P23 CBS gene variants are associated with conditions characterized by ischemia

Abstract

The CBS gene regulates the expression of cystathionine beta-synthase (CBS), a key enzyme in the production of hydrogen sulfide (H 2 S) by conversion of homocysteine (Hcy). H 2 S is a gasotransmitter that protects cells against ischemic damage by exerting vasodilatory, anti-inflammatory and antioxidant effects. Both renal transplantation and preeclampsia (PE) are conditions marked by ischemia. Renal ischemia/reperfusion impairs CBS activity and consequently H 2 S production. Partial restoration of CBS activity causes an increase in H 2 S levels and a reduction of ischemia/reperfusion damage. Also, H 2 S is involved in placental vascular tone regulation. Furthermore, preeclamptic women have hyperhomocysteinemia and a decreased placental expression of the CBS gene. We therefore hypothesize that variations in the CBS gene caused by single nucleotide polymorphisms (SNPs) affect both susceptibility to ischemic damage in renal transplantation and the onset of PE. The genotype of 1271 renal transplantation donor and recipient pairs in the University Medical Centre Groningen were determined for seven tag SNPs in the CBS locus. These SNPs were analyzed for association with primary non-function (PNF), delayed graft function, first years biopsy proven acute rejection, death-censored graft survival and patient survival. In the Oslo University Hospital, 99 controls and 60 severe and 39 mild cases of PE were genotyped for six of these seven tag SNPs. Severe and mild cases of PE were subdivided into early- (<34 weeks) and late-onset (>34 weeks of pregnancy). The SNPs were then analyzed for association with the onset of PE. Univariate analysis showed improved graft survival in kidney transplant recipients that homozygously carry the minor allele of rs11203172 (HR[95%CI] = 0.124[0.017–0.882], p = 0.013 (homozygous carriers of the minor allele versus others)). Furthermore, no PNF was seen in these patients. Multivariate analyses showed no significant associations, most probably due to the relatively low number of patients in this group and the number of parameters studied. Univariate analysis also showed patients carrying the minor allele of rs11203172 to have a reduced risk to develop severe PE (OR[95%CI] = 0.54[0.21–0.94], p = 0.023). Conversely, the minor allele of rs234706, which is known to be associated with low Hcy, increased the risk to develop mild, late-onset PE (2.10[1.15–3.85], p = 0.016). SNPs in the CBS gene are associated with both kidney graft survival and the risk to develop PE. Changes of the function or expression of CBS caused by SNPs may affect ischemic conditions through decreased H 2 S production or Hcy accumulation. Since CBS is markedly reduced under ischemic conditions we assume that these findings are of considerable importance. Further characterization of the effects of these CBS gene variants and their alleged role in ischemia is warranted.