To identify susceptibility alleles associated with rheumatoid arthritis, we genotyped 397 individuals with rheumatoid arthritis for 116,204 SNPs and carried out an association analysis in comparison to publicly available genotype data for 1,211 related individuals from the Framingham Heart Study 1 . After evaluating and adjusting for technical and population biases, we identified a SNP at 6q23 (rs10499194, ∼150 kb from TNFAIP3 and OLIG3) that was reproducibly associated with rheumatoid arthritis both in the genome-wide association (GWA) scan and in 5,541 additional case-control samples (P = 10 −3 , GWA scan; P < 10 −6 , replication; P = 10 −9 , combined). In a concurrent study, the Wellcome Trust Case Control Consortium (WTCCC) has reported strong association of rheumatoid arthritis susceptibility to a different SNP located 3.8 kb from rs10499194 (rs6920220; P = 5 × 10 −6 in WTCCC) 2 . We show that these two SNP associations are statistically independent, are each reproducible in the comparison of our data and WTCCC data, and define risk and protective haplotypes for rheumatoid arthritis at 6q23.Rheumatoid arthritis is the most common inflammatory arthritis, affecting up to 1% of the adult population 3 . Two loci (HLA-DRB14 and PTPN22 5 ) have previously been associated with rheumatoid arthritis susceptibility in individuals with circulating antibodies to cyclic citrullinated peptides (CCP). Most of the inheritance of rheumatoid arthritis remains unexplained.To identify additional common variants associated with risk of CCP antibody-associated (CCP + ) rheumatoid arthritis, we conducted a GWA study using the Affymetrix 100K GeneChip microarray in a longitudinal case series of individuals with CCP + rheumatoid arthritis (the Brigham Rheumatoid Arthritis Sequential Study (BRASS) cohort). As we lacked epidemiologically matched controls, we compared case data to publicly available genotype data collected using the same platform from 1,211 related Framingham Heart Study (FHS) participants 1 , drawn from the same geographical region as the individuals in our study (near Boston, Massachusetts, USA).Before comparing allele frequencies between cases and controls, we considered biases that may be introduced by the use of shared controls. Such biases, whether due to nonrandom distribution of technical artifacts 6 or to population differences between case and control data 7,8 , would result in a non-null distribution of test statistics with excess false-positive associations. In an initial analysis of unrelated case-control samples, we assessed the median distribution of test statistics with the genomic-control parameter λ GC 9 (where 1.0 indicates no inflation) and examined the tail of the distribution of association statistics in a comparison of observed and expected P values (Q-Q plot; Fig. 1).Using published data quality control parameters from early studies on this genotyping platform (genotype call rates > 90%, minor allele frequency (MAF) >5%) 1 , we observed λ GC = 1.19 and an excess of associations in the e...
Although the neurological injury associated with cerebral palsy (CP) is non‐progressive, adults with the disorder often develop musculoskeletal and neurological symptoms, such as severe pain, chronic fatigue, and a premature decline in mobility and function, as they age. Little is known about how to manage, much less prevent, these symptoms. This paper summarizes the findings of a multi‐disciplinary workshop, sponsored by the Cerebral Palsy International Research Foundation, the American Academy for Cerebral Palsy and Developmental Medicine, and Reaching for the Stars, convened to review current knowledge and begin to develop a blueprint for future research. The goals of the workshop were to (1) define the current incidence and prevalence of CP, (2) review the known complications for persons aging with CP, (3) review current understanding of physiological processes that may contribute to loss of function and premature aging in CP, (4) evaluate current treatment interventions in terms of long‐term outcomes, (5) identify cutting‐edge technologies in neurorehabilitation that may help prevent or treat the effects of accelerated aging for persons diagnosed with CP, and (6) identify strategies to ensure that individuals with CP receive evidence‐based care as they transition from pediatric to adult‐care services.
Background: HLA-DRB1 shared epitope (HLA-SE), PTPN22 and CTLA4 alleles are associated with cyclic citrullinated peptide (CCP) and rheumatoid arthritis (RA). Objective: We examined associations between HLA-SE, PTPN22, CTLA4 genotypes and RA phenotypes in a large cohort to (a) replicate prior associations with CCP status, and (b) determine associations with radiographic erosions and age of diagnosis. Methods: A total of 689 RA patients from the Brigham RA Sequential Study (BRASS) were genotyped for HLA-SE, PTPN22 (rs2476601) and CTLA4 (rs3087243). Association between genotypes and CCP, rheumatoid factor (RF) erosive phenotypes and age at diagnosis were assessed with multivariable models adjusting for age, sex and disease duration. Novel causal pathway analysis was used to test the hypothesis that genetic risk factors and CCP are in the causal pathway for predicting erosions. Results: In multivariable analysis, presence of any HLA-SE was strongly associated with CCP+ (odds ratio (OR) 3.05, 95% CI 2.18-4.25), and RF+ (OR 2.53, 95% CI 1.83-3.5) phenotypes; presence of any PTPN22 T allele was associated with CCP+ (OR 1.81, 95% CI 1.24-2.66) and RF+ phenotypes (OR 1.84, 95% CI 1.27-2.66). CTLA4 was not associated with CCP or RF phenotypes. While HLA-SE was associated with erosive RA phenotype (OR 1.52, 95% CI 1.01-2.17), this was no longer significant after conditioning on CCP. PTPN22 and CTLA4 were not associated with erosive phenotype. Presence of any HLA-SE was associated with an average 3.6 years earlier diagnosis compared with absence of HLA-SE (41.3 vs 44.9 years, p = 0.002) and PTPN22 was associated with a 4.2 years earlier age of diagnosis (39.5 vs 43.6 years, p = 0.002). CTLA4 genotypes were not associated with age at diagnosis of RA. Conclusions: In this large clinical cohort, we replicated the association between HLA-SE and PTPN22, but not CTLA4 with CCP+ and RF+ phenotypes. We also found evidence for associations between HLA-SE, and PTPN22 and earlier age at diagnosis. Since HLA-SE is associated with erosive phenotype in unconditional analysis, but is not significant after conditioning on CCP, this suggests that CCP is in the causal pathway for predicting erosive phenotype.Genetic factors are thought to be responsible for up to 50%-60% of rheumatoid arthritis (RA) risk.
Disease prevention models have shown individuals are more likely to engage in precautionary behavior if they have confidence in their ability to identify disease symptoms and understand health risks. In immigrant populations, communicating the risks poses greater challenges since linguistic and cultural barriers may impede acceptance of the new behavior. The Brazilian population on Martha's Vineyard, Massachusetts, is at high risk for Lyme disease (LD), the most common vector-borne illness in the United States largely preventable by limiting tick exposure. We surveyed 103 Brazilians on MV about their health beliefs and perceptions of LD risk and assessed their level of precautionary behaviors and the cultural factors influencing them. The population had only a moderate perception of risk and little understanding of LD. Forty-one percent did not think LD posed a risk, while 79% were not sure they could recognize symptoms. Accordingly, the population as a whole reported taking few precautions.
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