Is there an agreement between self-reported medical diagnosis in the CARTaGENE cohort and the Québec administrative health databases?

BACKGROUND: Population health studies often use existing databases that are not necessarily constituted for research purposes. The question arises as to whether different data sources such as in administrative health data (AHD) and self-report questionnaires are equivalent and lead to similar information. OBJECTIVES: The main objective of this study was to assess the level of agreement between self-reported medical conditions and medical diagnosis captured in AHD. A secondary objective was to identify predictors of agreement among medical conditions between the two data sources. Therefore, the purposes of the study were to explore the extent to which these two methods of commonly used public health data collection provide concordant records and identify the main predictors of statistical variations. METHODS: Data were extracted from CARTaGENE, a population-based cohort in Québec, Canada, which was linked to the provincial health insurance records of the same individuals, namely the MED-ÉCHO database from the Régie de l'assurance maladie du Québec (RAMQ) and the fee-for-service billing records provided by the physician, for the time period 1998-2012. Agreement statistics (kappa coefficient) along with sensitivity, specificity and predictive positive value were calculated for 19 chronic conditions and 12 types of cancers. Logistic regressions were used to identify predictors of concordance between self-report and AHD from significant covariates (sex, age groups, education, region, income, heavy utilization of health care system and Charlson comorbidity index). RESULTS: Agreement between self-reported data and AHD across diseases ranged from kappa of 0.09 for chronic renal failure to 0.86 for type 2 diabetes. Sensitivity of self-reported data was higher than 50% for 14 out of the 31 medical conditions studied, especially for myocardial infarction (88.62%), breast cancer (86.28%), and diabetes (85.06%). Specificity was generally high with a minimum value of 89.70%. Lower concordance between data sources was observed for higher frequency of health care utilization and higher comorbidity scores. CONCLUSION: Overall, there was moderate agreement between the two data sources but important variations were found depending on the type of disease. This suggests that CARTaGENE's participants were generally able to correctly identify the kind of diseases they suffer from, with some exceptions. These results may help researchers choose adequate data sources according to specific study objectives. These results also suggest that Québec's AHD seem to underestimate the prevalence of some chronic conditions, which might result in inaccurate estimates of morbidity with consequences for public health surveillance.

High prevalence of ventricular repolarization abnormalities in people carrying TGFßR2 mutations.

Mutations in the TGFßR2 gene have been associated with a life threatening risk of aortic dissection but no arrhythmic death has been previously reported. Two young females carrying a TGFßR2 mutation, initially diagnosed as Marfan syndrome or Loeys Dietz syndrome, presented sudden death with autopsy ruling out dissection. The ECGs of the 2 Sudden Cardiac Deaths revealed profound ventricular repolarization abnormalities with a sinusoidal T-U morphology associated with normal left ventricular ejection fraction. These data strongly suggest sudden cardiac arrhythmic deaths and prompted us to systematically study the repolarization pattern in the patients with TGFßR2 mutations. ECG findings from 58 mutation carriers patients (TGFßR2 group) were compared with those of 46 non-affected first degree relatives (control group). TGFßR2 mutation was associated with ventricular repolarization abnormalities in 47% of patients (p < 0.001 vs. controls), including a 19.6 ms (95%CI 8.7; 30.5) QTc interval prolongation compared to the non-affected first degree relatives (p < 0.001), higher prevalence of abnormal U waves (16% vs. 2%), and sinusoidal T-U morphology (10% vs. 0%). TGFßR2 mutations can be associated with abnormal ventricular repolarization pattern, longer QT interval than non-carrier relatives and an increased risk for sudden death.

[Returning to work after an acute coronary syndrome: When waiting is wasting]. / Retour au travail après un accident coronarien aigu.

