| 1. |
- Palmer, Nicholette D, et al.
(författare)
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A genome-wide association search for type 2 diabetes genes in African Americans.
- 2012
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Ingår i: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202-
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Tidskriftsartikel (refereegranskat)abstract
- African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
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| 2. |
- Adrianto, Indra, et al.
(författare)
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Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 43:3, s. 253-258
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE, MIM152700) is an autoimmune disease characterized by self-reactive antibodies resulting in systemic inflammation and organ failure. TNFAIP3, encoding the ubiquitin-modifying enzyme A20, is an established susceptibility locus for SLE. By fine mapping and genomic re-sequencing in ethnically diverse populations, we fully characterized the TNFAIP3 risk haplotype and identified a TT>A polymorphic dinucleotide (deletion T followed by a T to A transversion) associated with SLE in subjects of European (P = 1.58 x 10(-8), odds ratio = 1.70) and Korean (P = 8.33 x 10(-10), odds ratio = 2.54) ancestry. This variant, located in a region of high conservation and regulatory potential, bound a nuclear protein complex composed of NF-kappa B subunits with reduced avidity. Further, compared with the non-risk haplotype, the haplotype carrying this variant resulted in reduced TNFAIP3 mRNA and A20 protein expression. These results establish this TT>A variant as the most likely functional polymorphism responsible for the association between TNFAIP3 and SLE.
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| 3. |
- Chu, Audrey Y, et al.
(författare)
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Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation
- 2017
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:1, s. 125-130
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Tidskriftsartikel (refereegranskat)abstract
- Variation in body fat distribution contributes to the metabolic sequelae of obesity. The genetic determinants of body fat distribution are poorly understood. The goal of this study was to gain new insights into the underlying genetics of body fat distribution by conducting sample-size-weighted fixed-effects genome-wide association meta-analyses in up to 9,594 women and 8,738 men of European, African, Hispanic and Chinese ancestry, with and without sex stratification, for six traits associated with ectopic fat (hereinafter referred to as ectopic-fat traits). In total, we identified seven new loci associated with ectopic-fat traits (ATXN1, UBE2E2, EBF1, RREB1, GSDMB, GRAMD3 and ENSA; P < 5 × 10(-8); false discovery rate < 1%). Functional analysis of these genes showed that loss of function of either Atxn1 or Ube2e2 in primary mouse adipose progenitor cells impaired adipocyte differentiation, suggesting physiological roles for ATXN1 and UBE2E2 in adipogenesis. Future studies are necessary to further explore the mechanisms by which these genes affect adipocyte biology and how their perturbations contribute to systemic metabolic disease.
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| 4. |
- Chung, Jaeyoon, et al.
(författare)
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Genome-wide association study of cerebral small vessel disease reveals established and novel loci
- 2019
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 142:10, s. 3176-3189
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Tidskriftsartikel (refereegranskat)abstract
- Intracerebral haemorrhage and small vessel ischaemic stroke (SVS) are the most acute manifestations of cerebral small vessel disease, with no established preventive approaches beyond hypertension management. Combined genome-wide association study (GWAS) of these two correlated diseases may improve statistical power to detect novel genetic factors for cerebral small vessel disease, elucidating underlying disease mechanisms that may form the basis for future treatments. Because intracerebral haemorrhage location is an adequate surrogate for distinct histopathological variants of cerebral small vessel disease (lobar for cerebral amyloid angiopathy and non-lobar for arteriolosclerosis), we performed GWAS of intracerebral haemorrhage by location in 1813 subjects (755 lobar and 1005 non-lobar) and 1711 stroke-free