Instruct: Given a scientific claim, retrieve passages that support or refute the claim.
Query: ERAP1 SNPs are epistatic to HLA alleles for ankylosing spondylitis.
Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, although its role in the aetiology of AS remains elusive. To better understand the genetic basis of the MHC susceptibility loci, we genotyped 7,264 MHC SNPs in 22,647 AS cases and controls of European descent. We impute SNPs, classical HLA alleles and amino-acid residues within HLA proteins, and tested these for association to AS status. Here we show that in addition to effects due to HLA-B*27 alleles, several other HLA-B alleles also affect susceptibility. After controlling for the associated haplotypes in HLA-B, we observe independent associations with variants in the HLA-A, HLA-DPB1 and HLA-DRB1 loci. We also demonstrate that the ERAP1 SNP rs30187 association is not restricted only to carriers of HLA-B*27 but also found in HLA-B*40:01 carriers independently of HLA-B*27 genotype.
BACKGROUND Two inflammatory disorders, type 1 diabetes and celiac disease, cosegregate in populations, suggesting a common genetic origin. Since both diseases are associated with the HLA class II genes on chromosome 6p21, we tested whether non-HLA loci are shared. METHODS We evaluated the association between type 1 diabetes and eight loci related to the risk of celiac disease by genotyping and statistical analyses of DNA samples from 8064 patients with type 1 diabetes, 9339 control subjects, and 2828 families providing 3064 parent-child trios (consisting of an affected child and both biologic parents). We also investigated 18 loci associated with type 1 diabetes in 2560 patients with celiac disease and 9339 control subjects. RESULTS Three celiac disease loci--RGS1 on chromosome 1q31, IL18RAP on chromosome 2q12, and TAGAP on chromosome 6q25--were associated with type 1 diabetes (P<1.00x10(-4)). The 32-bp insertion-deletion variant on chromosome 3p21 was newly identified as a type 1 diabetes locus (P=1.81x10(-8)) and was also associated with celiac disease, along with PTPN2 on chromosome 18p11 and CTLA4 on chromosome 2q33, bringing the total number of loci with evidence of a shared association to seven, including SH2B3 on chromosome 12q24. The effects of the IL18RAP and TAGAP alleles confer protection in type 1 diabetes and susceptibility in celiac disease. Loci with distinct effects in the two diseases included INS on chromosome 11p15, IL2RA on chromosome 10p15, and PTPN22 on chromosome 1p13 in type 1 diabetes and IL12A on 3q25 and LPP on 3q28 in celiac disease. CONCLUSIONS A genetic susceptibility to both type 1 diabetes and celiac disease shares common alleles. These data suggest that common biologic mechanisms, such as autoimmunity-related tissue damage and intolerance to dietary antigens, may be etiologic features of both diseases.
There is strong evidence for a genetic contribution to epilepsy, but it is commonly assumed that this genetic contribution is limited to ‘generalized’ epilepsies, and that most forms of ‘partial’ epilepsy are nongenetic. In a linkage analysis of a single family containing 11 affected individuals, we obtained strong evidence for localization of a gene for partial epilepsy. This susceptibility gene maps to chromosome 10q, with a maximum two–point lod score for D10S192 of 3.99 at θ=0.0. All affected individuals share a single haplotype for seven tightly linked contiguous markers; the maximum lod score for this haplotype is 4.83 at θ=0.0. Key recombinants place the susceptibility locus within a 10 centimorgan interval.
The recommended treatment for patients with chronic hepatitis C, pegylated interferon-α (PEG-IFN-α) plus ribavirin (RBV), does not provide sustained virologic response (SVR) in all patients. We report a genome-wide association study (GWAS) to null virological response (NVR) in the treatment of patients with hepatitis C virus (HCV) genotype 1 within a Japanese population. We found two SNPs near the gene IL28B on chromosome 19 to be strongly associated with NVR (rs12980275, P = 1.93 × 10−13, and rs8099917, 3.11 × 10−15). We replicated these associations in an independent cohort (combined P values, 2.84 × 10−27 (OR = 17.7; 95% CI = 10.0–31.3) and 2.68 × 10−32 (OR = 27.1; 95% CI = 14.6–50.3), respectively). Compared to NVR, these SNPs were also associated with SVR (rs12980275, P = 3.99 × 10−24, and rs8099917, P = 1.11 × 10−27). In further fine mapping of the region, seven SNPs (rs8105790, rs11881222, rs8103142, rs28416813, rs4803219, rs8099917 and rs7248668) located in the IL28B region showed the most significant associations (P = 5.52 × 10−28–2.68 × 10−32; OR = 22.3–27.1). Real-time quantitative PCR assays in peripheral blood mononuclear cells showed lower IL28B expression levels in individuals carrying the minor alleles (P = 0.015).
Although most hepatitis C virus (HCV)-infected individuals develop chronic infection, about 25% of them are able to clear the virus spontaneously without any therapeutic intervention. The aim of the present study was to identify genes associated with spontaneous HCV clearance in a population of Iranian patients. We genotyped 110 single-nucleotide polymorphisms (SNPs) in 59 selected—candidate—genes in a cohort of 107 HCV-infected participants who spontaneously cleared the infection and 176 participants whose infection persisted. Three out of the 110 SNPs were found to be associated with HCV outcome (P-values<0.03). rs11506105 in EGFR (epidermal growth factor receptor gene), and rs11881222 and rs12979860 in IL28B (interferon-λ3 gene). Multivariate logistic regression of the three markers showed that the A/A genotypes in both rs11506105 (EFGR) and rs11881222 (IL28B), and the C/C genotype in rs12979860 (IL28B) are associated with HCV clearance (recessive model: odds ratio (OR)=2.06, 95% confidence interval (95% CI)=1.09–3.88, P=0.025; OR=2.09, 95% CI=1.23–3.60, P=0.007; and OR=1.95, 95% CI=1.15–3.35, P=0.014 for rs11506105, rs12979860 and rs11881222, respectively). In conclusion, EGFR and IL28B SNPs are strong independent predictive markers of spontaneous viral clearance.
Recent biological studies indicate the importance of anterior-pharynx defective-1 (APH-1) proteins in Alzheimer's disease (AD) pathogenesis. We scanned APH-1 genes for the presence of sequence variations by denaturing high performance liquid chromatography and analyzed their distribution in an Italian sample of 113 AD patients and 132 controls. We found six different polymorphisms: three of them, all in APH-1b, predict an aminoacid substitution (T27I, V199L and F217L); the others are either silent or in non-coding regions. None of them is significantly associated with the disease; data stratification by the apolipoprotein E epsilon4 carrier status show a trend for coexistence of the transversion c+651T>G (F217L) with the epsilon4 allele. Our data suggest that polymorphisms in APH-1a/b coding regions are not linked with higher risk for sporadic AD in our Italian population sample.
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with complicated genetic inheritance. Programmed death 1 (PD-1), a negative T cell regulator to maintain peripheral tolerance, induces negative signals to T cells during interaction with its ligands and is therefore a candidate gene in the development of SLE. In order to examine whether expression levels of PD-1 contribute to the pathogenesis of SLE, 30 patients with SLE and 30 controls were recruited and their PD-1 expression levels in peripheral blood mononuclear cells (PBMCs) were measured via flow cytometry and quantitative real-time-reverse transcription polymerase chain reaction (RT-PCR). Also, whether PD-1 expression levels are associated with the variant of the SNP rs36084323 and the SLE Disease Activity Index (SLEDAI) was studied in this work. The PD-1 expression levels of SLE patients were significantly increased compared with those of the healthy controls. The upregulated PD-1 expression levels in SLE patients were greatly associated with SLEDAI scores. No significant difference was found between PD-1 expression levels and SNP rs36084323. The results suggest that increased expression of PD-1 may correlate with the pathogenesis of SLE, upregulated PD-1 expression may be a biomarker for SLE diagnosis, and PD-1 inhibitor may be useful to SLE treatment.