BACKGROUND: Return to work (RTW) after acute coronary syndrome (ACS) is an important issue for the patient's future. AIMS: The study aim was to determine whether RTW practice complies with guidelines or is delayed by failure in patient management. We analysed the factors influencing RTW beyond the 90-day period recommended by guidelines. METHODS: We conducted a survey of 216 self-employed workers admitted to the hospital for ACS using self-report questionnaires and medical examination. Factors influencing RTW, occupational and cardiac features, and recall and source of medical information were investigated. RESULTS: Ninety-three of 216 patients did not return to work by 90 days, despite good cardiac performance in 30 cases (32 %). The mean sick leave duration was 93.3±103.7 days. Advice concerning return to work was completely missing for 44 % of patients. Cardiac performance was independent of sick leave duration, but was correlated with the likelihood of RTW (P<0.001). Patients assimilated about 70 % of the medical information they were provided, but only 53 % of work-related information. Recall of work-related information was better among patients admitted to a rehabilitation facility (65 %) compared to those who did not receive rehabilitation (P<0.05). CONCLUSION: Cardiologists should assess the patient's cardiac performance within 2 months after ACS. Patient management should also include cardiac rehabilitation or therapeutic education toward improving information recall.

Corrigendum to: 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases.

Corrigendum to: 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases [Eur Heart Journal (2014) 35, 2873­2926,doi:10.1093/eurheartj/ehu281]. In Table 3, the radiation for MRI is "0" and not "-". The corrected table is shown below.

The revised ghent nosology; reclassifying isolated ectopia lentis.

Inherited ectopia lentis (EL) is most commonly caused by Marfan syndrome (MFS), a multisystemic disorder caused by mutations in FBN1. Historically the diagnosis for patients with EL who have no systemic features of MFS is isolated EL (IEL). However, the Ghent nosology for MFS was updated in 2010 and made some important alterations. In particular, patients with EL and a FBN1 mutation are now categorically diagnosed with MFS, if their mutation has previously been described with aortic dilation/dissection. This carries significant systemic implications, as many patients previously diagnosed with IEL are now reclassified. We provide a review of all published cases of IEL caused by FBN1 mutations over the last 20 years to assess what impact the new Ghent nosology has on these. Indeed, 57/123 probands (46.3%) are now classified as MFS according to the revised Ghent nosology and 37/96 mutations (38.5%) reported to cause isolated EL have also been found in patients with aortic dilation/dissection. These findings suggest that EL caused by mutations in FBN1 is actually part of a spectrum of fibrillinopathies with MFS, and the term 'IEL' should be avoided in such cases.

[Is a patient's knowledge of cardiovascular risk factors better after the occurrence of a major ischemic event? Survey of 135 cases and 260 controls]. / La connaissance des facteurs de risque cardiovasculaire est-elle meilleure après la survenue d'un évènement ischémique majeur? Enquête auprès de 135 cas et 260 témoins.

AIM: We hypothezised that patients (cases) who are hospitalized for a major ischemic event--myocardial infarction, stroke, decompensation of peripheral arterial disease--acquire better knowledge than a control population--atheromatous patients without a major ischemic event, patients consulting for a vein disease or a diabetes evaluation, and accompanists--about cardiovascular risk factors (smoking, hypertension, diabetes, dyslipidemia, obesity) and have a better understanding of the usefulness of making changes in their lifestyle (quit smoking, regular exercise, Mediterranean diet, low salt diet, weight control, diabetes care). METHODS: A questionnaire was proposed at vascular surgery consultations and vascular and cardiac functional explorations, at the M Pavillon of the Édouard-Herriot hospital, Lyon, France. In five months, 395 questionnaires (135 cases and 260 controls) were analyzed. RESULTS: The global knowledge score was statistically higher for cases than for controls (cases 3.23±1.81; controls 2.77±2.03; P=0.037). Cases did not abide by monitoring and dietary rules better, except as regards the management of diabetes. Regular physical activity was statistically more prevalent among controls than among cases. Cases mainly received their information from their doctors (general practitioner for 59% of controls and 78% of cases, cardiologist for 25% of controls and 57% of cases) while controls got their information more through magazines or advertising. CONCLUSION: Our results show that after a major ischemic event, cases' knowledge of risk factors is better than the rest of the population without improved rules lifestyle changes. This suggests the usefulness of evaluating a therapeutic education program for atheromatous disease.

What do French patients and geneticists think about prenatal and preimplantation diagnoses in Marfan syndrome?

