Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations

A meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa (P = 1.6 x 10(-7), 4.3 x 10(-9)) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis-associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune-related genes. One is a low-frequency missense variant in TYK2, another is a missense variant in MTHFR that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain.publishedVersio

[Microscopic colitis - review]

Microscopic colitis (MC) is an encompassing term for two diseases; collagenous colitis and lymphocytic colitis. The colon appears normal by colonoscopy and a diagnosis is only obtained with a biopsy. The histopathology of collagenous colitis is mainly characterized by a thickening of the subepithelial basement membrane of the colonic mucosa with a band of collagen. Lymphocytic colitis is mainly characterized by an intraepithelial lymphocytosis without the collagen thickening. Even though the two diseases have a distinctive pathology their clinical symptoms are characterized by chronic watery diarrhea without bleeding. Microscopic colitis is thought to cause about 4-13% of all chronic diarrhea but their relative frequency is much higher among older people. The mean annual incidence for collagenous and lymphocytic colitis has been increasing. Steroids are the most effective treatment for microscopic colitis and budesonide is the most studied and effective therapy for MC. The aim of this paper is to give a review of two relatively new diseases which are among the most common cause of chronic diarrhea, especially among older people

In vivo calibration of esophageal pressure in the mechanically ventilated patient makes measurements reliable

open8siBackground: Esophageal pressure (Pes) can provide information to guide mechanical ventilation in acute respiratory failure. However, both relative changes and absolute values of Pes can be affected by inappropriate filling of the esophageal balloon and by the elastance of the esophagus wall. We evaluated the feasibility and effectiveness of a calibration procedure consisting in optimization of balloon filling and subtraction of the pressure generated by the esophagus wall (Pew). Methods: An esophageal balloon was progressively filled in 36 patients under controlled mechanical ventilation. VBEST was the filling volume associated with the largest tidal increase of Pes. Esophageal wall elastance was quantified and Pew was computed at each filling volume. Different filling strategies were compared by performing a validation occlusion test. Results: Fifty series of measurements were performed. VBEST was 3.5 ± 1.9 ml (range 0.5-6.0). Esophagus elastance was 1.1 ± 0.5 cmH2O/ml (0.3-3.1). Both Pew and the result of the occlusion test differed among filling strategies. At filling volumes of 0.5, VBEST and 4.0 ml respectively, Pew was 0.0 ± 0.1, 2.0 ± 1.9, and 3.0 ± 1.7 cmH2O (p < 0.0001), whereas the occlusion test was satisfactory in 22 %, 98 %, and 88 % of cases (p < 0.0001). Conclusions: Under mechanical ventilation, an increase of balloon filling above the conventionally recommended low volumes warrants complete transmission of Pes swings, but is associated with significant elevation of baseline. A simple calibration procedure allows finding the filling volume associated with the best transmission of tidal Pes change and subtracting the associated baseline artifact, thus making measurement of absolute values of Pes reliable.openMojoli, Francesco; Iotti, Giorgio Antonio; Torriglia, Francesca; Pozzi, Marco; Volta, Carlo Alberto; Bianzina, Stefania; Braschi, Antonio; Brochard, LaurentMojoli, Francesco; Iotti, Giorgio Antonio; Torriglia, Francesca; Pozzi, Marco; Volta, Carlo Alberto; Bianzina, Stefania; Braschi, Antonio; Brochard, Lauren

Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations

A meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa (P = 1.6 x 10(-7), 4.3 x 10(-9)) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis-associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune-related genes. One is a low-frequency missense variant in TYK2, another is a missense variant in MTHFR that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain

Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations

A meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa (P = 1.6 x 10(-7), 4.3 x 10(-9)) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis-associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune-related genes. One is a low-frequency missense variant in TYK2, another is a missense variant in MTHFR that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain