Menopausal hormone use and ovarian cancer risk: individual participant meta-analysis of 52 epidemiological studies.

BACKGROUND: Half the epidemiological studies with information about menopausal hormone therapy and ovarian cancer risk remain unpublished, and some retrospective studies could have been biased by selective participation or recall. We aimed to assess with minimal bias the effects of hormone therapy on ovarian cancer risk. METHODS: Individual participant datasets from 52 epidemiological studies were analysed centrally. The principal analyses involved the prospective studies (with last hormone therapy use extrapolated forwards for up to 4 years). Sensitivity analyses included the retrospective studies. Adjusted Poisson regressions yielded relative risks (RRs) versus never-use. FINDINGS: During prospective follow-up, 12 110 postmenopausal women, 55% (6601) of whom had used hormone therapy, developed ovarian cancer. Among women last recorded as current users, risk was increased even with <5 years of use (RR 1·43, 95% CI 1·31-1·56; p<0·0001). Combining current-or-recent use (any duration, but stopped <5 years before diagnosis) resulted in an RR of 1·37 (95% CI 1·29-1·46; p<0·0001); this risk was similar in European and American prospective studies and for oestrogen-only and oestrogen-progestagen preparations, but differed across the four main tumour types (heterogeneity p<0·0001), being definitely increased only for the two most common types, serous (RR 1·53, 95% CI 1·40-1·66; p<0·0001) and endometrioid (1·42, 1·20-1·67; p<0·0001). Risk declined the longer ago use had ceased, although about 10 years after stopping long-duration hormone therapy use there was still an excess of serous or endometrioid tumours (RR 1·25, 95% CI 1·07-1·46, p=0·005). INTERPRETATION: The increased risk may well be largely or wholly causal; if it is, women who use hormone therapy for 5 years from around age 50 years have about one extra ovarian cancer per 1000 users and, if its prognosis is typical, about one extra ovarian cancer death per 1700 users. FUNDING: Medical Research Council, Cancer Research UK.

Ethnic differences in breast cancer incidence in England are due to differences in known risk factors for the disease: prospective study.

BACKGROUND: In the United Kingdom, breast cancer incidence is lower in South Asian and Black women than in White women, but the extent to which this is due to known risk factors is unknown. In a large prospective study, we describe breast cancer incidence by ethnicity, before and after adjustment for known risk factors for the disease. METHODS: Women were recruited into the Million Women Study in 1996-2001, when information on reproductive and lifestyle factors known to influence the risk of breast cancer was obtained. Ethnicity was determined from study questionnaires and hospital admission data. Cox regression models were used to calculate adjusted relative risks (RR) for incident breast cancer in South Asians and Blacks compared with Whites. RESULTS: Analyses included 5877 South Asian, 4919 Black, and 1,038,144 White women in England. The prevalence of 8 out of the 9 risk factors for breast cancer examined, differed substantially by ethnicity (P<0.001 for each), such that South Asian and Black women were at a lower risk of the disease than White women. During 12.2 years of follow-up incident breast cancer occurred in 217 South Asians, 180 Blacks, and 45,191 Whites. As expected, breast cancer incidence was lower in South Asians (RR=0.82, 95% CI 0.72-0.94) and Blacks (RR=0.85, 0.73-0.98) than in Whites when the analyses were adjusted only for age and region of residence. However, after additional adjustment for the known risk factors for the disease, breast cancer incidence was similar to that of Whites, both in South Asians (0.95, 0.83-1.09) and in Blacks (0.91, 0.78-1.05). CONCLUSION: South Asian and Black women in England have lower incidence rates of breast cancer than White women, but this is largely, if not wholly, because of differences in known risk factors for the disease.

Ovarian cancer and smoking: individual participant meta-analysis including 28,114 women with ovarian cancer from 51 epidemiological studies.