control subjects. Intracerebral haemorrhage GWAS results by location were meta-analysed with GWAS results for SVS from MEGASTROKE, using 'Multi-Trait Analysis of GWAS' (MTAG) to integrate summary data across traits and generate combined effect estimates. After combining intracerebral haemorrhage and SVS datasets, our sample size included 241 024 participants (6255 intracerebral haemorrhage or SVS cases and 233 058 control subjects). Genome-wide significant associations were observed for non-lobar intracerebral haemorrhage enhanced by SVS with rs2758605 [MTAG P-value (P) = 2.6 × 10-8] at 1q22; rs72932727 (P = 1.7 × 10-8) at 2q33; and rs9515201 (P = 5.3 × 10-10) at 13q34. In the GTEx gene expression library, rs2758605 (1q22), rs72932727 (2q33) and rs9515201 (13q34) are significant cis-eQTLs for PMF1 (P = 1 × 10-4 in tibial nerve), NBEAL1, FAM117B and CARF (P < 2.1 × 10-7 in arteries) and COL4A2 and COL4A1 (P < 0.01 in brain putamen), respectively. Leveraging S-PrediXcan for gene-based association testing with the predicted expression models in tissues related with nerve, artery, and non-lobar brain, we found that experiment-wide significant (P < 8.5 × 10-7) associations at three genes at 2q33 including NBEAL1, FAM117B and WDR12 and genome-wide significant associations at two genes including ICA1L at 2q33 and ZCCHC14 at 16q24. Brain cell-type specific expression profiling libraries reveal that SEMA4A, SLC25A44 and PMF1 at 1q22 and COL4A1 and COL4A2 at 13q34 were mainly expressed in endothelial cells, while the genes at 2q33 (FAM117B, CARF and NBEAL1) were expressed in various cell types including astrocytes, oligodendrocytes and neurons. Our cross-phenotype genetic study of intracerebral haemorrhage and SVS demonstrates novel genome-wide associations for non-lobar intracerebral haemorrhage at 2q33 and 13q34. Our replication of the 1q22 locus previous seen in traditional GWAS of intracerebral haemorrhage, as well as the rediscovery of 13q34, which had previously been reported in candidate gene studies with other cerebral small vessel disease-related traits strengthens the credibility of applying this novel genome-wide approach across intracerebral haemorrhage and SVS.
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| 5. |
- Chung, Sharon A., et al.
(författare)
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Differential Genetic Associations for Systemic Lupus Erythematosus Based on Anti-dsDNA Autoantibody Production
- 2011
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 7:3, s. e1001323-
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is a clinically heterogeneous, systemic autoimmune disease characterized by autoantibody formation. Previously published genome-wide association studies (GWAS) have investigated SLE as a single phenotype. Therefore, we conducted a GWAS to identify genetic factors associated with anti-dsDNA autoantibody production, a SLE-related autoantibody with diagnostic and clinical importance. Using two independent datasets, over 400,000 single nucleotide polymorphisms (SNPs) were studied in a total of 1,717 SLE cases and 4,813 healthy controls. Anti-dsDNA autoantibody positive (anti-dsDNA +, n = 811) and anti-dsDNA autoantibody negative (anti-dsDNA -, n = 906) SLE cases were compared to healthy controls and to each other to identify SNPs associated specifically with these SLE subtypes. SNPs in the previously identified SLE susceptibility loci STAT4, IRF5, ITGAM, and the major histocompatibility complex were strongly associated with anti-dsDNA + SLE. Far fewer and weaker associations were observed for anti-dsDNA - SLE. For example, rs7574865 in STAT4 had an OR for anti-dsDNA + SLE of 1.77 (95% CI 1.57-1.99, p = 2.0E-20) compared to an OR for anti-dsDNA - SLE of 1.26 (95% CI 1.12-1.41, p = 2.4E-04), with (Pheterogeneity)<0.0005. SNPs in the SLE susceptibility loci BANK1, KIAA1542, and UBE2L3 showed evidence of association with anti-dsDNA + SLE and were not associated with anti-dsDNA - SLE. In conclusion, we identified differential genetic associations with SLE based on anti-dsDNA autoantibody production. Many previously identified SLE susceptibility loci may confer disease risk through their role in autoantibody production and be more accurately described as autoantibody propensity loci. Lack of strong SNP associations may suggest that other types of genetic variation or non-genetic factors such as environmental exposures have a greater impact on susceptibility to anti-dsDNA - SLE.
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| 6. |
- Chung, Sharon A, et al.
