Susceptibility Haplotype Research Articles

Association of rs7719175, located in the IL13 gene promoter, with Schistosoma haematobium infection levels and identification of a susceptibility haplotype

Urinary schistosomiasis is a parasitic disease caused by Schistosoma haematobium helminths. S. haematobium eggs may remain trapped within the bladder or the ureter walls, causing major pathological disorders in the urogenital system. The polymorphism rs1800925(C/T) of the IL13 gene promoter, which is functional, has previously been associated with susceptibility to S. haematobium infection. The aim of this study was to further our understanding and to determine whether, in the 5q31-q33 region, rs1800925 affects infection levels alone or in synergy with other polymorphisms. After sequencing the IL13 promoter and increasing the single-nucleotide polymorphism density, we performed a linkage disequilibrium analysis between rs1800925 and the other markers in a Malian population. Multivariate linear regression analysis and electrophoretic mobility shift assay (EMSA) were performed to characterized markers in linkage disequilibrium with rs1800925. An additional polymorphism, rs7719175, in the IL13 promoter was associated with controlling infection levels in multivariate analysis. The haplotype rs7719175T-rs1800925C was associated with high infection levels. EMSA indicated that rs7719175 affects the binding of transcriptional factors to the promoter region. Polymorphisms rs7719175 and rs1800925 have a synergistic role in the control of infection levels caused by S. haematobium and using them as a haplotype allows a better discrimination between infected subjects.

Association of Interleukin-1β (IL1B) Polymorphisms with Graves' Ophthalmopathy in Taiwan Chinese Patients

To evaluate whether variations in the IL1B gene could be associated with Graves' ophthalmopathy (GO) in patients with Graves' disease (GD). This case-control study included 471 Taiwan Chinese patients with GD (200 with GO and 271 without GO) and 160 healthy volunteers. Eight single-nucleotide polymorphisms (SNPs) in IL1B were genotyped with an allele-specific extension and ligation assay. In the IL1B SNPs examined, the C allele of rs1143634 was associated with GD, whereas the T/T genotype of the SNPs rs1143634 and rs16944 were less associated with the disease. The A/A genotype of the SNPs rs3917368 and rs1143643, which had the strongest interaction, may increase the risk of GO (P = 0.024 and P = 0.017, respectively). Several GD susceptibility and insusceptibility IL1B haplotypes have been identified, and the Ht4-GCGCCTCC haplotype, composed of eight SNPs and associated with low circulating IL1β levels, may be protective against the development of GO (P = 0.025). Moreover, that the GO-susceptible genotype was associated with lower plasma IL1β concentrations implies that the origin of GO may go beyond the IL1B polymorphism-associated elevation of circulating IL1β. The data for IL1B polymorphisms and the association of GD and GO with plasma IL1β levels show that IL1B polymorphisms may be associated with the development of GD and GO.

A susceptible haplotype within APOE gene influences BMD and intensifies the osteoporosis risk in postmenopausal women of Northwest India

Background The association of apolipoprotein E (APOE) genotypes with bone mineral density (BMD) and risk of osteoporosis have remained unclear. The influence of APOE gene polymorphisms on BMD as genetic mediators of osteoporosis risk needs to be explored in Indian postmenopausal females where this disease is rising rampantly. Methods and results The present study investigated the role and relevance of four pertinent APOE single nucleotide polymorphisms: 5′UTR G/C (rs440446), Int2 G/A (rs769450), Exon4 T/C (rs429358), Exon4 C/T (rs7412) in DEXA verified 133 osteoporotic, 57 osteopenic and 83 normal postmenopausal females of India, who were not taking hormone replacement therapy. Minor allele frequencies of rs440446 and rs429358 were higher in osteoporotic females (0.31, 0.18) than osteopenic (0.29, 0.15) and females having normal bone mass (0.16, 0.07). Disease association analysis revealed a susceptibility haplotype CGTC (in order of rs440446, rs769450, rs429358, rs7412) and the carriers of this haplotype has higher risk of osteopenia (OR 3.53, 95% CI 1.21–11.0, P = 0.017) and osteoporosis (OR 3.61, 95% CI 1.53–9.48, P = 0.002) after adjusting the confounding effect of age, BMI and years since menopause. Females who possess either one copy or two copies of the haplotype have lesser BMD values of lumbar spine (0.88 and 0.85 g/cm 2) and femoral neck (0.84 and 0.82 g/cm 2) than those females who possess zero copy (0.9 and 0.87 g/cm 2, respectively). Conclusions The present study exposed a susceptibility haplotype CGTC, within APOE gene, which was found to be associated with BMD and risk of osteopenia and osteoporosis in postmenopausal females of India.

