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1.  Diagnosis and management of hyponatraemia: AGREEing the guidelines 
BMC Medicine  2015;13:31.
Hyponatraemia is a common electrolyte disorder associated with significant complications and controversies regarding its optimal management. Clinical practice guidelines and consensus statements have attempted to provide clinicians with evidence-based diagnostic and treatment strategies for hyponatraemia. Recently published guidance documents differ in their methods employed to review the quality of available evidence. Nagler et al. used the Appraisal of Guideline for Research and Evaluation (AGREE II) instrument in a systematic review of guidelines and consensus statements for the diagnosis and management of hyponatraemia. Nagler and colleagues highlighted the variability in methodological rigour applied to guideline development and inconsistencies between publications in relation to management of hyponatraemia (including the recommended rate of correction of a low serum sodium concentration). These differences could cause confusion for practising physicians managing patients with hyponatraemia.
Please see related article:
PMCID: PMC4328520
Hyponatraemia; Guidelines; Systematic review
2.  Next-generation sequencing of the mitochondrial genome and association with IgA nephropathy in a renal transplant population 
Scientific Reports  2014;4:7379.
Kidneys are highly aerobic organs that are critically dependent on the normal functioning of mitochondria. Genetic variations disrupting mitochondrial function are associated with multifactorial disorders including kidney disease. This study sequenced the entire mitochondrial genome in a renal transplant cohort of 64 individuals, using next-generation sequencing, to evaluate the association of genetic variants with IgA nephropathy and end-stage renal disease (ESRD, n = 100).
PMCID: PMC4260226  PMID: 25488329
3.  Factors influencing survival after kidney transplant failure 
The failure of a kidney transplant is now a common reason for initiation of dialysis therapy. Kidney transplant recipients commencing dialysis have greater morbidity and mortality than transplant-naïve, incident dialysis patients. This study aimed to identify variables associated with survival after graft failure.
All recipients of first, deceased donor kidney transplants performed in Northern Ireland between 1986 and 2005 who had a functioning graft at 12 months were included (n = 585). Clinical and blood-derived variables (age, gender, primary renal disease, diabetic status, smoking status, human leukocyte antigen (HLA) mismatch, acute rejection episodes, immunosuppression, cardiovascular disease, graft survival, haemoglobin, albumin, phosphate, C reactive protein, estimated glomerular filtration rate (eGFR), rate of eGFR decline, dialysis modality, and access) were collected prospectively and investigated for association with re-transplantation and survival. The association between re-transplantation and survival was explored by modelling re-transplantation as a time-dependent covariate.
Median follow-up time was 12.1 years. Recipients with a failing graft (158/585) demonstrated rapid loss of eGFR prior to graft failure, reducing the time available to plan for alternative renal replacement therapy. Median survival after graft failure was 3.0 years. In multivariate analysis, age and re-transplantation were associated with survival after graft failure. Re-transplantation was associated with an 88% reduction in mortality.
Optimal management of kidney transplant recipients with failing grafts requires early recognition of declining function and proactive preparation for re-transplantation given the substantial survival benefit this confers. The survival benefit associated with re-transplantation persists after prolonged exposure to immunosuppressive therapy.
PMCID: PMC4178314  PMID: 25276347
Kidney transplantation; Survival; Graft failure; Re-transplantation
5.  Advances in the Genetics of Familial Renal Cancer 
The Oncologist  2010;15(6):532-538.
This review discusses the distinct phenotypes of inherited renal cancer syndromes and advances in diagnosis and management. Recommendations for screening in families are discussed.
Learning Objectives
After completing this couse, the reader will be able to: Apply presymptomatic gene testing to family members with familial renal cancer in order to facilitate earlier diagnosis and treatment for this population.Use genetic testing for timely detection of familial renal cancer in carriers to enable earlier use and increased efficacy of VEGF and mTOR pathway inhibiting drugs.
This article is available for continuing medical education credit at
We discuss recent advances in the diagnosis and management of renal cell cancer (RCC) given the enhanced molecular genetics knowledge in this area. A number of hereditary renal cancer syndromes have been described, including von Hippel-Lindau disease, Birt-Hogg-Dubé syndrome, hereditary leiomyomatosis/RCC syndrome, and hereditary papillary renal cancer. Early molecular diagnosis now facilitates the management and prevention of RCC in families. Recommendations for screening in families are discussed.
PMCID: PMC3227986  PMID: 20484339
Renal cancer; Familial; MET; Papillary; Clear cell
6.  Association Testing of Previously Reported Variants in a Large Case-Control Meta-analysis of Diabetic Nephropathy 
Diabetes  2012;61(8):2187-2194.
