Association between HLA-A gene polymorphism and early-onset preeclampsia in Chinese pregnant women early-onset.

BACKGROUND: Preeclampsia is an idiopathic disease during pregnancy. This study explores the correlation between HLA-A polymorphism and the onset of preeclampsia. METHODS: The Illumina HiSeq2500 sequencing platform was used to genotyping HLA-A allele in venous blood DNA of 50 preeclampsia pregnant women and 48 normal pregnant women and umbilical cord blood DNA of their children of Han nationality in China. The frequencies and distributions of alleles and genotypes among the mothers and their children were compared between the two groups. The differences of frequencies and distributions of genotypes were compared between the two groups according to the mothers' genotype compatibility. RESULTS: Twenty HLA-A alleles were detected in preeclampsia pregnant women and normal pregnant women; 21 HLA-A alleles were found in preeclampsia group fetuses and 22 HLA-A alleles in control group fetuses. There was no statistical difference in the HLA-A genes' frequency between the two groups of pregnant women and their fetuses. When the sharing antigen was 1, the number of maternal-fetal pairs in the preeclampsia group was more than that in the control group; the difference was statistically significant (P < 0.05). The frequency of neither mother nor fetus carrying the HLA-A * 24: 02 gene in the preeclampsia group was significantly lower than that in the control group (P < 0.05). HLA-A gene homozygosity in fetuses of early-onset preeclampsia group was substantially higher than that of the control group (P = 0.0148); there is no significant difference in pregnant women's genes homozygosity between early-onset preeclampsia group and the control group. CONCLUSIONS: HLA-A * 24: 02 may be a susceptibility gene for early preeclampsia.

Decreased HLA-C1 alleles in couples of KIR2DL2 positive women with recurrent pregnancy loss.

Specific killer cell immunoglobulin-like receptor (KIR) in women with recurrent pregnancy loss (RPL) and HLA ligands in couples invoke a susceptibility to RPL. However, the relationship between KIR2DL2 and its cognate ligand HLA-C1 has not been explored. In this prospective cohort study, 160 Caucasian women with RPL and 99 partners were included. KIR/HLA-C typing, NK assay, Th1/Th2 intracellular cytokine ratios, 25-(OH)-vitamin D level, and the presence of autoantibodies were analyzed. KIR2DL2 positive women (P = 0.023) and their partners (P = 0.017) had lower allele frequencies of HLA-C1 than those of KIR2DL2 negative women. KIR2DL2 positive women had significantly lower genotype frequency of HLA-C1C1 as compared to the North American Caucasian population controls (P < 0.05). In the partners of KIR2DL2 positive women, there was a substantially higher frequency of HLA-C2C2 than controls (P = 0.016). Besides, KIR2DL2 negative women had a higher prevalence of anti-ssDNA antibody as compared with that of KIR2DL2 positive women (P = 0.043). There were no differences in the distribution of HLA-C genotypes based on KIR2DL2, regardless of pregnancy outcome in women with RPL and their partners while on immunomodulation treatment. In conclusion, decreased ligands for inhibitory KIRs (inhKIR) could lead to insufficient inhibition of maternal uterine NK cells toward the trophoblast, thereby contributing to the pathogenesis of RPL. Specific KIR and HLA-C genotyping may predict the reproductive outcome of women with RPL.

Two Lineages of KLRA with Contrasting Transcription Patterns Have Been Conserved at a Single Locus during Ruminant Speciation.

Cattle possess the most diverse repertoire of NK cell receptor genes among all mammals studied to date. Killer cell receptor genes encoded within the NK complex and killer cell Ig-like receptor genes encoded within the leukocyte receptor complex have both been expanded and diversified. Our previous studies identified two divergent and polymorphic KLRA alleles within the NK complex in the Holstein-Friesian breed of dairy cattle. By examining a much larger cohort and other ruminant species, we demonstrate the emergence and fixation of two KLRA allele lineages (KLRA*01 and -*02) at a single locus during ruminant speciation. Subsequent recombination events between these allele lineages have increased the frequency of KLRA*02 extracellular domains. KLRA*01 and KLRA*02 transcription levels contrasted in response to cytokine stimulation, whereas homozygous animals consistently transcribed higher levels of KLRA, regardless of the allele lineage. KLRA*02 mRNA levels were also generally higher than KLRA*01 Collectively, these data point toward alternative functional roles governed by KLRA genotype and allele lineage. On a background of high genetic diversity of NK cell receptor genes, this KLRA allele fixation points to fundamental and potentially differential function roles.

Human neutrophil antigen frequency data for Malays, Chinese and Indians.

BACKGROUND: Human neutrophil antigens (HNAs) are implicated in several clinical disorders and their allelic variations have been reported for many populations. This new study was aimed to report the genotype and alleles frequencies of HNA-1, -3, -4 and -5 loci in Malays, Chinese and Indians in Peninsular Malaysia. METHODS: A total of 222 blood samples were collected from healthy, unrelated Malay, Chinese and Indian individuals. Their HNA-1, -3 and -4 and HNA-5 loci were genotyped using polymerase chain reaction-sequence specific primer (PCR-SSP) or PCR-restriction fragment length polymorphism (RFLP) assays. RESULTS: All HNA loci are polymorphic, except for HNA -4. Geneotypes HNA-1a/1b, -3a/3b and -4a/4a were observed most frequently at these three loci in all three ethnic groups. In contrast, HNA-5a/5b and -5a/5a were observed as the predominant genotypes in Malays vs. Chinese and Indians, respectively. The Malays, Chinese and Indians shared HNA -3a (0.505-0.527), HNA -4a (1.000) and -5a (0.676-0.854) as the most frequent alleles. However, HNA-1a was found to be the most common in Malays (0.506) and Chinese (0.504) and HNA-1b for Indians (0.525). CONCLUSION: Combined with HNA data that have been published for Malay subethnic and Orang Asli groups, this study provides the first fully comprehensive HNA dataset for populations to be found in Peninsular Malaysia. Overall, our findings provide further evidence of genetic complexity in the region. This now publicly available HNA dataset can be used as a reliable reference source for improving medical outcomes.

Assessment of the Association of D2 Dopamine Receptor Gene and Reported Allele Frequencies With Alcohol Use Disorders: A Systematic Review and Meta-analysis.

Importance: The association between the D2 dopamine receptor gene (DRD2) Taq1A locus (rs1800497) and alcohol use disorder (AUD) is enduring but the subject of long-standing controversy; meta-analysis of studies across 3 decades shows an association between rs1800497 and AUD, but genome-wide analyses have detected no role for rs1800497 in any phenotype. No evidence has emerged that rs1800497, which is located in ANKK1, perturbs the expression or function of DRD2. Objective: To resolve contradictions in previous studies by identifying hidden confounders and assaying for functional effects of rs1800497 and other loci in the DRD2 region. Data Sources: PubMed (882 studies), Embase (1056 studies), and Web of Science (501 studies) databases were searched through August 2018. Three clinical populations-Finnish, Native American, and African American participants-were genotyped for 208 to 277 informative single-nucleotide polymorphisms (SNPs) across the DRD2 region to test the associations of SNPs in this region with AUD. Study Selection: Eligible studies had diagnosis of AUD made by accepted criteria, reliable genotyping methods, sufficient genotype data to calculate odds ratios and 95% CIs, and availability of control allele frequencies or genotype frequencies. Data Extraction and Synthesis: After meta-analysis of 62 studies, metaregression was performed to detect between-study heterogeneity and to explore the effects of moderators, including deviations of cases and controls from allele frequencies in large population databases (ExAC and 1000 Genomes). Linkage to AUD and the effect on gene expression of rs1800497 were evaluated in the context of other SNPs in the DRD2 region. Data analysis was performed from August 2018 to March 2019. This study follows the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline. Main Outcomes and Measures: The effects of rs1800497 and other SNPs in the DRD2 region on gene expression were measured in human postmortem brain samples via differential allelic expression and evaluated in other tissues via publicly available expression quantitative locus data. Results: A total of 62 studies of DRD2 and AUD with 16 294 participants were meta-analyzed. The rs1800497 SNP was associated with AUD (odds ratio, 1.23; 95% CI, 1.14-1.31; P < .001). However, the association was attributable to spuriously low allele frequencies in controls in positive studies, which also accounted for some between-study heterogeneity (I2 = 43%; 95% CI, 23%-58%; Q61 = 107.20). Differential allelic expression of human postmortem brain and analysis of expression quantitative loci in public data revealed that a cis-acting locus or loci perturb the DRD2 transcript level; however, rs1800497 does not and is not in strong disequilibrium with such a locus. Across the DRD2 region, other SNPs are more strongly associated with AUD than rs1800497, although no DRD2 SNP was significantly associated in these 3 clinical samples. Conclusions and Relevance: In this meta-analysis, the significant association of DRD2 with AUD was reassessed. The DRD2 association was attributable to anomalously low control allele frequencies, not function, in positive studies. For genetic studies, statistical replication is not verification.