Worldwide distribution of the MYH9 kidney disease susceptibility alleles and haplotypes: evidence of historical selection in Africa.

MYH9 was recently identified as renal susceptibility gene (OR 3–8, p<10−8) for major forms of kidney disease disproportionately affecting individuals of African descent. The risk haplotype (E-1) occurs at much higher frequencies in African Americans (≥60%) than in European Americans (<4%), revealing a genetic basis for a major health disparity. The population distributions of MYH9 risk alleles and the E-1 risk haplotype and the demographic and selective forces acting on the MYH9 region are not well explored. We reconstructed MYH9 haplotypes from 4 tagging single nucleotide polymorphisms (SNPs) spanning introns 12–23 using available data from HapMap Phase II, and by genotyping 938 DNAs from the Human Genome Diversity Panel (HGDP). The E-1 risk haplotype followed a cline, being most frequent within sub-Saharan African populations (range 50–80%), less frequent in populations from the Middle East (9–27%) and Europe (0–9%), and rare or absent in Asia, the Americas, and Oceania. The fixation indexes (FST) for pairwise comparisons between the risk haplotypes for continental populations were calculated for MYH9 haplotypes; FST ranged from 0.27–0.40 for Africa compared to other continental populations, possibly due to selection. Uniquely in Africa, the Yoruba population showed high frequency extended haplotype length around the core risk allele (C) compared to the alternative allele (T) at the same locus (rs4821481, iHs = 2.67), as well as high population differentiation (FST(CEU vs. YRI) = 0.51) in HapMap Phase II data, also observable only in the Yoruba population from HGDP (FST = 0.49), pointing to an instance of recent selection in the genomic region. The population-specific divergence in MYH9 risk allele frequencies among the world's populations may prove important in risk assessment and public health policies to mitigate the burden of kidney disease in vulnerable populations.

MHC heterozygosity and survival in red junglefowl

Genes of the major histocompatibility complex (MHC) form a vital part of the vertebrate immune system and play a major role in pathogen resistance. The extremely high levels of polymorphism observed at the MHC are hypothesised to be driven by pathogen-mediated selection. Although the exact nature of selection remains unclear, three main hypotheses have been put forward; heterozygote advantage, negative frequency-dependence and fluctuating selection. Here, we report the effects of MHC genotype on survival in a cohort of semi-natural red junglefowl (Gallus gallus) that suffered severe mortality as a result of an outbreak of the disease coccidiosis. The cohort was followed from hatching until 250 days of age, approximately the age of sexual maturity in this species, during which time over 80% of the birds died. We show that on average birds with MHC heterozygote genotypes survived infection longer than homozygotes and that this effect was independent of genome-wide heterozygosity, estimated across microsatellite loci. This MHC effect appeared to be caused by a single susceptible haplotype (CD_c) the effect of which was masked in all heterozygote genotypes by other dominant haplotypes. The CD_c homozygous genotype had lower survival than all other genotypes, but CD_c heterozygous genotypes had survival probabilities equal to the most resistant homozygote genotype. Importantly, no heterozygotes conferred greater resistance than the most resistant homozygote genotype, indicating that the observed survival advantage of MHC heterozygotes was the product of dominant, rather than overdominant processes. This pattern and effect of MHC diversity in our population could reflect the processes ongoing in similarly small, fragmented natural populations.

