Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23.

AIMS: Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure. METHODS AND RESULTS: We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10-11 and 7.7 × 10-4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10-8 and 1.4 × 10-3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 3-fold increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene. CONCLUSION: This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure.

Whole-Blood miRNA Sequencing Profiling for Vasospasm in Patients With Aneurysmal Subarachnoid Hemorrhage.

Background and Purpose- Arterial vasospasm is a well-known delayed complication of aneurysmal subarachnoid hemorrhage (aSAH). However, no validated biomarker exists to help clinicians discriminating patients with aSAH who will develop vasospasm (VSP+) and identifying those who then deserve aggressive preventive therapy. We hypothesized that whole-blood miRNAs could be a source of candidate biomarkers for vasospasm. Methods- Using a next-generation sequencing approach, we performed whole-blood miRNA profiling between VSP+patients with aSAH and patients who did not develop vasospasm (VSP-) in a prospective cohort of 32 patients. Profiling was performed on the admission day and 3 days before vasospasm. Results- Four hundred forty-two miRNAs were highly expressed in whole blood of patients with aSAH. Among them, hsa-miR-3177-3p demonstrated significant ( P=5.9×10-5; PBonferronicorrected=0.03) lower levels in VSP- compared with VSP+ patients. Looking for whole-blood mRNA correlates of hsa-miR-3177-3p, we observed some evidence that the decrease in hsa-miR-3177-3p levels after aSAH was associated with an increase in LDHA mRNA levels in VSP- ( P<10-3) but not in VSP+ ( P=0.66) patients. Conclusions- Whole-blood miRNA levels of hsa-miR-3177-3p could serve as a biomarker for vasospasm. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01779713.

Genome-wide haplotype analysis of cis expression quantitative trait loci in monocytes.

In order to assess whether gene expression variability could be influenced by several SNPs acting in cis, either through additive or more complex haplotype effects, a systematic genome-wide search for cis haplotype expression quantitative trait loci (eQTL) was conducted in a sample of 758 individuals, part of the Cardiogenics Transcriptomic Study, for which genome-wide monocyte expression and GWAS data were available. 19,805 RNA probes were assessed for cis haplotypic regulation through investigation of ~2,1 × 10(9) haplotypic combinations. 2,650 probes demonstrated haplotypic p-values >10(4)-fold smaller than the best single SNP p-value. Replication of significant haplotype effects were tested for 412 probes for which SNPs (or proxies) that defined the detected haplotypes were available in the Gutenberg Health Study composed of 1,374 individuals. At the Bonferroni correction level of 1.2 × 10(-4) (~0.05/412), 193 haplotypic signals replicated. 1000 G imputation was then conducted, and 105 haplotypic signals still remained more informative than imputed SNPs. In-depth analysis of these 105 cis eQTL revealed that at 76 loci genetic associations were compatible with additive effects of several SNPs, while for the 29 remaining regions data could be compatible with a more complex haplotypic pattern. As 24 of the 105 cis eQTL have previously been reported to be disease-associated loci, this work highlights the need for conducting haplotype-based and 1000 G imputed cis eQTL analysis before commencing functional studies at disease-associated loci.

Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease.

The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction.

Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX.

BACKGROUND: Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease in which the risk of disease is influenced by complex genetic and environmental contributions. Alleles of HLA-DRB1, IRF5, and STAT4 are established susceptibility genes; there is strong evidence for the existence of additional risk loci. METHODS: We genotyped more than 500,000 single-nucleotide polymorphisms (SNPs) in DNA samples from 1311 case subjects with SLE and 1783 control subjects; all subjects were North Americans of European descent. Genotypes from 1557 additional control subjects were obtained from public data repositories. We measured the association between the SNPs and SLE after applying strict quality-control filters to reduce technical artifacts and to correct for the presence of population stratification. Replication of the top loci was performed in 793 case subjects and 857 control subjects from Sweden. RESULTS: Genetic variation in the region upstream from the transcription initiation site of the gene encoding B lymphoid tyrosine kinase (BLK) and C8orf13 (chromosome 8p23.1) was associated with disease risk in both the U.S. and Swedish case-control series (rs13277113; odds ratio, 1.39; P=1x10(-10)) and also with altered levels of messenger RNA in B-cell lines. In addition, variants on chromosome 16p11.22, near the genes encoding integrin alpha M (ITGAM, or CD11b) and integrin alpha X (ITGAX), were associated with SLE in the combined sample (rs11574637; odds ratio, 1.33; P=3x10(-11)). CONCLUSIONS: We identified and then confirmed through replication two new genetic loci for SLE: a promoter-region allele associated with reduced expression of BLK and increased expression of C8orf13 and variants in the ITGAM-ITGAX region.