OBJECTIVES: Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with manifestations mainly involving the skeletal, ocular, and cardiovascular systems. The phenotypic variability observed in MFS makes genetic counselling difficult. Prenatal diagnosis (PND) and preimplantation genetic diagnosis are technically feasible when a causal mutation is identified, but both raise many ethical questions in this condition. Little is known about opinions and practices in such reproductive issues in MFS. The goal of this study was to report on patients' points of view and geneticists' standard practices. METHODS: Two different questionnaires were produced. RESULTS: Fifty geneticists filled in the questionnaire. Twenty-two per cent thought that PND was acceptable, 72% debatable and 6% not acceptable. Preimplantation genetic diagnosis was more often reported acceptable (34% of answers). Results varied according to the physician's experience with the disease. Fifty-four answers were collected for patients' questionnaires. Most of them (74%) were favourable to the development of prenatal testing, and believed that the choice should be given to parents. However, only a minority would opt for prenatal diagnosis for themselves. CONCLUSION: This study showed that the majority of patients were in favour of PND and that opinions among practitioners varied widely, but that overall, practitioners favoured a systematic multidisciplinary evaluation of the couple's request.

The new Ghent criteria for Marfan syndrome: what do they change?

The diagnosis of Marfan syndrome (MFS) is challenging and international criteria have been proposed. The 1996 Ghent criteria were adopted worldwide, but new diagnostic criteria for MFS were released in 2010, giving more weight to aortic root aneurysm and ectopia lentis. We aimed to compare the diagnosis reached by applying this new nosology vs the Ghent nosology in a well-known series of 1009 probands defined by the presence of an FBN1 mutation. A total of 842 patients could be classified as MFS according to the new nosology (83%) as compared to 894 (89%) according to the 1996 Ghent criteria. The remaining 17% would be classified as ectopia lentis syndrome (ELS), mitral valve prolapse syndrome or mitral valve, aorta, skeleton and skin (MASS) syndrome, or potential MFS in patients aged less than 20 years. Taking into account the median age at last follow-up (29 years), the possibility has to be considered that these patients would go on to develop classic MFS with time. Although the number of patients for a given diagnosis differed only slightly, the new nosology led to a different diagnosis in 15% of cases. Indeed, 10% of MFS patients were reclassified as ELS or MASS in the absence of aortic dilatation; conversely, 5% were reclassified as MFS in the presence of aortic dilatation. The nosology is easier to apply because the systemic score is helpful to reach the diagnosis of MFS only in a minority of patients. Diagnostic criteria should be a flexible and dynamic tool so that reclassification of patients with alternative diagnosis is possible, requiring regular clinical and aortic follow-up.

Evidence of the contribution of the X chromosome to systemic sclerosis susceptibility: association with the functional IRAK1 196Phe/532Ser haplotype.

OBJECTIVE: Several autoimmune disorders, including systemic sclerosis (SSc), are characterized by a strong sex bias. To date, it is not known whether genes on the sex chromosomes influence SSc susceptibility. Recently, an IRAK1 haplotype that contains the 196Phe functional variant (rs1059702), located on Xq28, was found to confer susceptibility to systemic lupus erythematosus (SLE). This study was undertaken to test for an association between SSc and the IRAK1 SLE risk haplotype. METHODS: We tested for an association with the IRAK1 SLE risk haplotype in a discovery set of 849 SSc patients and 625 controls. IRAK1 rs1059702 was further genotyped in a replication set, which included Caucasian women from Italy (493 SSc patients and 509 controls) and Germany (466 SSc patients and 1,083 controls). RESULTS: An association between the IRAK1 haplotype and SSc was detected in the discovery set. In both the discovery and replication sets, the rs1059702 TT genotype was found to be associated with specific SSc subsets, highlighting a potential contribution to disease severity. A meta-analysis provided evidence of an association of both the T allele and TT genotype with the overall disease, with an odds ratio (OR) of 1.20 and 95% confidence interval (95% CI) of 1.06-1.35 for the T allele (P = 0.003) and an OR of 1.49 and 95% CI of 1.06-2.10 for the TT genotype (P = 0.023). However, the most notable associations were observed with the diffuse cutaneous, anti-topoisomerase I antibody positive, and SSc-related fibrosing alveolitis subsets (OR 2.35 [95% CI 1.51-3.66], P = 1.56 × 10(-4), OR 2.84 [95% CI 1.87-4.32], P = 1.07 × 10(-6), and OR 2.09 [95% CI 1.35-3.24], P = 9.05 × 10(-4), respectively). CONCLUSION: Our study provides the first evidence of an association between IRAK1 and SSc, demonstrating that a sex chromosome gene directly influences SSc susceptibility and its phenotypic heterogeneity.