Juvenile idiopathic arthritis and HLA Class I and Class II interactions and age‐at‐onset effects

The aim of this study was to quantitate risk and to examine heterogeneity for HLA at high resolution in patients with the most common subtypes of juvenile idiopathic arthritis (JIA), IgM rheumatoid factor-negative polyarticular JIA and oligoarticular JIA. Use of 4-digit comprehensive HLA typing enabled great precision, and a large cohort allowed for consideration of both age at disease onset and disease subtype. Polymerase chain reaction-based high-resolution HLA typing for class I and class II loci was accomplished for 820 patients with JIA and 273 control subjects. Specific HLA epitopes, potential interactions of alleles at specific loci and between loci (accounting for linkage disequilibrium and haplotypic associations), and an assessment of the current International League of Associations for Rheumatology classification criteria were considered. An HLA-DRB1/DQB1 effect was shown to be exclusively attributable to DRB1 and was similar between patients with oligoarticular JIA and a younger subgroup of patients with polyarticular JIA. Furthermore, patients with polyarticular JIA showed age-specific related effects, with disease susceptibility in the group older than age 6 years limited to an effect of the HLA-DRB1*08 haplotype, which is markedly different from the additional susceptibility haplotypes, HLA-DRB1*1103/1104, found in the group with oligoarticular JIA and the group of younger patients with polyarticular JIA. Also in contrast to findings for oligoarticular JIA, patients with polyarticular arthritis had no evidence of an HLA class I effect. Markers associated with a reduced risk of disease included DRB1*1501, DRB1*0401, and DRB1*0701. DRB1*1501 was shown to reduce risk across the whole cohort, whereas DRB1*0401 and DRB1*0701 were protective for selected JIA subtypes. Surprisingly, the disease predisposition mediated by DPB1*0201 in individuals without any disease-predisposing DRB1 alleles was great enough to overcome even the very strong protective effect observed for DRB1*1501. Inherited HLA factors in JIA show similarities overall as well as differences between JIA subtypes.

Haplotypes of IL12B promoter polymorphisms condition susceptibility to severe malaria and functional changes in cytokine levels in Thai adults

Polymorphic variability in immune response genes, such as IL12B, encoding the IL-12p40 subunit is associated with susceptibility to severe malaria in African populations. Since the role of genetic variation in conditioning severe malaria in Thai adults is largely unexplored, the functional association between IL12B polymorphisms [i.e. IL12Bpro (rs17860508) and IL12B 3' UTR T/G (rs3212227)], severe malaria and cytokine production was examined in patients with Plasmodium falciparum infections (n = 355) recruited from malaria endemic areas along the Thai-Myanmar border in northwest Thailand. Circulating IL-12p40 (p = 0.049) and IFN-gamma (p = 0.051) were elevated in patients with severe malaria, while only IL-12p40 was significantly higher in severe malaria patients with hyperparasitaemia (p = 0.046). Carriage of the IL12Bpro1.1 genotype was associated with enhanced severity of malaria (OR, 2.34; 95% CI, 0.94-5.81; p = 0.066) and hyperparasitaemia (OR, 3.42; 95% CI, 1.17-9.87; p = 0.025) relative to the IL12Bpro2.2 genotype (wild type). Individuals with the IL12Bpro1.1 genotype also had the lowest IL-12p40 (p = 0.002) and the highest IFN-gamma (p = 0.004) levels. Construction of haplotypes revealed that carriage of the IL12Bpro-2/3' UTR-T haplotype was associated with protection against severe malaria (OR, 0.51; 95% CI, 0.29-0.90; p = 0.020) and reduced circulating IFN-gamma (p = 0.06). Thus, genotypic and haplotypic variation at IL12Bpro and IL12B 3' UTR in this population influences susceptibility to severe malaria and functional changes in circulating IL-12p40 and IFN-gamma levels. Results presented here suggest that protection against severe malaria in Thai adults is associated with genotypic variants that condition enhanced IL-12p40 and reduced IFN-gamma levels.