Endoplasmic reticulum (ER)-associated aminopeptidase (ERAP)1 has been implicated in the final proteolytic processing of peptides presented by major histocompatibility complex (MHC) class I molecules. To evaluate the in vivo role of ERAP1, we have generated ERAP1-deficient mice. Cell surface expression of the class Ia molecules H-2Kb and H-2Db and of the class Ib molecule Qa-2 was significantly reduced in these animals. Although cells from mutant animals exhibited reduced capacity to present several self- and foreign antigens to Kb-, Db-, or Qa-1b–restricted CD8+ cytotoxic T cells, presentation of some antigens was unaffected or significantly enhanced. Consistent with these findings, mice generated defective CD8+ T cell responses against class I–presented antigens. These findings reveal an important in vivo role of ER-associated peptidase activity in tailoring peptides for presentation by MHC class Ia and class Ib molecules.
Autoimmune polyglandular syndrome type I (APS 1, also called APECED) is an autosomal-recessive disorder that maps to human chromosome 21q22.3 between markers D21S49 and D21S171 by linkage studies. We have isolated a novel gene from this region, AIRE (autoimmune regulator), which encodes a protein containing motifs suggestive of a transcription factor including two zinc-finger (PHD-finger) motifs, a proline-rich region and three LXXLL motifs. Two mutations, a C→T substitution that changes the Arg 257 (CGA) to a stop codon (TGA) and an A→G substitution that changes the Lys 83 (AAG) to a Glu codon (GAG), were found in this novel gene in Swiss and Finnish APECED patients. The Arg257stop (R257X) is the predominant mutation in Finnish APECED patients, accounting for 10/12 alleles studied. These results indicate that this gene is responsible for the pathogenesis of APECED. The identification of the gene defective in APECED should facilitate the genetic diagnosis and potential treatment of the disease and further enhance our general understanding of the mechanisms underlying autoimmune diseases.
Background: The relationship of LPA single nucleotide polymorphisms (SNPs), apolipoprotein(a) isoforms, and lipoprotein(a) [Lp(a)] levels with major adverse cardiovascular events (MACE) in different ethnic groups is not well known. Methods: LPA SNPs, apolipoprotein(a) isoforms, Lp(a), and oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) levels were measured in 1792 black, 1030 white, and 597 Hispanic subjects enrolled in the Dallas Heart Study. Their interdependent relationships and prospective association with MACE after median 9.5-year follow-up were determined. Results: LPA SNP rs3798220 was most prevalent in Hispanics (42.38%), rs10455872 in whites (14.27%), and rs9457951 in blacks (32.92%). The correlation of each of these SNPs with the major apolipoprotein(a) isoform size was highly variable and in different directions among ethnic groups. In the entire cohort, Cox regression analysis with multivariable adjustment revealed that quartiles 4 of Lp(a) and OxPL-apoB were associated with hazard ratios (95% confidence interval) for time to MACE of 2.35 (1.50–3.69, P<0.001) and 1.89 (1.26–2.84, P=0.003), respectively, versus quartile 1. Addition of the major apolipoprotein(a) isoform and the 3 LPA SNPs to these models attenuated the risk, but significance was maintained for both Lp(a) and OxPL-apoB. Evaluating time to MACE in specific ethnic groups, Lp(a) was a positive predictor and the size of the major apolipoprotein(a) isoform was an inverse predictor in blacks, the size of the major apolipoprotein(a) isoform was an inverse predictor in whites, and OxPL-apoB was a positive predictor in Hispanics. Conclusions: The prevalence and association of LPA SNPs with size of apolipoprotein(a) isoforms, Lp(a), and OxPL-apoB levels are highly variable and ethnicity-specific. The relationship to MACE is best explained by elevated plasma Lp(a) or OxPL-apoB levels, despite significant ethnic differences in LPA genetic markers.
