate this difference. Crosshatch: positions for which the two countries share one significant amino acid association, but each has an additional, unique association. Notably, no individual amino acid had an effect that differed in direction between the two countries (i.e., predisposing in one dataset but protective in the other).