Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis

Mells, George; Floyd, James A B; Morley, Katherine I.; Cordell, Heather J.; Franklin, Christopher S.; Shin, So–Youn; Heneghan, Michael A.; Neuberger, James; Donaldson, Peter; Day, Darren B.; Ducker, Samantha; Muriithi, Agnes W; Wheater, Elizabeth F; Hammond, Christopher J.; Dawwas, Muhammad F.; Jones, David; Peltonen, Leena; Alexander, Graeme; Sandford, Richard; Anderson, Carl A.

doi:10.1038/ng.789

Cited by 424 publications

(307 citation statements)

References 27 publications

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“…Taken together, these findings suggest that, whereas fatigue is a highly significant Control values are for an age-and sex-matched control population not preselected for symptom severity who completed a version of the PBC-40 (the PBC-40c) which was validated for completion by non-PBC patients for the purposes of this study and which was found to demonstrate construct validity (Supporting Table 1). In addition to the potentially generic symptom domains demonstrated in this figure, the impact of pruritus and general PBC symptoms was unsurprisingly greater in PBC patients than in matched controls (pruritus: PBC-40 pruritus domain score median 4 [interquartile range 0-9 in PBC patients versus 2 [0-3] in controls, P < 0.0001; general PBC symptoms 16 [12][13][14][15][16][17][18][19][20] versus 10 [8-13], P < 0.0001). Dotted lines for each symptom domain represent the cutoff for clinically significant symptoms (defined as mean value for normal subjects 12 SD).…”

Section: Resultsmentioning

confidence: 85%

“…A cross-sectional cohort study of patients recruited to the UK-PBC Patient Cohort, [14][15][16] which was established initially to undertake a UK PBC genome-wide association study (GWAS). 14,15 Patients were phenotyped with regard to symptoms and QOL using established and validated measures.…”

Section: Study Design and Subjectsmentioning

confidence: 99%

“…14,15 Patients were phenotyped with regard to symptoms and QOL using established and validated measures. 16 In order to compare the symptom values for PBC-related symptoms quantified using the PBC-40, a version of this measure suitable for completion by control subjects was developed and validated as part of the study protocol.…”

Section: Study Design and Subjectsmentioning

confidence: 99%

“…The aim of the current study was to use the unique resource of the UK-PBC Patient Cohort, the largest in the world, which has recruited participants from every clinical center in the UK [14][15][16] to address the issue of QOL impairment in PBC and those factors underpinning it.…”

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confidence: 99%

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Impact of primary biliary cirrhosis on perceived quality of life: The UK-PBC national study

et al. 2013

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,4 and the UK-PBC Consortium Primary biliary cirrhosis (PBC) has a complex clinical phenotype, with debate about the extent and specificity of frequently described systemic symptoms such as fatigue. The aim of this study was to use a national patient cohort of 2,353 patients recruited from all clinical centers in the UK to explore the impact of disease on perceived life quality. Clinical data regarding diagnosis, therapy, and biochemical status were collected and have been reported previously. Detailed symptom phenotyping using recognized and validated symptom assessment tools including the PBC-40 was also undertaken and is reported here. Perception of poor quality of life and impaired health status was common in PBC patients (35% and 46%, respectively) and more common than in an age-matched and sex-matched community control group (6% and 15%, P < 0.0001 for both). Fatigue and symptoms of social dysfunction were associated with impaired perceived quality of life using multivariate analysis. Fatigue was the symptom with the greatest impact. Depression was a significant factor, but appeared to be a manifestation of complex symptom burden rather than a primary event. Fatigue had its greatest impact on perceived quality of life when accompanied by symptoms of social dysfunction, suggesting that maintenance of social networks is critical for minimizing the impact of fatigue. Conclusion: The symptom burden in PBC, which is unrelated to disease severity or ursodeoxycholic acid response, is significant and complex and results in significant quality of life deficit. The complexity of symptom burden, and its lack of relation to disease severity and treatment response, suggest that specific approaches to symptom management are warranted that address both symptom biology and social impact. (HEPATOLOGY 2013;58:273-283)

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Section: Resultsmentioning

confidence: 85%

Section: Study Design and Subjectsmentioning

confidence: 99%

Section: Study Design and Subjectsmentioning

confidence: 99%

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Impact of primary biliary cirrhosis on perceived quality of life: The UK-PBC national study

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“…23 Judging from the previous reports that this region was associated with primary biliary cirrhosis 24 and multiple sclerosis, 25 PLCL2 might have a functional role in the immune system. Indeed, the experimental data on Plcl2-deficient mice indicated that Plcl2 regulates the proliferation of mature B cells in response to B-cell receptor crosslinking.…”