Previous studies have detected associations between mitochondrial haplogroups and schizophrenia (SZ). However, no study has examined the relationship between major mitochondrial DNA (mtDNA) haplogroups and SZ in the Chinese population. The aim of this study was to assess the association between mtDNA haplogroups and SZ genesis in the Chinese Han population. We used a case-control study and sequenced the mtDNA hypervariable regions (HVR1, HVR2, and HVR3) in the Han population. We analyzed mtDNA haplogroups and HVR polymorphisms in 298 SZ patients and 298 controls. The haplotypes were classified into 10 major haplogroups: A, B, CZ, D, F, G, M, N, N9a, and R. Statistical analysis revealed that only N9a showed a nominally significant association with protection from SZ [1.68% vs. 6.38%, p=0.004, OR=0.251 (0.092-0.680); after adjustment for age and sex: p=0.006, OR=0.246 (0.090-0.669)]. Three HVR polymorphisms were found to be nominally significantly different between subjects with SZ and controls, and all except one (m.204T>C) are linked to the N9a haplogroup. Our results indicate that mtDNA haplogroup N9a might be a protective factor for SZ.
OBJECTIVE Ankylosing spondylitis (AS) and spondyloarthropathy (SpA) are inflammatory diseases of unknown etiology. Various exogenous and endogenous (inherited) factors play a role in their development. Sulfasalazine (SSZ) is generally accepted as a disease modifying drug in the treatment of AS and SpA. Which part of SSZ, 5-acetylsalicylic acid (5-ASA, mesalazine) or sulfapyridine (SP), is the effective moiety is unknown. As the bowel, colon, and the ileum play an important role in the development of AS and SpA, it may be possible that 5-ASA is the effective moiety, with a similar mode of action as in the treatment of inflammatory bowel disease. To determine the efficacy of 5-ASA an open pilot study was done in 2 groups of patients with SpA.   METHODS Twenty patients with SpA, who were taking SSZ, were switched to 5-ASA (Pentasa), and 19 patients with active SpA were treated with 5-ASA without previous administration of SSZ. RESULTS In the first group, 17 (85%) patients responded with respect to the physician global clinical assessment compared to the previous SSZ treatment period; whereas in the second patient group a statistically significant improvement was obtained in erythrocyte sedimentation rate. CONCLUSION The results support our hypothesis that 5-ASA might be the active moiety of SSZ in the treatment of SpA.
Genome-wide association studies are now identifying disease-associated chromosome regions. However, even after convincing replication, the localization of the causal variant(s) requires comprehensive resequencing, extensive genotyping and statistical analyses in large sample sets leading to targeted functional studies. Here, we have localized the type 1 diabetes (T1D) association in the interleukin 2 receptor alpha (IL2RA) gene region to two independent groups of SNPs, spanning overlapping regions of 14 and 40 kb, encompassing IL2RA intron 1 and the 5′ regions of IL2RA and RBM17 (odds ratio = 2.04, 95% confidence interval = 1.70–2.45; P = 1.92 × 10−28; control frequency = 0.635). Furthermore, we have associated IL2RA T1D susceptibility genotypes with lower circulating levels of the biomarker, soluble IL-2RA (P = 6.28 × 10−28), suggesting that an inherited lower immune responsiveness predisposes to T1D.
