Major Histocompatibility Complex Variants Research Articles

Genetic and healthy lifestyle factors in relation to the incidence and prognosis of severe liver disease in the Chinese population.

Severe liver disease (SLD), including cirrhosis and liver cancer, constitutes a major disease burden in China. We aimed to examine the association of genetic and healthy lifestyle factors with the incidence and prognosis of SLD. The study population included 504,009 participants from the prospective China Kadoorie Biobank aged 30-79 years. The individuals were from 10 diverse areas in China without a history of cancer or liver disease at baseline. Cox regression was used to estimate adjusted hazard ratios (HRs) for incident SLD and death after SLD diagnosis associated with healthy lifestyle factors (smoking, alcohol, physical activity, and central adiposity). Additionally, the contribution of genetic risk for hepatitis B virus (HBV, assessed by genetic variants in major histocompatibility complex, class II, DP/DQ [ HLA - DP / DQ ] genes) was also estimated. Compared with those with 0-1 healthy lifestyle factor, participants with 2, 3, and 4 factors had 12% (HR 0.88 [95% confidence interval [CI] 0.85, 0.92]), 26% (HR 0.74 [95%CI: 0.69, 0.79]), and 44% (HR 0.56 [95%CI: 0.48, 0.65]) lower risks of SLD, respectively. Inverse associations were observed among participants with both low and high genetic risks (HR per 1-point increase 0.83 [95%CI: 0.74, 0.94] and 0.91 [95%CI: 0.82, 1.02], respectively; Pinteraction = 0.51), although with a non-significant trend among those with a high genetic risk. Inverse associations were also observed between healthy lifestyle factors and liver biomarkers regardless of the genetic risk. Despite the limited power, healthy lifestyle factors were associated with a lower risk of death after incident SLD among participants with a low genetic risk (HR 0.59 [95%CI: 0.37, 0.96]). Lifestyle modification may be beneficial in terms of lowering the risk of SLD regardless of the genetic risk. Moreover, it is also important for improving the prognosis of SLD in individuals with a low genetic risk. Future studies are warranted to examine the impact of healthy lifestyles on SLD prognosis, particularly among individuals with a high genetic risk.

Evolution of MHC IIB Diversity Across Cichlid Fish Radiations.

The genes of the major histocompatibility complex (MHC) are among the most polymorphic genes in vertebrates, and crucial for their adaptive immune response. These genes frequently show inconsistencies between allelic genealogies and species phylogenies. This phenomenon is thought to be the result of parasite-mediated balancing selection maintaining ancient alleles through speciation events (trans-species polymorphism, TSP). However, allele similarities may also arise from post-speciation mechanisms, such as convergence or introgression. Here, we investigated the evolution of MHC class IIB diversity in the cichlid fish radiations across Africa and the Neotropics by a comprehensive review of available MHC IIB DNA sequence information. We explored what mechanism explains the MHC allele similarities found among cichlid radiations. Our results showed extensive allele similarity among cichlid fish across continents, likely due to TSP. Functionality at MHC was also shared among species of the different continents. The maintenance of MHC alleles for long evolutionary times and their shared functionality may imply that certain MHC variants are essential in immune adaptation, even in species that diverged millions of years ago and occupy different environments.

Phenome-wide association study of the major histocompatibility complex region in the Korean population identifies novel association signals.

Human leukocyte antigen (HLA) gene variants in the major histocompatibility complex (MHC) region are associated with numerous complex human diseases and quantitative traits. Previous phenome-wide association studies (PheWAS) for this region demonstrated that HLA association patterns to the phenome have both population-specific and population-shared components. We performed MHC PheWAS in the Korean population by analyzing associations between phenotypes and genetic variants in the MHC region using the Korea Biobank Array project data samples from the Korean Genome and Epidemiology Study cohorts. Using this single-population dataset, we curated and analyzed 82 phenotypes for 125 673 Korean individuals after imputing HLA using CookHLA, a recently developed imputation framework. More than one-third of these phenotypes showed significant associations, confirming 56 known associations and discovering 13 novel association signals that were not reported previously. In addition, we analyzed heritability explained by the variants in the MHC region and genetic correlations among phenotypes based on the MHC variants.

MHC Variants Associated With Symptomatic Versus Asymptomatic SARS-CoV-2 Infection in Highly Exposed Individuals.

Despite the high number of individuals infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who develop coronavirus disease 2019 (COVID-19) symptoms worldwide, many exposed individuals remain asymptomatic and/or uninfected and seronegative. This could be explained by a combination of environmental (exposure), immunological (previous infection), epigenetic, and genetic factors. Aiming to identify genetic factors involved in immune response in symptomatic COVID-19 as compared to asymptomatic exposed individuals, we analyzed 83 Brazilian couples where one individual was infected and symptomatic while the partner remained asymptomatic and serum-negative for at least 6 months despite sharing the same bedroom during the infection. We refer to these as “discordant couples”. We performed whole-exome sequencing followed by a state-of-the-art method to call genotypes and haplotypes across the highly polymorphic major histocompatibility complex (MHC) region. The discordant partners had comparable ages and genetic ancestry, but women were overrepresented (65%) in the asymptomatic group. In the antigen-presentation pathway, we observed an association between HLA-DRB1 alleles encoding Lys at residue 71 (mostly DRB1*03:01 and DRB1*04:01) and DOB*01:02 with symptomatic infections and HLA-A alleles encoding 144Q/151R with asymptomatic seronegative women. Among the genes related to immune modulation, we detected variants in MICA and MICB associated with symptomatic infections. These variants are related to higher expression of soluble MICA and low expression of MICB. Thus, quantitative differences in these molecules that modulate natural killer (NK) activity could contribute to susceptibility to COVID-19 by downregulating NK cell cytotoxic activity in infected individuals but not in the asymptomatic partners.

Genetic Diversity of MHC B-F/B-L Region in 21 Chicken Populations.

The chicken major histocompatibility complex (MHC) on chromosome 16 is the most polymorphic region across the whole genome, and also an ideal model for genetic diversity investigation. The MHC B-F/B-L region is 92 kb in length with high GC content consisting of 18 genes and one pseudogene (Blec4), which plays important roles in immune response. To evaluate polymorphism of the Chinese indigenous chickens as well as to analyze the effect of selection to genetic diversity, we used WaferGen platform to identify sequence variants of the B-F/B-L region in 21 chicken populations, including the Red Jungle Fowl (RJF), Cornish (CS), White Leghorns (WLs), 16 Chinese domestic breeds, and two well-known inbred lines 63 and 72. A total of 3,319 single nucleotide polymorphism (SNPs) and 181 INDELs in the B-F/B-L region were identified among 21 populations, of which 2,057 SNPs (62%) and 159 INDELs (88%) were novel. Most of the variants were within the intron and the flanking regions. The average variation density was 36 SNPs and 2 INDELs per kb, indicating dramatical high diversity of this region. Furthermore, BF2 was identified as the hypervariable genes with 67 SNPs per kb. Chinese domestic populations showed higher diversity than the WLs and CS. The indigenous breeds, Nandan Yao (NY), Xishuangbanna Game (XG), Gushi (GS), and Xiayan (XY) chickens, were the top four with the highest density of SNPs and INDELs. The highly inbred lines 63 and 72 have the lowest diversity, which might be resulted from a long-term intense selection for decades. Collectively, we refined the genetic map of chicken MHC B-F/B-L region, and illustrated genetic diversity of 21 chicken populations. Abundant genetic variants were identified, which not only strikingly expanded the current Ensembl SNP database, but also provided comprehensive data for researchers to further investigate association between variants in MHC and immune traits.

The BS variant of C4 protects against age-related loss of white matter microstructural integrity.