A risk haplotype of STAT4 for systemic lupus erythematosus is over-expressed, correlates with anti-dsDNA and shows additive effects with two risk alleles of IRF5.

Systemic lupus erythematosus (SLE) is the prototype autoimmune disease where genes regulated by type I interferon (IFN) are over-expressed and contribute to the disease pathogenesis. Because signal transducer and activator of transcription 4 (STAT4) plays a key role in the type I IFN receptor signaling, we performed a candidate gene study of a comprehensive set of single nucleotide polymorphism (SNPs) in STAT4 in Swedish patients with SLE. We found that 10 out of 53 analyzed SNPs in STAT4 were associated with SLE, with the strongest signal of association (P = 7.1 x 10(-8)) for two perfectly linked SNPs rs10181656 and rs7582694. The risk alleles of these 10 SNPs form a common risk haplotype for SLE (P = 1.7 x 10(-5)). According to conditional logistic regression analysis the SNP rs10181656 or rs7582694 accounts for all of the observed association signal. By quantitative analysis of the allelic expression of STAT4 we found that the risk allele of STAT4 was over-expressed in primary human cells of mesenchymal origin, but not in B-cells, and that the risk allele of STAT4 was over-expressed (P = 8.4 x 10(-5)) in cells carrying the risk haplotype for SLE compared with cells with a non-risk haplotype. The risk allele of the SNP rs7582694 in STAT4 correlated to production of anti-dsDNA (double-stranded DNA) antibodies and displayed a multiplicatively increased, 1.82-fold risk of SLE with two independent risk alleles of the IRF5 (interferon regulatory factor 5) gene.

Variation in STAT4 is associated with systemic lupus erythematosus in a Finnish family cohort.

OBJECTIVES: To investigate whether 10 single nucleotide polymorphisms (SNPs) and haplotypes in the STAT4 gene, previously associated with systemic lupus erythematosus (SLE) in a Swedish case-control cohort, are also associated with SLE risk in a Finnish SLE family cohort. METHOD: Genotyping was performed in 192 Finnish families, with 237 affected subjects and their healthy relatives, using the SNPstream genotyping system. RESULTS: Transmission disequilibrium test analysis provided the strongest signal of association for two linked SNPs: rs7582694 (p=0.002, OR=2.57) and rs10181656 (p=0.001, OR=2.53). Haplotype association analysis using a sliding window approach was also performed and showed that the strongest association signal originates from SNPs in intron 3 of STAT4. CONCLUSION: The main association signal for STAT4 with SLE previously reported in Caucasians is the same in the Finnish population. This is the first study that confirms the association of STAT4 with SLE in a family cohort.

A STAT4 risk allele is associated with ischaemic cerebrovascular events and anti-phospholipid antibodies in systemic lupus erythematosus.