INTRODUCTION Deregulated or excessive host immune responses contribute to the pathogenesis of sepsis. Toll-like receptor (TLR) signaling pathways and their negative regulators play a pivotal role in the modulation of host immune responses and the development of sepsis. The objective of this study was to investigate the association of variants in the TLR signaling pathway genes and their negative regulator genes with susceptibility to sepsis in the Chinese Han population. METHODS Patients with severe sepsis (n = 378) and healthy control subjects (n = 390) were enrolled. Five genes, namely TLR2, TLR4, TLR9, MyD88 and TOLLIP, were investigated for their association with sepsis susceptibility by a tag single nucleotide polymorphism (SNP) strategy. Twelve tag SNPs were selected based on the data of Chinese Han in Beijing from the HapMap project and genotyped by direct sequencing. The mRNA expression levels of TOLLIP were determined using real-time quantitative Polymerase Chain Reaction (PCR) assays, and concentrations of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS Our results showed that the minor C-allele of rs5743867 in TOLLIP was significantly associated with the decreased risk of sepsis (Padj = 0.00062, odds ratio (OR)adj = 0.71, 95% confidence interval (CI) 0.59 to 0.86) after adjustment for covariates in multiple logistic regression analysis. A 3-SNP haplotype block harboring the associated SNP rs5743867 also displayed strong association with omnibus test P value of 0.00049. Haplotype GTC showed a protective role against sepsis (Padj = 0.0012), while haplotype GCT showed an increased risk for sepsis (Padj = 0.00092). After exposure to lipopolysaccharide (LPS), TOLLIP mRNA expression levels in peripheral blood mononuclear cells (PBMCs) from homozygotes for the rs5743867C allele were significantly higher than in heterozygotes and homozygotes for the rs5743867T allele (P = 0.013 and P = 0.01, respectively). Moreover, the concentrations of TNF-α and IL-6 in culture supernatants were significantly lower in the subjects of rs5743867CC genotype than in CT and TT genotype subjects (P = 0.016 and P = 0.003 for TNF-α; P = 0.01 and P = 0.002 for IL-6, respectively). CONCLUSIONS Our findings indicated that the variants in TOLLIP were significantly associated with sepsis susceptibility in the Chinese Han population.
Epstein-Barr virus (EBV) is associated with multiple sclerosis (MS), and antibodies to the EBV nuclear antigen-1 (EBNA-1) are consistently increased in MS patients. The hypothesis of this study is that anti-EBNA-1 antibodies cross-react with a self antigen in MS patients. We affinity purified anti-EBNA-1 antibodies from human plasma, used the anti-EBNA-1 to immunoprecipitate antigens from human brain, and identified bound antigens with mass spectrometry. Anti-EBNA-1 consistently bound heterogeneous nuclear ribonucleoprotein L (HNRNPL). We expressed both the long and short isoforms of this protein, and verified with Western blots and ELISA that the long isoform cross-reacts with EBNA-1. Immunohistochemistry demonstrated that anti-EBNA-1 bound to an antigen in the nucleus of cultured rat central nervous system cells. ELISA demonstrated the presence of antibodies to HNRNPL in the plasma of both healthy controls and MS patients, but anti-HNRNPL was not increased in MS patients. We conclude that HNRNPL is an autoantigen which cross-reacts with EBNA-1. The relevance of this autoantigen to MS and other autoimmune diseases remains to be investigated.
AIMS A recent genome-wide association study identified a haplotype block on chromosome 4q25 associated with atrial fibrillation (AF). We sought to replicate this association in four independent cohorts. METHODS AND RESULTS The Framingham Heart Study and Rotterdam Study are community-based longitudinal studies. The Vanderbilt AF Registry and German AF Network (AFNet) are case-control studies. Participants with AF (n = 3508) were more likely to be male and were older than referent participants (n = 12 173; Framingham 82 +/- 10 vs. 71 +/- 13 years; Rotterdam 73 +/- 8 vs. 69 +/- 9 years; Vanderbilt 54 +/- 14 vs. 57 +/- 14 years; AFNet 62 +/- 12 vs. 49 +/- 14 years). Single nucleotide polymorphism (SNP) rs2200733 was associated with AF in all four cohorts, with odds ratios (ORs) ranging from 1.37 in Rotterdam [95% confidence interval (CI) 1.18-1.59; P = 3.1 x 10(-5)] to 2.52 in AFNet (95% CI 2.22-2.8; P = 1.8 x 10(-49)). There also was a significant association between AF and rs10033464 in Framingham (OR 1.34; 95% CI 1.03-1.75; P = 0.031) and AFNet (OR 1.30; 95% CI 1.13-1.51; P = 0.0002), but not Vanderbilt (OR 1.16; 95% CI 0.86-1.56; P = 0.33). A meta-analysis of the current and prior AF studies revealed an OR of 1.90 (95% CI 1.60-2.26; P = 3.3 x 10(-13)) for rs2200733 and of 1.36 (95% CI 1.26-1.47; P = 6.7 x 10(-15)) for rs10033464. CONCLUSION The non-coding SNPs rs2200733 and rs10033464 are strongly associated with AF in four cohorts of European descent. These results confirm the significant relations between AF and intergenic variants on chromosome 4.
