Complex Genetic Susceptibility Research Articles

Polygenic Risk Score-Based Association Analysis of Speech-in-Noise and Hearing Threshold Measures in Healthy Young Adults with Self-reported Normal Hearing.

Speech-in-noise (SIN) traits exhibit high inter-subject variability, even for healthy young adults reporting normal hearing. Emerging evidence suggests that genetic variability could influence inter-subject variability in SIN traits. Genome-wide association studies (GWAS) have uncovered the polygenic architecture of various adult-onset complex human conditions. Polygenic risk scores (PRS) summarize complex genetic susceptibility to quantify the degree of genetic risk for health conditions. The present study conducted PRS-based association analyses to identify PRS risk factors for SIN and hearing threshold measures in 255 healthy young adults (18-40years) with self-reported normal hearing. Self-reported SIN perception abilities were assessed by the Speech, Spatial, and Qualities of Hearing Scale (SSQ12). QuickSIN and audiometry (0.25-16kHz) were performed on 218 participants. Saliva-derived DNA was used for low-pass whole genome sequencing, and 2620 PRS variables for various traits were calculated using the models derived from the polygenic risk score (PGS) catalog. The regression analysis was conducted to identify predictors for SSQ12, QuickSIN, and better ear puretone averages at conventional (PTA0.5-2), high (PTA4-8), and extended-high (PTA12.5-16) frequency ranges. Participants with a higher genetic predisposition to HDL cholesterol reported better SSQ12. Participants with high PRS to dementia revealed significantly elevated PTA4-8, and those with high PRS to atrial fibrillation and flutter revealed significantly elevated PTA12.5-16. These results indicate that healthy individuals with polygenic risk of certain health conditions could exhibit a subclinical decline in hearing health measures at young ages, decades before clinically meaningful SIN deficits and hearing loss could be observed. PRS could be used to identify high-risk individuals to prevent hearing health conditions by promoting a healthy lifestyle.

P115 Trehalose modulates Dextran Sulfate Sodium-induced colitis by regulating macrophage polarization

Abstract Background Inflammatory bowel disease (IBD) is a collective term for chronic inflammatory diseases resulting from complex genetic susceptibility, microbial flora, and immune abnormality. Due to the complicated pathogenesis, therapies for IBD are largely limited to the treatment of symptoms. However, these existing drugs sometimes fail or lead to adverse effects in long-term therapies. The development of new drugs and new therapies for IBD are still the top priorities. Trehalose (TRE) is an autophagy inducer through an mTOR-independent pathway. Given its safe and protective nature, TRE has gained significant attention for the potential application in disease treatment. It is a natural product that may be used as a harmless autophagy regulator. In our research, we use the Dextran Sulfate Sodium (DSS)-induced IBD model to explore the therapeutic effects of trehalose on autophagy and inflammation in mice. Methods 6-8 weeks old C57BL/6J male mice were used for experiments. Mice were given 2% DSS (MP Biomedicals) in autoclaved drinking water for 4 days to induce colitis, Then TRE (2 g/kg body weight, Sigma-Aldrich), rapamycin (1.25mg/kg body weight, MedChemExpress) or normal saline were intraperitoneally injected for 5 days. Mice were weighed daily, and stool consistency, diarrhea, or blood in the stools were monitored to calculate the disease activity index (DAI). At the end of the experiment, the colons were measured, opened longitudinally, and handled according to standard procedures. The tissue samples were collected for RNA, protein extraction, histology, and macrophage isolation respectively. Western Blot was used for autophagy analysis and flow cytometry was used for macrophage subtype and apoptosis analysis. Besides, Real-time quantitative PCR assay was used for examining the cytokine expression. Results In TRE-treated mice, the cessation of diarrhea and anal bleeding occurred earlier and hence the DAI scores decreased more rapidly when compared to the other groups. Correspondingly, the colons in TRE-treated mice shortened less than the saline treated control suggesting recovery from DSS-induced colitis. Even though no significant difference was observed in H&E staining and tissue scores for mice in different groups, significant difference in macrophage polarization and cytokine production was observed. DSS-induced intestinal CD86+ macrophages, whereas TRE treatment increased CD206+ macrophages and decreased the expression of pro-inflammatory cytokines, such as IL-6 and TNF-alpha. Conclusion Our results demonstrate that TRE decreases the symptoms of experimental colitis by regulating macrophage polarization, probably mediated by macrophage autophagy. These findings indicate the potential of TRE to be an adjuvant therapy for IBD.

The Immunoregulatory Role of the Signal Regulatory Protein Family and CD47 Signaling Pathway in Type 1 Diabetes.

BackgroundThe pathogenesis of type 1 diabetes (T1D) involves complex genetic susceptibility that impacts pathways regulating host immunity and the target of autoimmune attack, insulin-producing pancreatic β-cells. Interactions between risk variants and environmental factors result in significant heterogeneity in clinical presentation among those who develop T1D. Although genetic risk is dominated by the human leukocyte antigen (HLA) class II and insulin (INS) gene loci, nearly 150 additional risk variants are significantly associated with the disease, including polymorphisms in immune checkpoint molecules, such as SIRPG.Scope of ReviewIn this review, we summarize the literature related to the T1D-associated risk variants in SIRPG, which include a protein-coding variant (rs6043409, G>A; A263V) and an intronic polymorphism (rs2281808, C>T), and their potential impacts on the immunoregulatory signal regulatory protein (SIRP) family:CD47 signaling axis. We discuss how dysregulated expression or function of SIRPs and CD47 in antigen-presenting cells (APCs), T cells, natural killer (NK) cells, and pancreatic β-cells could potentially promote T1D development.Major ConclusionsWe propose a hypothesis, supported by emerging genetic and functional immune studies, which states a loss of proper SIRP:CD47 signaling may result in increased lymphocyte activation and cytotoxicity and enhanced β-cell destruction. Thus, we present several novel therapeutic strategies for modulation of SIRPs and CD47 to intervene in T1D.

IL-10 and IL-10 Receptor Mutations in Very Early Onset Inflammatory Bowel Disease.

Very early onset inflammatory bowel disease (VEO-IBD) is a unique disease entity with a complex genetic susceptibility in affected patients. Next-generation gene sequencing techniques have revealed various monogenetic mutations contributing to the pathogenesis of VEO-IBD, including interleukin 10 (IL-10) and IL-10 receptor (IL-10R) mutations. In this article, we reviewed the features of and effective therapeutic options for VEO-IBD with IL-10 and/or IL-10R mutations. The IL-10 signal pathway inhibits the release of several key cytokines and thereby has a significant anti-inflammatory effect in the gastrointestinal tract. Mutations of the genes encoding IL-10 and/or IL-10R have been detected in VEO-IBD patients among myriad populations throughout the world. VEO-IBD patients with IL-10 or IL-10R mutations often present with repeated bouts of bloody diarrhea, marked weight loss, growth retardation, and recurrent perianal problems, including abscesses, fistulas, and significant fissures. Moreover, some patients may have folliculitis and present with pulmonary infections. While the therapeutic efficacy of immunosuppressants is typically poor in these patients, allogeneic hematopoietic stem cell transplantation (HSCT) has been reported to improve symptoms significantly. However, the long-term prognosis of VEO-IBD patients with IL-10 or IL-10R gene mutations treated with HSCT requires further exploration to verify the efficacy and safety of this treatment. We concluded that clinicians should recognize the clinical phenotype of VEO-IBD, as mutational analysis of the IL-10 pathway can support the diagnosis and prompt early treatment of this complicated disease.

A Genetic Variant rs1020760at NFKB1 is Associated with Clinical Features of Psoriasis Vulgaris in a Han Chinese Population.

Psoriasis vulgaris is a chronic inflammatory skin disease associated with complex genetic susceptibility. Recently, we identified a single-nucleotide variant rs1020760 at NFKB1 significantly associated with psoriasis in a Han Chinese population in deep analysis of exome and targeted sequencing (P = 1.76 × 10(-8) ). To investigate the potential association between rs1020760 and phenotypes of psoriasis vulgaris, we performed a genotype-phenotype analysis. A total of 9946 cases and 9906 controls with detailed clinical and demographic information were involved in this study, while the genotype data of rs1020760 was available in the previous targeted sequencing study of psoriasis. Genotype-based association testing revealed the additive model might provide the best fit for rs1020760 (P = 5.44 × 10(-8) ). Case-only analysis showed that the distribution of allele G was significantly different between the cases with and without family history (Pallele = 4.07 × 10(-3) ,Pgenotype = 5.75 × 10(-3) ). The differences in allele and genotype frequencies were observed between all the subphenotypes and controls except for the genotype frequency of the late onset subgroup, while no difference was found in case-only analysis for the other two subphenotypes. Rs1020760 was preferentially associated with family history of psoriasis, implying that NFKB1 might not only play important roles in the development of psoriasis, but might also contribute to the special phenotypes of this disease.