OBJECTIVE: To investigate whether the risk allele for systemic lupus erythematosus (SLE) in the signal transducer and activator of transcription factor 4 (STAT4) gene, defined by the single nucleotide polymorphism (SNP) rs10181656(G), is associated with vascular events and/or presence of prothrombotic anti-phospholipid antibodies (aPL) in patients with SLE. METHODS: Two independent groups of unrelated patients with SLE of Swedish ethnicity (n=424 and 154) were genotyped, and occurrence of previous manifestations of ischaemic heart disease (IHD), ischaemic cerebrovascular disease (ICVD) and venous thromboembolic events (VTE) was tabulated. aPL values were measured by ELISA. Matched controls (n=492 and 194) were genotyped. RESULTS: The STAT4 risk allele was more frequent in patients with SLE with previous arterial events (combined OR (OR(c))=1.5, 95% CI 1.1 to 2.0) compared to patients without such events. The association was mainly attributable to an accumulation of the risk allele among patients with ICVD (OR(c)=2.3, CI 1.6 to 3.3). There was no association with IHD or VTE. The presence of two or more aPLs was associated with the risk allele (OR(c)=1.6, 95% CI 1.2 to 2.0). In multivariable-adjusted logistic regression analyses treatment for hypertension, at least one STAT4 risk allele, older age, IgG anti-cardiolipin antibodies and longer SLE duration remained independently associated with previous ICVD (p

Correction: Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy.

[This corrects the article DOI: 10.1371/journal.pone.0172995.].

Whole blood levels of S1PR4 mRNA associated with cerebral vasospasm after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: The authors sought to identify mRNA biomarkers of cerebral vasospasm in whole blood of patients suffering from aneurysmal subarachnoid hemorrhage (aSAH). METHODS: A prospective transcriptomic study for vasospasm was conducted in whole blood samples of 44 aSAH patients who developed (VSP+ group, n = 22) or did not develop (VSP- group, n = 22) vasospasm. Samples from all patients were profiled for 21,460 mRNA probes using the Illumina Human HT12v4.0 array. Differential statistical analysis was performed using a linear mixed model. RESULTS: Levels of sphingosine-1-phosphate receptor 4 (S1PR4) mRNA were significantly higher (p = 8.03 × 10-6) at presentation in patients who developed vasospasm after aSAH than in patients who did not. CONCLUSIONS: The results, which are consistent with findings of previous experimental investigations conducted in animal models, support the role of S1PR4 and its ligand, sphingosine-1-phosphate (S1P), in arterial-associated vasoconstriction, which suggests that S1PR4 could be used as a biomarker for cerebral vasospasm in aSAH patients.

Effect of weight reduction on quality of life and eating behaviors in obese women.

OBJECTIVE: To examine the impact of a 3-week weight-reducing program on body composition, physical condition, health-related quality of life, and eating behaviors of sedentary, obese (body mass index, 29-35 kg/m) women, according to menopausal status and menopause duration (<5, >or=5, and >or=10 y). DESIGN: Thirteen premenopausal and 27 postmenopausal women received a dietary plan of 1,400 +/- 200 kcal/day and completed 110-minute endurance exercise 6 days per week. Body mass index, fat mass, lean mass, distance walked in the Six-Minute Walk Test, health-related quality of life estimated by the 36-item Short Form Health Survey (SF-36), and eating behaviors (restriction, disinhibition, and susceptibility to hunger) assessed by the Three-Factor Eating Questionnaire were determined before and after weight reduction. RESULTS: Body mass index and fat mass decreased (P < 0.0001), whereas distance walked increased in both groups after weight reduction (P < 0.001). Although the SF-36 mental component score increased after weight loss in both groups (P < 0.0001), the SF-36 physical component score increased in postmenopausal women only (P < 0.001). Restriction increased (P < 0.0001), whereas disinhibition and susceptibility to hunger decreased after weight reduction (P < 0.001 and P < 0.01, respectively) in both groups. Distance walked and SF-36 physical component score after weight loss were higher in women whose menopause ranged between 5 and 9 years and exceeded 10 years, respectively (P < 0.01). CONCLUSIONS: Our study shows that a short-term weight-reducing program combining caloric restriction and physical activity has a favorable impact on women's body composition, physical condition, health-related quality of life, and eating behaviors irrespective of their menopausal status.

Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy.

AIMS: Dilated cardiomyopathy (DCM) is an important cause of heart failure with a strong familial component. We performed an exome-wide array-based association study (EWAS) to assess the contribution of missense variants to sporadic DCM. METHODS AND RESULTS: 116,855 single nucleotide variants (SNVs) were analyzed in 2796 DCM patients and 6877 control subjects from 6 populations of European ancestry. We confirmed two previously identified associations with SNVs in BAG3 and ZBTB17 and discovered six novel DCM-associated loci (Q-value<0.01). The lead-SNVs at novel loci are common and located in TTN, SLC39A8, MLIP, FLNC, ALPK3 and FHOD3. In silico fine mapping identified HSPB7 as the most likely candidate at the ZBTB17 locus. Rare variant analysis (MAF<0.01) demonstrated significant association for TTN variants only (P = 0.0085). All candidate genes but one (SLC39A8) exhibit preferential expression in striated muscle tissues and mutations in TTN, BAG3, FLNC and FHOD3 are known to cause familial cardiomyopathy. We also investigated a panel of 48 known cardiomyopathy genes. Collectively, rare (n = 228, P = 0.0033) or common (n = 36, P = 0.019) variants with elevated in silico severity scores were associated with DCM, indicating that the spectrum of genes contributing to sporadic DCM extends beyond those identified here. CONCLUSION: We identified eight loci independently associated with sporadic DCM. The functions of the best candidate genes at these loci suggest that proteostasis regulation might play a role in DCM pathophysiology.

Caloric restriction and aerobic exercise in sarcopenic and non-sarcopenic obese women: an observational and retrospective study.

BACKGROUND: Sarcopenic obese (SO) individuals are a unique subset of subjects that combines obesity and sarcopenia. Traditional weight loss programmes including aerobic exercises may worsen their condition by further reducing their lean mass. The objective of this observational and retrospective study was to verify the effect of a mixed weight loss programme combining caloric restriction and exercise on body composition, and lipid-lipoprotein profile of obese women according to their sarcopenic status. METHODS: One hundred and forty-six obese women (body mass index ≥ 30 kg/m(2) and fat mass ≥ 40%) participated to the 3 week usual and institutionalized weight-reducing programme combining a dietary plan (1400 ± 200 kcal/day) and aerobic exercise (1 h/day, 6 days/week) of a specialized medical institution. The lean body mass index (LMI; lean mass/height(2)) was calculated, and women in the lowest tertile of LMI were considered SO. RESULTS: At baseline, SO women were older, and their body weight and LMI were lower than non-sarcopenic obese (N-SO) women (p < 0.05). N-SO and SO women similarly lost fat mass and improved their lipid-lipoprotein profile (p < 0.05), while differences in LMI between groups persisted at the end of the weight-reducing programme. Indeed, N-SO women lost lean mass (p < 0.05) while SO did not. CONCLUSIONS: These findings suggest that a short weight loss programme combining caloric restriction and aerobic exercise may significantly reduce fat mass and improve lipid-lipoprotein profile in obese women, independently of their sarcopenic status. Such programmes may have deleterious effects on lean mass in N-SO subjects, only.

Food group preferences and energy balance in moderately obese postmenopausal women subjected to brisk walking program.

The objective of the study was to examine the effects of a 16-week walking program on food group preferences and energy balance of sedentary, moderately obese (body mass index, 29-35 kg/m(2)), postmenopausal Caucasian women, aged 60 ± 5 years old. One hundred and fifty-six volunteers were subjected to 3 sessions/week of 45 min of walking at 60% of heart rate reserve. Total energy intake (TEI) and food group preferences (3-day dietary record), total energy expenditure (TEE, 3-day physical activity diary), cardiorespiratory fitness (2-km walking test), anthropometry, and body composition (bioelectrical impedance) were measured before and after walking. Data were statistically analyzed using an ANOVA with repeated measures on 1 factor (time). The modest increase in TEE of 151 ± 24 kcal/day (p < 0.0001) leads to body weight, fat mass losses, and waist girth reduction (p < 0.0001). TEI remained unchanged despite a slight decrease in carbohydrate intake and a minor increase in protein intake (p < 0.05). Analysis of food records revealed a decreased consumption of fruits (p < 0.05) and sweet and fatty foods (p < 0.01), but an increase in oil consumption (p < 0.0001) after walking. Women with the highest body weight loss showed the greatest reduction in the consumption of fruits, sugar, sweet foods, and fatty foods (p < 0.05). Women with the greatest fat mass loss showed the highest decrease in fatty food intake (p < 0.05). In conclusion, although our walking program changed some food group consumption patterns, body weight loss was primarily because of the increased TEE.

Impact of brisk walking on perceived health evaluated by a novel short questionnaire in sedentary and moderately obese postmenopausal women.

OBJECTIVE: The first objective of this study was to evaluate the impact of brisk walking on moderately obese (body mass index, 29-35 kg/m) postmenopausal women's perceived health, assessed through a novel short perceived health questionnaire (SPHQ), and to verify whether improvements in six items examined were related to cardiorespiratory fitness (CRF) and/or fat mass changes (study 1). The second objective of this study was to test the SPHQ against validated generic instruments (study 2). METHODS: From the 270 women included in study 1, 181 participants were subjected to three 45-minute walking sessions per week at 60% of their heart rate reserve, whereas 58 women remained inactive for 4 months. Perceived health assessed through the SPHQ, body composition, and CRF were determined before and after the 4-month study period. Another sample of 20 women was selected to validate the SPHQ (study 2). RESULTS: Despite a lack of between-group differences in the amelioration of four perceived health items, ideal weight and stress level were improved in women subjected to our walking program exclusively (P < 0.0001). Improved perceived healthy balanced diet was positively correlated to fat mass reduction in the walking group (r = 0.15; P < 0.05) only (study 1). The SPHQ shows good reproducibility for five of six items (intraclass correlation coefficients ranging from 0.77 to 0.89; P < 0.0001), and three of them were validated against generic tools (0.45 < r < 0.54; P < 0.05; study 2). CONCLUSIONS: Additional studies are needed to more accurately determine the relationships between changes in perceived health and changes in body fatness and/or CRF after endurance training and to continue the validation of the SPHQ.

Fine-mapping, gene expression and splicing analysis of the disease associated LRRK2 locus.

Association studies have identified several signals at the LRRK2 locus for Parkinson's disease (PD), Crohn's disease (CD) and leprosy. However, little is known about the molecular mechanisms mediating these effects. To further characterize this locus, we fine-mapped the risk association in 5,802 PD and 5,556 controls using a dense genotyping array (ImmunoChip). Using samples from 134 post-mortem control adult human brains (UK Human Brain Expression Consortium), where up to ten brain regions were available per individual, we studied the regional variation, splicing and regulation of LRRK2. We found convincing evidence for a common variant PD association located outside of the LRRK2 protein coding region (rs117762348, A>G, P = 2.56×10(-8), case/control MAF 0.083/0.074, odds ratio 0.86 for the minor allele with 95% confidence interval [0.80-0.91]). We show that mRNA expression levels are highest in cortical regions and lowest in cerebellum. We find an exon quantitative trait locus (QTL) in brain samples that localizes to exons 32-33 and investigate the molecular basis of this eQTL using RNA-Seq data in n = 8 brain samples. The genotype underlying this eQTL is in strong linkage disequilibrium with the CD associated non-synonymous SNP rs3761863 (M2397T). We found two additional QTLs in liver and monocyte samples but none of these explained the common variant PD association at rs117762348. Our results characterize the LRRK2 locus, and highlight the importance and difficulties of fine-mapping and integration of multiple datasets to delineate pathogenic variants and thus develop an understanding of disease mechanisms.

A candidate gene study of the type I interferon pathway implicates IKBKE and IL8 as risk loci for SLE.

Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease in which the type I interferon pathway has a crucial role. We have previously shown that three genes in this pathway, IRF5, TYK2 and STAT4, are strongly associated with risk for SLE. Here, we investigated 78 genes involved in the type I interferon pathway to identify additional SLE susceptibility loci. First, we genotyped 896 single-nucleotide polymorphisms in these 78 genes and 14 other candidate genes in 482 Swedish SLE patients and 536 controls. Genes with P<0.01 in the initial screen were then followed up in 344 additional Swedish patients and 1299 controls. SNPs in the IKBKE, TANK, STAT1, IL8 and TRAF6 genes gave nominal signals of association with SLE in this extended Swedish cohort. To replicate these findings we extracted data from a genomewide association study on SLE performed in a US cohort. Combined analysis of the Swedish and US data, comprising a total of 2136 cases and 9694 controls, implicates IKBKE and IL8 as SLE susceptibility loci (P(meta)=0.00010 and P(meta)=0.00040, respectively). STAT1 was also associated with SLE in this cohort (P(meta)=3.3 × 10⁻5), but this association signal appears to be dependent of that previously reported for the neighbouring STAT4 gene. Our study suggests additional genes from the type I interferon system in SLE, and highlights genes in this pathway for further functional analysis.

Influence of a walking program on the metabolic risk profile of obese postmenopausal women.

OBJECTIVE: Menopause transition is associated with an increased prevalence of metabolic syndrome (MS), which may partly explain the higher coronary heart disease risk. The aim of this study was to examine the impact of a 16-week walking program on the metabolic risk profile of women 50 to 65 years old whose body mass index ranged from 29 to 35 kg/m. METHODS: A total of 153 postmenopausal women were subjected to three sessions per week of 45-minutes of walking at 60% of their heart rate reserve. At baseline, 46 and 84 women were characterized by one and two or more determinants of MS, respectively, whereas 23 women did not show this condition. Body composition, resting blood pressure, fasting lipid-lipoprotein profile, and cardiorespiratory fitness (CRF) were measured before and after exercise. RESULTS: In the whole sample of 153 women, CRF estimated by V(O2max) increased in response to walking (P < 0.0001). Endurance training promoted body weight and fat mass losses and reduced waist girth and blood pressure, whereas it decreased plasma triglyceride, cholesterol, and low-density lipoprotein cholesterol levels and increased high-density lipoprotein cholesterol concentrations (P < 0.0001). Improvements in lipid-lipoprotein levels were not associated with increases in CRF but seemed to be dependent on reduced body fatness. However, the greatest ameliorations in metabolic risk profile were found in women characterized by two or more determinants of MS at baseline than in the two other groups (0.05 < P < 0.0001). CONCLUSION: A moderate-intensity physical activity is thus sufficient to reduce the metabolic risk profile of postmenopausal women characterized by the presence of one or several clinical features of MS but without overt coronary heart disease.

Association of the X-chromosomal genes TIMP1 and IL9R with rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is an inflammatory joint disease with features of an autoimmune disease with female predominance. Candidate genes located on the X-chromosome were selected for a family trio-based association study. METHODS: A total of 1452 individuals belonging to 3 different sample sets were genotyped for 16 single-nucleotide polymorphisms (SNP) in 7 genes. The first 2 sets consisted of 100 family trios, each of French Caucasian origin, and the third of 284 additional family trios of European Caucasian origin. Subgroups were analyzed according to sex of patient and presence of anti-cyclic citrullinated peptide (anti-CCP) autoantibodies. RESULTS: Four SNP were associated with RA in the first sample set and were genotyped in the second set. In combined analysis of sets 1 and 2, evidence remained for association of 3 SNP in the genes UBA1, TIMP1, and IL9R. These were again genotyped in the third sample set. Two SNP were associated with RA in the joint analysis of all samples: rs6520278 (TIMP1) was associated with RA in general (p = 0.035) and rs3093457 (IL9R) with anti-CCP-positive RA patients (p = 0.037) and male RA patients (p = 0.010). A comparison of the results with data from whole-genome association studies further supports an association of RA with TIMPL The sex-specific association of rs3093457 (IL9R) was supported by the observation that men homozygous for rs3093457-CC are at a significantly higher risk to develop RA than women (risk ratio male/female = 2.98; p = 0.048). CONCLUSION: We provide evidence for an association of at least 2 X-chromosomal genes with RA: TIMP1 (rs6520278) and IL9R (rs3093457).