Age-related loss of white matter microstructural integrity is a major determinant of cognitive decline, dementia and gait disorders. However, the mechanisms and molecular pathways that contribute to this loss of integrity remain elusive. We performed a genome-wide association study of white matter microstructural integrity as quantified by diffusion MRI metrics (mean diffusivity and fractional anisotropy) in up to 31 128 individuals from UK Biobank (age 45-81 years) based on a two degrees of freedom (2df) test of single nucleotide polymorphism (SNP) and SNP × Age effects. We identified 18 loci that were associated at genome-wide significance with either mean diffusivity (n = 16) or fractional anisotropy (n = 6). Among the top loci was a region on chromosome 6 encoding the human major histocompatibility complex (MHC). Variants in the MHC region were strongly associated with both mean diffusivity [best SNP: 6:28866209_TTTTG_T, beta (standard error, SE) = -0.069 (0.009); 2df P = 6.5 × 10-15] and fractional anisotropy [best SNP: rs3129787, beta (SE) = -0.056 (0.008); 2df P = 3.5 × 10-12]. Of the imputed human leukocyte antigen (HLA) alleles and complement component 4 (C4) structural haplotype variants in the human MHC, the strongest association was with the C4-BS variant [for mean diffusivity: beta (SE) = -0.070 (0.010); P = 2.7 × 10-11; for fractional anisotropy: beta (SE) = -0.054 (0.011); P = 1.6 × 10-7]. After conditioning on C4-BS no associations with HLA alleles remained significant. The protective influence of C4-BS was stronger in older participants [age ≥ 65; interaction P = 0.0019 (mean diffusivity), P = 0.015 (fractional anisotropy)] and in participants without a history of smoking [interaction P = 0.00093 (mean diffusivity), P = 0.021 (fractional anisotropy)]. Taken together, our findings demonstrate a role of the complement system and of gene-environment interactions in age-related loss of white matter microstructural integrity.

Balancing selection, genetic drift, and human-mediated introgression interplay to shape MHC (functional) diversity in Mediterranean brown trout.

The extraordinary polymorphism of major histocompatibility complex (MHC) genes is considered a paradigm of pathogen‐mediated balancing selection, although empirical evidence is still scarce. Furthermore, the relative contribution of balancing selection to shape MHC population structure and diversity, compared to that of neutral forces, as well as its interaction with other evolutionary processes such as hybridization, remains largely unclear. To investigate these issues, we analyzed adaptive (MHC‐DAB gene) and neutral (11 microsatellite loci) variation in 156 brown trout (Salmo trutta complex) from six wild populations in central Italy exposed to introgression from domestic hatchery lineages (assessed with the LDH gene). MHC diversity and structuring correlated with those at microsatellites, indicating the substantial role of neutral forces. However, individuals carrying locally rare MHC alleles/supertypes were in better body condition (a proxy of individual fitness/parasite load) regardless of the zygosity status and degree of sequence dissimilarity of MHC, hence supporting balancing selection under rare allele advantage, but not heterozygote advantage or divergent allele advantage. The association between specific MHC supertypes and body condition confirmed in part this finding. Across populations, MHC allelic richness increased with increasing admixture between native and domestic lineages, indicating introgression as a source of MHC variation. Furthermore, introgression across populations appeared more pronounced for MHC than microsatellites, possibly because initially rare MHC variants are expected to introgress more readily under rare allele advantage. Providing evidence for the complex interplay among neutral evolutionary forces, balancing selection, and human‐mediated introgression in shaping the pattern of MHC (functional) variation, our findings contribute to a deeper understanding of the evolution of MHC genes in wild populations exposed to anthropogenic disturbance.

Unique Pathogen Peptidomes Facilitate Pathogen-Specific Selection and Specialization of MHC Alleles.