The immunological and genetic aspects in psoriasis

Psoriasis is a chronic and immune-mediated inflammatory skin disorder associated with complex genetic susceptibility. Studies focused on the immunological mechanism have revealed innate and adaptive immune activation in psoriatic lesions, including large numbers of immune cells activated to produce many cytokines, chemokines, and other inflammatory molecules. Knowledge on the genetic basis of psoriasis highlights genetic susceptibility factors that play a crucial role in regulation of immunity, epidermal proliferation, and skin barrier formation. Genetic susceptibility factors affecting both the immune system and epidermis could predispose to disease. Herein, we review the current knowledge on the role of genetic and immunological factors in the development of psoriasis.

Pharmaco-therapeutic challenges in cancer biology with focus on the immune- system related risk factors.

Over the past, progress has always been achieved in therapy of various human diseases with the introduction of novel methodologies from basic to clinical research. Recent advances in techniques, especially DNA sequencing and methylation analyses, faster miniaturized proteomics and live cellular stainings, are opening a new era in cancer research. Perhaps the difference this time can be envisaged as the beginning of the long-sought individualization of forthcoming cancer therapies. Cancer has complex genetic susceptibility that is wider than previously thought. Apart from genes encoding six functional capabilities of cancer - independent growth, avoidance of apoptosis, immortalization, multi-drug resistance, neovascularization, and invasiveness - predisposition includes four more factors that promote genome instability, inflammation, deregulation of metabolism as well as evasion of destruction by the immune system. The underlying genetic events, i.e. base-pair DNA mutations, are not the sole factors in cancer development. Additional novel controls of gene expression have been found in the epigenetic machinery, which has been increasingly important in assessing cancer risk in recent years. The predisposing factors, including their regulatory elements, are bona fide potential new targets in prospective cancer pharmacotherapy.

Targeting IL-17 in psoriasis: From cutaneous immunobiology to clinical application

Psoriasis vulgaris is a chronic, immune-mediated inflammatory skin disease associated with complex genetic susceptibility. Although the hallmark of psoriasis is characterized by cutaneous inflammation and keratinocyte hyperproliferation, recent studies show that the pathologic features observed in psoriasis arises as a result of innate and adaptive immune activation in genetically prone individuals. Studies focused on the microenvironment in the skin of psoriasis lesions have revealed novel cellular and cytokine abnormalities of the immune system. One pathway important is the role of the T(H)17/IL-17 dysregulation. The recent development of biologics that target the IL-17 cytokine pathway has confirmed the importance of T(H)17 and IL-17 homeostasis in the skin and yielded potent therapies in the treatment of psoriasis, and potentially other autoimmune diseases.

Complex genetic susceptibility to vascular dementia and an evidence for its underlying genetic factors associated with memory and associative learning

Genetic basis for vascular dementia (VD) as a typical complex disease has been limitedly reported from association studies conducted with candidate genes. Even recent genomewide association studies (GWAS) could hardly identify additional genetic factors for VD. Although a considerable complexity for its genetic architecture was suspected, there were some challenges to identify false negative associations that resulted from the GWAS. Challenges to identifying genetic factors and their functions after the trials of GWAS revealed that splicing of primary transcript was inhibited (SYK) or delayed (PHLDB2) by a nucleotide substitution of the corresponding gene. The studies gave us the lesson that integrated investigations with statistical genomics as well as functional genomics are needed to identify false negatives from the GWAS. Such endeavors would provide key insights into aspects of underlying nucleotide architectures of VD and incorporate the genetic factors into clinical practice. The recent genetic association studies for susceptibility to VD were briefly overviewed in this article. We also showed a challenge to understanding genetic dissection of VD by a genomic region enrichment analysis with distal cis-regulatory sequences. The analysis with a variant set of potential false negatives from the GWAS revealed that the variants were significantly enriched near genes involved in critical biological processes to VD.

