Allelic imbalance of multiple sclerosis susceptibility genes IKZF3 and IQGAP1 in human peripheral blood

Background Multiple sclerosis is a chronic inflammatory, demyelinating disease of the central nervous system. Recent genome-wide studies have revealed more than 110 single nucleotide polymorphisms as associated with susceptibility to multiple sclerosis, but their functional contribution to disease development is mostly unknown. Results Consistent allelic imbalance was observed for rs907091 in IKZF3 and rs11609 in IQGAP1, which are in strong linkage disequilibrium with the multiple sclerosis associated single nucleotide polymorphisms rs12946510 and rs8042861, respectively. Using multiple sclerosis patients and healthy controls heterozygous for rs907091 and rs11609, we showed that the multiple sclerosis risk alleles at IKZF3 and IQGAP1 are expressed at higher levels as compared to the protective allele. Furthermore, individuals homozygous for the multiple sclerosis risk allele at IQGAP1 had a significantly higher total expression of IQGAP1 compared to individuals homozygous for the protective allele. Conclusions Our data indicate a possible regulatory role for the multiple sclerosis-associated IKZF3 and IQGAP1 variants. We suggest that such cis-acting mechanisms may contribute to the multiple sclerosis association of single nucleotide polymorphisms at IKZF3 and IQGAP1

Incidence of cancer in multiple sclerosis before and after the treatment era– a registry- based cohort study

Background Whether disease-modifying therapies (DMTs) influence cancer in multiple sclerosis (MS) is uncertain. Objectives Assess incidence of cancer diagnosis among Norwegian MS patients compared to the general population in 1953 to 1995 and 1996 to 2017-reflecting era before and after introduction of DMTs. Methods We performed a nationwide cohort study comprising 6949 MS patients and 37,922 controls, matched on age, sex and county. The cohort was linked to Norwegian Cancer Registry, Cause of Death Registry and National Educational database. We used Poisson regression to calculate incidence rate ratio (IRR) of cancer. Results During 1953–1995 MS patients had similar cancer frequency compared to controls (IRR: 1.11 (95% Confidence Intervals (CI): 0.90–1.37)), although MS patients had increased frequency of cancer in endocrine glands (IRR: 2.51 (1.27–4.93). During 1996–2017 we identified significant increased frequency of cancer among MS patients compared to controls (IRR: 1.38 (95% CI: 1.28–1.52): in brain (IRR: 1.97 (1.41–2.78)), meninges (IRR: 2.44 (1.54–3.77)), respiratory organs (IRR: 1.96 (1.49–2.63)). The excess cancer diagnosis was most frequent among MS patients ≥ 60 years of age (HR 1.30 (1.15–1.47)). Conclusion Incidence of cancer among MS patients compared to controls was higher in 1996 to 2017, corresponding in time to the introduction of DMT for MS. This was observed more frequently among MS patients older than 60 years of age

Incidence of cancer in multiple sclerosis before and after the treatment era– a registry- based cohort study

Background: Whether disease-modifying therapies (DMTs) influence cancer in multiple sclerosis (MS) is uncertain. Objectives: Assess incidence of cancer diagnosis among Norwegian MS patients compared to the general population in 1953 to 1995 and 1996 to 2017-reflecting era before and after introduction of DMTs. Methods: We performed a nationwide cohort study comprising 6949 MS patients and 37,922 controls, matched on age, sex and county. The cohort was linked to Norwegian Cancer Registry, Cause of Death Registry and National Educational database. We used Poisson regression to calculate incidence rate ratio (IRR) of cancer. Results: During 1953–1995 MS patients had similar cancer frequency compared to controls (IRR: 1.11 (95% Confidence Intervals (CI): 0.90–1.37)), although MS patients had increased frequency of cancer in endocrine glands (IRR: 2.51 (1.27–4.93). During 1996–2017 we identified significant increased frequency of cancer among MS patients compared to controls (IRR: 1.38 (95% CI: 1.28–1.52): in brain (IRR: 1.97 (1.41–2.78)), meninges (IRR: 2.44 (1.54–3.77)), respiratory organs (IRR: 1.96 (1.49–2.63)). The excess cancer diagnosis was most frequent among MS patients ≥ 60 years of age (HR 1.30 (1.15–1.47)). Conclusion: Incidence of cancer among MS patients compared to controls was higher in 1996 to 2017, corresponding in time to the introduction of DMT for MS. This was observed more frequently among MS patients older than 60 years of age