Identification of a critical CYP2E1 epitope in patients with drug-induced liver injury from anesthetics (93.16)

Abstract Susceptible individuals develop immune-mediated drug-induced liver injury (DILI) after receiving halogenated anesthetics, anti-seizure medications, antibiotics or non-steroidal anti-inflammatory drugs. In anesthetic DILI, serum cytochrome P4502E1 (CYP2E1) autoantibodies and diminished CYP2E1 activity assist in confirming the diagnosis, while responsible epitopes are unknown. We hypothesize that anesthetic DILI is initiated by pathogenic CYP2E1 epitopes centered on the Ser129 active site and presented by MHC II molecules in susceptible haplotypes. To test our hypothesis, we identified 15 mer human CYP2E1 candidate epitopes centered on Ser129 that bind to mouse MHC II using competitive inhibition of OVA323 - 329 in I-Ad DO11.10 T cell hybridomas + LS102.9 activation. Next we measured splenocyte T cell proliferation to candidate epitopes using our model of anesthetic DILI in BALB/c mice two weeks following TFA-S100 immunizations. Two CYP2E1 epitopes were detected by competitive inhibition; however, only one epitope Gly113 - Leu135 was recognized by proliferation and human sera ELISA assays. SYFPEITHI prediction of the probability of binding confirmed H2-Ad and H2-Ed haplotypes in BALB/c mice and identified 6 human MHC II haplotypes that could bind this epitope: HLA-DRB1*0101, HLA-DRB1*0301 HLA-DRB1*0401, HLA-DRB1*0701 HLADRB*1101 and HLADRB1*1501. This is the first demonstration of a CYP2E1 epitope and MHC II haplotypes that may increase the risk of developing anesthetic DILI.

The 252A/G and 804C/A Polymorphisms ofLymphotoxin-alphais Associated to Onset of Acute Myocardial Infarction in Taiwan

Inflammation gene polymorphisms contributing to pro-atherosclerosis and pro-inflammation processes of infracted hearts were intensively investigated. In this study, we performed a case-control study involving 117 acute myocardial infarction (AMI) patients versus 165 unrelated normal subjects to distinguish associations of the onset of AMI with 252A/G, 804C/A polymorphisms of Lymphotoxin-alpha (LTA, also named TNF-β) gene, and 3279 C/T polymorphism of its binding partner, LGALS2 gene. An association concordant to the original study between LTA 252G and 804A homozygosity with the onset of AMI was found. In addition, 804C/A polymorphism more generally correlated to the prevalence of coronary artery disease (CAD) rather than the onset of AMI. The susceptible haplotype of LTA to AMI risk was found as the 252G allele couple with 804C or 804A allele among the Taiwanese population. More population-based studies are warranted to confirm these findings and evaluate its clinical impact on AMI diagnosis and prognosis.

Polymorphisms in CYP11B2 and CYP11B1 genes associated with primary hyperaldosteronism

Several frequent polymorphisms in the CYP11B2 gene are suggested to be associated with essential hypertension and aldosterone secretion. In this study, we investigated the association of polymorphisms in CYP11B2 and CYP11B1 genes with the risk of primary hyperaldosteronism (PH). Three polymorphisms in the CYP11B2 gene (intron 2 conversion, rs1799998 and rs4539) and two polymorphisms in the CYP11B1 gene (rs6410 and rs6387) were analyzed in patients with PH and in the normal population. The rs6410 allelic frequencies in patients with aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA) were significantly different from those in controls at P=1.09 x 10(-5) and 0.015, respectively. There was a relative excess of AA homozygotes and AG heterozygotes of the rs6410 allele in the APA group as compared with the control group (P=2.19 x 10(-4)). There were significantly different genotypes, AA and AG, of the rs6410 allele between the patients with IHA and the controls only after adjustments for age, gender and body mass index (odds ratio (OR)=4.06, 95% confidence interval (CI) 1.31-12.66; OR=2.41, 95% CI 1.02-5.72). One susceptible haplotype, AAAWT, was identified to be significantly associated with APA (OR=1.44, 95% CI 1.19-1.76), and three susceptible haplotypes, AAAWT, AGGWT and AGAWC, were identified to be significantly associated with IHA (OR=1.55, 95% CI 1.23-1.96; OR=1.49, 95% CI 1.17-1.89; OR=1.40, 95% CI 1.04-1.88). In contrast, one protective haplotype, GGAWT, showed a significant difference between the patients with APA and controls (OR=0.73, 95% CI 0.55-0.97). Several haplotypes were associated with ARR in both the controls and cases. Our data demonstrated that there was a significant association between polymorphisms in the CYP11B2 and CYP11B1 genes and a genetic predisposition to PH. The association with IHA seemed closer compared with APA.