(författare)
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European population substructure is associated with mucocutaneous manifestations and autoantibody production in systemic lupus erythematosus
- 2009
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 60:8, s. 2448-2456
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To determine whether genetic substructure in European-derived populations is associated with specific manifestations of systemic lupus erythematosus (SLE), including mucocutaneous phenotypes, autoantibody production, and renal disease. METHODS: SLE patients of European descent (n=1,754) from 8 case collections were genotyped for >1,400 ancestry informative markers that define a north-south gradient of European substructure. Using the Structure program, each SLE patient was characterized in terms of percent Northern (versus percent Southern) European ancestry based on these genetic markers. Nonparametric methods, including tests for trend, were used to identify associations between Northern European ancestry and specific SLE manifestations. RESULTS: In multivariate analyses, increasing levels of Northern European ancestry were significantly associated with photosensitivity (Ptrend=0.0021, odds ratio for highest quartile of Northern European ancestry versus lowest quartile [ORhigh-low] 1.64, 95% confidence interval [95% CI] 1.13-2.35) and discoid rash (Ptrend=0.014, ORhigh-low 1.93, 95% CI 0.98-3.83). In contrast, increasing levels of Northern European ancestry had a protective effect against the production of anticardiolipin autoantibodies (Ptrend=1.6x10(-4), ORhigh-low 0.46, 95% CI 0.30-0.69) and anti-double-stranded DNA autoantibodies (Ptrend=0.017, ORhigh-low 0.67, 95% CI 0.46-0.96). CONCLUSION: This study demonstrates that specific SLE manifestations vary according to Northern versus Southern European ancestry. Thus, genetic ancestry may contribute to the clinical heterogeneity and variation in disease outcomes among SLE patients of European descent. Moreover, these results suggest that genetic studies of SLE subphenotypes will need to carefully address issues of population substructure based on genetic ancestry.
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| 7. |
- de las Fuentes, Lisa, et al.
(författare)
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Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci
- 2021
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Ingår i: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. ; 26:6, s. 2111-2125
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Tidskriftsartikel (refereegranskat)abstract
- Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, “Some College” (yes/no) and “Graduated College” (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
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| 8. |
- de Vries, Paul S., et al.
(författare)
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Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions
- 2019
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Ingår i: American Journal of Epidemiology. - : Oxford University Press. - 0002-9262 .- 1476-6256. ; 188:6, s. 1033-1054
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Tidskriftsartikel (refereegranskat)abstract
- A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 x 10(-6)) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 x 10(-8) using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.
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| 9. |
- Falcone, Guido J., et al.
(författare)
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Burden of Risk Alleles for Hypertension Increases Risk of Intracerebral Hemorrhage
- 2012
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Ingår i: Stroke: a journal of cerebral circulation. - 1524-4628. ; 43:11, s. 2877-2883
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose-Genetic variation influences risk of intracerebral hemorrhage (ICH). Hypertension (HTN) is a potent risk factor for ICH and several common genetic variants (single nucleotide polymorphisms [SNPs]) associated with blood pressure levels have been identified. We sought to determine whether the cumulative burden of blood pressure-related SNPs is associated with risk of ICH and pre-ICH diagnosis of HTN. Methods-We conducted a prospective multicenter case-control study in 2272 subjects of European ancestry (1025 cases and 1247 control subjects). Thirty-nine SNPs reported to be associated with blood pressure levels were identified from the National Human Genome Research Institute genomewide association study catalog. Single-SNP association analyses were performed for the outcomes ICH and pre-ICH HTN. Subsequently, weighted and unweighted genetic risk scores were constructed using these SNPs and entered as the independent variable in logistic regression models with ICH and pre-ICH HTN as the dependent variables. Results-No single SNP was associated with either ICH or pre-ICH HTN. The blood pressure-based unweighted genetic risk score was associated with risk of ICH (OR, 1.11; 95% CI, 1.02-1.21; P=0.01) and the subset of ICH in deep regions (OR, 1.18; 95% CI, 1.07-1.30; P=0.001), but not with the subset of lobar ICH. The score was associated with a history of HTN among control subjects (OR, 1.17; 95% CI, 1.04-1.31; P=0.009) and ICH cases (OR, 1.15; 95% CI, 1.01-1.31; P=0.04). Similar results were obtained when using a weighted score. Conclusion-Increasing numbers of high blood pressure-related alleles are associated with increased risk of deep ICH as well as with clinically identified HTN. (Stroke. 2012; 43: 2877-2883.)
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| 10. |
- Falcone, Guido J., et al.