A key component of pathogen-specific adaptive immunity in vertebrates is the presentation of pathogen-derived antigenic peptides by major histocompatibility complex (MHC) molecules. The excessive polymorphism observed at MHC genes is widely presumed to result from the need to recognize diverse pathogens, a process called pathogen-driven balancing selection. This process assumes that pathogens differ in their peptidomes—the pool of short peptides derived from the pathogen’s proteome—so that different pathogens select for different MHC variants with distinct peptide-binding properties. Here, we tested this assumption in a comprehensive data set of 51.9 Mio peptides, derived from the peptidomes of 36 representative human pathogens. Strikingly, we found that 39.7% of the 630 pairwise comparisons among pathogens yielded not a single shared peptide and only 1.8% of pathogen pairs shared more than 1% of their peptides. Indeed, 98.8% of all peptides were unique to a single pathogen species. Using computational binding prediction to characterize the binding specificities of 321 common human MHC class-I variants, we investigated quantitative differences among MHC variants with regard to binding peptides from distinct pathogens. Our analysis showed signatures of specialization toward specific pathogens especially by MHC variants with narrow peptide-binding repertoires. This supports the hypothesis that such fastidious MHC variants might be maintained in the population because they provide an advantage against particular pathogens. Overall, our results establish a key selection factor for the excessive allelic diversity at MHC genes observed in natural populations and illuminate the evolution of variable peptide-binding repertoires among MHC variants.

What evolutionary processes maintain MHC IIꞵ diversity within and among populations of stickleback?

Major Histocompatibility Complex (MHC) genes code for proteins that recognize foreign protein antigens to initiate T‐cell‐mediated adaptive immune responses. They are often the most polymorphic genes in vertebrate genomes. How evolution maintains this diversity remains of debate. Three main hypotheses seek to explain the maintenance of MHC diversity by invoking pathogen‐mediated selection: heterozygote advantage, frequency‐dependent selection, and fluctuating selection across landscapes or through time. Here, we use a large‐scale field parasite survey in a stickleback metapopulation to test predictions derived from each of these hypotheses. We identify over 1000 MHC IIβ variants (alleles spanning paralogous genes) and find that many of them covary positively or negatively with parasite load, suggesting that these genes contribute to resistance or susceptibility. However, despite our large sample‐size, we find no evidence for the widely cited stabilizing selection on MHC heterozygosity, in which individuals with an intermediate number of MHC variants have the lowest parasite burden. Nor do we observe a rare‐variant advantage, or widespread fluctuating selection across populations. In contrast, we find that MHC diversity is best predicted by neutral genome‐wide heterozygosity and between‐population genomic divergence, suggesting neutral processes are important in shaping the pattern of metapopulation MHC diversity. Thus, although MHC IIβ is highly diverse and relevant to the type and intensity of macroparasite infection in these populations of stickleback, the main models of MHC evolution still provide little explanatory power in this system.

Evolutionary relationship and population structure of domestic Bovidae animals based on MHC-linked and neutral autosomal microsatellite markers

Major histocompatibility complex (MHC) genes are critical for disease resistance or susceptibility responsible for host-pathogen interactions determined mainly by extensive polymorphisms in the MHC genes. Here, we examined the diversity and phylogenetic pattern of MHC haplotypes reconstructed using three MHC-linked microsatellite markers in 55 populations of five Bovidae species and compared them with those based on neutral autosomal microsatellite markers (NAMs). Three-hundred-and-forty MHC haplotypes were identified in 1453 Bovidae individuals, suggesting significantly higher polymorphism and heterozygosity compared with those based on NAMs. The ambitious boundaries in population differentiation (phylogenetic network, pairwise FST and STRUCTURE analyses) within and between species assessed using the MHC haplotypes were different from those revealed by NAMs associated closely with speciation, geographical distribution, domestication and management histories. In addition, the mean FST was significantly correlated negatively with the number of observed alleles (NA), observed (HO) and expected (HE) heterozygosity and polymorphism information content (PIC) (P < 0.05) in the MHC haplotype dataset while there was no correction of the mean FST estimates (P> 0.05) between the MHC haplotype and NAMs datasets. Analysis of molecular variance (AMOVA) revealed a lower percentage of total variance (PTV) between species/groups based on the MHC-linked microsatellites than NAMs. Therefore, it was inferred that individuals within populations accumulated as many MHC variants as possible to increase their heterozygosity and thus the survival rate of their affiliated populations and species, which eventually reduced population differentiation and thereby complicated their classification and phylogenetic relationship inference. In summary, host-pathogen coevolution and heterozygote advantage, rather than demographic history, act as key driving forces shaping the MHC diversity within the populations and determining the interspecific MHC diversity.