Unraveling the genetics of otitis media: from mouse to human and back again

Otitis media (OM) is among the most common illnesses of early childhood, characterised by the presence of inflammation in the middle ear cavity. Acute OM and chronic OM with effusion (COME) affect the majority of children by school age and have heritability estimates of 40-70%. However, the majority of genes underlying this susceptibility are, as yet, unidentified. One method of identifying genes and pathways that may contribute to OM susceptibility is to look at mouse mutants displaying a comparable phenotype. Single-gene mouse mutants with OM have identified a number of genes, namely, Eya4, Tlr4, p73, MyD88, Fas, E2f4, Plg, Fbxo11, and Evi1, as potential and biologically relevant candidates for human disease. Recent studies suggest that this "mouse-to-human" approach is likely to yield relevant data, with significant associations reported between polymorphisms at the FBXO11, TLR4, and PAI1 genes and disease in humans. An association between TP73 and chronic rhinosinusitis has also been reported. In addition, the biobanks of available mouse mutants provide a powerful resource for functional studies of loci identified by future genome-wide association studies of OM in humans. Mouse models of OM therefore are an important component of current approaches attempting to understand the complex genetic susceptibility to OM in humans, and which aim to facilitate the development of preventative and therapeutic interventions for this important and common disease.

Familial neuromyelitis optica

Detection of aquaporin-4-specific immunoglobulin G (IgG) has expanded the spectrum of neuromyelitis optica (NMO). Rare reports of familial aggregation have suggested a component of genetic susceptibility but these reports mostly antedated the discovery of the NMO-IgG biomarker and recently updated diagnostic criteria. We report a case series describing the demographic, clinical, neuroimaging, and NMO-IgG serologic status of 12 multiplex NMO pedigrees with a total of 25 affected individuals. Twenty-one patients (84%) were women. Families were Asian (n = 5), Latino (n = 4), white (n = 1), or African (n = 2). Apparent transmission was either maternal (n = 5) or paternal (n = 2). In 1 family, 3 individuals had NMO; in the others, 2 individuals were affected. Sibling pairs (n = 6), parent-child (n = 4), and aunt-niece (n = 3) pairs were observed. Nineteen patients (76%) were NMO-IgG positive. Twelve (48%) had clinical or serologic evidence of another autoimmune disease. Familial occurrence of NMO occurs in approximately 3% of patients with well-established diagnosis of NMO. A small proportion of patients with NMO have relatives with this condition, but familial occurrence is more common than would be expected from its frequency in the general population. Familial NMO is indistinguishable from sporadic NMO based on clinical symptoms, age at onset, sex distribution, and frequency of NMO-IgG detection. One or 2 generations were affected and affected individuals represented a small fraction of family members. Taken together, these data suggest complex genetic susceptibility in NMO.

Recent advances in adrenal autoimmunity

Autoimmune Addison’s disease (AAD) results from the immune-mediated destruction of adrenocortical cells. AAD is a major component of the autoimmune polyendocrine syndromes type 1 (APS 1) and type 2. The adrenal autoimmune process is made evident by the apperance of circulating autoantibodies against the steroidogenic enzyme 21-hydroxylase. Detection of 21-hydroxylase in patients with endocrine autoimmune diseases enables the identification of subjects with preclinical AAD. An impaired response to a corticotrophin stimulation test marks the irreversible stage of preclinical AAD and predicts progression towards clinical AAD in over 80% of cases. APS 1 is caused by mutations of the autoimmune regulator (AIRE) gene, which encodes an activator of transcription, Aire, that induces the expression of autoantigens in thymic medullary epithelial cells and promotes immunological tolerance. Isolated and APS 2-related AAD is an autoimmune disease with evidence for complex genetic susceptibility caused by T-cell-mediated destruction of adrenocortical cells, with a major contribution of HLA genes. The target cells in the adrenal cortex participate in the immune reaction by releasing chemokines, such as CXCL-10, that attract Th1 cells.

Mapping Multiple Sclerosis Susceptibility to the HLA-DR Locus in African Americans

An underlying complex genetic susceptibility exists in multiple sclerosis (MS), and an association with the HLA-DRB1*1501-DQB1*0602 haplotype has been repeatedly demonstrated in high-risk (northern European) populations. It is unknown whether the effect is explained by the HLA-DRB1 or the HLA-DQB1 gene within the susceptibility haplotype, which are in strong linkage disequilibrium (LD). African populations are characterized by greater haplotypic diversity and distinct patterns of LD compared with northern Europeans. To better localize the HLA gene responsible for MS susceptibility, case-control and family-based association studies were performed for DRB1 and DQB1 loci in a large and well-characterized African American data set. A selective association with HLA-DRB1*15 was revealed, indicating a primary role for the DRB1 locus in MS independent of DQB1*0602. This finding is unlikely to be solely explained by admixture, since a substantial proportion of the susceptibility chromosomes from African American patients with MS displayed haplotypes consistent with an African origin.