(författare)
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Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage
- 2020
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Ingår i: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 88:1, s. 56-66
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Observational studies point to an inverse correlation between low-density lipoprotein (LDL) cholesterol levels and risk of intracerebral hemorrhage (ICH), but it remains unclear whether this association is causal. We tested the hypothesis that genetically elevated LDL is associated with reduced risk of ICH. Methods: We constructed one polygenic risk score (PRS) per lipid trait (total cholesterol, LDL, high-density lipoprotein [HDL], and triglycerides) using independent genomewide significant single nucleotide polymorphisms (SNPs) for each trait. We used data from 316,428 individuals enrolled in the UK Biobank to estimate the effect of each PRS on its corresponding trait, and data from 1,286 ICH cases and 1,261 matched controls to estimate the effect of each PRS on ICH risk. We used these estimates to conduct Mendelian Randomization (MR) analyses. Results: We identified 410, 339, 393, and 317 lipid-related SNPs for total cholesterol, LDL, HDL, and triglycerides, respectively. All four PRSs were strongly associated with their corresponding trait (all p < 1.00 × 10-100). While one SD increase in the PRSs for total cholesterol (odds ratio [OR] = 0.92; 95% confidence interval [CI] = 0.85–0.99; p = 0.03) and LDL cholesterol (OR = 0.88; 95% CI = 0.81–0.95; p = 0.002) were inversely associated with ICH risk, no significant associations were found for HDL and triglycerides (both p > 0.05). MR analyses indicated that 1mmol/L (38.67mg/dL) increase of genetically instrumented total and LDL cholesterol were associated with 23% (OR = 0.77; 95% CI = 0.65–0.98; p = 0.03) and 41% lower risks of ICH (OR = 0.59; 95% CI = 0.42–0.82; p = 0.002), respectively. Interpretation: Genetically elevated LDL levels were associated with lower risk of ICH, providing support for a potential causal role of LDL cholesterol in ICH. ANN NEUROL 2020.
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| 11. |
- Feitosa, Mary F., et al.
(författare)
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Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries
- 2018
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Ingår i: PLOS ONE. - : Public library science. - 1932-6203. ; 13:6
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Tidskriftsartikel (refereegranskat)abstract
- Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in approximate to 131 K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P <1.0 x 10(-5)). In Stage 2, these SNVs were tested for independent external replication in individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10(-8)). For African ancestry samples, we detected 18 potentially novel BP loci (P< 5.0 x 10(-8)) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2 have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
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| 12. |
- Freitag, Daniel F., et al.
(författare)
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Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis
- 2015
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Ingår i: The Lancet Diabetes & Endocrinology. - 2213-8595. ; 3:4, s. 243-253
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Tidskriftsartikel (refereegranskat)abstract
- Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1 alpha and IL-1 beta); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p=9.3 x 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1,7%; p=3.5 x 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p=7.7 x 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p=1.8 x 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p=3.9 x 10(-10)). Perallele odds ratios were 0.97 (0.95-0.99; p=9.9 x 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p=0.47) for type 2 diabetes, 1.00 (0.98-1.02; p=0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p=1.8 x 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Interpretation Human genetic data suggest that long-term dual IL-1 alpha/beta inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. Copyright (C) The Interleukin 1 Genetics Consortium. Open Access article distributed under the terms of CC-BY-NC-ND.
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| 13. |
- Harley, Isaac T. W., et al.
(författare)
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The Role of Genetic Variation Near Interferon-Kappa in Systemic Lupus Erythematosus
- 2010
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Ingår i: Journal of Biomedicine and Biotechnology. - : Hindawi Limited. - 1110-7243 .- 1110-7251. ; , s. 706825-
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by increased type I interferons (IFNs) and multiorgan inflammation frequently targeting the skin. IFN-kappa is a type I IFN expressed in skin. A pooled genome-wide scan implicated the IFNK locus in SLE susceptibility. We studied IFNK single nucleotide polymorphisms (SNPs) in 3982 SLE cases and 4275 controls, composed of European (EA), African-American (AA), and Asian ancestry. rs12553951C was associated with SLE in EA males (odds ratio = 1.93, P = 2.5 x 10(-4)), but not females. Suggestive associations with skin phenotypes in EA and AA females were found, and these were also sex-specific. IFNK SNPs were associated with increased serum type I IFN in EA and AA SLE patients. Our data suggest a sex-dependent association between IFNK SNPs and SLE and skin phenotypes. The serum IFN association suggests that IFNK variants could influence type I IFN producing plasmacytoid dendritic cells in affected skin.
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| 14. |
- Harley, John B., et al.