Influence of genetic variants of gamma interferon, interleukins 10 and 12 on Visceral Leishmaniasis in an endemic area, Iran.

Visceral leishmaniasis (VL) is a life threatening disease in which a variety of cytokines regulating the immune responses can determine its outcome. As based on their region in the gene, some single nucleotide polymorphisms (SNP) can influence the expression of their corresponding proteins, this study aimed to investigate the association between SNP in the IL-10, IL-12, IFN-γ genes and susceptibility to VL. The study was carried out on 120 patients with VL, 67 patients' families (family group), and 102 healthy individuals with positive leishmanin skin test as positive control group. SNPs in IL-10 (-592, -819, -1082), IL-12 (+1188) were analyzed using PCR-RFLP and allele specific polymerase chain reaction (ASPCR) was used to analyze SNPs in IFN-γ (+874 A/T). The results showed that at position +874 of IFN-γ, AT genotype was significantly more frequent in patients than that in families and controls, but TT genotype was significantly more frequent in families than in patients. Distributions of IFN-γ alleles were not significantly different between the study groups. As for IL-12 and IL-10 genotypes and alleles, no significant difference was observed between the groups. Although a strong linkage disequilibrium was observed between alleles -592, -819 and -1082 of IL-10, distributions of the most common haplotypes and haplogenotypes reconstructed from IL-10 alleles were not significantly different between the study groups. It could be suggested that heritage of AT genotype at position +874 of IFN-γ may predispose and TT genotype can resist individual to VL in an endemic area in the southwest of Iran.

Association of Single Nucleotide Polymorphisms in TNFA and IL10 Genes with Disease Severity in Influenza A/H1N1pdm09 Virus Infections: A Study from Western India.

Susceptibility to severe influenza A/H1N1pdm09 virus is multifactorial. The present study was carried out in 246 patients infected with A/H1N1pdm09 virus to find out whether single nucleotide polymorphisms (SNPs) in the genes coding for proinflammatory and anti-inflammatory cytokines are associated with disease severity. Among the cases, 129 had mild disease, whereas 117 had severe disease. There were 27 fatal cases. TNFA rs1800629, IFNG rs2430561, IL10 rs1800872, IL10 rs1800896, and CCL2 rs1024611 SNPs were genotyped by polymerase chain reaction-based methods. A significantly higher frequency of TNFA rs1800629 "G/A" genotype was observed in severe and fatal cases compared with mild and survived cases, respectively. In a dominant mode, IL10 rs1800896 "G" allele was significantly negatively associated with disease severity. IL10 rs1800896 "C/A" genotype was significantly associated with fatality in influenza A/H1N1pdm09 infections. The results suggest that SNPs in the IL10 and TNFA genes might be associated with disease severity in influenza A/H1N1pdm09-infected patients.

The distribution of HLA haplotypes in the ethnic groups that make up the Brazilian Bone Marrow Volunteer Donor Registry (REDOME).

