Nancy E. Maher

Two independent alleles at 6q23 associated with risk of rheumatoid arthritis

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. 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). 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.

Genome-wide scan for Parkinson's disease: The Gene PD Study

Article abstract— A genome-wide scan for idiopathic PD in a sample of 113 PD-affected sibling pairs is reported. Suggestive evidence for linkage was found for chromosomes 1 (214 cM, lod = 1.20), 9 (136 cM, lod = 1.30), 10 (88 cM, lod = 1.07), and 16 (114 cM, lod = 0.93). The chromosome 9 region overlaps the genes for dopamine β-hydroxylase and torsion dystonia. Although no strong evidence for linkage was found for any locus, these results may be of value in comparison with similar studies by others.

PARK3 Influences Age at Onset in Parkinson Disease: A Genome Scan in the GenePD Study

Parkinson disease (PD) is a late-onset neurodegenerative disorder. The mean age at onset is 61 years, but the disease can range from juvenile cases to cases in the 8th or 9th decade of life. The parkin gene on chromosome 6q and loci on chromosome 1p35-36 and 1p36 are responsible for some cases of autosomal recessive early-onset parkinsonism, but they do not appear to influence susceptibility or variability of age at onset for idiopathic PD. We have performed a genomewide linkage analysis using variance-component methodology to identify genes influencing age at onset of PD in a population of affected relatives (mainly affected sibling pairs) participating in the GenePD study. Four chromosomal loci showed suggestive evidence of linkage: chromosome 2p (maximum multipoint LOD [MaxLOD] = 2.08), chromosome 9q (MaxLOD = 2.00), chromosome 20 (MaxLOD = 1.82), and chromosome 21 (MaxLOD = 2.21). The 2p and 9q locations that we report here have previously been reported as loci influencing PD affection status. Association between PD age at onset and allele 174 of marker D2S1394, located on 2p13, was observed in the GenePD sample (P=.02). This 174 allele is common to the PD haplotype observed in two families that show linkage to PARK3 and have autosomal dominant PD, which suggests that this allele may be in linkage disequilibrium with a mutation influencing PD susceptibility or age at onset of PD.

Epidemiologic study of 203 sibling pairs with Parkinson’s disease: The GenePD study

Objective: To examine patterns of familial aggregation and factors influencing onset age in a sample of siblings with PD. Methods: Sibling pairs (n = 203) with PD were collected as part of the GenePD study. Standardized family history, medical history, and risk factor data were collected and analyzed. Results: The mean age at onset was 61.4 years and did not differ according to sex, exposure to coffee, alcohol, or pesticides. Head trauma was associated with younger onset (p = 0.03) and multivitamin use with later onset (p = 0.007). Age at onset correlation between sibling pairs was significant (r = 0.56, p = 0.001) and was larger than the correlation in year of onset (r = 0.29). The mean difference in onset age between siblings was 8.7 years (range, 0 to 30 years). Female sex was associated with increased frequency of relatives with PD. The frequency of affected parents (7.0%) and siblings (5.1%) was increased when compared with frequency in spouses (2.0%). Conclusions: The greater similarity for age at onset than for year of onset in sibling pairs with PD, together with increased risk for biological relatives over spouses of cases, supports a genetic component for PD. Risk to siblings in this series is increased over that seen in random series of PD cases; however, patients in this sample have similar ages at onset and sex distribution as seen for PD generally. These analyses suggest that factors influencing penetrance are critical to the understanding of this disease.

Associations between Human leukocyte antigen, PTPN22, CTLA4 genotypes and rheumatoid arthritis phenotypes of autoantibody status, age at diagnosis and erosions in a large cohort study

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.

Hand bone mineral density is associated with both total hip and lumbar spine bone mineral density in post-menopausal women with RA

OBJECTIVE RA is associated with localized bone loss in the hands, as well as generalized osteoporosis. We evaluated the relationship between hand digital X-ray radiogrammetry BMD (DXR-BMD) and total hip and lumbar spine BMD. METHODS We conducted a cross-sectional study of 138 post-menopausal women with RA. The DXR-BMD was calculated based on digitized hand radiographs. Measurements of the total hip and lumbar spine BMD were performed by a DXA-BMD (BMDa) scan. Patient and physician questionnaires and laboratory samples supplied information on relevant covariates. Separate multivariate linear regression models were constructed to determine the cross-sectional relationship between hand DXR-BMD (independent variable) and total hip or lumbar spine BMD (dependent variables). RESULTS The cohort comprised women with a median age of 61 years and RA disease duration of 13 years. Seventy-six per cent were either RF and/or anti-cyclic citrullinated peptide (anti-CCP) positive and most had moderate disease activity [median disease activity score-28 joint count (DAS28) 3.7]. Hand DXR-BMD was significantly associated with total hip BMD (beta = 0.61; P < 0.0001) and lumbar spine BMD (beta = 0.62; P < 0.0008) in adjusted models. CONCLUSIONS This study suggests that hand DXR-BMD is associated with both the total hip and lumbar spine BMD among post-menopausal women with RA. The relationship between bone loss in the hands and generalized osteoporosis should be further explored in longitudinal studies of patients with RA.