The genetic epidemiology of multiple sclerosis

Multiple sclerosis (MS) is a debilitating immunological and neurodegenerative disorder. Epidemiological studies have provided overwhelming evidence of complex genetic susceptibility to MS. However, with the exception of the human leukocyte antigen (HLA) locus, genetic studies have failed to consistently identify significant linkage or association with genes that modulate MS disease expression. Numerous functional candidate gene studies, linkage genomic screens, and locational candidate gene studies have been performed in an attempt to identify additional loci. However, these methods have demonstrated insufficient power to consistently identify genes or epigenetic factors for MS. More current approaches integrate information from a variety of sources (e.g. consistent linkage data, gene expression profiling, and functional characterization studies) and utilize high throughput methods (e.g. genotyping high density markers, utilizing pooling schemes and performing new statistical analyses) in an attempt to overcome power issues. The following article presents a review of MS genetics research and a brief overview of methods that are currently being developed and utilized for fine localization of MS loci, such as the method employed in the Genetic Analysis of Multiple sclerosis in EuropeanS (GAMES) study that is presented elsewhere in this journal. It is the hope of researchers that these methods will lead to the identification of susceptibility genes for MS that aid in elucidating pathogenic mechanisms and potential therapeutic strategies for this debilitating disease.

Genetic basis for clinical expression in multiple sclerosis.

Multiple sclerosis is a clinically heterogeneous demyelinating disease and an important cause of acquired neurological disability. An underlying complex genetic susceptibility plays an important role in multiple sclerosis aetiology; however, the role of genetic factors in determining clinical features of multiple sclerosis is unknown. We studied 184 stringently ascertained Caucasian multiple sclerosis families with multiple affected cases. A detailed evaluation of patient histories identified clinical variables including age of onset, initial clinical manifestations and disease severity. The concordance within families for continuous and categorical clinical variables was investigated using an intraclass correlation or Cohen's kappa coefficient, respectively. Genetic analyses included model-dependent, model-independent and association methodology. Linear and logistic regression models were used to evaluate the effect of human leucocyte antigen (HLA)-DR2 (DRB1*1501, DQB1*0602) on clinical outcome, taking account of correlation within families. Significant concordance for early clinical manifestations within families was observed for individuals with exclusive optic neuritis and/or spinal cord involvement as first and second multiple sclerosis attacks (P < 10(-6)). Linkage (LOD = 3.80, theta = 0.20) and association (P = 0.0002) to HLA-DR were present in the dataset; however, linkage was restricted to families in which the DR2 haplotype was present in at least one nuclear member. No evidence for linkage to HLA-DR in DR2-negative families was observed. When families were stratified by concordance of early clinical manifestations, a significant DR2 association was present in all subgroups. Concordance for early manifestations of multiple sclerosis was present in this familial dataset, but was not associated with HLA-DR2. The association of DR2 in families with different clinical presentations suggests that a common basis exists for susceptibility in multiple sclerosis. However, non-HLA genes or other epigenetic factors must modulate disease expression. Locus heterogeneity at the HLA region suggests a distinct immunopathogenesis in DR2 negative patients.

Hypertension in children and adolescents: definition, pathophysiology, risk factors, and long-term sequelae

Background: Awareness of hypertension as an adult public health issue has increased dramatically during the past 3 decades, leading to substantial decreases in morbidity and mortality related to stroke and coronary artery disease. Awareness of blood pressure issues in the pediatric population also has increased, leading to conceptual changes in the diagnosis and treatment of childhood hypertension. The current focus has shifted to early identification of mild to moderate hypertension in asymptomatic, otherwise healthy children and adolescents. Objective: The purpose of this article was to define hypertension in the pediatric population and describe the secondary causes of childhood hypertension, risk factors and potential pathophysiology of essential hypertension in childhood, and the long-term sequelae for individuals with hypertension identified during childhood. Methods: Information regarding pediatric hypertension was identified through a MEDLINE ® search of the literature from 1985 to 2000. Results: Definitions of pediatric hypertension have been carefully refined over the past 30 years, and normative data are available for children and adolescents, based on age, sex, and height. Childhood hypertension may be identified during evaluation of an acutely ill child, but is increasingly identified during routine blood pressure screening, particularly in adolescents. Although, historically, most pediatric hypertension was believed to be secondary in origin (related to an identifiable underlying disorder), recent data suggest that almost 90% of hypertensive adolescents have essential hypertension. The proposed factors that may be involved in the pathophysiology of essential hypertension include familial and genetic influences, race, and salt sensitivity. Although an essential hypertension gene has not yet been identified, several monogenic forms of hypertension have been described, which may account for a minority of individuals with presumed essential hypertension. In addition, a number of candidate genes that may be involved in the complex genetic susceptibility to hypertension have been described. There is growing evidence concerning adverse long-term consequences of hypertension identified in childhood and adolescence, including increased incidence of cardiovascular and coronary heart disease. Conclusions: Based on the generally accepted concept that essential hypertension begins in childhood, early optimization of blood pressure control in childhood may reduce an individual's lifetime risk of cardiovascular morbidity and mortality. In addition, aggressive treatment of cardiovascular risk factors during childhood and adolescence may have a major impact on the prevalence of adult cardiovascular disease.