The Registries of Bone Marrow Donors around the world include more than 30 million volunteer donors from 57 different countries, and were responsible for over 17,000 hematopoietic stem cell transplants in 2016. The Brazilian Bone Marrow Volunteer Donor Registry (REDOME) was established in 1993 and is the third largest registry in the world with more than 4.3 million donors. We characterized HLA allele and haplotypes frequencies from REDOME comparing them with the donor self-reported race group classification. Five-locus haplotype frequencies (A~C~B~DRB1~DQB1) were estimated for each of the six race groups, resolving phase and allelic ambiguity using the expectation-maximization (EM) algorithm. The top 100 haplotypes in the race groups were separated into eight clusters of haplotypes, based on haplotype similarity, using CLUTO. We present HLA allele and haplotype frequency data from six race groups from 2,938,259 individuals from REDOME. The most frequent haplotype was the same for all groups: A*01:01g~C*07:01g~B*08:01g~DRB1*03:01g~DQB1*02:01g. Some frequent haplotypes such as A*02:01g~C*16:01g~B*44:03~DRB1*07:01g~DQB1*02:01g was not found in people with Preta (Sub-Saharan African descent). A cluster including Branca (European) and Parda or non-informed (admixed) could be distinguished from both Preta (SubSaharan) and Indígena (Amerindian) groups, and from the Amarela (Asian) ones, which clustered with their original population. These results have implications on cross-population matching and can help in donor searches and population-based recruitment strategies.

Population genetics of immune-related multilocus copy number variation in Native Americans.

While multiallelic copy number variation (mCNV) loci are a major component of genomic variation, quantifying the individual copy number of a locus and defining genotypes is challenging. Few methods exist to study how mCNV genetic diversity is apportioned within and between populations (i.e. to define the population genetic structure of mCNV). These inferences are critical in populations with a small effective size, such as Amerindians, that may not fit the Hardy-Weinberg model due to inbreeding, assortative mating, population subdivision, natural selection or a combination of these evolutionary factors. We propose a likelihood-based method that simultaneously infers mCNV allele frequencies and the population structure parameter f, which quantifies the departure of homozygosity from the Hardy-Weinberg expectation. This method is implemented in the freely available software CNVice, which also infers individual genotypes using information from both the population and from trios, if available. We studied the population genetics of five immune-related mCNV loci associated with complex diseases (beta-defensins, CCL3L1/CCL4L1, FCGR3A, FCGR3B and FCGR2C) in 12 traditional Native American populations and found that the population structure parameters inferred for these mCNVs are comparable to but lower than those for single nucleotide polymorphisms studied in the same populations.

Differences in the frequencies of HLA-class I and II alleles between German patients with renal cell carcinoma and healthy controls.

The human leukocyte antigen (HLA) system is a major part of the human immune system and has an impact on tumor initiation, tumor progression, and immunosurveillance. Renal cell carcinoma tumors are considered to be immunogenic. Therefore, we studied the allele frequencies of four gene loci (HLA-A, -B, -C, and HLA-DR) in a cohort of German renal cell carcinoma (RCC) patients and in healthy controls. HLA-A-C were determined using serological methods, whereas HLA-C12, C14, C16, C18, and HLA-DR were characterized through the use of standard molecular biological methods. The occurrence of the HLA-C*12 allele was significantly increased in German RCC patients compared with healthy controls (P < 0.005; Fisher's exact test), whereas the occurrence of the HLA-DRB1*04 allele was significantly reduced in RCC patients compared with healthy controls (P < 0.05; Fisher's exact test). However, the presence of allele HLA-C*12 was not significantly associated with 10 year overall survival. We suggest that the frequency of HLA alleles can affect development of RCC and could add knowledge as predictive marker for future immunotherapies.

Tissue-Specific Education of Decidual NK Cells.

During human pregnancy, fetal trophoblast cells invade the decidua and remodel maternal spiral arteries to establish adequate nutrition during gestation. Tissue NK cells in the decidua (dNK) express inhibitory NK receptors (iNKR) that recognize allogeneic HLA-C molecules on trophoblast. Where this results in excessive dNK inhibition, the risk of pre-eclampsia or growth restriction is increased. However, the role of maternal, self-HLA-C in regulating dNK responsiveness is unknown. We investigated how the expression and function of five iNKR in dNK is influenced by maternal HLA-C. In dNK isolated from women who have HLA-C alleles that carry a C2 epitope, there is decreased expression frequency of the cognate receptor, KIR2DL1. In contrast, women with HLA-C alleles bearing a C1 epitope have increased frequency of the corresponding receptor, KIR2DL3. Maternal HLA-C had no significant effect on KIR2DL1 or KIR2DL3 in peripheral blood NK cells (pbNK). This resulted in a very different KIR repertoire for dNK capable of binding C1 or C2 epitopes compared with pbNK. We also show that, although maternal KIR2DL1 binding to C2 epitope educates dNK cells to acquire functional competence, the effects of other iNKR on dNK responsiveness are quite different from those in pbNK. This provides a basis for understanding how dNK responses to allogeneic trophoblast affect the outcome of pregnancy. Our findings suggest that the mechanisms that determine the repertoire of iNKR and the effect of self-MHC on NK education may differ in tissue NK cells compared with pbNK.

