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- Bonfiglio, F., et al.
(författare)
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Female-Specific Association Between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome
- 2018
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 155:1, s. 168-179
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Tidskriftsartikel (refereegranskat)abstract
- 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. METHODS: We studied 7,287,191 high-quality single nucleotide polymorphisms in individuals who self-reported a doctor's diagnosis of IBS (cases; n = 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. RESULTS: We identified a genome-wide significant association on chromosome 9q31.2 (single nucleotide polymorphism rs10512344; P = 3.57 x 10(-8)) in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P < 5.0 x 10(-6)). Sex-stratified analyses revealed that the variants at 9q31.2 affect risk of IBS in women only (P = 4.29 x 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 9q31.2 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKB-KAP), which is mutated in patients with familial dysautonomia. CONCLUSIONS: In a sufficiently powered GWAS of IBS, we associated variants at the locus 9q31.2 with risk of IBS in women. This observation may provide additional rationale for investigating the role of sex hormones and autonomic dysfunction in IBS.
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| 4. |
- Henstrom, M., et al.
(författare)
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Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome
- 2018
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Ingår i: Gut. - : BMJ. - 0017-5749 .- 1468-3288. ; 67:2, s. 263-270
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Tidskriftsartikel (refereegranskat)abstract
- Objective IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucraseisomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase-isomaltase (SI) gene variants for their potential relevance in IBS. Design We sequenced SI exons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p. Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a common SI coding polymorphism (p.Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p.Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population. Results CSID mutations were more common in patients than asymptomatic controls (p=0.074; OR=1.84) and Exome Aggregation Consortium reference sequenced individuals (p=0.020; OR=1.57). 15Phe was detected in 6/7 sequenced familial cases, and increased IBS risk in case-control and population-based cohorts, with best evidence for diarrhoea phenotypes (combined p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency (p=0.026) and Parabacteroides faecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (p<0.05). Conclusions SI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.
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| 5. |
- Wallerstedt, Sven, 1944, et al.
(författare)
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Abdominal tenderness in ascites patients indicates spontaneous bacterial peritonitis
- 2007
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Ingår i: European journal of internal medicine. - : Elsevier BV. - 0953-6205 .- 1879-0828. ; 18:1, s. 44-47
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Tidskriftsartikel (refereegranskat)abstract
- Background: Spontaneous bacterial peritonitis (SBP), which has been reported to be present in 10-30% of patients with cirrhotic ascites, may easily be overlooked. An important aim of our study was to determine whether there are any clinical signs which, in clinical practice, may predict or exclude SBP. Methods: We studied 133 patients with cirrhotic ascites from medical units at nine Swedish university hospitals where there had been at least one diagnostic ascites tap with analysis of polymorphonuclear leukocytes in the ascites fluid. The patients had initially been questioned about background factors and physically examined according to a standardized case record form. Samples of blood, urine, and ascites were then drawn for analysis according to a structured schedule. Results: SBP could be excluded in 80% of all the cases and was confirmed in 8% of the 133 patients in the final analysis. Abdominal pain and abdominal tenderness were more common in patients with SBP (p < 0.01), but no other physical sign or laboratory test could separate SBP cases from the others. Conclusions: SBP was present in about one-tenth of the hospitalized patients with cirrhotic ascites in this cohort. Performing repeated physical examinations and paying particular attention to abdominal tenderness may be the best way to become aware of the possible development of this complication.
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| 6. |
- Wallerstedt, Sven, 1944, et al.
(författare)
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Moderate hyperkalemia in hospitalized patients with cirrhotic ascites indicates a poor prognosis
- 2013
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa Healthcare. - 0036-5521 .- 1502-7708. ; 48:3, s. 358-365
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Development of ascites in patients with liver cirrhosis is an ominous sign with a poor outcome. A liver transplantation must be considered, and it then becomes important to know if there are any factors indicating a worsened prognosis. Material and methods. We used official registers for a follow-up study of at least 5 years considering the prognosis of 155 prospectively recruited in-patients with cirrhotic ascites from medical units at nine Swedish university hospitals. All patients had undergone at least one diagnostic ascites tap, and had initially been questioned about background factors and physically examined according to a standardized case record form, followed by sampling of blood, urine, and ascites. Results. Death occurred within 1 year after inclusion in 53% of the cases, and was primarily liver-related in 70%. In a multivariable analysis, the two ordinary variables that showed the strongest correlation with risk of death were serum potassium and abdominal tenderness. All 22 patients with a serum potassium concentration of at least 4.8 mmol/L (maximum 5.8 mmol/L) died within 1 year after inclusion. Potassium concentration was related to renal function and potassium-saving drugs. Conclusion. This follow-up study of a prospectively recruited cohort of in-patients with cirrhotic ascites confirms their poor prognosis. Awareness of an elevated serum potassium value, which would reflect a threatened renal function, seems essential, because it may offer a simple way to identify cases with the worst prognosis. An area for further research should be to explore the significance of including serum potassium in prognostic models.
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