Association of the CD226 Ser(307) variant with systemic sclerosis: evidence of a contribution of costimulation pathways in systemic sclerosis pathogenesis.

OBJECTIVE: The nonsynonymous polymorphism rs763361 of the CD226 gene, which encodes DNAX accessory molecule 1, which is involved in T cell costimulation pathways, has recently been identified as a genetic risk factor for autoimmunity. The purpose of this study was to test for association of the CD226 rs763361 polymorphism with systemic sclerosis (SSc) in European Caucasian populations. METHODS: CD226 rs763361 was genotyped in 3,632 individuals, consisting of a discovery sample (991 SSc patients and 1,008 controls) and a replication sample (999 SSc patients and 634 controls). All study subjects were of European Caucasian origin. Expression of CD226 was assessed on peripheral blood mononuclear cells obtained from 21 healthy donors genotyped for CD226 rs763361. RESULTS: The CD226 rs763361 T allele was found to be associated with SSc in both the discovery and the replication samples, showing the following results in the combined populations: odds ratio (OR) 1.22 (95% confidence interval [95% CI] 1.10-1.34), P = 5.69 × 10(-5) . The CD226 T allele was also associated with various SSc subsets, highlighting a potential contribution to disease severity. The most remarkable associations of the CD226 TT risk genotype were observed with the diffuse cutaneous SSc subtype, the anti-topoisomerase I antibody-positive, and SSc-related fibrosing alveolitis subsets: OR 1.86 (95% CI 1.42-2.43), P = 5.15 × 10(-6) , OR 1.82 (95% CI 1.38-2.40), P = 2.16 × 10(-5) , and OR 1.61 (95% CI 1.25-2.08), P = 2.73 × 10(-4) , respectively. CD226 expression was not significantly influenced by CD226 rs763361 genotypes whatever the T cell subtype investigated. CONCLUSION: Our results establish CD226 as a new SSc genetic susceptibility factor underlying the contribution of costimulation pathways in the pathogenesis of SSc. Further work is nevertheless needed to define the causal variant at the CD226 locus as well as the functional consequences.

NLRP1 influences the systemic sclerosis phenotype: a new clue for the contribution of innate immunity in systemic sclerosis-related fibrosing alveolitis pathogenesis.

BACKGROUND: Recent evidence has highlighted a potential role of interleukin 1ß (IL-1ß) in systemic sclerosis (SSc). NLRP1 provides a scaffold for the assembly of the inflammasome that promotes the processing and maturation of pro-IL-1ß. In addition, NLRP1 variants were found to confer susceptibility to autoimmune disorders. OBJECTIVE: /st> To study a possible association of the NLRP1 rs6502867, rs2670660 and rs8182352, rs12150220 and rs4790797 with SSc in the European Caucasian population. METHODS: NLRP1 single nucleotide polymorphisms were genotyped in 3227 individuals comprising a discovery set (870 SSc patients and 962 controls) and a replication set including individuals from Germany (532 SSc patients and 324 controls) and Italy (527 SSc patients and 301 controls), all individuals being of European Caucasian origin. RESULTS: Conditional analyses revealed a significant association for the NLRP1 rs8182352 variant with both anti-topoisomerase-positive and SSc-related fibrosing alveolitis (FA) subsets under an additive model: p=0.0042, OR 1.23 (95% CI 1.07 to 1.41) and p=0.0065 OR 1.19 (95% CI 1.05 to 1.36), respectively. Logistic regression analysis showed an additive effect of IRF5 rs2004640, STAT4 rs7574865 and NLRP1 rs8182352 risk alleles on SSc-related FA. CONCLUSIONS: Our results establish NLRP1 as a new genetic susceptibility factor for SSc-related pulmonary fibrosis and anti-topoisomerase-positive SSc phenotypes. This provides new insights into the pathogenesis of SSc, underlining the potential role of innate immunity in particular in the FA-positive SSc subphenotype, which represents a severe subset of the disease.

Immunogenetics of systemic sclerosis.