Annotation and genetic diversity of the chicken collagenous lectins.

Collectins and ficolins are multimeric proteins present in various tissues and are actively involved in innate immune responses. In chickens, six different collagenous lectins have been characterized so far: mannose-binding lectin (MBL), surfactant protein A (SP-A), collectin 10 (COLEC10), collectin 11 (COLEC11), collectin 12 (COLEC12), lung lectin (LL) and one ficolin (FCN). However, the structural and functional features of the chicken collectins and ficolin are still not fully understood. Therefore, the aims of this study were: (i) to make an overview of the genetic structure and function of chicken collectins and the ficolin, (ii) to investigate the variation in the chicken collectins and the ficolin gene in different chicken populations, and (iii) to assess the presence of MBL gene variants in different chicken populations. We performed comparative genomic analysis using publically available data. The obtained results showed that collectins and ficolins have conserved protein sequences and gene structure across all vertebrate groups and this is especially notable for COLEC10, COLEC11 and COLEC12. For the purpose of studying the genetic variation, 179 animals from 14 populations were genotyped using 31 SNPs covering five genomic regions. The obtained results revealed low level of heterozygosity in the collagenous lectins except for the COLEC12 gene and the LL-SPA-MBL region compared to heterozygosity at neutral microsatellite markers. In addition, the MBL gene variants were assessed in different chicken populations based on the polymorphisms in the promoter region. We observed 10 previously identified MBL variants with A2/A8 and A4 as the most frequent alleles.

Designing peptide-based HIV vaccine for Chinese.

CD4+ T cells are central to the induction and maintenance of CD8+ T cell and antibody-producing B cell responses, and the latter are essential for the protection against disease in subjects with HIV infection. How to elicit HIV-specific CD4+ T cell responses in a given population using vaccines is one of the major areas of current HIV vaccine research. To design vaccine that targets specifically Chinese, we assembled a database that is comprised of sequences from 821 Chinese HIV isolates and 46 human leukocyte antigen (HLA) DR alleles identified in Chinese population. We then predicted 20 potential HIV epitopes using bioinformatics approaches. The combination of these 20 epitopes has a theoretical coverage of 98.1% of the population for both the prevalent HIV genotypes and also Chinese HLA-DR types. We suggest that testing this vaccine experimentally will facilitate the development of a CD4+ T cell vaccine especially catered for Chinese.

Association of the HLA-B*52 allele with non-progression to AIDS in Brazilian HIV-1-infected individuals.

Several human leukocyte antigen (HLA) class I alleles are associated with the susceptibility to human immunodeficiency virus-1 (HIV-1) infection and/or AIDS progression. Of these, the HLA-B alleles are considered the strongest genetic determinant of disease outcome. We evaluated the influence of the HLA-B alleles on AIDS progression among HIV-1-positive individuals from Rio de Janeiro, Brazil, who were categorized as rapid progressors (RPs), typical progressors (TPs) or long-term non-progressors (LTNPs). In this study, significant differences in HLA-B allele frequencies were observed among the three progression groups for the B*48, B*49 and B*52 alleles. After controlling for other factors associated with AIDS progression, the presence of the B*52 allele was shown to be a significant protective factor (hazard ratio (HR) 0.49 (95% confidence interval (CI) 0.27-0.90) P<0.03). Although no direct association was observed between the presence of the B*27 or B*57 allele and the LTNP profile compared with the TP or RP groups, the adjusted model confirmed that these alleles are protective factors against AIDS progression (HR 0.62 (95% CI 0.38-0.99) P<0.05), as previously described. These data corroborate the existence of significant differences in HLA-B allele frequencies among the distinct AIDS progression profiles and further elucidate the role of HLA alleles in the outcome of HIV infections in diverse populations.