We formed the GEnetics of Nephropathy–an International Effort (GENIE) consortium to examine previously reported genetic associations with diabetic nephropathy (DN) in type 1 diabetes. GENIE consists of 6,366 similarly ascertained participants of European ancestry with type 1 diabetes, with and without DN, from the All Ireland-Warren 3-Genetics of Kidneys in Diabetes U.K. and Republic of Ireland (U.K.-R.O.I.) collection and the Finnish Diabetic Nephropathy Study (FinnDiane), combined with reanalyzed data from the Genetics of Kidneys in Diabetes U.S. Study (U.S. GoKinD). We found little evidence for the association of the EPO promoter polymorphism, rs161740, with the combined phenotype of proliferative retinopathy and end-stage renal disease in U.K.-R.O.I. (odds ratio [OR] 1.14, P = 0.19) or FinnDiane (OR 1.06, P = 0.60). However, a fixed-effects meta-analysis that included the previously reported cohorts retained a genome-wide significant association with that phenotype (OR 1.31, P = 2 × 10−9). An expanded investigation of the ELMO1 locus and genetic regions reported to be associated with DN in the U.S. GoKinD yielded only nominal statistical significance for these loci. Finally, top candidates identified in a recent meta-analysis failed to reach genome-wide significance. In conclusion, we were unable to replicate most of the previously reported genetic associations for DN, and significance for the EPO promoter association was attenuated.
PMCID: PMC3402313  PMID: 22721967
7.  TGFβ and CCN2/CTGF mediate actin related gene expression by differential E2F1/CREB activation 
BMC Genomics  2013;14:525.
CCN2/CTGF is an established effector of TGFβ driven responses in diabetic nephropathy. We have identified an interaction between CCN2 and TGFβ leading to altered phenotypic differentiation and inhibited cellular migration. Here we determine the gene expression profile associated with this phenotype and define a transcriptional basis for differential actin related gene expression and cytoskeletal function.
From a panel of genes regulated by TGFβ and CCN2, we used co-inertia analysis to identify and then experimentally verify a subset of transcription factors, E2F1 and CREB, that regulate an expression fingerprint implicated in altered actin dynamics and cell hypertrophy. Importantly, actin related genes containing E2F1 and CREB binding sites, stratified by expression profile within the dataset. Further analysis of actin and cytoskeletal related genes from patients with diabetic nephropathy suggests recapitulation of this programme during the development of renal disease. The Rho family member Cdc42 was also found uniquely to be activated in cells treated with TGFβ and CCN2; Cdc42 interacting genes were differentially regulated in diabetic nephropathy.
TGFβ and CCN2 attenuate CREB and augment E2F1 transcriptional activation with the likely effect of altering actin cytoskeletal and cell growth/hypertrophic gene activity with implications for cell dysfunction in diabetic kidney disease. The cytoskeletal regulator Cdc42 may play a role in this signalling response.
PMCID: PMC3765338  PMID: 23902294
TGF beta; CTGF/CCN2; Actin; CREB; E2F1
8.  Caveolin-1 Single Nucleotide Polymorphism in Antineutrophil Cytoplasmic Antibody Associated Vasculitis 
PLoS ONE  2013;8(7):e69022.
Immunosuppression is cornerstone treatment of antineutrophil cytoplasmic antibody associated vasculitis (AAV) but is later complicated by infection, cancer, cardiovascular and chronic kidney disease. Caveolin-1 is an essential structural protein for small cell membrane invaginations known as caveolae. Its functional role has been associated with these complications. For the first time, caveolin-1 (CAV1) gene variation is studied in AAV.
CAV1 single nucleotide polymorphism rs4730751 was analysed in genomic DNA from 187 white patients with AAV from Birmingham, United Kingdom. The primary outcome measure was the composite endpoint of time to all-cause mortality or renal replacement therapy. Secondary endpoints included time to all-cause mortality, death from sepsis or vascular disease, cancer and renal replacement therapy. Validation of results was sought from 589 white AAV patients, from two European cohorts.
The primary outcome occurred in 41.7% of Birmingham patients. In a multivariate model, non-CC genotype variation at the studied single nucleotide polymorphism was associated with increased risk from: the primary outcome measure [HR 1.86; 95% CI: 1.14-3.04; p=0.013], all-cause mortality [HR:1.83; 95% CI: 1.02-3.27; p=0.042], death from infection [HR:3.71; 95% CI: 1.28-10.77; p=0.016], death from vascular disease [HR:3.13; 95% CI: 1.07-9.10; p=0.037], and cancer [HR:5.55; 95% CI: 1.59-19.31; p=0.007]. In the validation cohort, the primary outcome rate was far lower (10.4%); no association between genotype and the studied endpoints was evident.