BACKGROUND: Smoking has been linked to mucinous ovarian cancer, but its effects on other ovarian cancer subtypes and on overall ovarian cancer risk are unclear, and the findings from most studies with relevant data are unpublished. To assess these associations, we review the published and unpublished evidence. METHODS: Eligible epidemiological studies were identified by electronic searches, review articles, and discussions with colleagues. Individual participant data for 28,114 women with and 94,942 without ovarian cancer from 51 epidemiological studies were analysed centrally, yielding adjusted relative risks (RRs) of ovarian cancer in smokers compared with never smokers. FINDINGS: After exclusion of studies with hospital controls, in which smoking could have affected recruitment, overall ovarian cancer incidence was only slightly increased in current smokers compared with women who had never smoked (RR 1·06, 95% CI 1·01-1·11, p=0·01). Of 17,641 epithelial cancers with specified histology, 2314 (13%) were mucinous, 2360 (13%) endometrioid, 969 (5%) clear-cell, and 9086 (52%) serous. Smoking-related risks varied substantially across these subtypes (p(heterogeneity)<0·0001). For mucinous cancers, incidence was increased in current versus never smokers (1·79, 95% CI 1·60-2·00, p<0·0001), but the increase was mainly in borderline malignant rather than in fully malignant tumours (2·25, 95% CI 1·91-2·65 vs 1·49, 1·28-1·73; p(heterogeneity)=0·01; almost half the mucinous tumours were only borderline malignant). Both endometrioid (0·81, 95% CI 0·72-0·92, p=0·001) and clear-cell ovarian cancer risks (0·80, 95% CI 0·65-0·97, p=0·03) were reduced in current smokers, and there was no significant association for serous ovarian cancers (0·99, 95% CI 0·93-1·06, p=0·8). These associations did not vary significantly by 13 sociodemographic and personal characteristics of women including their body-mass index, parity, and use of alcohol, oral contraceptives, and menopausal hormone therapy. INTERPRETATION: The excess of mucinous ovarian cancers in smokers, which is mainly of tumours of borderline malignancy, is roughly counterbalanced by the deficit of endometrioid and clear-cell ovarian cancers. The substantial variation in smoking-related risks by tumour subtype is important for understanding ovarian carcinogenesis. FUNDING: Cancer Research UK and MRC.

Role of MYH9 and APOL1 in African and non-African populations with lupus nephritis.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by autoantibody production and organ damage. Lupus nephritis (LN) is one of the most severe manifestations of SLE. Multiple studies reported associations between renal diseases and variants in the non-muscle myosin heavy chain 9 (MYH9) and the neighboring apolipoprotein L 1 (APOL1) genes. We evaluated 167 variants spanning MYH9 for association with LN in a multiethnic sample. The two previously identified risk variants in APOL1 were also tested for association with LN in European-Americans (EAs) (N = 579) and African-Americans (AAs) (N = 407). Multiple peaks of association exceeding a Bonferroni corrected P-value of P < 2.03 × 10(-3) were observed between LN and MYH9 in EAs (N = 4620), with the most pronounced association at rs2157257 (P = 4.7 × 10(-4), odds ratio (OR) = 1.205). A modest effect with MYH9 was also detected in Gullah (rs8136069, P = 0.0019, OR = 2.304). No association between LN and MYH9 was found in AAs, Asians, Amerindians or Hispanics. This study provides the first investigation of MYH9 in LN in non-Africans and of APOL1 in LN in any population, and presents novel insight into the potential role of MYH9 in LN in EAs.

A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease with diverse clinical manifestations characterized by the development of pathogenic autoantibodies manifesting in inflammation of target organs such as the kidneys, skin and joints. Genome-wide association studies have identified genetic variants in the UBE2L3 region that are associated with SLE in subjects of European and Asian ancestry. UBE2L3 encodes an ubiquitin-conjugating enzyme, UBCH7, involved in cell proliferation and immune function. In this study, we sought to further characterize the genetic association in the region of UBE2L3 and use molecular methods to determine the functional effect of the risk haplotype. We identified significant associations between variants in the region of UBE2L3 and SLE in individuals of European and Asian ancestry that exceeded a Bonferroni-corrected threshold (P<1 × 10(-4)). A single risk haplotype was observed in all associated populations. Individuals harboring the risk haplotype display a significant increase in both UBE2L3 mRNA expression (P=0.0004) and UBCH7 protein expression (P=0.0068). The results suggest that variants carried on the SLE-associated UBE2L3 risk haplotype influence autoimmunity by modulating UBCH7 expression.

Primary Sjogren's syndrome: cognitive symptoms, mood, and cognitive performance.