Single nucleotide polymorphisms in the interferon gamma gene are associated with distinct types of retinochoroidal scar lesions presumably caused by Toxoplasma gondii infection.

The association of single nucleotide polymorphisms (SNPs) in the interferon (IFN)-γ gene ( IFNG ) with different types of retinal scar lesions presumably caused by toxoplasmosis were investigated in a cross-sectional population-based genetic study. Ten SNPs were investigated and after Bonferroni correction, only the associations between SNPs rs2069718 and rs3181035 with retinal/retinochoroidal scar lesions type A (most severe scar lesions) and C (least severe scar lesions), respectively, remained significant. The associations of two different IFNG SNPs with two different types of retinal lesions attributable to toxoplasmosis support the hypothesis that different inflammatory mechanisms underlie the development of these lesions. The in vitro analysis of IFN-γ secretion by peripheral blood mononuclear cells stimulated with Toxoplasma gondii antigens was also investigated. The association between SNP rs2069718 and type A scar lesions revealed that differential IFN-γ levels are correlated with distinct genotypes. However, no correlation was observed with IFN-γ secretion levels and the SNP rs3181035 , which was significantly associated with type C scar lesions. Our findings strongly suggest that immunogenetic studies of individuals with congenital or postnatally acquired infection are needed to better understand the role of IFN-γ and its polymorphisms in the pathogenesis of ocular toxoplasmosis.

Single nucleotide polymorphisms in the interferon gamma gene are associated with distinct types of retinochoroidal scar lesions presumably caused by Toxoplasma gondii infection

The association of single nucleotide polymorphisms (SNPs) in the interferon (IFN)-γ gene ( IFNG ) with different types of retinal scar lesions presumably caused by toxoplasmosis were investigated in a cross-sectional population-based genetic study. Ten SNPs were investigated and after Bonferroni correction, only the associations between SNPs rs2069718 and rs3181035 with retinal/retinochoroidal scar lesions type A (most severe scar lesions) and C (least severe scar lesions), respectively, remained significant. The associations of two different IFNG SNPs with two different types of retinal lesions attributable to toxoplasmosis support the hypothesis that different inflammatory mechanisms underlie the development of these lesions. The in vitro analysis of IFN-γ secretion by peripheral blood mononuclear cells stimulated with Toxoplasma gondii antigens was also investigated. The association between SNP rs2069718 and type A scar lesions revealed that differential IFN-γ levels are correlated with distinct genotypes. However, no correlation was observed with IFN-γ secretion levels and the SNP rs3181035 , which was significantly associated with type C scar lesions. Our findings strongly suggest that immunogenetic studies of individuals with congenital or postnatally acquired infection are needed to better understand the role of IFN-γ and its polymorphisms in the pathogenesis of ocular toxoplasmosis.

Functional polymorphisms in Toll-like receptor genes for innate immunity in farm animals.

The exploitation of the genetic factors affecting the health status of farm animals represents an alternative approach to controlling the diseases caused by microbial pathogens. The determination of innate immunity based on the genotype of the germplasm cells is a constraint for specificity but becomes an advantage in breeding schemes. The structural deviations among Toll-like receptors (TLRs), as the most frequently studied innate immunity components, have been documented at all levels, i.e., interspecific, inter- and intravarietal, in the main farm species. The current computational methods facilitate the prediction of the functional consequences of the observed mutations. Subsequently, these predictions can be verified through immunological responsiveness and population-wide association studies. The frequency and haplotype grouping of individual polymorphisms are used to track the origin and selection coefficient as independent indicators of functional changes. The Toll-like receptor variants associated with mastitis and mycobacterial infection have been identified in cattle, consequently, the targeting of these proteins in breeding could contribute to disease control. The range of infections affected by TLR polymorphisms suggests that the improvement of innate resistance is feasible in more species. Thus, the traditional breeds and wild populations should be regarded as the resources of genetic variability accessible for these purposes.

The link between some alleles on human leukocyte antigen system and autism in children.