The presence of a CC genotype in Birmingham is associated with protection from adverse outcomes of immunosuppression treated AAV. Lack of replication in the European cohort may have resulted from low clinical event rates. These findings are worthy of further study in larger cohorts.
PMCID: PMC3716813  PMID: 23894397
9.  Haplotype association analysis of genes within the WNT signalling pathways in diabetic nephropathy 
BMC Nephrology  2013;14:126.
Renal interstitial fibrosis and glomerular sclerosis are hallmarks of diabetic nephropathy (DN) and several studies have implicated members of the WNT pathways in these pathological processes. This study comprehensively examined common genetic variation within the WNT pathway for association with DN.
Genes within the WNT pathways were selected on the basis of nominal significance and consistent direction of effect in the GENIE meta-analysis dataset. Common SNPs and common haplotypes were examined within the selected WNT pathway genes in a white population with type 1 diabetes, discordant for DN (cases: n = 718; controls: n = 749). SNPs were genotyped using Sequenom or Taqman assays. Association analyses were performed using PLINK, to compare allele and haplotype frequencies in cases and controls. Correction for multiple testing was performed by either permutation testing or using false discovery rate.
A logistic regression model including collection centre, duration of diabetes, and average HbA1c as covariates highlighted three SNPs in GSK3B (rs17810235, rs17471, rs334543), two in DAAM1 (rs1253192, rs1252906) and one in NFAT5 (rs17297207) as being significantly (P < 0.05) associated with DN, however these SNPs did not remain significant after correction for multiple testing. Logistic regression of haplotypes, with ESRD as the outcome, and pairwise interaction analyses did not yield any significant results after correction for multiple testing.
These results indicate that both common SNPs and common haplotypes of WNT pathway genes are not strongly associated with DN. However, this does not completely exclude these or the WNT pathways from association with DN, as unidentified rare genetic or copy number variants could still contribute towards the genetic architecture of DN.
PMCID: PMC3701522  PMID: 23777469
Diabetic nephropathy; WNT signalling pathway; Association study; End-stage renal disease
10.  Comprehensive Investigation of the Caveolin 2 Gene: Resequencing and Association for Kidney Transplant Outcomes 
PLoS ONE  2013;8(5):e63358.
Caveolae are plasma membrane structures formed from a complex of the proteins caveolin-1 and caveolin-2. Caveolae interact with pro-inflammatory cytokines and are dysregulated in fibrotic disease. Although caveolae are present infrequently in healthy kidneys, they are abundant during kidney injury. An association has been identified between a CAV1 gene variant and long term kidney transplant survival. Chronic, gradual decline in transplant function is a persistent problem in kidney transplantation. The aetiology of this is diverse but fibrosis within the transplanted organ is the common end point. This study is the first to investigate the association of CAV2 gene variants with kidney transplant outcomes. Genomic DNA from donors and recipients of 575 kidney transplants performed in Belfast was investigated for common variation in CAV2 using a tag SNP approach. The CAV2 SNP rs13221869 was nominally significant for kidney transplant failure. Validation was sought in an independent group of kidney transplant donors and recipients from Dublin, Ireland using a second genotyping technology. Due to the unexpected absence of rs13221869 from this cohort, the CAV2 gene was resequenced. One novel SNP and a novel insertion/deletion in CAV2 were identified; rs13221869 is located in a repetitive region and was not a true variant in resequenced populations. CAV2 is a plausible candidate gene for association with kidney transplant outcomes given its proximity to CAV1 and its role in attenuating fibrosis. This study does not support an association between CAV2 variation and kidney transplant survival. Further analysis of CAV2 should be undertaken with an awareness of the sequence complexities and genetic variants highlighted by this study.
PMCID: PMC3646761  PMID: 23667606
11.  Association Analysis of Dyslipidemia-Related Genes in Diabetic Nephropathy 
PLoS ONE  2013;8(3):e58472.
