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Developmental biology - Female Hormones|
Genetic link to IBS identified in women
Irritable bowel syndrome is the most common gastrointestinal disorder. More than 10 per cent of the population, women more than men, suffer from recurrent symptoms including abdominal pain, gas, diarrhoea and constipation. What causes IBS is largely unknown, which hampers effective treatment for many. Genetic predisposition to IBS is recognised, although poorly investigated.
Now an international research team led by scientists from Karolinska Institutet in Sweden have identified DNA variants that are associated with increased risk of IBS, but only in women.
"Exploiting the large Unighted Kingdom (UK) Biobank resource, as well as several patient cohorts from European and United States (US) expert centres, we have been able to study genetic predisposition to IBS with increased statistical power, better than ever before."
The researchers used genotype data from more than 300,000 UK Biobank participants in a genome-wide association study (GWAS), to find DNA variants associated with increased risk of a doctor's diagnosis of IBS in women but not in men. The variants were specifically from a region on chromosome 9 previously reported to also influence puberty timing in women (age at first menstruation).
By following up this result in 2,045 patients from IBS expert centres in Sweden, Belgium, the Netherlands, Italy and the US, researchers observed further associations with constipation-predominant IBS as well as harder stools, again only in women.
"Although we cannot point to individual genes at this early stage, we believe these results are exciting, as they converge with existing data on female preponderance and a role of sex-hormones in IBS," explains Mauro D'Amato.
In addition to Karolinska Institutet, researchers and clinicians from several other institutions participated in the study, including the Mayo Clinic and University of California Los Angeles in the US, IKMB in Kiel Germany, TARGID in Leuven Belgium, BioDonostia HRI in San Sebastian Spain, the Universities of Bologna in Italy, Groningen and Maastricht in the Netherlands, and others.
Background & Aims
Genetic factors are believed to affect risk for irritable bowel syndrome (IBS), but there have been no sufficiently powered and adequately sized studies. To identify DNA variants associated with IBS risk, we performed a genome-wide association study (GWAS) of the large UK Biobank population-based cohort, which includes genotype and health data from 500,000 participants.
We studied 7,287,191 high-quality single-nucleotide polymorphisms in individuals who self-reported a doctor’s diagnosis of IBS (cases; m=9576) compared to the remainder of the cohort (controls; n=336,499) (mean age of study subjects, 40–69 years). Genome-wide significant findings were further investigated in 2045 patients with IBS from tertiary centers and 7955 population controls from Europe and the United States, and a small general population sample from Sweden (n=249). Functional annotation of GWAS results was carried out by integrating data from multiple biorepositories, to obtain biological insights from the observed associations.
We identified a genome-wide significant association on chromosome 9q31.2 (SNP rs10512344; P=3.57×10–8), in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P<5.0×10–6). Sex-stratified analyses revealed that the variants at 9q32.1 affect risk of IBS in only women (P=4.29×10–10 in UK Biobank) and also associate with constipation-predominant IBS in women (P=.015 in the tertiary cohort) and harder stools in women (P=.0012 in the population-based sample). Functional annotation of the 9q32.1 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKBKAP), which is mutated in patients with familial dysautonomia.
In a sufficiently powered GWAS of IBS, we associated variants at the locus 9q32.1 with risk of IBS in women. This observation may provide additional rationale for investigating the role of sex hormones and autonomic dysfunction in IBS.
Authors: Ferdinando Bonfiglio, Tenghao Zheng, Koldo Garcia-Etxebarria, Fatemeh Hadizadeh, Luis Bujanda, Francesca Bresso, Lars Agreus, Anna Andreasson, Aldona Dlugosz, Greger Lindberg, Peter T. Schmidt, Pontus Karling, Bodil Ohlsson, Magnus Simren, Susanna Walter, Gerardo Nardone, Rosario Cuomo, Paolo Usai-Satta, Francesca Galeazzi, Matteo Neri, Piero Portincasa, Massimo Bellini, Giovanni Barbara, Anna Latiano, Matthias Hübenthal, Vincent Thijs, Mihai G. Netea, Daisy Jonkers, Lin Chang, Emeran A. Mayer, Mira M. Wouters, Guy Boeckxstaens, Michael Camilleri, Andre Franke, Alexandra Zhernakova, Mauro D’Amato
Competing Financial Interests: The authors declare no conflict of interest
Grant Support: This study was supported by grants from the Swedish Research Council (VR project nrs 2013-03862 and 2017-02403), the Health Department of the Basque Government (grant 2015111133), and the Spanish Ministry of Economy and Competitiveness (ISCIII grant FIS PI17/00308) to MDA, and NIH grants 1P50 DK64539, R01 DK048351, P30 DK 41301 to EAM and LC. The research leading to these results has received funding from the EU FP7 under grant nr 313010 (BBMRI-LPC). MGN was supported by an ERC Consolidator Grant (#310372) and a Spinoza Grant of the Netherlands Organization for Scientific Research.
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Genetic factors are believed to affect risk for irritable bowel syndrome (IBS), but until this study, no research of a sufficiently sized population had been studied. Image credit: Wikipedia.