The matrix metalloproteinase-3 (MMP-3) 5A/6A promoter polymorphism is not associated with ischaemic heart disease: Analysis employing a family based approach

Matrix metalloproteinase-3 (MMP-3) has been proposed as an important mediator of the atherosclerotic process. The possible role of the functional -1612(.)5A/6A polymorphism of the MMP-3 gene in the susceptibility to ischaemic heart disease (IHD) was investigated in a well-defined Irish population using two recently described family based tests of association. One thousand and twelve individuals from 386 families with at least one member prematurely affected with IHD were genotyped. Using the combined transmission disequilibrium test (TDT)/sib-TDT and the pedigree disequilibrium test (PDT), no association between the MMP-3 -1612 5A/6A polymorphism and IHD was found. Our data demonstrate that, in an Irish population, the MMP-3 -1612 5A/6A polymorphism is not associated with IHD.

Association of Caveolin-1 gene polymorphism with kidney transplant fibrosis and allograft failure

Context: Caveolin-1 (CAV1) is an inhibitor of tissue fibrosis.
Objective: To study the association of CAV1 gene variation with kidney transplant outcome, using kidney transplantation as a model of accelerated fibrosis.
Design, Setting, and Patients: Candidate gene association and validation study. Genomic DNA from 785 white kidney transplant donors and their respective recipients (transplantations in Birmingham, England, between 1996 and 2006; median followup, 81 months) were analyzed for common variation in CAV1 using a singlenucleotide polymorphism (SNP) tagging approach. Validation of positive findings was sought in an independent kidney transplant donor-recipient cohort (transplantations in Belfast, Northern Ireland, between 1986 and 2005; n=697; median follow-up, 69 months). Association between genotype and allograft failure was initially assessed by Kaplan-Meier analysis, then in an adjusted Cox model.
Main Outcome Measure: Death-censored allograft failure, defined as a return to dialysis or retransplantation.
Results: The presence of donor AA genotype for the CAV1 rs4730751 SNP was associated with increased risk of allograft failure in the Birmingham group (donor AA vs non-AA genotype in adjusted Cox model, hazard ratio [HR], 1.97; 95% confidence interval [CI], 1.29-3.16; P=.002). No other tag SNPs showed a significant association. This finding was validated in the Belfast cohort (in adjusted Cox model, HR, 1.56; 95% CI, 1.07-2.27; P=.02). Overall graft failure rates were as follows: for the Birmingham cohort, donor genotype AA, 22 of 57 (38.6%); genotype CC, 96 of 431 (22.3%); and genotype AC, 66 of 297 (22.2%); and for the Belfast cohort, donor genotype AA, 32 of 48 (67%); genotype CC, 150 of 358 (42%); and genotype AC, 119 of 273 (44%).
Conclusion: Among kidney transplant donors, the CAV1 rs4730751 SNP was significantly associated with allograft failure in 2 independent cohorts.

Genetic Polymorphisms in Nitric Oxide Synthase 3 Gene and Implications for Kidney Disease: A Meta-Analysis

Background/Aims: The NOS3 gene is a biological and positional candidate for diabetic nephropathy. However, the relationship between NOS3 polymorphisms and renal disease is inconclusive. This study aimed to clarify the association of NOS3 variants with nephropathy in individuals with type 1 diabetes. Methods: We conducted a case-control study examining all common SNPs in the NOS3 gene by a tag SNP approach. Individuals with type 1 diabetes and persistent proteinuria (cases, n = 718) were compared with individuals with type 1 diabetes but no evidence of renal disease (controls, n = 749). Our replication collection comprised 1,105 individuals with type 1 diabetes recruited to a nephropathy case group and 862 control individuals with normal urinary albumin excretion rates. Meta-analysis was conducted for SNPs where more than three genotype datasets were available. Results: A novel association was identified in the discovery collection (rs1800783, p(genotype) = 0.006, p(allele) = 0.002, OR = 1.26, 95% CI: 1.08-1.47) and supported by independent replication using a tag SNP (rs4496877, pairwise r(2) = 0.96 with rs1800783) in the replication collection (p(genotype) = 0.002, p(allele) = 0.0006, OR = 1.27, 95% CI: 1.10-1.45). Conclusion: The A allele of rs1800783 is a significant risk factor for nephropathy in individuals with type 1 diabetes, and further comprehensive studies are warranted to confirm the definitive functional variant in the NOS3 gene. Copyright (C) 2010 S. Karger AG, Basel

No Association of Dysbindin With Symptom Factors of Schizophrenia in an Irish Case-Control Sample

Robust associations between the dysbindin gene (DTNBP1) and schizophrenia have been demonstrated in many but not all samples, and evidence that this gene particularly predisposes to negative symptoms in this illness has been presented. The current study sought to replicate the previously reported negative symptom associations in an Irish case-control sample. Association between dysbindin and schizophrenia has been established in this cohort, and a factor analysis of the assessed symptoms yielded three factors, Positive, Negative, and Schneiderian. The sequential addition method was applied using UNPHASED to assess the relationship between these symptom factors and the high-risk haplotype. No associations were detected for any of the symptom factors indicating that the dysbindin risk haplotype does not predispose to a particular group of symptoms in this sample. Several possibilities, such as differing risk haplotypes, may explain this finding. (C) 2009 Wiley-Liss, Inc.

Meta-analysis of 32 genome-wide linkage studies of schizophrenia

A genome scan meta-analysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (P-SR) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142-168 Mb) and 2q (103-134 Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119-152 Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for 'aggregate' genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16-33 Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies. Molecular Psychiatry (2009) 14, 774-785; doi:10.1038/mp.2008.135; published online 30 December 2008