A knowledge-driven interaction analysis reveals potential neurodegenerative mechanism of multiple sclerosis susceptibility.

Gene-gene interactions are proposed as an important component of the genetic architecture of complex diseases, and are just beginning to be evaluated in the context of genome-wide association studies (GWAS). In addition to detecting epistasis, a benefit to interaction analysis is that it also increases power to detect weak main effects. We conducted a knowledge-driven interaction analysis of a GWAS of 931 multiple sclerosis (MS) trios to discover gene-gene interactions within established biological contexts. We identify heterogeneous signals, including a gene-gene interaction between CHRM3 (muscarinic cholinergic receptor 3) and MYLK (myosin light-chain kinase) (joint P=0.0002), an interaction between two phospholipase C-β isoforms, PLCβ1 and PLCβ4 (joint P=0.0098), and a modest interaction between ACTN1 (actinin alpha 1) and MYH9 (myosin heavy chain 9) (joint P=0.0326), all localized to calcium-signaled cytoskeletal regulation. Furthermore, we discover a main effect (joint P=5.2E-5) previously unidentified by single-locus analysis within another related gene, SCIN (scinderin), a calcium-binding cytoskeleton regulatory protein. This work illustrates that knowledge-driven interaction analysis of GWAS data is a feasible approach to identify new genetic effects. The results of this study are among the first gene-gene interactions and non-immune susceptibility loci for MS. Further, the implicated genes cluster within inter-related biological mechanisms that suggest a neurodegenerative component to MS

Liver function disturbances in Guillain-Barre syndrome:A prospective longitudinal study in 100 patients

In 100 consecutive patients with Guillain-Barre syndrome, we assessed liver function on admission and at fixed intervals after either intravenous immunoglobulin (IgIV) or plasma-exchange (PE) treatment. On admission, 38% showed a plasma alanine aminotransferase elevation, gamma glutamyl transferase elevation, or both of more than 1.5 times the upper limit of normal. Ten of these patients had serologic evidence of recent cytomegalovirus infection. The remaining 28 patients were negative for other known causes of liver damage, including infection with Epstein-Barr virus or hepatitis A, B, and C; alcohol abuse; hepatotoxic drugs; recent surgery; and concurrent liver disease. In a hospital control group of 100 consecutive patients with subarachnoid hemorrhage, only 5 had unexplained liver function disturbances on admission (p <0.0001). In the IgIV-treated group, the percentage of patients with elevated liver function tests increased from 35% before to 69% shortly after treatment at 2 weeks postadmission (p <0.005). In the PE-treated group, this percentage decreased somewhat from 41% to 36% (not significant). There was also a significant rise in median plasma activity of the various liver enzymes in the IgIV group. At 1 month, however, significant difference had disappeared. At 3 and 6 months, the percentage of patients with liver function disturbances reached a significantly lower level in both treatment groups compared with the time of admission. We concluded that many patients with Guillain-Barre syndrome had mild liver function disturbances without obvious cause. In addition, IgIV treatment was associated with mild transient liver function disturbances through an unknown mechanism

Liver function disturbances in Guillain-Barre syndrome: A prospective longitudinal study in 100 patients

In 100 consecutive patients with Guillain-Barre syndrome, we assessed liver function on admission and at fixed intervals after either intravenous immunoglobulin (IgIV) or plasma-exchange (PE) treatment. On admission, 38% showed a plasma alanine aminotransferase elevation, gamma glutamyl transferase elevation, or both of more than 1.5 times the upper limit of normal. Ten of these patients had serologic evidence of recent cytomegalovirus infection. The remaining 28 patients were negative for other known causes of liver damage, including infection with Epstein-Barr virus or hepatitis A, B, and C; alcohol abuse; hepatotoxic drugs; recent surgery; and concurrent liver disease. In a hospital control group of 100 consecutive patients with subarachnoid hemorrhage, only 5 had unexplained liver function disturbances on admission (p <0.0001). In the IgIV-treated group, the percentage of patients with elevated liver function tests increased from 35% before to 69% shortly after treatment at 2 weeks postadmission (p <0.005). In the PE-treated group, this percentage decreased somewhat from 41% to 36% (not significant). There was also a significant rise in median plasma activity of the various liver enzymes in the IgIV group. At 1 month, however, significant difference had disappeared. At 3 and 6 months, the percentage of patients with liver function disturbances reached a significantly lower level in both treatment groups compared with the time of admission. We concluded that many patients with Guillain-Barre syndrome had mild liver function disturbances without obvious cause. In addition, IgIV treatment was associated with mild transient liver function disturbances through an unknown mechanism

A knowledge-driven interaction analysis reveals potential neurodegenerative mechanism of multiple sclerosis susceptibility.

Gene-gene interactions are proposed as an important component of the genetic architecture of complex diseases, and are just beginning to be evaluated in the context of genome-wide association studies (GWAS). In addition to detecting epistasis, a benefit to interaction analysis is that it also increases power to detect weak main effects. We conducted a knowledge-driven interaction analysis of a GWAS of 931 multiple sclerosis (MS) trios to discover gene-gene interactions within established biological contexts. We identify heterogeneous signals, including a gene-gene interaction between CHRM3 (muscarinic cholinergic receptor 3) and MYLK (myosin light-chain kinase) (joint P=0.0002), an interaction between two phospholipase C-? isoforms, PLC?1 and PLC?4 (joint P=0.0098), and a modest interaction between ACTN1 (actinin alpha 1) and MYH9 (myosin heavy chain 9) (joint P=0.0326), all localized to calcium-signaled cytoskeletal regulation. Furthermore, we discover a main effect (joint P=5.2E-5) previously unidentified by single-locus analysis within another related gene, SCIN (scinderin), a calcium-binding cytoskeleton regulatory protein. This work illustrates that knowledge-driven interaction analysis of GWAS data is a feasible approach to identify new genetic effects. The results of this study are among the first gene-gene interactions and non-immune susceptibility loci for MS. Further, the implicated genes cluster within inter-related biological mechanisms that suggest a neurodegenerative component to MS