Systemic sclerosis (SSc) is an orphan, complex, inflammatory disease affecting the immune system and connective tissue. SSc stands out as a severely incapacitating and life-threatening inflammatory rheumatic disease, with a largely unknown pathogenesis. We have designed a two-stage genome-wide association study of SSc using case-control samples from France, Italy, Germany, and Northern Europe. The initial genome-wide scan was conducted in a French post quality-control sample of 564 cases and 1,776 controls, using almost 500 K SNPs. Two SNPs from the MHC region, together with the 6 loci outside MHC having at least one SNP with a P<10−5 were selected for follow-up analysis. These markers were genotyped in a post-QC replication sample of 1,682 SSc cases and 3,926 controls. The three top SNPs are in strong linkage disequilibrium and located on 6p21, in the HLA-DQB1 gene: rs9275224, P = 9.18×10−8, OR = 0.69, 95% CI [0.60–0.79]; rs6457617, P = 1.14×10−7 and rs9275245, P = 1.39×10−7. Within the MHC region, the next most associated SNP (rs3130573, P = 1.86×10−5, OR = 1.36 [1.18–1.56]) is located in the PSORS1C1 gene. Outside the MHC region, our GWAS analysis revealed 7 top SNPs (P<10−5) that spanned 6 independent genomic regions. Follow-up of the 17 top SNPs in an independent sample of 1,682 SSc and 3,926 controls showed associations at PSORS1C1 (overall P = 5.70×10−10, OR:1.25), TNIP1 (P = 4.68×10−9, OR:1.31), and RHOB loci (P = 3.17×10−6, OR:1.21). Because of its biological relevance, and previous reports of genetic association at this locus with connective tissue disorders, we investigated TNIP1 expression. A markedly reduced expression of the TNIP1 gene and also its protein product were observed both in lesional skin tissue and in cultured dermal fibroblasts from SSc patients. Furthermore, TNIP1 showed in vitro inhibitory effects on inflammatory cytokine-induced collagen production. The genetic signal of association with TNIP1 variants, together with tissular and cellular investigations, suggests that this pathway has a critical role in regulating autoimmunity and SSc pathogenesis.

In this paper, we study the ability of convergent subdivision schemes to reproduce polynomials in the sense that for initial data, which is sampled from some polynomial function, the scheme yields the same polynomial in the limit. This property is desirable because the reproduction of polynomials up to some degree d implies that a scheme has approximation order d + 1. We first show that any convergent, linear, uniform, and stationary subdivision scheme reproduces linear functions with respect to an appropriately chosen parameterization. We then present a simple algebraic condition for polynomial reproduction of higher order. All results are given for subdivision schemes of any arity m ≥ 2 and we use them to derive a unified definition of general m-ary pseudo-splines. Our framework also covers non-symmetric schemes and we give an example where the smoothness of the limit functions can be increased by giving up symmetry.

Abstract-Essential hypertension is a multifactorial disorder and is the main risk factor for renal and cardiovascular complications. The research on the genetics of hypertension has been frustrated by the small predictive value of the discovered genetic variants. The HYPERGENES Project investigated associations between genetic variants and essential hypertension pursuing a 2-stage study by recruiting cases and controls from extensively characterized cohorts recruited over many years ). A meta-analysis, using other in silico/de novo genotyping data for a total of 21 714 subjects, resulted in an overall odds ratio of 1.34 (95% CI: 1.25-1.44; Pϭ1.032 ⅐ 10 Ϫ14). The quantitative analysis on a population-based sample revealed an effect size of 1.91 (95% CI: 0.16 -3.66) for systolic and 1.40 (95% CI: 0.25-2.55) for diastolic blood pressure. We identified in silico a potential binding site for ETS transcription factors directly next to rs3918226, suggesting a potential modulation of endothelial NO synthase expression. Biological evidence links endothelial NO synthase with hypertension, because it is a critical mediator of cardiovascular homeostasis and blood pressure control via vascular tone regulation. This finding supports the hypothesis that there may be a causal genetic variation at this locus. (Hypertension. 2012;59:248-255.) • Online Data Supplement Key Words: genetic epidemiology Ⅲ risk factors Ⅲ genetics association studies Ⅲ NO Ⅲ essential hypertension E ssential hypertension (EH) is a clinical condition affecting a large proportion (25% to 30%) of the adult population and is a major risk factor for cardiovascular and renal diseases. 1,2 It is a complex trait influenced by multiple susceptibility genes, environmental, and lifestyle factors and their interactions. 3 In the last years, huge efforts have been performed in recruiting and genotyping tens of thousands of individuals and meta-analyzing dozens of cross-sectional, population-based studies. In spite of this, the research on the genetics of EH has been frustrated by the small predictive value of the discovered genetic variants and by the fact that these variants explain a small proportion of the phenotypic variation. 4 -13 EH is a late-onset disease and, therefore, the small discovered effect sizes could in part be because of the effect of misclassification, sample selection bias, and inappropriate phenotyping of cases and controls. 9,14,15 The selection of cases and controls may have important effects on the results, because misclassification bias can lead to loss of power. For common traits, such as EH, this bias can be remedied by defining more stringent selection criteria, by recruiting hypernormal controls and adopting a more stringent case definition. 14,15 The HYPERGENES Project pursued a 2-stage study to investigate novel genetic determinants of EH. Cases and controls were recruited from extensively characterized cohorts over many years in different European regions using standardized clinical ascertainment. Particular care was devoted to c...

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