OBJECTIVE: To investigate the relationships between self-reported cognitive abilities, psychological symptoms and neuropsychological outcomes in PSS. METHODS: Patients with Primary Sjogren's syndrome (PSS) and healthy controls completed a comprehensive neuropsychometric battery and questionnaires: the Centers for Epidemiological Scale-Depression, the Profile of Fatigue-mental domain (Prof-M) for cognitive symptoms, Fatigue Severity Scale, and the Short-Form McGill Pain Questionnaire. RESULTS: Female patients with PSS (N = 39) were similar to controls (N = 17) in estimated premorbid intellectual function, age and education. Depression (P = 0.002), cognitive symptoms (P = 0.001), fatigue (P = 0.000003), and pain (P = 0.024) scores were greater in the patient group. Patients with PSS demonstrated inferior performance relative to controls in psychomotor processing (P = 0.027) and verbal reasoning (P = 0.007). Patients with PSS with and without depression had similar performance on multiple tests, but depressed patients had significantly lower scores for executive function (P = 0.041). Cognitive symptoms correlated with verbal memory (P = 0.048), whereas pain correlated with executive function measures (Stroop, P = 0.017) and working memory (Trails B, P = 0.036). In the regression model, depression and verbal memory were independent predictors that accounted for 61% of the variance in cognitive symptoms. CONCLUSION: The Prof-M is a simple self-report measure which could be useful in screening PSS subjects who may benefit from detailed psychometric evaluation. Our results are consistent with the hypothesis that depression and verbal memory impairment are overlapping but independent aspects of neural involvement in PSS. While pain and depression are significant confounders of cognitive function in PSS, this study suggests that impaired verbal reasoning ability in PSS is not attributable to pain or depression.

Isotopic and geochemical data from Barry Lake, Canada: A 900-year record of environmental change.

The data reported here consist of oxygen and hydrogen isotope compositions for 145 modern water samples, and geochemical measurements for gravity cores of sediment, all collected from Barry Lake, a small kettle lake located in Ontario, Canada. The geochemical measurements for the sediment organic matter include organic carbon and total nitrogen isotope compositions, organic carbon and total nitrogen contents and chlorophyll a content. The carbon and oxygen isotope compositions of marl contained in these sediments are also reported, along with the calcite and quartz contents of the sediment sample. Mass accumulation rates of total organic carbon, total nitrogen, chlorophyll a and calcite are reported. Dating of these sediments shows that they span ∼900 years. The stable isotope compositions of the modern waters and marl are useful to researchers studying how effective moisture (the net of water inputs vs outputs) changed in southern Ontario across the last ∼900 years. Proxies derived from the organic fraction of the lake sediments will be of interest to researchers of small Ontario lakes seeking to contextualize recent increases in primary production related to eutrophication. A discussion of these data, and a comparison of these data to other cores in the Great Lakes Region, is available in "A 900-year record of effective moisture in the Great Lakes Region" (Doyle et al., 2021).

The rs4774 CIITA missense variant is associated with risk of systemic lupus erythematosus.

The major histocompatibility complex (MHC) class II transactivator gene (CIITA) encodes an important transcription factor required for human leukocyte antigens (HLA) class II MHC-restricted antigen presentation. MHC genes, including the HLA class II DRB1*03:01 allele, are strongly associated with systemic lupus erythematosus (SLE). Recently the rs4774 CIITA missense variant (+1632G/C) was reported to be associated with susceptibility to multiple sclerosis. In the current study, we investigated CIITA, DRB1*03:01 and risk of SLE using a multi-stage analysis. In stage 1, 9 CIITA variants were tested in 658 cases and 1363 controls (N=2021). In stage 2, rs4774 was tested in 684 cases and 2938 controls (N=3622). We also performed a meta-analysis of the pooled 1342 cases and 4301 controls (N=5643). In stage 1, rs4774(*)C was associated with SLE (odds ratio (OR)=1.24, 95% confidence interval (95% CI)=1.07-1.44, P=4.2 × 10(-3)). Similar results were observed in stage 2 (OR=1.16, 95% CI=1.02-1.33, P=8.5 × 10(-3)) and the meta-analysis of the combined data set (OR=1.20, 95% CI=1.09-1.33, P(meta)=2.5 × 10(-4)). In all three analyses, the strongest evidence for association between rs4774(*)C and SLE was present in individuals who carried at least one copy of DRB1*03:01 (P(meta)=1.9 × 10(-3)). Results support a role for CIITA in SLE, which appears to be stronger in the presence of DRB1*03:01.

Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disorder with a complex pathogenesis in which genetic, hormonal and environmental factors have a role. Rare mutations in the TREX1 gene, the major mammalian 3'-5' exonuclease, have been reported in sporadic SLE cases. Some of these mutations have also been identified in a rare pediatric neurological condition featuring an inflammatory encephalopathy known as Aicardi-Goutières syndrome (AGS). We sought to investigate the frequency of these mutations in a large multi-ancestral cohort of SLE cases and controls. A total of 40 single-nucleotide polymorphisms (SNPs), including both common and rare variants, across the TREX1 gene, were evaluated in ∼8370 patients with SLE and ∼7490 control subjects. Stringent quality control procedures were applied, and principal components and admixture proportions were calculated to identify outliers for removal from analysis. Population-based case-control association analyses were performed. P-values, false-discovery rate q values, and odds ratios (OR) with 95% confidence intervals (CI) were calculated. The estimated frequency of TREX1 mutations in our lupus cohort was 0.5%. Five heterozygous mutations were detected at the Y305C polymorphism in European lupus cases but none were observed in European controls. Five African cases incurred heterozygous mutations at the E266G polymorphism and, again, none were observed in the African controls. A rare homozygous R114H mutation was identified in one Asian SLE patient, whereas all genotypes at this mutation in previous reports for SLE were heterozygous. Analysis of common TREX1 SNPs (minor allele frequency (MAF)>10%) revealed a relatively common risk haplotype in European SLE patients with neurological manifestations, especially seizures, with a frequency of 58% in lupus cases compared with 45% in normal controls (P=0.0008, OR=1.73, 95% CI=1.25-2.39). Finally, the presence or absence of specific autoantibodies in certain populations produced significant genetic associations. For example, a strong association with anti-nRNP was observed in the European cohort at a coding synonymous variant rs56203834 (P=2.99E-13, OR=5.2, 95% CI=3.18-8.56). Our data confirm and expand previous reports and provide additional support for the involvement of TREX1 in lupus pathogenesis.

Anti-PF4 VITT antibodies are oligoclonal and variably inhibited by heparin.

BACKGROUND: COVID-19 vaccines have been associated with a rare thrombotic and thrombocytopenic reaction, Vaccine-induced immune thrombotic thrombocytopenia (VITT) characterized by platelet-activating anti-PF4 antibodies. This study sought to assess clonality of VITT antibodies and evaluate their characteristics in antigen-based and functional platelet studies. METHODS: Anti-PF4 antibodies were isolated from five patients with VITT secondary to ChAdOx1 nCoV-19 (n=1) or Ad26.COV2.S (n=4) vaccination. For comparative studies with heparin-induced thrombocytopenia (HIT), anti-PF4 antibodies were isolated from one patient with spontaneous HIT, another with "classical" HIT, and two patients with non-pathogenic (non-platelet activating) anti-PF4 antibodies. Isolated antibodies were subject to ELISA and functional testing, and mass spectrometric evaluation for clonality determination. RESULTS: All five VITT patients had oligoclonal anti-PF4 antibodies (3 monoclonal, one bi- and one tri-clonal antibodies), while HIT anti-PF4 antibodies were polyclonal. Notably, like VITT antibodies, anti-PF4 antibodies from a spontaneous HIT patient were monoclonal. The techniques employed did not detect non-pathogenic anti-PF4 antibodies. The ChAdOx1 nCoV-19-associated VITT patient made an excellent recovery with heparin treatment. In vitro studies demonstrated strong inhibition of VITT antibody-induced platelet activation with therapeutic concentrations of heparin in this and one Ad26.COV2.S-associated VITT patient. Oligoclonal VITT antibodies with persistent platelet-activating potential were detected at 6 and 10 weeks after acute presentation in two patients tested. Two of the 5 VITT patients had recurrence of thrombocytopenia and one patient had focal seizures several weeks after acute presentation. CONCLUSION: Oligoclonal anti-PF4 antibodies mediate VITT. Heparin use in VITT needs to be further studied.

Evaluation of recorded video-observed therapy for anti-tuberculosis treatment.

