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Primary sclerosing cholangitis (PSC) is a chronic bile duct disease affecting 2.4–7.5% of individuals with inflammatory bowel disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10−16 and P = 4.1 × 10−8, respectively).

The parity-odd perturbation operator for the inelastic electron-nucleon scattering by weak neutral currents ͑exchange of virtual Z 0 bosons͒ has been implemented into a fully relativistic four-component Dirac-Hartree-Fock scheme. Dirac-Hartree-Fock electronic structure calculations on H 2 O 2 , H 2 S 2 , H 2 Se 2 , H 2 Te 2 , and H 2 Po 2 provides a demonstration of the higher than Z 5 scaling of the parity-violating energy shift (Z is the nuclear charge͒ in chiral molecules. To our knowledge, the calculations for H 2 Te 2 and H 2 Po 2 are the first for molecules containing heavy elements from period 5 or 6 of the Periodic Table, and the parity-violating energy shifts are some of the highest reported in any ab initio study. It has been shown that special care is needed in the basis set expansion of the wave function because of the coupling between the large and small components of the Dirac wave function through the ␥ 5 matrix. Estimates of the remaining errors in the calculations have been given. A comparison with the calculated parity-violating energy shift of H 2 TeO have confirmed the importance of the single-center theorem, which states that the parity-violating energy shift is suppressed in molecules containing only a single heavy atomic center. Due to the close correspondence between parity-violating energy shifts and observable parity-odd properties, our results have important consequences for the current search for an experimental confirmation of parity-odd effects in molecular physics: ͑i͒ The experiments should be performed on molecules containing heavy ͑period 5 or 6͒ elements. ͑ii͒ Molecules with more than one heavy atomic center will be extremely favorable due to the single-center theorem. ͓S1050-2947͑99͒03712-9͔

Background & Aims A limited number of genetic risk factors have been reported in primary sclerosing cholangitis (PSC). To discover further genetic susceptibility factors for PSC, we followed up on a second tier of single nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS). Methods We analyzed 45 SNPs in 1221 PSC cases and 3508 controls. The association results from the replication analysis and the original GWAS (715 PSC cases and 2962 controls) were combined in a meta-analysis comprising 1936 PSC cases and 6470 controls. We performed an analysis of bile microbial community composition in 39 PSC patients by 16S rRNA sequencing. Results Seventeen SNPs representing 12 distinct genetic loci achieved nominal significance (Preplication<0.05) in the replication. The most robust novel association was detected at chromosome 1p36 (rs3748816; Pcombined=2.1×10−8) where the MMEL1 and TNFRSF14 genes represent potential disease genes. Eight additional novel loci showed suggestive evidence of association (Prepl<0.05). FUT2 at chromosome 19q13 (rs602662; Pcomb=1.9×10−6, rs281377; Pcomb = 2.1×10−6 and rs601338; Pcomb=2.7×10−6) is notable due to its implication in altered susceptibility to infectious agents. We found that FUT2 secretor status and genotype defined by rs601338 significantly influences biliary microbial community composition in PSC patients. Conclusions We identify multiple new PSC risk loci by extended analysis of a PSC GWAS. FUT2 genotype needs to be taken into account when assessing the influence from microbiota on biliary pathology in PSC.

Endogenous DNA damage induced by hydrolysis, reactive oxygen species and alkylation modifies DNA bases and the structure of the DNA duplex. Numerous mechanisms have evolved to protect cells from these deleterious effects. Base excision repair is the major pathway for removing base lesions. However, several mechanisms of direct base damage reversal, involving enzymes such as transferases, photolyases and oxidative demethylases, are specialized to remove certain types of photoproducts and alkylated bases. Mismatch excision repair corrects for misincorporation of bases by replicative DNA polymerases. The determination of the 3D structure and visualization of DNA repair proteins and their interactions with damaged DNA have considerably aided our understanding of the molecular basis for DNA base lesion repair and genome stability. Here, we review the structural biochemistry of base lesion recognition and initiation of one-step direct reversal (DR) of damage as well as the multistep pathways of base excision repair (BER), nucleotide incision repair (NIR) and mismatch repair (MMR).

Fully relativistic four-component electronic structure ab initio calculations including neutral current corrections are reported for a number of small chiral molecules that are of interest in the experimental search for differences in the vibrational spectra of the two enantiomers of handed molecules. The largest vibrational energy differences, of the order 0.2 Hz, are found in chiral methane derivatives which include an iodine substituent. The vibrational energy differences in CHBrClF are 7 and 2 mHz for the carbon-chlorine and carbon-fluorine stretching modes, respectively, which are 3 to 4 orders of magnitude smaller than the precision reported in recent experiments.

Approximately 60%-80% of patients with primary sclerosing cholangitis (PSC) have concurrent ulcerative colitis (UC). Previous genome-wide association studies (GWAS) in PSC have detected a number of susceptibility loci that also show associations in UC and other immune-mediated diseases. We aimed to systematically compare genetic associations in PSC with genotype data in UC patients with the aim of detecting new susceptibility loci for PSC. We performed combined analyses of GWAS for PSC and UC comprising 392 PSC cases, 987 UC cases, and 2,977 controls and followed up top association signals in an additional 1,012 PSC cases, 4,444 UC cases, and 11,659 controls. We discovered novel genome-wide significant associations with PSC at 2q37 [rs3749171 at G-protein-coupled receptor 35 (GPR35); P 5 3.0 3 10 29 in the overall study population, combined odds ratio [OR] and 95% confidence interval [CI] of 1.39 (1.24-1.55)] and at 18q21 [rs1452787 at transcription factor 4 (TCF4); P 5 2.61 3 10 28, OR (95% CI) 5 0.75 (0.68-0.83)]. In addition, several suggestive PSC associations were detected. The GPR35 rs3749171 is a missense single nucleotide polymorphism resulting in a shift from threonine to methionine. Structural modeling showed that rs3749171 is located in the third transmembrane helix of GPR35 and could possibly alter efficiency of signaling through the GPR35 receptor. Conclusion: By refining the analysis of a PSC GWAS by parallel assessments in a UC GWAS, we were able to detect two novel risk loci at genome-wide significance levels. GPR35 shows associations in both UC and PSC, whereas TCF4 represents a PSC risk locus not associated with UC. Both loci may represent previously unexplored aspects of PSC pathogenesis. (HEPATOLOGY 2013;58:1074-1083 Abbreviations: CARD9, caspase-recruitment domain family, member 9; CI, confidence interval; CON1/2, control panel 1/2; GPR35, G-protein-coupled receptor