In the field of genetics of SSc, we are currently reaching a period of rapid data production. Several themes are already rising from the first wave of results. First, some genetic variants clearly predispose to multiple autoimmune diseases, thus providing evidence for a shared autoimmune genetic background. Second, multiple genes are involved in the SSc predisposition and as expected the genetic associations are quite modest. Third, unless for a small number of exceptions, the causative genetic variations have not been definitively identified yet. Lastly, to date, the most convincing associations detected relate to genes playing a pivotal role in both innate and adaptative immunity. Indeed, additionally to the MHC, candidate gene studies have convincingly and reproducibly identified PTPN22, IRF5, STAT4, C8orf13-BLK, BANK1 and TNFSF4 as SSc susceptibility genes. Although these results have substantially advanced our understanding of the SSc pathogenesis, both gene-gene and gene-environment studies are now awaited in order to further improve our understanding of this multifacet disease. Finally, we should keep in mind that SSc is a very severe that is until now unfortunately free of effective therapy. Therefore, the identification of new susceptibility genes may offer a rich source of new hypotheses and experimental directions to follow that we should try to assembly in a near future to generate innovative therapies to fight this dramatic disease.

Association of the TNFAIP3 rs5029939 variant with systemic sclerosis in the European Caucasian population.

BACKGROUND: TNFAIP3 encodes the ubiquitin-modifying enzyme, a key regulator of inflammatory signalling pathways. Convincing associations between TNFAIP3 variants and autoimmune diseases have been reported. OBJECTIVE: To investigate the association of TNFAIP3 polymorphisms with systemic sclerosis (SSc). METHODS: Three single nucleotide polymorphisms (SNPs) in a set of 1018 patients with SSc and 1012 controls of French Caucasian origin were genotyped. Two intergenic SNPs, rs10499194 and rs6920220, and one located in TNFAIP3 intron 2, rs5029939, were selected. The TNFAIP3 rs5029939 found to be associated with SSc in this first set was then genotyped in a second set of 465 patients with SSc and 182 controls from Germany and 184 patients with SSc and 124 controls from Italy. Pooled odd ratios were calculated by Mantel-Haenszel meta-analysis. RESULTS: The rs5029939 G allele was found to be significantly associated with SSc susceptibility (pooled OR=2.08 (95% CI 1.59 to 2.72); p=1.16×10⁻7), whereas the rs10499194 and rs6920220 variants displayed no association. Only one of the predicted haplotypes investigated in the French sample was significantly associated with SSc (p=8.91×10⁻8), and this haplotype was discriminating only in the presence of the rs5029939 risk allele, suggesting that this SNP tags the association signal. The strongest associations of rs5029939 with subphenotypes, having large magnitudes for complex genetic disorders, were observed for diffuse cutaneous SSc (pooled OR=2.71 (1.94 to 3.79), p=5.2×10⁻9), fibrosing alveolitis (pooled OR=2.26 (1.61 to 3.17), p=2.5×10⁻6) and pulmonary arterial hypertension (pooled OR=3.11 (1.86 to 5.17), p=1.3×10⁻5). CONCLUSION: These results suggest that TNFAIP3 is a genetic susceptibility factor for SSc.

Association of a KCNA5 gene polymorphism with systemic sclerosis-associated pulmonary arterial hypertension in the European Caucasian population.

OBJECTIVE: Pulmonary arterial hypertension (PAH) has emerged as a leading cause of death in systemic sclerosis (SSc). The genetic basis of PAH has been unraveled in recent years, with a major role played by transforming growth factor ß receptors; however, some other candidate genes have also been advocated, including potassium voltage-gated channel, shaker-related subfamily, member 5 (KCNA5). We undertook this study to determine whether KCNA5 polymorphisms confer susceptibility to SSc and its vascular phenotype, including PAH. METHODS: Four KCNA5 single-nucleotide polymorphisms (SNPs), rs10744676, rs1860420, rs3741930, and rs2284136, were genotyped in a discovery set of 638 SSc patients and 469 controls. In addition, rs10744676 was genotyped in an independent replication sample (938 SSc patients and 564 controls) and in a cohort of 168 patients with different PAH subtypes. RESULTS: The KCNA5 rs10744676 variant was found to be associated with SSc in the discovery sample, with an odds ratio (OR) of 0.62 (95% confidence interval [95% CI] 0.48-0.79, adjusted P = 0.0003) in comparison with controls (C allele frequency 11.4% versus 17.2%). When subphenotypes were investigated, an association was found solely for PAH associated with SSc (OR 0.31 [95% CI 0.13-0.71], adjusted P = 0.04). The other KCNA5 SNPs tested were not associated with any SSc subset. The above association with PAH associated with SSc was replicated in the second set. In the combined population, rs10744676 was strongly associated with PAH associated with SSc in comparison with controls (OR 0.36 [95% CI 0.21-0.63], P = 0.0002). In the independent cohort of patients with PAH, after investigating PAH subtypes, only rs10744676 showed an association with PAH associated with SSc. CONCLUSION: Our results provide the first evidence for an association between the KCNA5 rs10744676 variant and PAH associated with SSc.