Mating preferences can drive expansion or contraction of major histocompatibility complex gene family.

Major histocompatibility complex (MHC)-based mating rules can evolve as a way to avoid inbreeding or to increase offspring immune competence. While the role of mating preference in shaping the MHC diversity in vertebrates has been acknowledged, its impact on individual MHC diversity has not been considered. Here, we use computer simulations to investigate how simple mating rules favouring MHC-dissimilar partners affect the evolution of the number of MHC variants in individual genomes, accompanying selection for resistance to parasites. We showed that the effect of such preferences could sometimes be dramatic. If preferences are aimed at avoiding identical alleles, the equilibrium number of MHC alleles is much smaller than under random mating. However, if the mating rule minimizes the ratio of shared to different alleles in partners, MHC number is higher than under random mating. Additionally, our simulations revealed that a negative correlation between the numbers of MHC variants in mated individuals can arise from simple rules of MHC-disassortative mating. Our results reveal unexpected potential of MHC-based mating preferences to drive MHC gene family expansions or contractions and highlight the need to study the mechanistic basis of such preferences, which is currently poorly understood.

Germline-Encoded TCR-MHC Contacts Promote TCR V Gene Bias in Umbilical Cord Blood T Cell Repertoire.

T cells recognize antigens as peptides bound to major histocompatibility complex (MHC) proteins through T cell receptors (TCRs) on their surface. To recognize a wide range of pathogens, each individual possesses a substantial number of TCRs with an extremely high degree of variability. It remains controversial whether germline-encoded TCR repertoire is shaped by MHC polymorphism and, if so, what is the preference between MHC genetic variants and TCR V gene compatibility. To investigate the “net” genetic association between MHC variations and TRBV genes, we applied quantitative trait locus (QTL) mapping to test the associations between MHC polymorphism and TCR β chain V (TRBV) genes usage using umbilical cord blood (UCB) samples of 201 Chinese newborns. We found TRBV gene and MHC loci that are predisposed to interact with one another differ from previous conclusions. The majority of MHC amino acid residues associated with the TRBV gene usage show spatial proximities in known structures of TCR-pMHC complexes. These results show for the first time that MHC variants bias TRBV gene usage in UCB of Chinese ancestry and indicate that germline-encoded contacts influence TCR-MHC interactions in intact T cell repertoires.

Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression

BackgroundThe prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a plausible explanation for the overlap, and in this study we tested whether genetic variation in the major histocompatibility complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression. MethodsWe fine-mapped the classical MHC (chr6: 29.6–33.1 Mb), imputing 216 human leukocyte antigen (HLA) alleles and 4 complement component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium Major Depressive Disorder Working Group and the UK Biobank. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants, applying both a region-wide significance threshold (3.9 × 10−6) and a candidate threshold (1.6 × 10−4). ResultsNo HLA alleles or C4 haplotypes were associated with depression at the region-wide threshold. HLA-B*08:01 was associated with modest protection for depression at the candidate threshold for testing in HLA genes in the meta-analysis (odds ratio = 0.98, 95% confidence interval = 0.97–0.99). ConclusionsWe found no evidence that an increased risk for depression was conferred by HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia. These results suggest that any HLA or C4 variants associated with depression either are rare or have very modest effect sizes.