Section: Discussionmentioning

confidence: 97%

A genome-wide association study identifies PLCL2 and AP3D1-DOT1L-SF3A2 as new susceptibility loci for myocardial infarction in Japanese

et al. 2014

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Despite considerable progress in preventive and therapeutic strategies, myocardial infarction (MI) is one of the leading causes of death throughout the world. A total of 55 susceptibility genes have been identified mostly in European genome-wide association studies (GWAS). Nevertheless, large-scale GWAS from other population could possibly find additional susceptibility loci. To identify as many MI susceptibility loci as possible, we performed a large-scale genomic analysis in Japanese population. To identify MI susceptibility loci in Japanese, we conducted a GWAS using 1666 cases and 3198 controls using the Illumina Human610-Quad BeadChip and HumanHap550v3 Genotyping BeadChip. We performed replication studies using a total of 11 412 cases and 28 397 controls in the Japanese population. Our study identified two novel susceptibility loci for MI: PLCL2 on chromosome 3p24.3 (rs4618210:A4G, P ¼ 2.60 Â 10 À9 , odds ratio (OR) ¼ 0.91) and AP3D1-DOT1L-SF3A2 on chromosome 19p13.3 (rs3803915:A4C, P ¼ 3.84 Â 10 À9 , OR ¼ 0.89). Besides, a total of 14 previously reported MI susceptibility loci were replicated in our study. In particular, we validated a strong association on chromosome 12q24 (rs3782886:A4G: P ¼ 1.14 Â 10 À14 , OR ¼ 1.46). Following pathway analysis using 265 genes related to MI or coronary artery disease, we found that these loci might be involved in the pathogenesis of MI via the promotion of atherosclerosis. In the present large-scale genomic analysis, we identified PLCL2 and AP3D1-DOT1L-SF3A2 as new susceptibility loci for MI in the Japanese population. Our findings will add novel findings for MI susceptibility loci. INTRODUCTIONMyocardial infarction (MI), the severest form of coronary artery disease (CAD), is characterized by the occlusion of the coronary artery, resulting in ischemic damage of the myocardium. The occlusion of the coronary artery is characterized by abrupt plaque rupture with thrombogenesis 1 following the atherosclerotic process, which has recently been regarded as a chronic inflammatory condition involving lipid accumulation, abnormal extracellular matrix metabolism, innate immunity with macrophages, and the adaptive immune response with T and B lymphocytes. 2 Despite recent dramatic advances in preventive and/or therapeutic strategies, MI is still one of the leading causes of death in Asian populations as well as European populations.The pathogenesis of MI is considered to be the cumulative effect of multiple genetic and environmental factors. For the genetic aspect, a

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Genetics of Primary Biliary Cirrhosis

Mells

Hirschfield

2013

Encyclopedia of Life Sciences

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Primary biliary cirrhosis (PBC) is an autoimmune liver disease affecting 0.1% of women over the age of 40 years. PBC is characterised by autoreactive T‐cells and B‐cells specific for mitochondrial self‐antigens, typically the E2‐domain of pyruvate dehydrogenase complex (PDC‐E2), which mediate progressive destruction of the small, intrahepatic bile ducts, eventually leading to cirrhosis. It is believed that environmental factors trigger loss of immune tolerance to PDC‐E2 in those individuals with a genetic predisposition towards PBC. Knowledge of the genetic basis of PBC has improved following four genome‐wide association studies and two immunochip association studies of PBC, undertaken in large case‐control cohorts from North America, Europe and Japan. These studies have clarified the well‐established human leucocyte antigen (HLA) association and identified 27 non‐HLA risk loci, which harbour highly plausible candidate genes, mainly involved in regulation of the immune system. Key Concepts: Primary biliary cirrhosis (PBC) is a chronic, cholestatic liver disease characterised by progressive, autoimmune destruction of the small, interlobular bile ducts, leading in many cases to end‐stage liver disease with attendant need for liver transplantation. PBC is a complex disorder, meaning that it results from an interaction of genetic and environmental factors. Genome‐wide association studies (GWAS) and iCHIP studies of PBC have substantially improved knowledge of the genetic architecture of PBC. To date, four GWAS and two iCHIP studies of PBC have been undertaken in populations of European or Japanese ancestry. The HLA complex makes an important contribution to the genetic basis of PBC. Risk haplotypes associated with PBC include those carrying DRB1*08 and DRB1*04 alleles. Protective haplotypes include those carrying DRB1*11 and DRB1*15 alleles. A total of 27 non‐HLA risk loci for PBC have been identified in GWAS or iCHIP studies. Many loci harbour highly plausible candidate genes, mainly involved in innate or acquired immune processes. Many risk loci for PBC are also the risk loci for other autoimmune conditions, such as multiple sclerosis, coeliac disease or inflammatory bowel disease. The genetic architecture of PBC in the Japanese population appears to be distinct from the genetic architecture of PBC in populations of European ancestry. This suggests that susceptibility to PBC is characterised by genetic heterogeneity. Known independent risk variants for PBC account for less than 20% of PBC heritability. This is an example of ‘missing heritability’. The iCHIP studies of PBC suggest that PBC risk loci may be polymorphic. The iCHIP studies of PBC suggest that rare and low‐frequency variants make a substantial contribution to the genetic variance of the diseases; identification of rare variants will require large‐scale sequencing efforts.

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Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis

Cited by 424 publications

References 27 publications

Impact of primary biliary cirrhosis on perceived quality of life: The UK-PBC national study

Impact of primary biliary cirrhosis on perceived quality of life: The UK-PBC national study

A genome-wide association study identifies PLCL2 and AP3D1-DOT1L-SF3A2 as new susceptibility loci for myocardial infarction in Japanese

Genetics of Primary Biliary Cirrhosis

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