BACKGROUND: Asynchronous video directly observed therapy (VDOT) may reduce tuberculosis (TB) program costs and the burden on patients. We compared VDOT performance across three cities in the United States, each of which have TB incidence rates above the national average.METHODS: Patients aged ≥18 years who are currently receiving directly observed anti-TB treatment were invited to use VDOT for monitoring treatment. Pre- and post-treatment interviews and medical records were used to assess site differences in treatment adherence and patient characteristics and perceptions.RESULTS: Participants were enrolled in New York City, NY (n = 48), San Diego, CA (n = 52) and San Francisco, CA, USA (n = 49). Overall, the mean age was 41 years (range 18-87); 59% were male; most were Asian (45%) or Hispanic/Latino (30%); and 77% were foreign-born. The median fraction of expected doses observed (FEDO) was 88% (IQR 76-96). At follow-up, 97% thought VDOT was "very or somewhat easy to use" and 95% would recommend VDOT to other TB patients. Age, race/ethnicity, annual income, and country of birth differed by city (P < 0.05), but FEDO and VDOT perceptions did not.CONCLUSIONS: TB programs in three large US cities observed a high FEDO using VDOT while minimizing staff time and travel. Similar findings across sites support VDOT adoption by other large, urban TB programs.

Recent insights into the genetic basis of systemic lupus erythematosus.

Genetic variation was first shown to be important in systemic lupus erythematosus (SLE or lupus) in the 1970s with associations in the human leukocyte antigen region. Almost four decades later, and with the help of increasingly powerful genetic approaches, more than 25 genes are now known to contribute to the mechanisms that predispose individuals to lupus. Over half of these loci have been discovered in the past 2 years, underscoring the extraordinary success of genome-wide association approaches in SLE. Well-established risk factors include alleles in the major histocompatibility complex region (multiple genes), IRF5, ITGAM, STAT4, BLK, BANK1, PDCD1, PTPN22, TNFSF4, TNFAIP3, SPP1, some of the Fcgamma receptors, and deficiencies in several complement components, including C1q, C4 and C2. As reviewed here, many susceptibility genes fall into key pathways that are consistent with previous studies implicating immune complexes, host immune signal transduction and interferon pathways in the pathogenesis of SLE. Other loci have no known function or apparent immunological role and have the potential to reveal novel disease mechanisms. Certainly, as our understanding of the genetic etiology of SLE continues to mature, important new opportunities will emerge for developing more effective diagnostic and clinical management tools for this complex autoimmune disease.

Variation in the ATP-binding cassette transporter 2 gene is a separate risk factor for systemic lupus erythematosus within the MHC.

The ATP-binding cassette transporter (TAP) proteins are functionally relevant candidates for predisposition to systemic lupus erythematosus (SLE) by virtue of their role in autoantigen presentation and location in the major histocompatibility complex (MHC). We tested if variation in the TAP genes (TAP1 and TAP2) is associated with SLE. We genotyped tag single nucleotide polymorphisms (SNPs) and performed family-based association analysis on 390 Caucasian pedigrees. We found significant evidence of association between TAP2 and SLE (rs241453, P=1.33 x 10(-6)). Conditional logistic regression analysis suggests that this TAP2 effect is separate from the HLA-DRB1 alleles. Our analyses show that both rs241453 (P=1.6 x 10(-4)) and HLA-DRB1*03xx (P=2.3 x 10(-4)) have significant autonomous effects not due to linkage disequilibrium. Moreover, these loci exhibit a significant statistical interaction (P<1.0 x 10(-6)), demonstrated by an increase in the odds ratio for the TAP2 association from OR=2.00 (95% confidence interval (CI)=1.17-3.42) in HLA-DRB1*03xx-negative subjects to OR=4.29 (CI=1.88-9.76) in the subjects with at least one HLA-DRB1*03xx allele group. We report the largest association study of the TAP genes with SLE to date, and the first to test for its separate effect and interaction with the HLA alleles consistently associated with SLE.

Peripheral blood gene expression profiling in Sjögren's syndrome.

Sjögren's syndrome (SS) is a common chronic autoimmune disease characterized by lymphocytic infiltration of exocrine glands. The affected cases commonly present with oral and ocular dryness, which is thought to be the result of inflammatory cell-mediated gland dysfunction. To identify important molecular pathways involved in SS, we used high-density microarrays to define global gene expression profiles in the peripheral blood. We first analyzed 21 SS cases and 23 controls, and identified a prominent pattern of overexpressed genes that are inducible by interferons (IFNs). These results were confirmed by evaluation of a second independent data set of 17 SS cases and 22 controls. Additional inflammatory and immune-related pathways with altered expression patterns in SS cases included B- and T-cell receptor, insulin-like growth factor-1, granulocyte macrophage-colony stimulating factor, peroxisome proliferator-activated receptor-alpha/retinoid X receptor-alpha and PI3/AKT signaling. Exploration of these data for relationships to clinical features of disease showed that expression levels for most interferon-inducible genes were positively correlated with titers of anti-Ro/SSA (P<0.001) and anti-La/SSB (P<0.001) autoantibodies. Diagnostic and therapeutic approaches targeting interferon-signaling pathway may prove most effective in the subset of SS cases that produce anti-Ro/SSA and anti-La/SSB autoantibodies. Our results strongly support innate and adaptive immune processes in the pathogenesis of SS, and provide numerous candidate disease markers for further study.