АЛЕЛЬНИЙ ПОЛІМОРФІЗМ СИСТЕМИ HLA У ХВОРИХ НА ХРОНІЧНУ МІЄЛОЇДНУ ЛЕЙКЕМІЮ З е13а2 та е14а2 ТРАНСКРИПТАМИ ГЕНА BCR/ABL1

To study the associative relation of polymorphic HLA gene variants and BCR/ABL1 transcript types in patients with chronic myeloid leukemia (CML) 87 CML patients were examined. 42 patients had e13a2 BCR/ABL1 transcript and 45 patients had e14a2 BCR/ABL1 transcript. The prevalence of the genes allelic variants of major histocompatibility complex was analyzed and the association coefficients for the disease risk depending on the presence of certain types of BCR/ABL1 transcripts were calculated.&#x0D; Unconditional markers of increased risk of CML (HLA-DRB1*11) and markers of resistance to CML (HLA-A*03) were highlighted. The allele frequencies of HLA-A*03, HLA-A*68, HLA-B*08, HLA-B*15, HLA-B*40, HLA-DRB1*04, DQB1*06 were significantly reduced and allele frequencies of HLA-DRB1*12 and DRB1*11 were increased in patients with the e13a2 transcript compared to healthy people. The allele frequencies of HLA-A*03, HLA-A*11, HLA-B*08, HLA-B*14, HLA-B*40, HLA-DRB1*04 and DQB1* 03 were significantly reduced and the allele frequency of HLA-DRB1*11 was significantly increased in patients with e14a2 transcript compared to healthy persons. Thus, the individual analysis of the complex of fusion proteins e13a2 and e14a2 and HLA alleles in CML patients could indicate the additive effect of both molecular structures joint carrier for CML developing risk.

Multi-Ancestry Genome-Wide Association Study of Spontaneous Clearance of Hepatitis C Virus

Spontaneous clearance of hepatitis C virus (HCV) occurs in approximately 30% of infected persons and less often in populations of African ancestry. Variants in major histocompatibility complex (MHC) and in interferon lambda genes are associated with spontaneous HCV clearance, but there have been few studies of these variants in persons of African ancestry. We performed a dense multi-ancestry genome-wide association study of spontaneous clearance of HCV, focusing on individuals of African ancestry. We performed genotype analyses of 4423 people from 3 ancestry groups: 2201 persons of African ancestry (445 with HCV clearance and 1756 with HCV persistence), 1739 persons of European ancestry (701 with HCV clearance and 1036 with HCV persistence), and 486 multi-ancestry Hispanic persons (173 with HCV clearance and 313 with HCV persistence). Samples were genotyped using Illumina (San Diego, CA) arrays and statistically imputed to the 1000 Genomes Project. For each ancestry group, the association of single-nucleotide polymorphisms with HCV clearance was tested by log-additive analysis, and then a meta-analysis was performed. In the meta-analysis, significant associations with HCV clearance were confirmed at the interferon lambda gene locus IFNL4-IFNL3 (19q13.2) (P= 5.99× 10-50) and the MHC locus 6p21.32 (P= 1.15× 10-21). We also associated HCV clearance with polymorphisms in the G-protein-coupled receptor 158 gene (GPR158) at 10p12.1 (P= 1.80× 10-07). These 3 loci had independent, additive effects of HCV clearance, and account for 6.8% and 5.9% of the variance of HCV clearance in persons of European and African ancestry, respectively. Persons of African or European ancestry carrying all 6 variants were 24-fold and 11-fold, respectively, more likely to clear HCV infection compared with individuals carrying none or 1 of the clearance-associated variants. In a meta-analysis of data from 3 studies, we found variants in MHC genes, IFNL4-IFNL3, and GPR158 to increase odds of HCV clearance in patients of European and African ancestry. These findings could increase our understanding of immune response to and clearance of HCV infection.

