No evidence for linkage in the promoter region of the inducible nitric oxide synthase gene (NOS2) in a Danish type 1 diabetes population

Abstract

Exposure of human pancreatic islets to a mixture of cytokines induces expression of inducible nitric oxide synthase (iNOS), impairs beta-cell function and induces apoptosis. Exposing human islets to high amounts of NO from chemical NO-donors causes DNA strand breaks and mitochondrial damage, suggesting that NO is deleterious to human beta-cells. Hence, we consider the gene encoding iNOS in beta-cells, NOS2, a candidate gene for type 1 diabetes in humans. In the present study we have tested three identified polymorphisms within the promoter sequence of the human NOS2 gene in a type 1 diabetic family material comprising 154 affected sib-pair families and 103 affected simplex families (1143 individuals in total). PCR-based amplification of the polymorphic loci were established. Linkage analysis was performed using the extended transmission disequilibrium testing (ETDT). A Bsal RFLP was found not to be polymorphic in 20 type 1 diabetic patients and 14 healthy control subjects and was not analysed further. In affected cases a nine allele CCTTT repeat and a bi-allelic TAAA repeat revealed allelewise P etdt of 0.52 and 0.60, respectively. ETDT applied to {(TAAA)n; (CCTTT)n} haplotypes demonstrated random transmission from heterozygous parents to affected offspring. In conclusion, the tested polymorphisms within the NOS2 gene promoter did not show evidence for linkage to type 1 diabetes in a Danish family material. Genes and Immunity (2000) 1, 362-366.

Genetic determinants of rheumatoid arthritis: the inducible nitric oxide synthase (NOS2) gene promoter polymorphism

“…This is consistent with former studies where it has always been shown nonpolymorphic in Caucasian populations. 7,13 Regarding the bi-allelic TAAA marker (for methods see Glenn et al 14 13,14 and confirm that the (TAAA) n marker is not very informative in detecting association due to its limited degree of polymorphism. The multiallelic (CCTTT) n repeat is on the contrary an attractive disease-causing candidate, being a highly polymorphic marker with a recently suggested effect in NOS2 transcription.…”

“…The (TAAA) n and (CCTTT) n ms at the NOS2 promoter region have been analysed for association with the susceptibility to IDDM, other autoimmune and complex genetic condition, in which iNOS mediated NO production has been implicated, and similar to us, no linkage of the two NOS2 promoter microsatellites was observed in a large collection of families. 13 Likewise, no association was identified when TAAA-CCTTT haplotypes were constructed and analysed in our RA case-control cohort. Of note no linkage disequilibrium (LD) was found between the two markers.…”

“…In addition, the reported genetic heterogeneity within and between ethnic groups in the highly polymorphic promoter (CCTTT) n repeat 13 raises the possibility that a (CCTTT) n allele might be associated with the disease in a different population. Detailed functional assays, epidemiological studies in different populations and searching of existence of additional polymorphisms in both the promoter region and the codon region of the NOS2 could be useful to address the potential involvement of the NOS2 gene in the genetic predisposition to RA.…”

The association between chronic pancreatitis and the iNOS-2087A>G polymorphism

“…These single nucleotide polymorphisms seem to be ethnically specific, taking into account the results of the previous studies [27]. As to the Romanian population, there is no study with respect to the iNOS2 -2087A>G polymorphism.…”

Genetic Determinants of Microvascular Complications in Type 1 Diabetes

“…In diabetic milieu as long as NOS3 expression is low, the induction of NOS2 expression may occur in an attempt to achieve homeostasis, being crucial in preventing or delaying pathological alterations in the microcirculation (Warpeha & Chakravarthy 2003). In studies of diabetic complications, as DR and DN, influenced by vascular functional disturbances, the increased NO formation via NOS2 expression has been reported (Johannesen et al, 2000a). In human NOS2A gene has been identified a large number of polymorphisms.…”