Genetic analysis of four consanguineous multiplex families with inflammatory bowel disease

Abstract

Background Family studies support a genetic predisposition to inflammatory bowel diseases (IBD), but known genetic variants only partially explain the disease heritability. Families with multiple affected individuals potentially harbour rare and high-impact causal variants. Long regions of homozygosity due to recent inbreeding may increase the risk of individuals bearing homozygous loss-of-function variants. This study aimed to identify rare and homozygous genetic variants contributing to IBD. Methods Four families with known consanguinity and multiple cases of IBD were recruited. In a family-specific analysis, we utilised homozygosity mapping complemented by whole-exome sequencing. Results We detected a single region of homozygosity shared by Crohn's disease cases from a family of Druze ancestry, spanning 2.6 Mb containing the NOD2 gene. Whole-exome sequencing did not identify any potentially damaging variants within the region, suggesting that non-coding variation may be involved. In addition, affected individuals in the families harboured several rare and potentially damaging homozygous variants in genes with a role in autophagy and innate immunity including LRRK1, WHAMM, DENND3, and C5. Conclusion This study examined the potential contribution of rare, high-impact homozygous variants in consanguineous families with IBD. While the analysis was not designed to achieve statistical significance, our findings highlight genes or loci that warrant further research. Non-coding variants affecting NOD2 may be of importance in Druze patients with Crohn's disease.

Cell Type-Specific Induction of Inflammation-Associated Genes in Crohn’s Disease and Colorectal Cancer

“…With approximately 1.6 million individuals affected and 70,000 new diagnoses each year in the US alone, inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), represents a major health burden [ 1 ]. Nearly 250 single nucleotide polymorphism (SNP)-tagged loci [ 2 , 3 , 4 , 5 ] and chromosomal alterations [ 6 , 7 ], as well as splicing variants [ 8 , 9 ], were linked to an elevated risk of developing IBD. In addition, several studies investigated IBD-induced gene expression changes in the past, including expression quantitative trait loci (eQTL) approaches [ 10 ].…”

Proteomics profiles reveal the potential roles of proteins involved in chicken macrophages stimulated by Lipopolysaccharide

“…Another toxic factor on the surface of S. aureus staphylococcal superantigen-like protein 7 (SSL7) also combines immunoglobulin A (IgA) with complement C5 (van den Berg et al 2011). Under normal conditions, C5 is cleaved into C5a, a potent chemoattractant, and C5b, which forms the membrane attack complex formation: C5b-9 (Ko et al 2013, Jongerius et al 2019, Ben-Yosef et al 2021). SSL7 effectively inhibits phagocytosis and inhibits the membrane attack complex from being formed in the (West and Damania 2010).…”

Rare variant burden analysis from exomes of three consanguineous families reveals LILRB1 and PRSS3 as potential key proteins in inflammatory bowel disease pathogenesis

“…However, rare and highly penetrant variations identified through population-specific cohorts or family-focused research have immense potential to catch the variants with high effect size on complex diseases such as IBD (8,12). Although, studying the familial cases may uncover rare causal variants, their heritability of disease in unrelated patient cohorts is still uncertain (23). Unlike VEO-IBD, which has a causal monogenic factor, late-onset is a complex and multifactorial disorder that cannot be explained by classical genetic segregation methods (16,24,25).…”