The reason behind the initiation of autoimmunity to brain in some patients with autism is not well understood. There is an association between some autoimmune disorders and specific alleles of human leukocyte antigen (HLA) system. Thus, we examined the frequency of some HLA-DRB1 alleles in 100 autistic children and 100 healthy matched-children by differential hybridization with sequence-specific oligonucleotide probes. The risk of association between acquisition or absence of these alleles and autism and also a history of autoimmune diseases in autistic relatives was studied. Autistic children had significantly higher frequency of HLA-DRB1*11 allele than controls (P<0.001). In contrast, autistic children had significantly lower frequency of HLA-DRB1*03 allele than controls (P<0.001). Acquisition of HLA-DRB1*011 and absence of HLA-DRB1*3 had significant risk for association with autism (odds ratio: 3.21 and 0.17, respectively; 95% CI: 1.65-6.31 and 0.06-0.45, respectively). HLA-DRB1*11 had a significant risk for association with a family history of autoimmunity in autistic children (odds ratio: 5.67; 95% CI: 2.07-16.3). In conclusions, the link of some HLA alleles to autism and to family history of autoimmunity indicates the possible contributing role of these alleles to autoimmunity in some autistic children. Despite a relatively small sample size, we are the first to report a probable protective association of HLA-DRB1*03 allele with autism. It warrants a replication study of a larger sample to validate the HLA-DRB1 genetic association with autism. This is important to determine whether therapeutic modulations of the immune function are legitimate avenues for novel therapy in selected cases of autism.

Allelic combinations of immune-response genes as possible composite markers of IFN-ß efficacy in multiple sclerosis patients.

BACKGROUND: IFN-ß is widely used as the first-line disease-modifying treatment for multiple sclerosis. However, 30-50% of multiple sclerosis patients do not respond to this therapy. Identification of genetic variants and their combinations that predict responsiveness to IFN-ß could be useful for treatment prognosis. MATERIALS & METHODS: The combinations of alleles of nine polymorphic loci in immune-response genes were analyzed in 253 Russian multiple sclerosis patients as possible determinants of clinically optimal IFN-ß treatment response using APSampler software. RESULTS: Carriage of TGFB1*-509C and CCR5*d was associated with favorable IFN-ß response by itself. CCR5*d, IFNAR1*16725G, IFNG*874T and IFNB1*153T/T were the components of the combinations, associated with clinically optimal response to IFN-ß. Carriage of composite markers (CCR5*d + IFNAR1*G + IFNB1*T/T) or (CCR5*d + IFNAR1*G + IFNG*T) is beneficial for IFN-ß treatment efficacy. DISCUSSION: The data obtained provides evidence of the cumulative effect of immune-response genes on IFN-ß treatment efficacy. This joint contribution may reflect the additive effect of independent allelic variants and epistatic interactions between some of them.

The genetic polymorphisms of HLA are strongly correlated with the disease severity after Hantaan virus infection in the Chinese Han population.

The polymorphism of human leukocyte antigen (HLA), which is a genetic factor that influences the progression of hemorrhagic fever with renal syndrome (HFRS) after Hantaan virus (HTNV) infection, was incompletely understood. In this case-control study, 76 HFRS patients and 370 healthy controls of the Chinese Han population were typed for the HLA-A, -B, and -DRB1 loci. The general variation at the HLA-DRB1 locus was associated with the onset of HFRS (P < 0.05). The increasing frequencies of HLA-DRB1∗09 and HLA-B*46-DRB1*09 in HFRS patients were observed as reproducing a previous study. Moreover, the HLA-B*51-DRB1*09 was susceptible to HFRS (P = 0.037; OR = 3.62; 95% CI: 1.00-13.18). The increasing frequencies of HLA-B*46, HLA-B*46-DRB1*09, and HLA-B*51-DRB1*09 were observed almost in severe/critical HFRS patients. The mean level of maximum serum creatinine was higher in HLA-B∗46-DRB1*09 (P = 0.011), HLA-B*51-DRB1*09 (P = 0.041), or HLA-B*46 (P = 0.011) positive patients than that in the negative patients. These findings suggest that the allele HLA-B*46 and haplotypes HLA-B*46-DRB1*09 and HLA-B*51-DRB1*09 in patients could contribute to a more severe degree of HFRS and more serious kidney injury, which improve our understanding of the HLA polymorphism for a different outcome of HTNV infection.