Variation in the upstream region of P-Selectin (SELP) is a risk factor for SLE.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease. Genome-wide linkage studies implicated a region containing the adhesion molecule P-Selectin. This family-based study revealed two regions of association within P-Selectin. The strongest signal, from a 21.4-kb risk haplotype, stretched from the promoter into the first two consensus repeat (CR) regions (P=8 x 10(-4)), with a second association from a 14.6-kb protective haplotype covering CR 2-9 (P=0.0198). The risk haplotype is tagged by the rare C allele of rs3753306, which disrupts the binding site of the trans-activating transcription factor HNF-1. One other variant (rs3917687) on the risk haplotype was significant after permutation (P(10000)<1 x 10(-5)), replicated in independent pseudo case-control analysis and was significant by meta-analysis (P=4.37 x 10(-6)). A third associated variant on the risk haplotype (rs3917657) replicated in 306 US SLE families and was significant in a joint UK-SLE data set after permutation. The protective haplotype is tagged by rs6133 (a non-synonymous variant in CR8 (P=9.00 x 10(-4)), which also shows association in the pseudo case-control analysis (P=1.09 x 10(-3)) and may contribute to another signal in P-Selectin. We propose that polymorphism in the upstream region may reduce expression of P-Selectin, the mechanism by which this promotes autoimmunity is unknown, although it may reduce the production of regulatory T cells.

Meta-analysis and imputation identifies a 109 kb risk haplotype spanning TNFAIP3 associated with lupus nephritis and hematologic manifestations.

TNFAIP3 encodes the ubiquitin-modifying enzyme, A20, a key regulator of inflammatory signaling pathways. We previously reported association between TNFAIP3 variants and systemic lupus erythematosus (SLE). To further localize the risk variant(s), we performed a meta-analysis using genetic data available from two Caucasian case-control datasets (1453 total cases, 3381 total control subjects) and 713 SLE trio families. The best result was found at rs5029939 (P=1.67 x 10(-14), odds ratio=2.09, 95% confidence interval 1.68-2.60). We then imputed single nucleotide polymorphisms (SNPs) from the CEU Phase II HapMap using genotypes from 431 SLE cases and 2155 control subjects. Imputation identified 11 SNPs in addition to three observed SNPs, which together, defined a 109 kb SLE risk segment surrounding TNFAIP3. When evaluating whether the rs5029939 risk allele was associated with SLE clinical manifestations, we observed that heterozygous carriers of the TNFAIP3 risk allele at rs5029939 have a twofold increased risk of developing renal or hematologic manifestations compared to homozygous non-risk subjects. In summary, our study strengthens the genetic evidence that variants in the region of TNFAIP3 influence risk for SLE, particularly in patients with renal and hematologic manifestations, and narrows the risk effect to a 109 kb DNA segment that spans the TNFAIP3 gene.

Evaluation of C1q genomic region in minority racial groups of lupus.

Complement cascade plasma proteins play a complex role in the etiopathogenesis of systemic lupus erythematosus (SLE). Hereditary C1q deficiency has been strongly related to SLE; however, there are very few published SLE studies that evaluate the polymorphisms of genes encoding for C1q (A, B and C). In this study, we evaluated 17 single nucleotide polymorphisms (SNPs) across 37 kb of C1QA, C1QB and C1QC in a lupus cohort of individuals of the African-American and Hispanic origin. In a case-only analysis, a significant association at multiple SNPs in the C1QA gene was detected in African Americans with kidney nephritis (best P=4.91 x 10(-6)). In addition, C1QA was associated with SLE in African Americans with a lack of nephritis and accompanying photosensitivity when compared with that in normal controls (P=6.80 x 10(-6)). A similar trend was observed in the Hispanic subjects (P=0.003). Quantitative analysis showed that some SNPs in C1q genes might be correlated with C3 complement levels in an additive model among African Americans (best P=0.0001). The C1QA gene is associated with subphenotypes of lupus in the African-American and Hispanic subjects. Further studies with higher SNP densities in this region and other complement components are necessary to elucidate the complex genetics and phenotypic interactions between complement components and SLE.