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is the only described systemic autoimmune disease with established monogenic background, and the first autoimmune disorder localized outside the major histocompatibility complex (MHC) region. The primary biochemical defect in APECED is unknown. We have isolated a novel gene, AIRE, encoding for a putative nuclear protein featuring two PHD-type zinc-finger motifs, suggesting its involvement in transcriptional regulation. Five mutations in AIRE are reported in individuals with this disorder. This is the first report of a single-gene defect causing a systemic human autoimmune disease, providing a tool for exploring the molecular basis of autoimmunity.
Multiple genetic loci associated with obesity or body mass index (BMI) have been identified through genome-wide association studies conducted predominantly in populations of European ancestry. We performed a meta-analysis of associations between BMI and approximately 2.4 million SNPs in 27,715 east Asians, which was followed by in silico and de novo replication studies in 37,691 and 17,642 additional east Asians, respectively. We identified ten BMI-associated loci at genome-wide significance (P < 5.0 × 10(-8)), including seven previously identified loci (FTO, SEC16B, MC4R, GIPR-QPCTL, ADCY3-DNAJC27, BDNF and MAP2K5) and three novel loci in or near the CDKAL1, PCSK1 and GP2 genes. Three additional loci nearly reached the genome-wide significance threshold, including two previously identified loci in the GNPDA2 and TFAP2B genes and a newly identified signal near PAX6, all of which were associated with BMI with P < 5.0 × 10(-7). Findings from this study may shed light on new pathways involved in obesity and demonstrate the value of conducting genetic studies in non-European populations.
BACKGROUND Recent genome-wide association studies (GWAS) have mapped several novel loci influencing blood lipid levels in Caucasians. We sought to explore whether the genetic variants at newly identified lipid-associated loci were associated with CHD susceptibility in a Chinese Han population. METHODOLOGY/PRINCIPAL FINDINGS We conducted a two-stage case-control study in a Chinese Han population. The first-stage, consisting of 1,376 CHD cases and 1,376 sex and age- frequency matched controls, examined 5 novel lipid-associated single-nucleotide polymorphisms (SNPs) identified from GWAS among Caucasians in relation to CHD risk in Chinese. We then validated significant SNPs in the second-stage, consisting of 1,269 cases and 2,745 controls. We also tested associations between SNPs within the five novel loci and blood lipid levels in 4,121 controls. We identified two novel SNPs (rs599839 in CELSR2-PSRC1-SORT1 and rs16996148 in NCAN-CILP2) that were significantly associated with reduced CHD risk in Chinese (odds ratios (95% confidence intervals) in the dominant model 0.76 (0.61-0.90; P = 0.001), 0.67 (0.57-0.77; P = 3.4×10(-8)), respectively). Multiple linear regression analyses using dominant model showed that rs599839 was significantly associated with decreased LDL levels (P = 0.022) and rs16996148 was significantly associated with increased LDL and HDL levels (P = 2.9×10(-4) and 0.001, respectively). CONCLUSIONS/SIGNIFICANCE We identified two novel SNPs (rs599839 and rs16996148) at newly identified lipid-associated loci that were significantly associated with CHD susceptibility in a Chinese Han population.
