Association of a Multigenetic Pro-Inflammatory Profile with Ischaemic Stroke

Abstract

Objective: A multigenetic pro-inflammatory profile may increase stroke risk. We investigated whether a higher number of pro-inflammatory genetic variants are associated with ischaemic stroke risk and whether other risk factors further elevate this risk. Methods: In a case-control study with 470 ischaemic stroke patients (cases) and 807 population controls, we investigated 23 haplotypes or alleles in 16 inflammatory genes (interleukin [IL]1A, IL1B, IL1 receptor antagonist, IL6, IL6 receptor, IL10, tumour necrosis factor-a; C-C motif chemokine ligand 2, C-C motif chemokine receptor 5, C-reactive protein (CRP), intercellular adhesion molecule 1, transforming growth factor β1, E-Selectin, selenoprotein S, cluster determinant 14, histone deacetylase 9 [HDAC9]). We constructed an extended gene score (EGS) as the sum of all individual risk alleles and analysed its effect on stroke, just as its association and interaction with cardiovascular risk factors and infectious scores (IgG antibodies against 5 respectively IgA antibodies against 4 microbial antigens). Results: Cases were less likely to carry the minor allele of IL10 rs1800872 and more likely to carry the HDAC9 allele rs11984041 and the pro-inflammatory haplotype of CRP, although the latter was not statistically significant in our study. Overall, cases tended to have more pro-inflammatory alleles and haplotypes than controls (mean ± SD 13.25 ± 2.25 and 13.04 ± 2.41, respectively). However, the EGS only slightly and not significantly increased the risk of stroke (OR 1.04, 95% CI 0.99-1.09). Its effect was neither associated with included risk factors nor with IgA and IgG infectious scores, and we found no significant interaction effects. Conclusion: A more pro-inflammatory genetic profile might increase stroke risk to some extent. This potential effect is most likely independent of established cardiovascular risk factors and the infectious burden of an individual.

TNF-α (G-308A) Polymorphism, Circulating Levels of TNF-α and IGF-1: Risk Factors for Ischemic Stroke—An Updated Meta-Analysis

“…Strictly following the inclusion criteria, 47 properly controlled full-length studies, including 23 rs1800629 genotype-related studies ( Um et al, 2003 ; Balding et al, 2004 ; Lee et al, 2004 ; Um and Kim, 2004 ; Karahan et al, 2005 ; Rubattu et al, 2005 ; Harcos et al, 2006 ; Lalouschek et al, 2006 ; Llamas Sillero et al, 2007 ; Banerjee et al, 2008 ; Shi et al, 2009 ; Kim et al, 2010 ; Tong et al, 2010 ; Sultana et al, 2011 ; Cui et al, 2012 ; Tuttolomondo et al, 2012 ; Zhao et al, 2012 ; Djordjevic et al, 2013 ; Wawrzynek et al, 2014 ; Gu et al, 2015 ; Kumar et al, 2016 ; Palm et al, 2020 ; Kamdee et al, 2021 ) and 13 case reports ( Zaremba and Losy, 2001a , b ; Intiso et al, 2004 ; Domac et al, 2007 ; Jefferis et al, 2009 ; Cure et al, 2013 ; Bokhari et al, 2014 ; de Sousa Parreira et al, 2015 ; Wytrykowska et al, 2016 ; Billinger et al, 2017 ; Shishkova et al, 2018 ; Zhang Y. Y. et al, 2018 ; Ma et al, 2020 ) on the circulating level of TNF-α were finally selected for the meta-analysis ( Figure 1 ). Genotype-related literature included a total of 9,120 patients and 9,249 healthy controls (Caucasian, n = 10; Asian, n = 15).…”

Genetic Variation of Inflammatory Genes to Ischemic Stroke Risk in a Chinese Han Population

“…Inflammatory genes, such as C-reactive protein ( CRP ), interleukin ( IL ) 6, transforming growth factor β1 ( TGFB1 ), were identified to contribute to stroke risk. 11 , 32–34 It is well known that the elevated levels of inflammatory markers may reflect a high burden of atherosclerosis and thrombosis, which contribute to the occurrence of IS. 13 , 35 …”

“…Inflammatory genes, such as C-reactive protein (CRP), interleukin (IL) 6, transforming growth factor β1 (TGFB1), were identified to contribute to stroke risk. 11,[32][33][34] It is well known that the elevated levels of inflammatory markers may reflect a high burden of atherosclerosis and thrombosis, which contribute to the occurrence of IS. 13,35 PTGS2, with loci on chromosome 1, is an inducible enzyme that catalyzes arachidonic acid into prostaglandins and plays a vital role in inflammation.…”

“… 9 , 10 Multiple inflammation-associated mediators are involved in the process. 11 For example, the interleukin (IL)-1 family, as a highly active proinflammatory cytokine, is a main regulator of inflammation and triggers inflammatory cascade response by binding to the IL1 receptor. 12 IL1A and IL1B are distinct members of IL1 genes and encode IL1α and IL1β, respectively.…”

Genetic Variation in LRP1 Associates with Stanford Type B Aortic Dissection Risk and Clinical Outcome

“…From the "genetic and socioeconomic determinants of ischemic stroke" GENESIS study [15], 768 healthy individuals were genotyped for the same LRP1 rs11172113 SNV variant and used as a control reference group. All patients and controls were of the white Caucasian ethnicity from mid-west Germany.…”