Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis

We genotyped 2,861 cases of primary biliary cirrhosis (PBC) from the UK PBC Consortium and 8,514 UK population controls across 196,524 variants within 186 known autoimmune risk loci. We identified 3 loci newly associated with PBC (at P <5 × 10(-8)), increasing the number of known susceptibility loci to 25. The most associated variant at 19p12 is a low-frequency nonsynonymous SNP in TYK2, further implicating JAK-STAT and cytokine signaling in disease pathogenesis. An additional five loci contained nonsynonymous variants in high linkage disequilibrium (LD; r(2) > 0.8) with the most associated variant at the locus. We found multiple independent common, low-frequency and rare variant association signals at five loci. Of the 26 independent non-human leukocyte antigen (HLA) signals tagged on the Immunochip, 15 have SNPs in B-lymphoblastoid open chromatin regions in high LD (r(2) > 0.8) with the most associated variant. This study shows how data from dense fine-mapping arrays coupled with functional genomic data can be used to identify candidate causal variants for functional follow-up.

Improved prognosis for congenital nephrotic syndrome of the Finnish type in Irish families

Congenital nephrotic syndrome of the Finnish type is a rare autosomal recessive disease with a high infant mortality without aggressive treatment. The biochemical basis of the disease is not understood fully but the disease locus has been mapped recently to chromosome 19q12-q13.1 in Finnish families. This paper describes the clinical features and outcome of 20 patients in Ireland with congenital nephrotic syndrome of the Finnish type who have presented since 1980. Before 1987, all infants died by the age of 3 years. After the introduction of daily intravenous albumin infusion, nutritional support, elective bilateral nephrectomy, and renal transplantation, mortality in the past decade has fallen to 30%, with no deaths in the past five years. Genetic linkage analysis was performed in six families in whom DNA was available and the locus responsible was mapped to the same region on chromosome 19 as in Finnish families, suggesting that Irish families share the same disease locus.

Possible association between CTLA4 DNA polymorphisms and early onset type 1 diabetes in a UK population

Linkage and association has been reported between CTLA4 DNA markers and susceptibility to type 1 diabetes in some populations, but not others. We performed case-control and family-based association studies to assess if the CTLA4 A49G and intron 1 C/T polymorphisms were associated with development of early onset type 1 diabetes in the Northern Ireland population. The distribution of A49G and C/T alleles in cases (n = 144) was similar to those observed in controls (n = 307). In contrast, significant distortions in allele transmissions from informative parents to probands were observed for both the A49G (P = 0.02) and C/T (P = 0.01) polymorphisms employing 297 nuclear families. Our results suggest that the CTLA4 gene may play a minor role in the overall genetic predisposition to type 1 diabetes in this UK population.

Measuring party organization: The vertical dimension of the multilevel organization of statewide parties in Spain and the UK

Over the past few years, attention to the role of state-wide political parties in multi-level polities has increased in recognition of their linkage function between levels of government, as these parties compete in both state-wide and regional elections across their countries. This article presents a coding scheme designed to describe the relationship between central and regional levels of state-wide parties. It evaluates the involvement of the regional branches in central decision-making and their degree of autonomy in the management of regional party affairs. This coding scheme is applied to state-wide parties in Spain (the socialist PSOE and the conservative Partido Popular) and in the UK (Labour, the Conservatives and the Liberal Democrats). It is an additional tool with which to analyse party organization and it facilitates the comparison of parties across regions and in different countries.

Design, recruitment, logistics, and data management of the GEHA (Genetics of Healthy Ageing) project

In 2004, the integrated European project GEHA (Genetics of Healthy Ageing) was initiated with the aim of identifying genes involved in healthy ageing and longevity. The first step in the project was the recruitment of more than 2500 pairs of siblings aged 90 years or more together with one younger control person from 15 areas in 11 European countries through a coordinated and standardised effort. A biological sample, preferably a blood sample, was collected from each participant, and basic physical and cognitive measures were obtained together with information about health, life style, and family composition. From 2004 to 2008 a total of 2535 families comprising 5319 nonagenarian siblings were identified and included in the project. In addition, 2548 younger control persons aged 50-75 years were recruited. A total of 2249 complete trios with blood samples from at least two old siblings and the younger control were formed and are available for genetic analyses (e.g. linkage studies and genome-wide association studies). Mortality follow-up improves the possibility of identifying families with the most extreme longevity phenotypes. With a mean follow-up time of 3.7 years the number of families with all participating siblings aged 95 years or more has increased by a factor of 5 to 750 families compared to when interviews were conducted. Thus, the GEHA project represents a unique source in the search for genes related to healthy ageing and longevity.

Investigation of Genetic Variation in Scavenger Receptor Class B, Member 1 (SCARB1) and Association with Serum Carotenoids

Objective: To investigate association of scavenger receptor class B, member 1 (SCARB1) genetic variants with serum carotenoid levels of lutein (L) and zeaxanthin (Z) and macular pigment optical density (MPOD).
Design: A cross-sectional study of healthy adults aged 20 to 70.
Participants: We recruited 302 participants after local advertisement.
Methods: We measured MPOD by customized heterochromatic flicker photometry. Fasting blood samples were taken for serum L and Z measurement by high-performance liquid chromatography and lipoprotein analysis by spectrophotometric assay. Forty-seven single nucleotide polymorphisms (SNPs) across SCARB1 were genotyped using Sequenom technology. Association analyses were performed using PLINK to compare allele and haplotype means, with adjustment for potential confounding and correction for multiple comparisons by permutation testing. Replication analysis was performed in the TwinsUK and Carotenoids in Age-Related Eye Disease Study (CAREDS) cohorts.
Main Outcome Measures: Odds ratios for MPOD area, serum L and Z concentrations associated with genetic variations in SCARB1 and interactions between SCARB1 and gender.
Results: After multiple regression analysis with adjustment for age, body mass index, gender, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, smoking, and dietary L and Z levels, 5 SNPs were significantly associated with serum L concentration and 1 SNP with MPOD (P<0.01). Only the association between rs11057841 and serum L withstood correction for multiple comparisons by permutation testing (P<0.01) and replicated in the TwinsUK cohort (P = 0.014). Independent replication was also observed in the CAREDS cohort with rs10846744 (P = 2×10-4), an SNP in high linkage disequilibrium with rs11057841 (r2 = 0.93). No interactions by gender were found. Haplotype analysis revealed no stronger association than obtained with single SNP analyses.
Conclusions: Our study has identified association between rs11057841 and serum L concentration (24% increase per T allele) in healthy subjects, independent of potential confounding factors. Our data supports further evaluation of the role for SCARB1 in the transport of macular pigment and the possible modulation of age-related macular degeneration risk through combating the effects of oxidative stress within the retina.
Financial Disclosure(s): Proprietary or commercial disclosures may be found after the references. Ophthalmology 2013;120:1632–1640 © 2013 by the American Academy of Ophthalmology.