We performed genome-wide analyses to identify genomic loci that interact with sodium to influence blood pressure (BP) using single-marker-based (1 and 2 df joint tests) and gene-based tests among 1876 Chinese participants of the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study. Among GenSalt participants, the average of 3 urine samples was used to estimate sodium excretion. Nine BP measurements were taken using a random zero sphygmomanometer. A total of 2.05 million single-nucleotide polymorphisms were imputed using Affymetrix 6.0 genotype data and the Chinese Han of Beijing and Japanese of Tokyo HapMap reference panel. Promising findings (P<1.00×10(-4)) from GenSalt were evaluated for replication among 775 Chinese participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Single-nucleotide polymorphism and gene-based results were meta-analyzed across the GenSalt and MESA studies to determine genome-wide significance. The 1 df tests identified interactions for UST rs13211840 on diastolic BP (P=3.13×10(-9)). The 2 df tests additionally identified associations for CLGN rs2567241 (P=3.90×10(-12)) and LOC105369882 rs11104632 (P=4.51×10(-8)) with systolic BP. The CLGN variant rs2567241 was also associated with diastolic BP (P=3.11×10(-22)) and mean arterial pressure (P=2.86×10(-15)). Genome-wide gene-based analysis identified MKNK1 (P=6.70×10(-7)), C2orf80 (P<1.00×10(-12)), EPHA6 (P=2.88×10(-7)), SCOC-AS1 (P=4.35×10(-14)), SCOC (P=6.46×10(-11)), CLGN (P=3.68×10(-13)), MGAT4D (P=4.73×10(-11)), ARHGAP42 (P≤1.00×10(-12)), CASP4 (P=1.31×10(-8)), and LINC01478 (P=6.75×10(-10)) that were associated with at least 1 BP phenotype. In summary, we identified 8 novel and 1 previously reported BP loci through the examination of single-nucleotide polymorphism and gene-based interactions with sodium.
Although genetic association studies have been with us for many years, even for the simplest analyses there is little consensus on the most appropriate statistical procedures. Here I give an overview of statistical approaches to population association studies, including preliminary analyses (Hardy–Weinberg equilibrium testing, inference of phase and missing data, and SNP tagging), and single-SNP and multipoint tests for association. My goal is to outline the key methods with a brief discussion of problems (population structure and multiple testing), avenues for solutions and some ongoing developments.
The CC genotype of the interleukin (IL)-28B.rs12979860 gene has been associated with spontaneous hepatitis C virus (HCV) clearance and treatment response. The distribution and correlation of an IL28B.rs12979860 single-nucleotide polymorphism (SNP) with HCV-specific cell-mediated immune (CMI) responses among Egyptian healthcare workers (HCWs) is not known. We determined this relationship in 402 HCWs who serve a patient cohort with ~85 % HCV prevalence. We enrolled 402 HCWs in four groups: group 1 (n = 258), seronegative aviremic subjects; group 2 (n = 25), seronegative viremic subjects; group 3 (n = 41), subjects with spontaneously resolved HCV infection; and group 4 (n = 78), chronic HCV patients. All subjects were tested for an HCV-specific CMI response using an ex-vivo interferon-gamma (IFNγ) ELISpot assay with nine HCV genotype-4a overlapping 15-mer peptide pools corresponding to all of the HCV proteins. All subjects were tested for IL28B.rs12979860 SNP by real-time PCR. An HCV-specific CMI was demonstrated in ~27 % of the seronegative aviremic HCWs (group 1), suggesting clearance of infection after low-level exposure to HCV. The frequency of IL28B.rs12979860 C allele homozygosity in the four groups was 49 %, 48 %, 49 %, and 23 %, while that of the T allele was 14 %, 16 %, 12 and 19 %, respectively, suggesting differential distributions among subjects with different HCV status. As reported, IL28B.rs12979860 predicted the outcome of HCV infection (p < 0.05), but we did not find any relationship between the IL28B genotypes and the outcome of HCV-specific CMI responses in the four groups (p > 0.05). The data show differential IL28B.rs12979860 genotype distribution among Egyptian HCWs with different HCV status and could not predict the outcome of HCV-specific CMI responses.
Impaired erythropoiesis in the deletion 5q (del(5q)) subtype of myelodysplastic syndrome (MDS) has been linked to heterozygous deletion of RPS14, which encodes the ribosomal protein small subunit 14. We generated mice with conditional inactivation of Rps14 and demonstrated an erythroid differentiation defect that is dependent on the tumor suppressor protein p53 (encoded by Trp53 in mice) and is characterized by apoptosis at the transition from polychromatic to orthochromatic erythroblasts. This defect resulted in age-dependent progressive anemia, megakaryocyte dysplasia and loss of hematopoietic stem cell (HSC) quiescence. As assessed by quantitative proteomics, mutant erythroblasts expressed higher levels of proteins involved in innate immune signaling, notably the heterodimeric S100 calcium-binding proteins S100a8 and S100a9. S100a8—whose expression was increased in mutant erythroblasts, monocytes and macrophages—is functionally involved in the erythroid defect caused by the Rps14 deletion, as addition of recombinant S100a8 was sufficient to induce a differentiation defect in wild-type erythroid cells, and genetic inactivation of S100a8 expression rescued the erythroid differentiation defect of Rps14-haploinsufficient HSCs. Our data link Rps14 haploinsufficiency in del(5q) MDS to activation of the innate immune system and induction of S100A8-S100A9 expression, leading to a p53-dependent erythroid differentiation defect.
The hemoglobinopathies are probably the world's most common genetic diseases: The World Health Organization has estimated that at least 5% of the population are carriers for one or other of the most serious forms, the alpha- and beta-thalassemias and the structural variant hemoglobins S, C, and E, which are found at polymorphic frequencies in many countries. All these hemoglobinopathies are believed to provide protection against malaria, and it is thought that, in malarial regions of the world, natural selection has been responsible for elevating and maintaining their gene frequencies, an idea first proposed 50 years ago by J.B.S. Haldane. Epidemiological studies undertaken in the 1950s on hemoglobin S in Africa provided support for the "malaria hypothesis," but until recently it has proved extremely difficult to verify it for the thalassemias. The application of molecular methods has, however, provided new opportunities to address this old question. Population and molecular genetic analysis of thalassemia variants, and microepidemiological studies of the relationship between alpha-thalassemia and malaria in the southwest Pacific, have provided unequivocal evidence for protection. Surprisingly, some of this protection appears to derive from enhanced susceptibility in very young thalassemic children to both Plasmodium falciparum and, especially, P. vivax, and this early exposure appears to provide the basis for better protection in later life.
Thiopurine therapy, commonly used in autoimmune conditions, can be complicated by life-threatening leukopenia. This leukopenia is associated with genetic variation in TPMT (encoding thiopurine S-methyltransferase). Despite a lower frequency of TPMT mutations in Asians, the incidence of thiopurine-induced leukopenia is higher in Asians than in individuals of European descent. Here we performed an Immunochip-based 2-stage association study in 978 Korean subjects with Crohn's disease treated with thiopurines. We identified a nonsynonymous SNP in NUDT15 (encoding p. Arg139Cys) that was strongly associated with thiopurine-induced early leukopenia (odds ratio (OR) = 35.6; Pcombined = 4.88 × 10−94). In Koreans, this variant demonstrated sensitivity and specificity of 89.4% and 93.2%, respectively, for thiopurine-induced early leukopenia (in comparison to 12.1% and 97.6% for TPMT variants). Although rare, this SNP was also strongly associated with thiopurine-induced leukopenia in subjects with inflammatory bowel disease of European descent (OR = 9.50; P = 4.64 × 10−4). Thus, NUDT15 is a pharmacogenetic determinant for thiopurine-induced leukopenia in diverse populations.