Type 1 diabetes (T1D) increases risk of the development of microvascular complications and cardiovascular disease (CVD). Dyslipidemia is a common risk factor in the pathogenesis of both CVD and diabetic nephropathy (DN), with CVD identified as the primary cause of death in patients with DN. In light of this commonality, we assessed single nucleotide polymorphisms (SNPs) in thirty-seven key genetic loci previously associated with dyslipidemia in a T1D cohort using a case-control design. SNPs (n = 53) were genotyped using Sequenom in 1467 individuals with T1D (718 cases with proteinuric nephropathy and 749 controls without nephropathy i.e. normal albumin excretion). Cases and controls were white and recruited from the UK and Ireland. Association analyses were performed using PLINK to compare allele frequencies in cases and controls. In a sensitivity analysis, samples from control individuals with reduced renal function (estimated glomerular filtration rate<60 ml/min/1.73 m2) were excluded. Correction for multiple testing was performed by permutation testing. A total of 1394 samples passed quality control filters. Following regression analysis adjusted by collection center, gender, duration of diabetes, and average HbA1c, two SNPs were significantly associated with DN. rs4420638 in the APOC1 region (odds ratio [OR]  = 1.51; confidence intervals [CI]: 1.19–1.91; P = 0.001) and rs1532624 in CETP (OR = 0.82; CI: 0.69–0.99; P = 0.034); rs4420638 was also significantly associated in a sensitivity analysis (P = 0.016) together with rs7679 (P = 0.027). However, no association was significant following correction for multiple testing. Subgroup analysis of end-stage renal disease status failed to reveal any association. Our results suggest common variants associated with dyslipidemia are not strongly associated with DN in T1D among white individuals. Our findings, cannot entirely exclude these key genes which are central to the process of dyslipidemia, from involvement in DN pathogenesis as our study had limited power to detect variants of small effect size. Analysis in larger independent cohorts is required.
PMCID: PMC3608831  PMID: 23555584
12.  Genetic Examination of SETD7 and SUV39H1/H2 Methyltransferases and the Risk of Diabetes Complications in Patients With Type 1 Diabetes 
Diabetes  2011;60(11):3073-3080.
Hyperglycemia plays a pivotal role in the development and progression of vascular complications, which are the major sources of morbidity and mortality in diabetes. Furthermore, these vascular complications often persist and progress despite improved glucose control, possibly as a result of prior episodes of hyperglycemia. Epigenetic modifications mediated by histone methyltransferases are associated with gene-activating events that promote enhanced expression of key proinflammatory molecules implicated in vascular injury. In this study, we investigated genetic polymorphisms of the SETD7, SUV39H1, and SUV39H2 methyltransferases as predictors of risk for micro- and macrovascular complications in type 1 diabetes.
In the Finnish Diabetic Nephropathy Study (FinnDiane) cohort, 37 tagging single nucleotide polymorphisms (SNPs) were genotyped in 2,991 individuals with type 1 diabetes and diabetic retinopathy, diabetic nephropathy, and cardiovascular disease. Seven SNPs were genotyped in the replication cohorts from the Steno Diabetes Center and All Ireland/Warren 3/Genetics of Kidneys in Diabetes (GoKinD) U.K. study.
In a meta-analysis, the minor T allele of the exonic SNP rs17353856 in the SUV39H2 was associated with diabetic retinopathy (genotypic odds ratio 0.75, P = 1.2 × 10−4). The same SNP showed a trend toward an association with diabetic nephropathy as well as cardiovascular disease in the FinnDiane cohort.
Our findings propose that a genetic variation in a gene coding for a histone methyltransferase is protective for a diabetic microvascular complication. The pathophysiological implications of this polymorphism or other genetic variation nearby for the vascular complications of type 1 diabetes remain to be investigated.
