New insights into the chemical and isotopic composition of human-body biominerals. I: Cholesterol gallstones from England and Greece.

We have analyzed gallstones from four patients of Europe and particularly from England (including samples from a mother and a daughter) and Greece. According to the XRD, FTIR, NMR and laser micro-Raman results the studied materials correspond to typical cholesterol monohydrate (ChM). The micro-morphology of cholesterol microcrystals was investigated by means of SEM-EDS. The XRF results revealed that Ca is the dominant non-organic metal in all gallstones (up to ∼1.95wt.%) together with Fe, Cu, Pb and Ni (up to ~19ppm for each metal). Gallstones from England contain additional Mn (up to ~87ppm) and Zn (up to ∼6ppm) while the sample of the mother contains negligible Zn and Mn, compared to that of her daughter, but significant As (~4.5ppm). All cholesterol gallstones examined are well enriched in potentially toxic metals (Pb, as well as Ni in one case) and metalloids (As also in one case) as compared to the global average. The position of Zn, which is a characteristic biometal, in the structure of cholesterol, was investigated by molecular simulation using the Accelrys Materials Studio(®) software. On the basis of IRMS results, all gallstones examined exhibit a very light δ(13)C signature (average δ(13)C ~-24‰ PDB). Gamma-ray spectrometry measurements indicate the presence of (214)Pb and (214)Bi natural radionuclides due to the (238)U series as well as an additional amount of (40)K.

Evaluation of the rheumatoid arthritis susceptibility loci HLA-DRB1, PTPN22, OLIG3/TNFAIP3, STAT4 and TRAF1/C5 in an inception cohort.

INTRODUCTION: This study investigated five confirmed rheumatoid arthritis (RA) susceptibility genes/loci (HLA-DRB1, PTPN22, STAT4, OLIG3/TNFAIP3 and TRAF1/C5) for association with susceptibility and severity in an inception cohort. METHODS: The magnitude of association for each genotype was assessed in 1,046 RA subjects from the Yorkshire Early RA cohort and in 5,968 healthy UK controls. Additional exploratory subanalyses were undertaken in subgroups defined by autoantibody status (rheumatoid factor and anti-cyclic citrullinated peptide) or disease severity (baseline articular erosions, Health Assessment Questionnaire (HAQ) score and swollen joint count (SJC)). RESULTS: In the total RA inception cohort, the HLA-DRB1 shared epitope (per-allele odds ratio (OR) = 2.1, trend P < 0.0001), PTPN22 (per-allele OR = 1.5, trend P < 0.0001), OLIG3/TNFAIP3 locus (per-allele OR = 1.2, trend P = 0.009) and TRAF1/C5 locus (per-allele OR = 1.1, trend P = 0.04) were associated with RA. The magnitude of association for these loci was increased in those patients who were autoantibody-positive. PTPN22 was associated with autoantibody-negative RA (per-allele OR = 1.3, trend P = 0.04). There was no evidence of association between these five genetic loci and baseline erosions or SJC in the total RA cohort, after adjustment for symptom duration. TRAF1/C5 was significantly associated with baseline HAQ, however, following adjustment for symptom duration (P trend = 0.03). CONCLUSIONS: These findings support the mounting evidence that different genetic loci are associated with autoantibody-positive and autoantibody-negative RA, possibly suggesting that many of the genes identified to date are associated with autoantibody production. Additional studies with a specific focus on autoantibody-negative RA will be needed to identify the genes predisposing to this RA subgroup. The TRAF1/C5 locus in particular warrants further investigation in RA as a potential disease severity locus.

The shared epitope hypothesis in rheumatoid arthritis: evaluation of alternative classification criteria in a large UK Caucasian cohort.

OBJECTIVE: Many classification systems for the HLA-DRB1 allelic association with rheumatoid arthritis (RA) have been reported, but few have been validated in additional populations. We sought to evaluate 3 different DRB1 allele classification systems in a large cohort of Caucasian RA patients and control subjects in the UK. METHODS: HLA-DRB1 typing was undertaken in 1,325 Caucasian RA patients and 462 healthy Caucasian controls who were residents of the UK. Logistic regression analyses were performed to investigate the different classification systems. RESULTS: We confirmed the association between the susceptibility alleles S2 and S3P, as proposed by Tezenas du Montcel, and the presence of RA in UK Caucasians. A significant hierarchy of risk was observed within the S3P allele group. There was no evidence of a significant association between DRB1*1001 and RA. Our data did not support the hypothesis that an isoleucine at position 67 conferred protection against RA, other than in contrast to the susceptibility alleles. However, the presence of an aspartic acid at amino acid 70 did appear to confer some degree of protection. CONCLUSION: We were unable to fully substantiate any of the 3 recent revisions of the shared epitope hypothesis in this large cohort of Caucasian RA patients and control subjects in the UK. This reinforces the importance of evaluating disease susceptibility alleles in different Caucasian populations as well as in other ethnic groups. In particular, it will be important to clarify the precise DRB1 association in a given population before DRB1 genotyping is incorporated into clinical diagnostic or treatment algorithms.