Functionally Significant Differences in Expression of Disease-Associated IL-7 Receptor α Haplotypes in CD4 T Cells and Dendritic Cells

Common genetic variants of IL-7 receptor alpha (IL-7Ralpha) have recently been shown to affect susceptibility to multiple sclerosis (MS) and type 1 diabetes, and survival following bone marrow transplantation. Transcription of the gene produces two dominant isoforms, with or without exon 6, which code for membrane-bound or soluble IL-7Ralpha, respectively. The haplotypes produce different isoform ratios. We have tested IL-7Ralpha mRNA expression in cell subsets and in models of T cell homeostasis, activation, tolerance, and differentiation into regulatory T cell/Th1/Th2/Th17, memory, and dendritic cells (DCs) under the hypothesis that the conditions in which haplotype differences are maximal are those likely to be the basis for their association with disease pathogenesis. Maximal differences between haplotypes were found in DCs, where the ligand is mainly thymic stromal lymphopoietin (TSLP). The MS-protective haplotype produces a much lower ratio of soluble to membrane-bound receptor, and so potentially, DCs of this haplotype are more responsive to TSLP. The TSLP/IL-7Ralpha interaction on DCs is known to be critical for production of thymic regulatory T cells, and reduced production of these cells in MS susceptibility haplotypes may be a basis for its association with this disease. IL-7Ralpha mRNA expression varies greatly through cell differentiation so that it may be a useful marker for cell states. We also show that serum levels of soluble receptor are much higher for the MS susceptibility haplotype (p = 4 x 10(-13)). Because signaling through IL-7Ralpha controls T cell regulation, this haplotype difference is likely to affect the immunophenotype and disease pathogenesis.

The multiple sclerosis whole blood mRNA transcriptome and genetic associations indicate dysregulation of specific T cell pathways in pathogenesis

Multiple sclerosis (MS) is an autoimmune disease with a genetic component, caused at least in part by aberrant lymphocyte activity. The whole blood mRNA transcriptome was measured for 99 untreated MS patients: 43 primary progressive MS, 20 secondary progressive MS, 36 relapsing remitting MS and 45 age-matched healthy controls. The ANZgene Multiple Sclerosis Genetics Consortium genotyped more than 300 000 SNPs for 115 of these samples. Transcription from genes on translational regulation, oxidative phosphorylation, immune synapse and antigen presentation pathways was markedly increased in all forms of MS. Expression of genes tagging T cells was also upregulated (P < 10(-12)) in MS. A T cell gene signature predicts disease state with a concordance index of 0.79 with age and gender as co-variables, but the signature is not associated with clinical course or disability. The ANZgene genome wide association screen identified two novel regions with genome wide significance: one encoding the T cell co-stimulatory molecule, CD40; the other a region on chromosome 12q13-14. The CD40 haplotype associated with increased MS susceptibility has decreased gene expression in MS (P < 0.0007). The second MS susceptibility region includes 17 genes on 12q13-14 in tight linkage disequilibrium. Of these, only 13 are expressed in leukocytes, and of these the expression of one, FAM119B, is much lower in the susceptibility haplotype (P < 10(-14)). Overall, these data indicate dysregulation of T cells can be detected in the whole blood of untreated MS patients, and supports targeting of activated T cells in therapy for all forms of MS.

