A genome-wide association study identifies four novel susceptibility loci underlying inguinal hernia

Jorgenson, Eric; Makki, Nadja; Shen, Lei; Chen, David C.; Tian, Chao; Eckalbar, Walter L.; Hinds, David A.; Ahituv, Nadav; Avins, Andrew L.

doi:10.1038/ncomms10130

Cited by 74 publications

(76 citation statements)

References 68 publications

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“…Mutations in bone morphogenetic protein receptor type 1B (BMPR1B) underlie autosomal recessive Hunter-Thompson41 type of acromesomelic dysplasia. EGF-containing fibulin extracellular matrix protein 1 ( EFEMP1 ) has been associated with polygenic susceptibility to inguinal hernia42 and varicose veins 43 . EFEMP1 encodes fibulin-3, an extracellular matrix protein.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms

Schafmayer¹,

Harrison²,

Buch³

et al. 2019

Gut

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ObjectiveDiverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease.DesignDiscovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry.ResultsWe discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3×10−10 and 0.002 (ORallelic=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33).ConclusionIn silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.

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Section: Discussionmentioning

confidence: 99%

Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms

Schafmayer¹,

Harrison²,

Buch³

et al. 2019

Gut

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“…They cause severe economic loss in the pig breeding industry [7]. Hernia development is caused by both multiple genes and environmental factors [8]. To date, candidate genes related to the development of inguinal/scrotal hernias have been inspected.…”

Section: Introductionmentioning

confidence: 99%

“…Four candidate genes (ELF5, KIF18A, COL23A1 and NPTX1) for the defects on Sus scrofa chromosomes (SSC) 2 and 12 were identified from 6 commercial pig breeds and there was no overlap in the significant SNPs from different pig breeds [11]; Ding et al (2009) detected the most remarkable loci on SSC 7,8, and 10 in a White Duroc×Erhualian resource population of F2 pigs [12]. Sevillano et al (2015) identified five distinct QTL regions that strongly affected the inguinal/scrotal hernias detected in both Large White and Landrace datasets [13].…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: Genome-wide association analysis of inguinal/scrotal hernia in pigs using specific length amplified fragment (SLAF) sequencing

Zou¹,

Zuo²,

Zhu³

et al. 2017

Oncotarget

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Inguinal and scrotal hernias are the most frequent congenital disorders in pigs, and they may cause severe economic loss in the pig breeding industry. Genetic factors play a significant role in the susceptibility to hernias, but the genetic mechanisms of inguinal/scrotal hernia are poorly understood. In this study, we performed a genome-wide association study (GWAS) with specific-locus amplified fragment sequencing (SLAF-seq) on 120 (59 cases and 61 controls) full and half sib pigs to identify genetic loci underlying variations in inguinal/scrotal hernias. A total of 218,460 high-quality SNPs were generated for further statistical analysis with casecontrols and the farmCPU model. Based on these two methods, a total of 59 SNPs were significantly (P < 0.01) associated with inguinal/scrotal hernia. Finally, 14 novel candidate genes implicated in the defect were identified, and 5 genes (CPNE5, DEGS1, PLCG2, PRKCE and NUAK1) were related to cell apoptosis, which is one of the pivotal pathogenesis factors of inguinal/scrotal hernia. In addition, 4 of them were shown strong associations with the hernia were confirmed in 270 samples (P < 0.05). This finding provides new evidence that genes related to cell apoptosis may be associated with inguinal/scrotal hernias.

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“…ADAMTS6 transforms procollagen to collagen [170]. An inguinal hernia genetic susceptibility locus near the ADAMTS6 gene has been reported, indicating that collagen deregulation could be involved in the progress of inguinal hernias [171]. Mutations in the ADAMTS10 gene have been reported in Weill-Marchesani syndrome (WMS), a disorder characterized by abnormalities in the eye and skeletal development [172].…”

Section: Other Adamtssmentioning

confidence: 99%

Profile of Matrix-Remodeling Proteinases in Osteoarthritis: Impact of Fibronectin

Pérez‐García

Carrión

Gutiérrez‐Cañas

et al. 2019

Cells

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The extracellular matrix (ECM) is a complex and specialized three-dimensional macromolecular network, present in nearly all tissues, that also interacts with cell surface receptors on joint resident cells. Changes in the composition and physical properties of the ECM lead to the development of many diseases, including osteoarthritis (OA). OA is a chronic degenerative rheumatic disease characterized by a progressive loss of synovial joint function as a consequence of the degradation of articular cartilage, also associated with alterations in the synovial membrane and subchondral bone. During OA, ECM-degrading enzymes, including urokinase-type plasminogen activator (uPA), matrix metalloproteinases (MMPs), and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs), cleave ECM components, such as fibronectin (Fn), generating fibronectin fragments (Fn-fs) with catabolic properties. In turn, Fn-fs promote activation of these proteinases, establishing a degradative and inflammatory feedback loop. Thus, the aim of this review is to update the contribution of ECM-degrading proteinases to the physiopathology of OA as well as their modulation by Fn-fs.

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A genome-wide association study identifies four novel susceptibility loci underlying inguinal hernia

Cited by 74 publications

References 68 publications

Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms

Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms

WITHDRAWN: Genome-wide association analysis of inguinal/scrotal hernia in pigs using specific length amplified fragment (SLAF) sequencing

Profile of Matrix-Remodeling Proteinases in Osteoarthritis: Impact of Fibronectin

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