Confirmation of ADAMTSL4 mutations for autosomal recessive isolated bilateral ectopia lentis.

Ectopia lentis (EL) is a zonular disease where alteration of the zonular fibers leads progressively to lens dislocation. It is most often associated with systemic diseases such as Marfan syndrome, Weill-Marchesani syndrome or homocystinuria. Isolated non syndromic ectopia lentis (IEL) is reported in families with autosomal inheritance, with dominant forms being more common than recessive. LTBP2 truncating mutations have been described as a cause of autosomal recessive ectopia lentis as a primary or secondary feature in patients showing ocular (eg, glaucoma) or extraocular manifestations (eg, Marfanoid habitus). Recently, ADAMTSL4 has been shown to be responsible for isolated autosomal recessive ectopia lentis in an inbred family. Herein we show a consanguineous family that carries a novel homozygous splice mutation IVS4-1G>A/IVS4-1G>A in ADAMTSL4 responsible for isolated autosomal recessive EL, thus confirming the involvement of this gene in this condition and underlining the major role of ADAMTS proteases in zonular fibers homeostasis.

BANK1 is a genetic risk factor for diffuse cutaneous systemic sclerosis and has additive effects with IRF5 and STAT4.

OBJECTIVE: To determine whether the functional BANK1 variants rs3733197 and rs10516487 are associated with systemic sclerosis (SSc) in 2 European Caucasian populations and to investigate the putative gene-gene interactions between BANK1 and IRF5 as well as STAT4. METHODS: BANK1 single-nucleotide polymorphisms were genotyped in a total population of 2,432 individuals. The French cohort consisted of 874 SSc patients and 955 controls (previously genotyped for both IRF5 rs2004640 and STAT4 rs7574865). The German cohort consisted of 421 SSc patients and 182 controls. RESULTS: The BANK1 variants were found to be associated with diffuse cutaneous SSc (dcSSc) in both cohorts, providing an odds ratio (OR) of 0.77 for the rs10516487 T rare allele in the combined populations of dcSSc patients as compared with the combined populations of controls (95% confidence interval [95% CI] 0.64-0.93) and an OR of 0.73 (95% CI 0.61-0.87) for the rs3733197 A rare allele. BANK1 haplotype analysis found the A-T haplotype to be protective in dcSSc patients (OR 0.70 [95% CI 0.57-0.86], P = 3.39 x 10(-4)) and the G-C haplotype to be a risk factor (OR 1.25 [95% CI 1.06-1.47], P = 0.008). Significant differences were also observed when the limited cutaneous subset of SSc was compared with the dcSSc subset, both for the rare alleles and for the haplotypes. The BANK1, IRF5, and STAT4 risk alleles displayed a multiplicatively increased risk of dcSSc of 1.43-fold. CONCLUSION: Our results establish BANK1 as a new SSc genetic susceptibility factor and show that BANK1, IRF5, and STAT4 act with additive effects.

STAT4 is a genetic risk factor for systemic sclerosis having additive effects with IRF5 on disease susceptibility and related pulmonary fibrosis.