Human genome search in celiac disease using gliadin cDNA as probe

Celiac disease is a wheat gliadin-promoted disorder that displays a complex genetic susceptibility associated with HLA-DQ2, and one or more unknown factor(s), possibly gliadin-like. The presence of mammalian proteins with partial gliadin similarity was suggested by transglutaminase-independent multi-tissue reactivity of gliadin-immunopurified antibodies from celiac patients. No non-plant sequence, however, was identified in gliadin peptide epitope searches of non-redundant and EST databanks via TBLASTN, BLASTP and FASTA, even at E values as high as 20. Therefore, an α-gliadin cDNA screen of human cDNA and genomic libraries was undertaken, an approach in keeping with positive human Northern and Southern analyses with the same probe. Four distinct cDNA clones were obtained, the most stringent of which (3.2 and 5.1 kb) were novel, and featured potential open reading frames with high gliadin domain II and domain IV homologies (BestFit quality scores ⩾295 and 322, respectively, versus random value 126-127). Both were also homologous to ESTs. An additional 5′ gliadin oligonucleotide screen identified the widely distributed cytoplasmic protein acyl coA hydrolase whose homology was restricted to the oligonucleotide probe (BestFit quality=215 versus 100 for random); and achaete-scute homologous protein, which displays particularly high gliadin domain II homology (BestFit quality 316 versus 111 for random). Genomic screening uncovered 16 positives, one of which was the ALR gene, whose similarity to three of gliadin’s five domains (I, II and IV; BestFit quality 322-473 versus 121-154 for random) was remarkable. More extensive was novel genomic clone 2, with fragments hybridizing to cDNA probes approximating gliadin domains I, II+IV, V and the gliadin 5′ untranslated region, and mapping by FISH to 19q13.11-13.12. Two fragments were sequenced; one was exonic, as predicted by four different programs; and test oligonucleotides suggested widespread 4 and/or 2 kb mRNA expression, even at high stringency (tm−8.8 deg. C). Taken together, it is apparent that several genes with partial gliadin homology exist in the human genome. Many bear gliadin-like T-cell epitopes, are expressed in intestine and, like transglutaminase, are cytoplasmic. Glutamine to glutamic acid or other mutation within such epitopes followed by injury or infection-related release could explain enhanced disease susceptibility in affected families.

Influence of human leukocyte antigen and tumour necrosis factor genes on the development of pre-eclampsia.

Pre-eclampsia is a syndrome with a strong familial component. Autosomal recessive inheritance acting only in the mother is not consistent with the epidemiological data, and a more complex genetic susceptibility, involving interactions between maternal and fetal genomes, seems likely. The human leukocyte antigen (HLA) system has been implicated, but many of the findings reported have been inconsistent or contradictory. Pre-eclampsia is unlikely to be the simple result of excessive HLA-class II antigen sharing between mother and fetus, as was first thought, but a more complex mechanism involving feto-maternal compatibility cannot be excluded. The reported increase in HLA-DR4 in mothers and babies from pre-eclamptic pregnancies has not been independently confirmed for mothers, and no further studies have been conducted with babies. Consequently, the allegedly stronger relationship with HLA-DR4 sharing between mother and fetus has neither been confirmed nor refuted. Certain (B44-DR7)-containing haplotypes appear to confer increased risk for pre-eclampsia on the basis of independent analyses of American and Scottish populations. HLA-DR53 may be associated with the antiphospholipid antibody syndrome, which is itself a strong risk factor for pre-eclampsia. The tumour necrosis factor (TNF)-alpha allele, TNF1, may be associated with pre-eclampsia and certainly elevated concentrations of the cytokine appear to be a feature of the disease. The inducibility of TNF-alpha is HLA-class II-dependent, and the relevance of HLA-class II genes might be entirely in relation to TNF-alpha synthesis and secretion.