5 research outputs found
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
The Role of Gut Dysfunction and Nutritional Factors in Liver Cirrhosis
Malnutrition is a common finding in patients with liver cirrhosis. Malnutrition has been
shown to be associated with increased morbidity and mortality. Its pathogenesis remains
unclear but both poor dietary intake and increased energy expenditure have been reported.
Spontaneous bacterial peritonitis is an important clinical problem in cirrhotics. It may
occur as a consequence of repeated access of bacteria from the intestinal lumen (translocation)
to the mesenteric lymph nodes. One of the mechanisms proposed to explain bacterial
translocation in cirrhosis includes increased intestinal permeability.
The aims of the present study were to evaluate GI symptoms in cirrhotic patients and
their possible relation to nutritional status, to assess whether gastric sensorimotor dysfunction
or metabolic disturbances are associated with reduced food intake, and to investigate the role
of ascites in intestinal permeability in patients with liver cirrhosis.
Gastrointestinal symptoms and health-related quality of life (HRQOL) were assessed
with the aid of two questionnaires. Gastric sensorimotor function was measured by means of
an electronic barostat. Food intake, as assessed with a food diary, was related to fasting and
postprandial glucose, insulin, leptin, and ghrelin concentrations. Intestinal permeability was
evaluated by a 51Cr-EDTA permeability test.
Cirrhotics were found to have increased severity of GI symptoms compared with
reference values from the general population. A relationship between GI symptoms and
compromised HRQOL as well as weight loss was observed.
Proximal stomach relaxation to a meal was increased in patients with liver cirrhosis as
compared with healthy controls but the relation between gastric accommodation and energy
intake was found to be disturbed in these patients. Gastric sensitivity to distension was shown
to be related to GI symptom severity and to liver cirrhosis severity scores.
Patients with liver cirrhosis exhibited higher postprandial insulin and glucose
concentrations compared to controls. Cirrhotics had higher fasting leptin that fell significantly
postmeal and they showed an attenuated increase of ghrelin before the next expected meal.
Altered glucose and hormonal levels in patients with cirrhosis were associated with poor food
intake.
Only a few patients with cirrhosis had increased intestinal permeability, as assessed by a
51Cr-EDTA test, which was not influenced to a major extent by ascites.
Conclusions: In patients with liver cirrhosis GI symptom severity is high and it is
associated with impaired HRQOL and weight loss. Gastric accommodation is not involved in
the poor food intake observed in cirrhotics and gastric sensitivity seems to be a relevant factor
for GI symptom generation in these patients. Altered postprandial glucose, leptin, and ghrelin
levels are correlated to reduced energy intake in this patient group. Increased intestinal
permeability is probably of limited importance in the pathophysiology of bacterial infections
in patients with liver cirrhosis and ascites
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