Opposing effects of the D70 mutation and the shared epitope in HLA-DR4 on disease activity and certain disease phenotypes in rheumatoid arthritis

Background: Certain sequences present in the hypervariable region of human leucocyte antigen (HLA)-DRB1 known as the shared epitope (SE) are hypothesised to increase the risk of rheumatoid arthritis (RA), whereas alleles encoding aspartic acid at position 70 (D70 alleles) may have a protective effect. Methods: Patient HLA-DRB1 serotypes were assessed and the genotypes encoding the SE motif or the putatively protective D70 motif identified in a large RA cohort. Logistic regression was used to analyse associations of genotype with presence of disease, comorbidities and disease severity, and association between genotype and change in disease activity over time. Results: The 689 patients enrolled had a mean (SD) age of 57.9 (13.7) years and mean (SD) disease duration of 15.3 (12.7) years. In a comparison with 482 ethnicity matched population-based controls, the D70 sequence exerted a strong protective effect (OR = 0.52, p<0.001) that remained significant when the SE at the same locus was accounted for (OR = 0.72, 95% CI 0.60 to 0.86, p<0.001). The SE assessed on all HLA-DRB1 serotypic backgrounds except DR1 was associated with RA susceptibility (additive OR = 2.43, p<0.001). Associations were found between SE and serum levels of rheumatoid factor (p<0.001, with correlation of 0.18) and anti-cyclic citrullinated peptide antibodies (p<0.001, with correlation of 0.25) but not with serum C-reactive protein. Conclusion: The D70 allele has a significant protective effect that is mitigated but still significant when the risk effect of the SE at the same locus is taken into account. The presence of the SE on DR4 is associated with greater RA susceptibility and certain disease-activity measures.

Behavioral and Attitudes Survey About Lyme Disease Among a Brazilian Population in the Endemic Area of Martha’s Vineyard, Massachusetts

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.

Anti-superoxide dismutase antibodies are associated with survival in patients with sporadic amyotrophic lateral sclerosis

Abstract Our objective was to test the hypothesis that aberrantly modified forms of superoxide dismutase (SOD1) influence the disease course for sporadic amyotrophic lateral sclerosis (SALS). We probed for anti-SOD1 antibodies (IgM and IgG) against both the normal and aberrantly oxidized-SOD1 (SODox) antigens in sera from patients with SALS, subjects diagnosed with other neurological disorders and healthy individuals, and correlated the levels of these antibodies to disease duration and/or severity. Anti-SOD1 antibodies were detected in all cohorts; however, a subset of ∼5–10% of SALS cases exhibited elevated levels of anti-SOD1 antibodies. Those SALS cases with relatively high levels of IgM antibodies against SODox exhibit a longer survival of 6.4 years, compared to subjects lacking these antibodies. By contrast, SALS subjects expressing higher levels of IgG antibodies reactive for the normal WT-SOD1 antigen exhibit a shorter survival of 4.1 years. Anti-SOD1 antibody levels did not correlate with disease severity in either the Alzheimers or Parkinsons disease cohorts. In conclusion, the association of longer survival with elevated levels of anti-SODox antibodies suggests that these antibodies may be protective. By extension, these data implicate aberrantly modified forms of WT-SOD1 (e.g. oxidized SOD1) in SALS pathogenesis. In contrast, an immune response against the normal WT-SOD1 appears to be disadvantageous in SALS, possibly because the anti-oxidizing activity of normal WT-SOD1 is beneficial to SALS individuals.

Association of SNCA with Parkinson: replication in the Harvard NeuroDiscovery Center Biomarker Study

Mutations in the α‐synuclein gene (SNCA) cause autosomal dominant forms of Parkinsons disease, but the substantial risk conferred by this locus to the common sporadic disease has only recently emerged from genome‐wide association studies.