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Eur J Hum Genet. 2016 Jul;24(7):1041-8. doi: 10.1038/ejhg.2015.231. Epub 2015 Oct 28.

Polymorphisms of cystathionine beta-synthase gene are associated with susceptibility to sepsis.

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Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.
Genome Analysis, Leibniz Institute for Age Research-Fritz Lipmann Institute, Jena, Germany.
Department of Anaesthesiology and Intensive Care Therapy, Jena University Hospital, Jena, Germany.
Research group Clinical Epidemiology, CSCC, Jena University Hospital, Jena, Germany.
Systems Biology and Bioinformatics Group, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute, Jena, Germany.
School of Biology, College of Science, University of Tehran, Tehran, Iran.
4th Department of Internal Medicine, University of Athens, Medical School, Athens, Greece.
Department of Internal Medicine, Larissa University Hospital, Larissa, Greece.
2nd Department of Internal Medicine, Sismanogleion General Hospital, Athens, Greece.
Department of Internal Medicine, Argos General Hospital, Argos, Greece.
2nd Department of Surgery, University of Thessaloniki, Medical School, Thessaloniki, Greece.
1st Department of Internal Medicine, 'G. Gennimatas' General Hospital, Athens, Greece.


Sepsis is the systemic inflammatory host response to infection. Cystathionine beta-synthase (CBS)-dependent homocysteine (Hcy) pathway was demonstrated to affect disease severity and mortality in patients with severe sepsis/septic shock. Independent studies identified a single-nucleotide polymorphism (SNP, rs6586282, hg19 chr21:g.44478497C>T) in intron 14 of the CBS-coding gene (CBS) associated with Hcy plasma levels. We aimed to describe the association of this SNP and variants of a splice donor-affecting variable-number tandem repeat (VNTR, NG_008938.1:g.22763_22793[16_22]) 243 bp downstream of rs6586282 with severe human sepsis. We analyzed the VNTR structure and genotyped variants of rs6586282 and a neighboring SNP (rs34758144, hg19 chr21:g.44478582G>A) in two case-control studies including patients with severe sepsis/septic shock from Germany (n=168) and Greece (n=237). In both studies, we consistently observed an association of CBS VNTR alleles with sepsis susceptibility. Risk linearly increased with number of tandem repeats (per allele odds ratio in the adjusted analysis 1.34; 95% confidence interval (CI)=1.17-1.55; P<0.001). Association had also been shown for rs34758144 whose risk allele is in linkage disequilibrium with one long VNTR allele (19 repeat). In contrast, we observed no evidence for an effect on 28-day survival in patients with severe sepsis/septic shock (per allele hazard ratio in the adjusted analysis for VNTR 1.10; 95% CI=0.95-1.28; P=0.20). In a minigene approach, we demonstrated alternative splicing in distinct VNTR alleles, which, however, was independent of the number of tandem units. In conclusion, there is no ordinary conjunction between human CBS and severe sepsis/septic shock, but CBS genotypes are involved in disease susceptibility.

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