(författare)
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Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci
- 2008
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 40:2, s. 204-10
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with complex etiology but strong clustering in families (lambda(S) = approximately 30). We performed a genome-wide association scan using 317,501 SNPs in 720 women of European ancestry with SLE and in 2,337 controls, and we genotyped consistently associated SNPs in two additional independent sample sets totaling 1,846 affected women and 1,825 controls. Aside from the expected strong association between SLE and the HLA region on chromosome 6p21 and the previously confirmed non-HLA locus IRF5 on chromosome 7q32, we found evidence of association with replication (1.1 x 10(-7) < P(overall) < 1.6 x 10(-23); odds ratio = 0.82-1.62) in four regions: 16p11.2 (ITGAM), 11p15.5 (KIAA1542), 3p14.3 (PXK) and 1q25.1 (rs10798269). We also found evidence for association (P < 1 x 10(-5)) at FCGR2A, PTPN22 and STAT4, regions previously associated with SLE and other autoimmune diseases, as well as at > or =9 other loci (P < 2 x 10(-7)). Our results show that numerous genes, some with known immune-related functions, predispose to SLE.
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| 15. |
- Haycock, Philip C., et al.
(författare)
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Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases A Mendelian Randomization Study
- 2017
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Ingår i: JAMA Oncology. - : American Medical Association. - 2374-2437 .- 2374-2445. ; 3:5, s. 636-651
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [ 95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [ 95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [ 95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [ 95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [ 95% CI, 0.05-0.15]). CONCLUSIONS AND RELEVANCE: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.
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| 16. |
- Kottyan, Leah C., et al.
(författare)
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The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share.
- 2015
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 24:2, s. 582-596
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Tidskriftsartikel (refereegranskat)abstract
- Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10(-49); OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3 (P-valuesEU = 10(-27)-10(-32), OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credible set of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögrens syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3.
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| 17. |
- Langefeld, Carl D., et al.
(författare)
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Transancestral mapping and genetic load in systemic lupus erythematosus
- 2017
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (similar to 50% of these regions have multiple independent associations); these include 24 novel SLE regions (P < 5 x 10(-8)), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.
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| 18. |
- Lessard, Christopher J., et al.
(författare)
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Identification of a Systemic Lupus Erythematosus Susceptibility Locus at 11p13 between PDHX and CD44 in a Multiethnic Study
- 2011
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 88:1, s. 83-91
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is considered to be the prototypic autoimmune disease, with a complex genetic architecture influenced by environmental factors. We sought to replicate a putative association at 11p13 not yet exceeding genome-wide significance (p < 5 x 10(-8)) identified in a genome-wide association study (GWAS). Our GWA scan identified two intergenic SNPs located between PDHX and CD44 showing suggestive evidence of association with SLE in cases of European descent (rs2732552, p = 0.004, odds ratio [OR] = 0.78; rs387619, p = 0.003, OR = 0.78). The replication cohort consisted of >15,000 subjects, including 3562 SLE cases and 3491 controls of European ancestry, 1527 cases and 1811 controls of African American (AA) descent, and 1265 cases and 1260 controls of Asian origin. We observed robust association at both rs2732552 (p = 9.03 x 10(-8), OR = 0.83) and rs387619 (p = 7.7 x 10(-7), OR = 0.83) in the European samples with p(meta) = 1.82 x 10(-9) for rs2732552. The AA and Asian SLE cases also demonstrated association at rs2732552 (p = 5 x 10(-3), OR = 0.81 and p = 4.3 x 10(-4), OR = 0.80, respectively). A meta-analysis of rs2732552 for all racial and ethnic groups studied produced p(meta) = 2.36 x 10(-13). This locus contains multiple regulatory sites that could potentially affect expression and functions of CD44, a cell-surface glycoprotein influencing immunologic, inflammatory, and oncologic phenotypes, or PDHX, a subunit of the pyruvate dehydrogenase complex.
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| 19. |
- Lessard, Christopher J., et al.