Mechanism by which HLA-DR4 regulates sex-bias of arthritis in humanized mice

HLA class II allele DRB1*0401 is associated with predisposition to Rheumatoid Arthritis in humans as well as collagen-induced arthritis in mice. Predominantly females develop arthritis in humans and DR4 transgenic mice; however the mechanism of sex-bias is still unknown. We have investigated the molecular basis by which DR4 is associated with sex-bias of arthritis. Here we show that differential antigen-specific immune mechanisms in DR4 male and female mice lead to increased susceptibility in female mice. B cells are hyperactive and present DR-restricted peptides robustly in females compared to males. Antigen-specific response showed that females produced B cell modulating cytokines like IL-13 while males produced IFNγ. Male transgenic mice have higher number of T and B regulatory cells. An exogenous supply of 17β estradiol in male mice led to enhanced expression of DR4 and antigen-specific response to DR4-restricted peptides. On the other hand, castration increased the incidence of arthritis. We propose that sex-bias in arthritis involves B cells and presentation of antigen by HLA-DR4 leading to activation of autoreactive cells and autoantibodies production in females, while regulatory B cells in males protect them from pathogenesis. The transgenic mice expressing RA susceptible haplotype simulate human RA and may be valuable to study gender differences observed in patients.

Analysis of the Iddm14 Rat Diabetes Susceptibility Locus in Multiple Rat Strains: Identification of a Susceptibility Haplotype in the Tcrb-V13 Gene and Prevention of Diabetes by Depletion of Vbeta13+ T Cells

Analysis of the Iddm14 Rat Diabetes Susceptibility Locus in Multiple Rat Strains: Identification of a Susceptibility Haplotype in the Tcrb-V13 Gene and Prevention of Diabetes by Depletion of Vbeta13+ T Cells

Role of the urate transporter SLC2A9 gene in susceptibility to gout in New Zealand Māori, Pacific Island, and Caucasian case-control sample sets.

To examine the role of genetic variation in the renal urate transporter SLC2A9 in gout in New Zealand sample sets of Māori, Pacific Island, and Caucasian ancestry and to determine if the Māori and Pacific Island samples could be useful for fine-mapping. Patients (n= 56 Māori, 69 Pacific Island, and 131 Caucasian) were recruited from rheumatology outpatient clinics and satisfied the American College of Rheumatology criteria for gout. The control samples comprised 125 Māori subjects, 41 Pacific Island subjects, and 568 Caucasian subjects without arthritis. SLC2A9 single-nucleotide polymorphisms rs16890979 (V253I), rs5028843, rs11942223, and rs12510549 were genotyped (possible etiologic variants in Caucasians). Association of the major allele of rs16890979, rs11942223, and rs5028843 with gout was observed in all sample sets (P = 3.7 x 10(-7), 1.6 x 10(-6), and 7.6 x 10(-5) for rs11942223 in the Māori, Pacific Island, and Caucasian samples, respectively). One 4-marker haplotype (1/1/2/1; more prevalent in the Māori and Pacific Island control samples) was not observed in a single gout case. Our data confirm a role of SLC2A9 in gout susceptibility in a New Zealand Caucasian sample set, with the effect on risk (odds ratio >2.0) greater than previous estimates. We also demonstrate association of SLC2A9 with gout in samples of Māori and Pacific Island ancestry and a consistent pattern of haplotype association. The presence of both alleles of rs16890979 on susceptibility and protective haplotypes in the Māori and Pacific Island sample is evidence against a role for this nonsynonymous variant as the sole etiologic agent. More extensive linkage disequilibrium in Māori and Pacific Island samples suggests that Caucasian samples may be more useful for fine-mapping.