Complement receptor 2 polymorphisms associated with systemic lupus erythematosus modulate alternative splicing.

Genetic factors influence susceptibility to systemic lupus erythematosus (SLE). A recent family-based analysis in Caucasian and Chinese populations provided evidence for association of single-nucleotide polymorphisms (SNPs) in the complement receptor 2 (CR2/CD21) gene with SLE. Here we confirmed this result in a case-control analysis of an independent European-derived population including 2084 patients with SLE and 2853 healthy controls. A haplotype formed by the minor alleles of three CR2 SNPs (rs1048971, rs17615, rs4308977) showed significant association with decreased risk of SLE (30.4% in cases vs 32.6% in controls, P=0.016, OR=0.90 (0.82-0.98)). Two of these SNPs are in exon 10, directly 5' of an alternatively spliced exon preferentially expressed in follicular dendritic cells (FDC), and the third is in the alternatively spliced exon. Effects of these SNPs and a fourth SNP in exon 11 (rs17616) on alternative splicing were evaluated. We found that the minor alleles of these SNPs decreased splicing efficiency of exon 11 both in vitro and ex vivo. These findings further implicate CR2 in the pathogenesis of SLE and suggest that CR2 variants alter the maintenance of tolerance and autoantibody production in the secondary lymphoid tissues where B cells and FDCs interact.

Identification of new SLE-associated genes with a two-step Bayesian study design.

In our earlier study, we utilized a Bayesian design to probe the association of approximately 1000 genes (approximately 10,000 single-nucleotide polymorphisms (SNPs)) with systemic lupus erythematosus (SLE) on a moderate number of trios of parents and children with SLE. Two genes associated with SLE, with a multitest-corrected false discovery rate (FDR) of <0.05, were identified, and a number of noteworthy genes with FDR of <0.8 were also found, pointing out a future direction for the study. In this report, using a large population of controls and adult- or childhood-onset SLE cases, we have extended the earlier investigation to explore the SLE association of 10 of these noteworthy genes (109 SNPs). We have found that seven of these genes exhibit a significant (FDR<0.05) association with SLE, both confirming some genes that have earlier been found to be associated with SLE (PTPN22 and IRF5) and presenting novel findings of genes (KLRG1, interleukin-16, protein tyrosine phosphatase receptor type T, toll-like receptor (TLR)8 and CASP10), which have not been reported earlier. The results signify that the two-step candidate pathway design is an efficient way to study the genetic foundations of complex diseases. Furthermore, the novel genes identified in this study point to new directions in both the diagnosis and the eventual treatment of this debilitating disease.

Genetic associations of LYN with systemic lupus erythematosus.

We targeted LYN, a src-tyosine kinase involved in B-cell activation, in case-control association studies using populations of European-American, African-American and Korean subjects. Our combined European-derived population, consisting of 2463 independent cases and 3131 unrelated controls, shows significant association with rs6983130 in a female-only analysis with 2254 cases and 2228 controls (P=1.1 x 10(-4), odds ratio (OR)=0.81 (95% confidence interval: 0.73-0.90)). This single nucleotide polymorphism (SNP) is located in the 5' untranslated region within the first intron near the transcription initiation site of LYN. In addition, SNPs upstream of the first exon also show weak and sporadic association in subsets of the total European-American population. Multivariate logistic regression analysis implicates rs6983130 as a protective factor for systemic lupus erythematosus (SLE) susceptibility when anti-dsDNA, anti-chromatin, anti-52 kDa Ro or anti-Sm autoantibody status were used as covariates. Subset analysis of the European-American female cases by American College of Rheumatology classification criteria shows a reduction in the risk of hematological disorder with rs6983130 compared with cases without hematological disorders (P=1.5 x 10(-3), OR=0.75 (95% CI: 0.62-0.89)). None of the 90 SNPs tested show significant association with SLE in the African American or Korean populations. These results support an association of LYN with European-derived individuals with SLE, especially within autoantibody or clinical subsets.