(författare)
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Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as Susceptibility Loci for Systemic Lupus Erythematosus in a Large-Scale Multiracial Replication Study
- 2012
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 90:4, s. 648-660
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is a chronic heterogeneous autoimmune disorder characterized by the loss of tolerance to self-antigens and dysregulated interferon responses. The etiology of SLE is complex, involving both heritable and environmental factors. Candidate-gene studies and genome-wide association (GWA) scans have been successful in identifying new loci that contribute to disease susceptibility; however, much of the heritable risk has yet to be identified. In this study, we sought to replicate 1,580 variants showing suggestive association with SLE in a previously published GWA scan of European Americans; we tested a multiethnic population consisting of 7,998 SLE cases and 7,492 controls of European, African American, Asian, Hispanic, Gullah, and Amerindian ancestry to find association with the disease. Several genes relevant to immunological pathways showed association with SLE. Three loci exceeded the genome-wide significance threshold: interferon regulatory factor 8 (IRF8; rs11644034; p(meta-Euro) = 2.08 x 10(-10)), transmembrane protein 39A (TMEM39A; rs1132200; p(meta-all) 8.62 x 10(-9)), and 17q21 (rs1453560; p(meta-all) = 3.48 x 10(-10)) between IKAROS family of zinc finger 3 (AIOLOS; IKZF3) and zona pellucida binding protein 2 (ZPBP2). Fine mapping, resequencing, imputation, and haplotype analysis of IRF8 indicated that three independent effects tagged by rs8046526, rs450443, and rs4843869, respectively, were required for risk in individuals of European ancestry. Eleven additional replicated effects (5 x 10(-8) < p(meta-Euro) < 9.99 x 10(-5)) were observed with CFHR1, CADM2, LOC730109/IL12A, LPP, LOC63920, SLU7, ADAMTSL1, C10orf64, OR8D4 FAM19A2, and STXBP6. The results of this study increase the number of confirmed SLE risk loci and identify others warranting further investigation.
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| 20. |
- Liu, Ke, et al.
(författare)
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X Chromosome Dose and Sex Bias in Autoimmune Diseases
- 2016
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Ingår i: Arthritis & Rheumatology. - : WILEY-BLACKWELL. - 2326-5191 .- 2326-5205. ; 68:5, s. 1290-1300
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Tidskriftsartikel (refereegranskat)abstract
- Objective. More than 80% of autoimmune disease predominantly affects females, but the mechanism for this female bias is poorly understood. We suspected that an X chromosome dose effect accounts for this, and we undertook this study to test our hypothesis that trisomy X (47, XXX; occurring in similar to 1 in 1,000 live female births) would be increased in patients with female-predominant diseases (systemic lupus erythematosus [SLE], primary Sjogrens syndrome [SS], primary biliary cirrhosis, and rheumatoid arthritis [RA]) compared to patients with diseases without female predominance (sarcoidosis) and compared to controls. Methods. All subjects in this study were female. We identified subjects with 47, XXX using aggregate data from single-nucleotide polymorphism arrays, and, when possible, we confirmed the presence of 47, XXX using fluorescence in situ hybridization or quantitative polymerase chain reaction. Results. We found 47, XXX in 7 of 2,826 SLE patients and in 3 of 1,033 SS patients, but in only 2 of 7,074 controls (odds ratio in the SLE and primary SS groups 8.78 [95% confidence interval 1.67-86.79], P = 0.003 and odds ratio 10.29 [95% confidence interval 1.18-123.47], P = 0.02, respectively). One in 404 women with SLE and 1 in 344 women with SS had 47, XXX. There was an excess of 47, XXX among SLE and SS patients. Conclusion. The estimated prevalence of SLE and SS in women with 47, XXX was similar to 2.5 and similar to 2.9 times higher, respectively, than that in women with 46, XX and similar to 25 and similar to 41 times higher, respectively, than that in men with 46, XY. No statistically significant increase of 47, XXX was observed in other female-biased diseases (primary biliary cirrhosis or RA), supporting the idea of multiple pathways to sex bias in autoimmunity.
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| 21. |
- Liu, Ke, et al.
(författare)
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X Chromosome Dose and Sex Bias in Autoimmune Diseases : Increased 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome
- 2016
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Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 68:5, s. 1290-1300
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE:More than 80% of autoimmune disease is female dominant, but the mechanism for this female bias is poorly understood. We suspected an X chromosome dose effect and hypothesized that trisomy X (47,XXX, 1 in ∼1,000 live female births) would be increased in female predominant diseases (e.g. systemic lupus erythematosus [SLE], primary Sjögren's syndrome [SS], primary biliary cirrhosis [PBC] and rheumatoid arthritis [RA]) compared to diseases without female predominance (sarcoidosis) and controls.METHODS:We identified 47,XXX subjects using aggregate data from single nucleotide polymorphism (SNP) arrays and confirmed, when possible, by fluorescent in situ hybridization (FISH) or quantitative polymerase chain reaction (q-PCR).RESULTS:We found 47,XXX in seven of 2,826 SLE and three of 1,033 SS female patients, but only in two of the 7,074 female controls (p=0.003, OR=8.78, 95% CI: 1.67-86.79 and p=0.02, OR=10.29, 95% CI: 1.18-123.47; respectively). One 47,XXX subject was present for ∼404 SLE women and ∼344 SS women. 47,XXX was present in excess among SLE and SS subjects.CONCLUSION:The estimated prevalence of SLE and SS in women with 47,XXX was respectively ∼2.5 and ∼2.9 times higher than in 46,XX women and ∼25 and ∼41 times higher than in 46,XY men. No statistically significant increase of 47,XXX was observed in other female-biased diseases (PBC or RA), supporting the idea of multiple pathways to sex bias in autoimmunity. This article is protected by copyright. All rights reserved.