Capture of Type 1 Diabetes–Susceptible HLA DR-DQ Haplotypes in Japanese Subjects Using a Tag Single Nucleotide Polymorphism

OBJECTIVETo identify type 1 diabetes–susceptible HLA DR-DQ haplotypes using tag single nucleotide polymorphisms (SNPs) and to estimate the disease risk using these tag SNPs.RESEARCH DESIGN AND METHODSFive tag SNPs were typed in a total of 211 Japanese subjects including 201 patients with type 1 diabetes who had already been typed for HLA-DRB1, -DQA1, and -DQB1 alleles and 300 control subjects.RESULTSTag SNP rs2395185 captured haplotypes involving all DR4 specificities and DR9 specificity with a sensitivity of 98.5% and specificity of 94.9%. Using the T allele of rs2395185, we obtained an odds ratio (95% CI) of 2.87 (2.21–3.74) for type 1 diabetes. In addition, rs3129888 captured haplotypes involving HLA-DRB1*0802 with a sensitivity of 92.3% and specificity of 98.9%.CONCLUSIONSTyping of two tag SNPs (rs2395185 and rs3129888) may be useful for the screening of Japanese subjects at genetic risk of type 1 diabetes.

Differential association of HLA with three subtypes of type 1 diabetes: fulminant, slowly progressive and acute-onset

We sought to clarify similarities and differences in the contribution of HLA to genetic susceptibility to three subtypes of type 1 diabetes: acute-onset, fulminant and slowly progressive. We genotyped 545 Japanese patients with type 1 diabetes (338 acute-onset, 80 fulminant, 127 slowly progressive) and 396 control participants at HLA-DRB1, -DQB1, -A, -B and -C, and at 101 candidate single nucleotide polymorphisms (SNPs) in an 8.5 Mb region of the extended HLA. DRB1*0405-DQB1*0401, DRB1*0802-DQB1*0302 and DRB1*0901-DQB1*0303 were associated with acute-onset type 1 diabetes, with the DRB1*0405-DQB1*0401/DRB1*0802-DQB1*0302 genotype achieving the highest odds ratio of 42.7. DRB1*1501-DQB1*0602 and DRB1*1502-DQB1*0601 were negatively associated with acute-onset type 1 diabetes. A similar tendency was observed for slowly progressive type 1 diabetes. In contrast, only DRB1*0405-DQB1*0401 was associated with fulminant type 1 diabetes, with the DRB1*0405-DQB1*0401/DRB1*0405-DQB1*0401 genotype showing the highest odds ratio of 11.2. DRB1*0802-DQB1*0302, DRB1*0405-DQB1*0401/DRB1*0802-DQB1*0302 and DRB1*1501-DQB1*0602 were not associated with fulminant type 1 diabetes. The association of class I alleles and a panel of SNPs in an extended HLA region with fulminant type 1 diabetes was also different from that seen for the acute-onset and slowly progressive forms. The presence of both one and two susceptible haplotypes conferred susceptibility to slowly progressive type 1 diabetes, whereas the presence of two susceptible haplotypes was required to confer susceptibility to acute-onset and fulminant type 1 diabetes. These data suggest that HLA associations with fulminant type 1 diabetes are qualitatively different from those with other subtypes of type 1 diabetes, whereas the HLA contribution to slowly progressive type 1 diabetes is qualitatively similar to, but quantitatively different from, that in acute-onset type 1 diabetes.

Purinergic receptor P2Y, G-protein coupled, 2 (P2RY2) gene is associated with cerebral infarction in Japanese subjects