Fine mapping the MHC region identified rs4997052 as a new variant associated with nonobstructive azoospermia in Han Chinese males

To investigate the association between genetic variants in the major histocompatibility complex (MHC) region and nonobstructive azoospermia (NOA) susceptibility. MHC region fine-mapping analysis based on previous NOA genome-wide association study (GWAS) data. Medical university. Nine hundred and eighty-one men with NOA and 1,657 normal fertile male controls. None. The MHC region imputation assessed with SNP2HLA software, taking the specific Han-MHC database as a reference panel; statistical significance of the MHC variants calculated using logistic regression models; functional annotation based on online public databases; and phenotypic variances explained by specific groups of genetic variants estimated using the fixed effects model from individual associations. Two independent risk loci, rs7194 (odds ratio [OR] 1.37) at MHC class II molecules and rs4997052 (OR 1.30) at MHC class I molecules, were identified. Functional annotation showed rs7194 may tag the effect of multiple amino acid residues and the expression of HLA-DQB1 and HLA-DRB1; while rs4997052 showed the effect of amino acid changes of HLA-B at position 116 as well as the expression of HLA-B and CCHCR1, which coexpressed with genes enriched in pathways of spermatogenesis and male gamete generation. The novel variant rs4997052 identified in our study can explain another approximately 0.66% of the phenotypic variances of NOA. We fine-mapped the MHC region and identified two loci that independently drove NOA susceptibility. These results provide a deeper understanding of the association mechanisms of MHC and NOA risk.

Genetic potential for disease resistance in critically endangered amphibians decimated by chytridiomycosis

AbstractHundreds of amphibian species have declined worldwide after the emergence of the amphibian fungal pathogen Batrachochytrium dendrobatidis (Bd). Despite captive breeding efforts, it is unlikely that wild populations for many species will be reestablished unless Bd resistance increases. We performed a Bd‐challenge study in the functionally extinct southern corroboree frog Pseudophryne corroboree to investigate differences in Bd susceptibility among individuals and populations, identify genetic [major histocompatibility complex (MHC) class I] and genome‐wide variants associated with Bd resistance, and measure genetic diversity and population genetic structure. We found three MHC variants and one MHC supertype associated with Bd infection load and survival along with a suggestively associated single nucleotide polymorphism. We also showed that genome‐wide heterozygosity is associated with increased survival. Additionally, we found evidence of significant population structure among the four P. corroboree populations studied and high MHC genetic diversity. Our results indicate that there are immunogenetic differences among captive southern corroboree frogs; such differences could be manipulated to increase disease resistance and mitigate the significant threat of chytridiomycosis. These results demonstrate a potential long‐term solution to chytridiomycosis that could include breeding more resistant individuals and returning them to the wild.

Immunogenetic novelty confers a selective advantage in host–pathogen coevolution

The major histocompatibility complex (MHC) is crucial to the adaptive immune response of vertebrates and is among the most polymorphic gene families known. Its high diversity is usually attributed to selection imposed by fast-evolving pathogens. Pathogens are thought to evolve to escape recognition by common immune alleles, and, hence, novel MHC alleles, introduced through mutation, recombination, or gene flow, are predicted to give hosts superior resistance. Although this theoretical prediction underpins host-pathogen "Red Queen" coevolution, it has not been demonstrated in the context of natural MHC diversity. Here, we experimentally tested whether novel MHC variants (both alleles and functional "supertypes") increased resistance of guppies (Poecilia reticulata) to a common ectoparasite (Gyrodactylus turnbulli). We used exposure-controlled infection trials with wild-sourced parasites, and Gyrodactylus-naïve host fish that were F2 descendants of crossed wild populations. Hosts carrying MHC variants (alleles or supertypes) that were new to a given parasite population experienced a 35-37% reduction in infection intensity, but the number of MHC variants carried by an individual, analogous to heterozygosity in single-locus systems, was not a significant predictor. Our results provide direct evidence of novel MHC variant advantage, confirming a fundamental mechanism underpinning the exceptional polymorphism of this gene family and highlighting the role of immunogenetic novelty in host-pathogen coevolution.

