Common NOD2 risk variants in African Americans with Crohnʼs disease are due exclusively to recent Caucasian admixture

Adeyanju, Oloruntosin; Okou, David T.; Huang, Clifton; Kumar, Archana; Sauer, Cary G.; Galloway, Courtney; Prasad, Mahadev; Waters, Jon; Cutler, David J.; Zwick, Michael E.; Dhere, Tanvi; Kugathasan, Subra

doi:10.1002/ibd.22944

Cited by 20 publications

(9 citation statements)

References 14 publications

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“…In contrast to prior reports, in which ASCAs were known to be associated with white populations, ileal involvement, and NOD2 status, the association between ASCA and complicated disease and disease requiring surgery is not the result of European admixture. 9, 32 Our findings do concur with prior literature regarding the association between anti-OmpC with complicated disease and the need for surgery in NE populations. 5, 33, 34 …”

Section: Discussionsupporting

confidence: 89%

IBD Serology and Disease Outcomes in African Americans With Crohn’s Disease

Bertha

Vasantharoopan

Kumar

et al. 2017

Inflammatory Bowel Diseases

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Backgrounds Recent studies have identified the role of serologic markers in characterizing disease phenotype, location, complications, and severity among Northern Europeans (NE) with Crohn’s disease (CD). However, very little is known about the role of serology in CD among African Americans (AA). Our study explored the relationship between serology and disease phenotype in AA with CD, while controlling for genetic ancestry. Methods AAs with CD were enrolled as participants through multicenter collaborative efforts. Serological levels of IgA anti-Saccharomyces cervisiae antibody (ASCA), IgG ASCA, E. coli outermembrane porin C, anti-CBir1, and ANCA were measured using enzyme-linked immunosorbent assays. Genotyping was performed using Illumina immunochip technology; an admixture rate was calculated for each subject. Multiple imputation by chained equations was performed to account for data missing at random. Logistic regression was used to calculate adjusted odds ratio (OR) for associations between serological markers and both complicated disease and disease requiring surgery. Results A total of 358 patients were included in the analysis. The majority of our patients had inflammatory, noncomplicated disease (58.4%), perianal disease (55.7%), and documented colonic inflammation (86.8%). On multivariable analysis, both IgG ASCA and OmpC were associated with complicated disease (OR, 2.67; 95% CI, 1.67–4.28; OR, 2.23; 95% CI, 1.41–3.53, respectively) and disease requiring surgery (OR, 2.51; 95% CI, 1.49–4.22; OR, 3.57; 95% CI, 2.12–6.00). NE admixture to the African genome did not have any associations or interactions in relation to clinical outcome. Conclusions Our study comprises the largest cohort of AAs with CD. The utility of serological markers for the prognosis of CD in NE applies equally to AA populations.

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Section: Discussionsupporting

confidence: 89%

IBD Serology and Disease Outcomes in African Americans With Crohn’s Disease

Bertha

Vasantharoopan

Kumar

et al. 2017

Inflammatory Bowel Diseases

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“…Some studies have shown that disease markers identified in European ancestry populations may also be observed in admixed populations. For example, the frameshift NOD2 risk variant found in European populations are also associated with CD in African Americans, albeit at much lower allele frequencies, consistent with the recent European admixture present in African Americans 41, 42 …”