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| 22. |
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| 23. |
- Marouli, Eirini, et al.
(författare)
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Rare and low-frequency coding variants alter human adult height
- 2017
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
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Tidskriftsartikel (refereegranskat)abstract
- Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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| 24. |
- Namjou, Bahram, et al.
(författare)
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Evaluation of TRAF6 in a large multiancestral lupus cohort
- 2012
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 64:6, s. 1960-1969
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Tidskriftsartikel (refereegranskat)abstract
- Objective Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with significant immune system aberrations resulting from complex heritable genetics as well as environmental factors. We undertook to study the role of TRAF6 as a candidate gene for SLE, since it plays a major role in several signaling pathways that are important for immunity and organ development. Methods Fifteen single-nucleotide polymorphisms (SNPs) across TRAF6 were evaluated in 7,490 SLE patients and 6,780 control subjects from different ancestries. Population-based casecontrol association analyses and meta-analyses were performed. P values, false discovery rate q values, and odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. Results Evidence of associations was detected in multiple SNPs. The best overall P values were obtained for SNPs rs5030437 and rs4755453 (P = 7.85 x 10(-5) and P = 4.73 x 10(-5), respectively) without significant heterogeneity among populations (P = 0.67 and P = 0.50, respectively, in Q statistic). In addition, SNP rs540386, which was previously reported to be associated with rheumatoid arthritis (RA), was found to be in linkage disequilibrium with these 2 SNPs (r2 = 0.95) and demonstrated evidence of association with SLE in the same direction (meta-analysis P = 9.15 x 10(-4), OR 0.89 [95% CI 0.830.95]). The presence of thrombocytopenia improved the overall results in different populations (meta-analysis P = 1.99 x 10(-6), OR 0.57 [95% CI 0.450.72], for rs5030470). Finally, evidence of family-based association in 34 African American pedigrees with the presence of thrombocytopenia was detected in 1 available SNP (rs5030437) with a Z score magnitude of 2.28 (P = 0.02) under a dominant model. Conclusion Our data indicate the presence of association of TRAF6 with SLE, consistent with the previous report of association with RA. These data provide further support for the involvement of TRAF6 in the pathogenesis of autoimmunity.
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| 25. |
- Namjou, Bahram, et al.
(författare)
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High-density genotyping of STAT4 reveals multiple haplotypic associations with systemic lupus erythematosus in different racial groups
- 2009
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 60:4, s. 1085-1095
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disorder, with complex etiology and a strong genetic component. Recently, gene products involved in the interferon pathway have been under intense investigation in terms of the pathogenesis of SLE. STAT-1 and STAT-4 are transcription factors that play key roles in the interferon and Th1 signaling pathways, making them attractive candidates for involvement in SLE susceptibility. METHODS: Fifty-six single-nucleotide polymorphisms (SNPs) across STAT1 and STAT4 on chromosome 2 were genotyped using the Illumina platform, as part of an extensive association study in a large collection of 9,923 lupus patients and control subjects from different racial groups. DNA samples were obtained from the peripheral blood of patients with SLE and control subjects. Principal components analyses and population-based case-control association analyses were performed, and the P values, false discovery rate q values, and odds ratios with 95% confidence intervals were calculated. RESULTS: We observed strong genetic associations with SLE and multiple SNPs located within STAT4 in different ethnic groups (Fisher's combined P = 7.02 x 10(-25)). In addition to strongly confirming the previously reported association in the third intronic region of this gene, we identified additional haplotypic association across STAT4 and, in particular, a common risk haplotype that is found in multiple racial groups. In contrast, only a relatively weak suggestive association was observed with STAT1, probably due to its proximity to STAT4. CONCLUSION: Our findings indicate that STAT4 is likely to be a crucial component in SLE pathogenesis in multiple racial groups. Knowledge of the functional effects of this association, when they are revealed, might improve our understanding of the disease and provide new therapeutic targets.
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