Genetic risk factors for pediatric-onset multiple sclerosis

Background: Strong evidence supports the role of both genetic and environmental factors in pediatric-onset multiple sclerosis (POMS) etiology. Objective: We comprehensively investigated the association between established major histocompatibility complex (MHC) and non-MHC adult multiple sclerosis (MS)-associated variants and susceptibility to POMS. Methods: Cases with onset <18 years (n = 569) and controls (n = 16,251) were included from the United States and Sweden. Adjusted logistic regression and meta-analyses were performed for individual risk variants and a weighted genetic risk score (wGRS) for non-MHC variants. Results were compared to adult MS cases (n = 7588). Results: HLA–DRB1*15:01 was strongly associated with POMS (odds ratio (OR)meta = 2.95, p < 2.0 × 10−16). Furthermore, 28 of 104 non-MHC variants studied (23%) were associated (p < 0.05); POMS cases carried, on average, a higher burden of these 28 variants compared to adults (ORavg = 1.24 vs 1.13, respectively), though the difference was not significant. The wGRS was strongly associated with POMS (ORmeta = 2.77, 95% confidence interval: 2.33, 3.32, p < 2.0 × 10−16) and higher, on average, when compared to adult cases. Additional class III risk variants in the MHC region associated with POMS were revealed after accounting for HLA–DRB1*15:01 and HLA–A*02. Conclusion: Pediatric and adult MS share many genetic variants suggesting similar biological processes are present. MHC variants beyond HLA–DRB1*15:01 and HLA–A*02 are also associated with POMS.

SNP Variants in Major Histocompatibility Complex Are Associated with Sarcoidosis Susceptibility-A Joint Analysis in Four European Populations.

Sarcoidosis is a multiorgan inflammatory disorder with heritability estimates up to 66%. Previous studies have shown the major histocompatibility complex (MHC) region to be associated with sarcoidosis, suggesting a functional role for antigen-presenting molecules and immune mediators in the disease pathogenesis. To detect variants predisposing to sarcoidosis and to identify genetic differences between patient subgroups, we studied four genes in the MHC Class III region (LTA, TNF, AGER, BTNL2) and HLA-DRA with tag-SNPs and their relation to HLA-DRB1 alleles. We present results from a joint analysis of four study populations (Finnish, Swedish, Dutch, and Czech). Patients with sarcoidosis (n = 805) were further subdivided based on the disease activity and the presence of Löfgren’s syndrome. In a joint analysis, seven SNPs were associated with non-Löfgren sarcoidosis (NL; the strongest association with rs3177928, P = 1.79E−07, OR = 1.9) and eight with Löfgren’s syndrome [Löfgren syndrome (LS); the strongest association with rs3129843, P = 3.44E−12, OR = 3.4] when compared with healthy controls (n = 870). Five SNPs were associated with sarcoidosis disease course (the strongest association with rs3177928, P = 0.003, OR = 1.9). The high linkage disequilibrium (LD) between SNPs and an HLA-DRB1 challenged the result interpretation. When the SNPs and HLA-DRB1 alleles were analyzed together, independent association was observed for four SNPs in the HLA-DRA/BTNL2 region: rs3135365 (NL; P = 0.015), rs3177928 (NL; P < 0.001), rs6937545 (LS; P = 0.012), and rs5007259 (disease activity; P = 0.002). These SNPs act as expression quantitative trait loci (eQTL) for HLA-DRB1 and/or HLA-DRB5. In conclusion, we found novel SNPs in BTNL2 and HLA-DRA regions associating with sarcoidosis. Our finding further establishes that polymorphisms in the HLA-DRA and BTNL2 have a role in sarcoidosis susceptibility. This multi-population study demonstrates that at least a part of these associations are HLA-DRB1 independent (e.g., not due to LD) and shared across ancestral origins. The variants that were independent of HLA-DRB1 associations acted as eQTL for HLA-DRB1 and/or -DRB5, suggesting a role in regulating gene expression.