OBJECTIVE: Systemic sclerosis (SSc) belongs to the group of connective tissue disorders (CTDs), among which are several disorders characterized by a type I interferon (IFN) signature. The recent identification of an association between IRF5 and SSc further highlights a key role for IFN. STAT4, which encodes STAT-4, contributes to IFN signaling, and its genetic variants were found to be associated with CTDs. The aim of this study was to determine whether the STAT4 rs7574865 single-nucleotide polymorphism is associated with SSc, and whether it interacts with IRF5. METHODS: Both the STAT4 rs7574865 and IRF5 rs2004640 polymorphisms were genotyped in 1,855 individuals of French Caucasian origin comprising a discovery set of 440 patients with SSc and 485 control subjects and a replication set of 445 patients with SSc and an additional 485 control subjects. RESULTS: STAT4 rs7574865 was shown to be associated with SSc (P=0.001, odds ratio [OR] 1.29, 95% confidence interval [95% CI] 1.11-1.51). This association was not restricted to a particular phenotype. An additive effect of the STAT4 rs7574865 T allele and the IRF5 rs2004640 T allele was observed, resulting in a multiple increased 1.28-fold risk of SSc. The OR for SSc was 2.72 (95% CI 1.86-3.99) for combinations of genotypes with >or=3 risk alleles. An additive effect was also detected for fibrosing alveolitis: carriage of at least 3 risk alleles appeared to be an independent risk factor (P=2.2x10(-4), OR 1.97, 95% CI 1.28-3.04). CONCLUSION: Our results establish STAT4 rs7574865 as a new SSc genetic susceptibility factor. STAT4 and IRF5 act with additive effects in terms of susceptibility to both SSc and SSc-related fibrosing alveolitis.

Pathogenic FBN1 mutations in 146 adults not meeting clinical diagnostic criteria for Marfan syndrome: further delineation of type 1 fibrillinopathies and focus on patients with an isolated major criterion.

Mutations in the FBN1 gene cause Marfan syndrome (MFS) and have been associated with a wide range of milder overlapping phenotypes. A proportion of patients carrying a FBN1 mutation does not meet diagnostic criteria for MFS, and are diagnosed with "other type I fibrillinopathy." In order to better describe this entity, we analyzed a subgroup of 146 out of 689 adult propositi with incomplete "clinical" international criteria (Ghent nosology) from a large collaborative international study including 1,009 propositi with a pathogenic FBN1 mutation. We focused on patients with only one major clinical criterion, [including isolated ectopia lentis (EL; 12 patients), isolated ascending aortic dilatation (17 patients), and isolated major skeletal manifestations (1 patient)] or with no major criterion but only minor criteria in 1 or more organ systems (16 patients). At least one component of the Ghent nosology, insufficient alone to make a minor criterion, was found in the majority of patients with isolated ascending aortic dilatation and isolated EL. In patients with isolated EL, missense mutations involving a cysteine were predominant, mutations in exons 24-32 were underrepresented, and no mutations leading to a premature truncation were found. Studies of recurrent mutations and affected family members of propositi with only one major clinical criterion argue for a clinical continuum between such phenotypes and classical MFS. Using strict definitions, we conclude that patients with FBN1 mutation and only one major clinical criterion or with only minor clinical criteria of one or more organ system do exist but represent only 5% of the adult cohort.

Association of hypoxia-inducible factor 1A (HIF1A) gene polymorphisms with systemic sclerosis in a French European Caucasian population.

OBJECTIVE: Systemic sclerosis (SSc) is a connective tissue disease characterized by generalized microangiopathy leading to chronic hypoxia. The aim of this study was to determine whether polymorphisms of the hypoxia-inducible factor 1A gene (HIF1A) affects susceptibility to SSc in a large French European Caucasian population. METHODS: A case-control study was performed in 659 SSc patients and 511 healthy matched controls. Three tag single nucleotide polymorphisms (SNPs) of the HIF1A gene (rs12434438 A/G, rs1957757 C/T, and rs11549465 C/T) were genotyped allowing whole gene coverage according to HapMap data. RESULTS: The frequency of genotypes carrying at least one G allele (A/G and/or GG) of the rs12434438 SNP was significantly higher in SSc patients than in controls [p(corr) = 0.018, odds ratio (OR) 1.44, 95% confidence interval (CI) 1.08-1.91]. Regarding SSc subgroup analyses, the heterozygous genotype A/G was associated with SSc (p(corr) = 0.012, OR 1.47, 95% CI 1.13-1.9), with the limited cutaneous form of SSc (p(corr) = 0.04, OR 1.43, 95% CI 1.08-1.91), and with positive anti-centromere antibodies (ACA; p(corr) = 0.016, OR 1.61, 95% CI 1.16-2.23). No association was detected for the remaining two HIF1A SNPs tested. Haplotype analyses did not detect any association with SSc. CONCLUSIONS: We observed an association between the HIF1A gene and SSc in a European Caucasian population, supporting a role for HIF1 in the pathophysiology of SSc.