Section: Population Differences In Ibdmentioning

confidence: 70%

Genetics of Inflammatory Bowel Diseases

2015

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In this Review, we provide an update on genome-wide association studies (GWAS) in inflammatory bowel disease (IBD). In addition, we summarize progress in defining the functional consequences of associated alleles for coding and non-coding genetic variation. In the small minority of loci where major association signals correspond to non-synonymous variation, we summarize studies defining their functional effects and implications for therapeutic targeting. Importantly, the large majority of GWAS-associated loci involve non-coding variation, many of which modulate levels of gene expression. Recent expression quantitative trait loci (eQTL) studies have established that expression of the large majority of human genes is regulated by non-coding genetic variation. Significant advances in defining the epigenetic landscape have demonstrated that IBD GWAS signals are highly enriched within cell-specific active enhancer marks. Studies in European ancestry populations have dominated the landscape of IBD genetics studies, but increasingly, studies in Asian and African-American populations are being reported. Common variation accounts for only a modest fraction of the predicted heritability and the role of rare genetic variation of higher effects (i.e. odds ratios markedly deviating from one) is increasingly being identified through sequencing efforts. These sequencing studies have been particularly productive in very-early onset, more severe cases. A major challenge in IBD genetics will be harnessing the vast array of genetic discovery for clinical utility, through emerging precision medicine initiatives. We discuss the rapidly evolving area of direct to consumer genetic testing, as well as the current utility of clinical exome sequencing, especially in very early onset, severe IBD cases. We summarize recent progress in the pharmacogenetics of IBD with respect of partitioning patient responses to anti-TNF and thiopurine therapies. Highly collaborative studies across research centers and across subspecialties and disciplines will be required to fully realize the promise of genetic discovery in IBD.

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“…For the meta-analysis of R702W, L1007fs and G908R, we included data from 89, 90 and 96 published articles(for R702W, G908 and L1007fs, respectively) with a combined total of 23,703 cases and 22,873 controls, which were published before December 31 st , 2016( D’Addabbo et al 2009 ; Schoultz et al 2009 ; Yazdanyar et al 2009 ; Csöngei et al 2010 ; Dassopoulos et al 2010 ; Gazouli et al 2010 ; Glas et al 2010 ; Hoffmann et al 2010 ; Lacher et al 2010 ; Sventoraityte et al 2010 ; Yazdanyar et al 2010 ; Naderi et al 2011 ; Adeyanju et al 2012 ; Azzam et al 2012 ; Hama et al 2012 ; Kanaan et al 2012 ; Akyuz et al 2013 ; Meddour et al 2014 ; Boukercha et al 2015 ; Salkic et al 2015 ), and conducted the analysis in R using the ‘meta’ package. We calculated the odds ratios for the three variants in the meta-analysis using DerSimonian-Laird statistics as a random-effects model.…”

Section: Methodsmentioning

confidence: 99%

Targeted Gene Sequencing in Children with Crohn’s Disease and Their Parents: Implications for Missing Heritability

Chen

Kugathasan

et al. 2018

G3 Genes|Genomes|Genetics

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Crohn’s disease is a complex genetic trait characterized by chronic relapsing intestinal inflammation. Genome wide association studies (GWAS) have identified more than 170 loci associated with the disease, accounting for ∼14% of the disease variance. We hypothesized that rare genetic variation in GWAS positional candidates also contribute to disease pathogenesis. We performed targeted, massively-parallel sequencing of 101 genes in 205 children with Crohn’s disease, including 179 parent-child trios and 200 controls, both of European ancestry. We used the gene burden test implemented in VAAST and estimated effect sizes using logistic regression and meta-analyses. We identified three genes with nominally significant p-values: NOD2, RTKN2, and MGAT3. Only NOD2 was significant after correcting for multiple comparisons. We identified eight novel rare variants in NOD2 that are likely disease-associated. Incorporation of rare variation and compound heterozygosity nominally increased the proportion of variance explained from 0.074 to 0.089. We estimated the population attributable risk and total heritability of variation in NOD2 to be 32.9% and 3.4%, respectively, with 3.7% and 0.25% accounted for by rare putatively functional variants. Sequencing probands (as opposed to genotyping) to identify rare variants and incorporating phase by sequencing parents can recover a portion of the missing heritability of Crohn’s disease.

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Common NOD2 risk variants in African Americans with Crohnʼs disease are due exclusively to recent Caucasian admixture

Cited by 20 publications

References 14 publications

IBD Serology and Disease Outcomes in African Americans With Crohn’s Disease

IBD Serology and Disease Outcomes in African Americans With Crohn’s Disease

Genetics of Inflammatory Bowel Diseases

Targeted Gene Sequencing in Children with Crohn’s Disease and Their Parents: Implications for Missing Heritability

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