G-protein-coupled purinergic receptor P2Y2 (P2RY2) has an important role in the process of atherosclerosis related to cerebral infarction (CI). The aim of this study was to investigate the relationship between the P2RY2 gene and CI through a haplotype-based case-control study, including the separate analysis of two gender groups. A total of 237 CI patients and two control groups (control 1, 254; control 2, 255) were genotyped for five single nucleotide polymorphisms (SNPs) in the human P2RY2 gene (rs4944831, rs1783596, rs4944832, rs4382936, rs10898909). Among women, the distribution of the dominant rs4944832 phenotype (GG vs. GA+AA) differed significantly between the CI patients and the control 1 group (P=0.043) and between the CI patients and the control 2 group (P=0.029). Logistic regression analysis showed that the GG genotype of rs4944832 was significantly more prevalent in the female CI patients than in the control 1 (P=0.021) and control 2 groups (P=0.005). For all subjects, the overall distribution of the haplotype established by rs1783596-rs4382936-rs10898909 was significantly different between the CI patients and the control 1 group (P=0.027). For all subjects, the frequency of the T-A-G haplotype (rs1783596-rs4382936-rs10898909) was also significantly higher (P=0.031), whereas the frequency of the T-C-G haplotype (rs1783596-rs4382936-rs10898909) was significantly lower (P=0.029) in the CI patients than in the control 1 group. The present results indicate that the T-A-G haplotype of the human P2RY2 gene is a susceptibility haplotype for CI in Japanese subjects, and that the GG genotype is a genetic marker for CI, particularly in Japanese women.

DAOA/G72 predicts the progression of prodromal syndromes to first episode psychosis

The genetic factors determining the progression of prodromal syndromes to first episode schizophrenia have remained enigmatic to date. In a unique prospective multicentre trial, we assessed whether variants at the d-amino acid oxidase activator (DAOA)/G72 locus influence progression to psychosis. Young subjects with a prodromal syndrome were observed prospectively for up to 2 years to assess the incidence of progression to schizophrenia or first episode psychosis. Of the 82 probands with a prodromal syndrome, 21 probands experienced progression to psychosis within the observation period. Assessment of nine common variants in the DAOA/G72 locus yielded two variants with the predictive value for symptom progression: all four probands with the rs1341402 CC genotype developed psychosis compared with 17 out of 78 probands with the TT or CT genotypes (χ2 = 12.348; df = 2; p = 0.002). The relative risk for progression to psychosis was significantly increased in the CC genotype: RR = 4.588 (95% CI = 2.175–4.588). Similarly, for rs778294, 50% of probands with the AA genotype, but only 22% of probands with a GG or GA genotype progressed to psychosis (χ2 = 7.027; df = 2; p = 0.030). Moreover, haplotype analysis revealed a susceptibility haplotype for progression to psychosis. This is one of the first studies to identify a specific genetic factor for the progression of prodromal syndromes to schizophrenia, and further underscores the importance of the DAOA/G72 gene for schizophrenia.

A haplotype in STAT4 gene associated with rheumatoid arthritis in Caucasians is not associated in the Han Chinese population, but with the presence of rheumatoid factor

Several studies have shown that a haplotype (rs11889341, rs7574865, rs8179673 and rs10181656) in STAT4 is associated with the development of RA in Caucasian, Korean and Japanese populations. The aim of this study was to investigate the effect of STAT4 on susceptibility to RA in the Han Chinese population. Unrelated 750 RA patients and individually matched 750 healthy controls were genotyped for single nucleotide polymorphism (SNP), rs11889341, in STAT4, which tags the susceptibility haplotype. Association analyses were performed on the whole data set and on sex subsets. Significant relationships were determined between clinical variables and rs11889341 for each disease subtype in the studied groups. There was no evidence of a significant association between rs11889341 and RA. The heterozygous CT genotype was associated with RA in female group [P = 0.027; odds ratio (OR) 1.31; 95% CI 1.03, 1.65]. No association was found in male group and in any subsets of RA based on sex, RF and anti-cyclic citrullinated peptide (anti-CCP) antibody. However, in the Han Chinese population with RA disease, we observed a significantly decreased frequency of the minor T allele and TT genotype in the RF-positive subgroup compared with RF-negative subgroup (T allele: P = 0.024; OR 0.73; 95% CI 0.56, 0.95; TT genotype P = 0.013; OR 0.49; 95% CI 0.28, 0.86). The STAT4 RA-susceptibility haplotype identified in other previously reported populations has not been replicated in the Han Chinese population with individually matched case-control study design. It is associated only with the presence of RF in the Han Chinese population with RA disease.