HLA class II genotyping of admixed Brazilian patients with type 1 diabetes according to self-reported color/race in a nationwide study

Abstract

The HLA region is responsible for almost 50% of the genetic risk of type 1 diabetes (T1D). However, haplotypes and their effects on risk or protection vary among different ethnic groups, mainly in an admixed population. We aimed to evaluate the HLA class II genetic profile of Brazilian individuals with T1D and its relationship with self-reported color/race. This was a nationwide multicenter study conducted in 10 Brazilian cities. We included 1,019 T1D individuals and 5,116 controls matched for the region of birth and self-reported color/race. control participants belonged to the bone marrow transplant donor registry of Brazil (REDOME). HLA-class II alleles (DRB1, DQA1, and DQB1) were genotyped using the SSO and NGS methods. The most frequent risk and protection haplotypes were HLA~DRB1*03:01~DQA1*05:01 g~DQB1*02:01 (OR 5.8, p < 0.00001) and HLA~DRB1*07:01~DQA1*02:01~DQB1*02:02 (OR 0.54, p < 0.0001), respectively, regardless of self-reported color/race. Haplotypes HLA~DRB1*03:01~DQA1*05:01 g~DQB1*02:01 and HLA~DRB1*04:02~DQA1*03:01 g~DQB1*03:02 were more prevalent in the self-reported White group than in the Black group (p = 0.04 and p = 0.02, respectively). The frequency of haplotype HLA~DRB1*09:01~DQA1*03:01 g~DQB1*02:02 was higher in individuals self-reported as Black than White (p = <0.00001). No difference between the Brazilian geographical regions was found. Individuals with T1D presented differences in frequencies of haplotypes within self-reported color/race, but the more prevalent haplotypes, regardless of self-reported color/race, were the ones described previously in Europeans. We hypothesize that, in the T1D population of Brazil, although highly admixed, the disease risk alleles come mostly from Europeans as a result of centuries of colonization and migration.Type 1 diabetes (T1D) is a chronic polygenic disease that arises from the combination of multiple genetic and environmental factors 1 . The HLA region on chromosome 6p21 is known to be responsible for almost 50% of the genetic risk, and it has been associated with diabetes since the 1970s 2 . Even though HLA Class I genes and non-HLA genes also contribute to T1D risk, Class II alleles such as DR and DQ demonstrate the strongest associations with the disease 1,3 .Susceptibility to T1D is mainly associated with haplotype DRB1*04~DQA1*03:01~DQB1*03:02, followed by DRB1*03:01~DQA1*05:01~DQB1*02:01 3 . More than 90% of patients carry one of those two haplotypes, and 30% carry both of them, while the prevalence in the general population is 2% 4-6 , including previous data from regional populations and familial studies from Brazil 7-9 .In recent years, several risk scores for the diagnosis and risk assessment of T1D have been proposed, using growing and extensive knowledge about T1D genetics 1 . Most of them are based on the presence of high-risk HLA alleles described in previous studies 10-12 .

Genetic Ancestry Inferred From Autosomal and Y Chromosome Markers and HLA&nbsp;Genotypes in Type 1 Diabetes From an Admixed Brazilian Population.

“…As expected, our results showed that when comparing our T1D group, the CRsr and regional REDOME controls, the DRB1 * 03 and DRB1 * 04 alleles showed an odds ratio of risk for association with T1D, with DRB1 * 04 (30.26%), DRB1 * 03 (29.93%) and the DR3 / DR4 heterozygous genotype (26.32%) as the most frequents. In a large analysis of the T1D population in all Brazilian regions, a result similar to ours was found 46 . It is reported that approximately 30% of individuals with T1D have DR3/DR4 in heterozygosity 6,47 , corroborating our ndings.…”

“…We still found that the most frequent DQA1 alleles were 05:01 (29.14%), and 03:01 (26.82%), and the most frequent DQB1 alleles were 03:02 (32.57%), 02:01 (26.32%), compatible with the fact that these are the most frequent DQA1 and DQB1 alleles associated with T1D 4 . In a study performed by Santos et al, it was observed that in Brazilian individuals with T1D, the same haplotype, DRB1*03:01~DQA1*05:01~DQB1*02:01 (DR3-DQ2), was the most frequently found in this subpopulation of individuals 46 .…”

“…In patients of African origin, additional haplotypes are associated with risk, such as DRB1 * 09: 01~DQA1* 03:01~DQB1* 02:01 and DRB1* 07:01~DQA1* 03:01~DQB1* 02:01 8 . It is also important to note that same haplotype, such as DR7 molecule, is often seen in Europeans with a protective effect and as a risk factor in African-American populations for T1D, being the most frequent protective haplotype in a study of Brazilian T1D patients, regardless of self-reported color-race 9 .…”

Apolipoprotein CIII Is an Important Piece in the Type-1 Diabetes Jigsaw Puzzle

“…T1D is an autoimmune disease and there are several biomarkers serving as risk indicators. A genetic predisposition is required and certain high-risk human leukocyte antigen (HLA) genotypes have been identified [ 1 , 2 , 3 ]. There is a genetic inheritance, but only 15% of patients with T1D have a first-degree relative with the disease.…”

How Ancestry Influences the Chances of Finding Unrelated Donors: An Investigation in Admixed Brazilians

“…In admixed populations, individuals who self-identify to the same group frequently have extremely variable genetic ancestries. This is expected, since self-identification involves a complex interplay of social and genealogical components (19) and varies among geographic regions in Brazil (20,21).…”