PMCID: PMC3198095  PMID: 21896933
13.  New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes 
Sandholm, Niina | Salem, Rany M. | McKnight, Amy Jayne | Brennan, Eoin P. | Forsblom, Carol | Isakova, Tamara | McKay, Gareth J. | Williams, Winfred W. | Sadlier, Denise M. | Mäkinen, Ville-Petteri | Swan, Elizabeth J. | Palmer, Cameron | Boright, Andrew P. | Ahlqvist, Emma | Deshmukh, Harshal A. | Keller, Benjamin J. | Huang, Huateng | Ahola, Aila J. | Fagerholm, Emma | Gordin, Daniel | Harjutsalo, Valma | He, Bing | Heikkilä, Outi | Hietala, Kustaa | Kytö, Janne | Lahermo, Päivi | Lehto, Markku | Lithovius, Raija | Österholm, Anne-May | Parkkonen, Maija | Pitkäniemi, Janne | Rosengård-Bärlund, Milla | Saraheimo, Markku | Sarti, Cinzia | Söderlund, Jenny | Soro-Paavonen, Aino | Syreeni, Anna | Thorn, Lena M. | Tikkanen, Heikki | Tolonen, Nina | Tryggvason, Karl | Tuomilehto, Jaakko | Wadén, Johan | Gill, Geoffrey V. | Prior, Sarah | Guiducci, Candace | Mirel, Daniel B. | Taylor, Andrew | Hosseini, S. Mohsen | Parving, Hans-Henrik | Rossing, Peter | Tarnow, Lise | Ladenvall, Claes | Alhenc-Gelas, François | Lefebvre, Pierre | Rigalleau, Vincent | Roussel, Ronan | Tregouet, David-Alexandre | Maestroni, Anna | Maestroni, Silvia | Falhammar, Henrik | Gu, Tianwei | Möllsten, Anna | Cimponeriu, Danut | Ioana, Mihai | Mota, Maria | Mota, Eugen | Serafinceanu, Cristian | Stavarachi, Monica | Hanson, Robert L. | Nelson, Robert G. | Kretzler, Matthias | Colhoun, Helen M. | Panduru, Nicolae Mircea | Gu, Harvest F. | Brismar, Kerstin | Zerbini, Gianpaolo | Hadjadj, Samy | Marre, Michel | Groop, Leif | Lajer, Maria | Bull, Shelley B. | Waggott, Daryl | Paterson, Andrew D. | Savage, David A. | Bain, Stephen C. | Martin, Finian | Hirschhorn, Joel N. | Godson, Catherine | Florez, Jose C. | Groop, Per-Henrik | Maxwell, Alexander P.
PLoS Genetics  2012;8(9):e1002921.
Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ∼2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2×10−8) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0×10−9). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-β1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1×10−7), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.
Author Summary
The global prevalence of diabetes has reached epidemic proportions, constituting a major health care problem worldwide. Diabetic kidney disease, or diabetic nephropathy (DN)—the major long term microvascular complication of diabetes—is associated with excess mortality among patients with type 1 diabetes. Even though DN has been shown to cluster in families, the underlying genetic and molecular pathways remain poorly defined. We have undertaken the largest genome-wide association study and meta-analysis to date on DN and on its most severe form of kidney disease, end-stage renal disease (ESRD). We identified new loci significantly associated with diabetic ESRD: AFF3 and an intergenic locus on chromosome 15q26 residing between RGMA and MCTP2. Our functional analyses suggest that AFF3 influences renal tubule fibrosis, a pathological hallmark of severe DN. Another locus in ERBB4 was suggestively associated with DN and resides in the same intronic region as a variant affecting the expression of ERBB4. Subsequent pathway analysis of the genes co-expressed with ERBB4 indicated involvement of fibrosis.
PMCID: PMC3447939  PMID: 23028342
14.  Novel Susceptibility Locus at 22q11 for Diabetic Nephropathy in Type 1 Diabetes 
PLoS ONE  2011;6(9):e24053.
Diabetic nephropathy (DN) affects about 30% of patients with type 1 diabetes (T1D) and contributes to serious morbidity and mortality. So far only the 3q21–q25 region has repeatedly been indicated as a susceptibility region for DN. The aim of this study was to search for new DN susceptibility loci in Finnish, Danish and French T1D families.
Methods and Results
We performed a genome-wide linkage study using 384 microsatellite markers. A total of 175 T1D families were studied, of which 94 originated from Finland, 46 from Denmark and 35 from France. The whole sample set consisted of 556 individuals including 42 sib-pairs concordant and 84 sib-pairs discordant for DN. Two-point and multi-point non-parametric linkage analyses were performed using the Analyze package and the MERLIN software. A novel DN locus on 22q11 was identified in the joint analysis of the Finnish, Danish and French families by genome-wide multipoint non-parametric linkage analysis using the Kong and Cox linear model (NPLpairs LOD score 3.58). Nominal or suggestive evidence of linkage to this locus was also detected when the three populations were analyzed separately. Suggestive evidence of linkage was found to six additional loci in the Finnish and French sample sets.
This study identified a novel DN locus at chromosome 22q11 with significant evidence of linkage to DN. Our results suggest that this locus may be of importance in European populations. In addition, this study supports previously indicated DN loci on 3q21–q25 and 19q13.
PMCID: PMC3164698  PMID: 21909410
15.  Association Analysis of Canonical Wnt Signalling Genes in Diabetic Nephropathy 
PLoS ONE  2011;6(8):e23904.
Several studies have provided compelling evidence implicating the Wnt signalling pathway in the pathogenesis of diabetic nephropathy. Gene expression profiles associated with renal fibrosis have been attenuated through Wnt pathway modulation in model systems implicating Wnt pathway members as potential therapeutic targets for the treatment of diabetic nephropathy. We assessed tag and potentially functional single nucleotide polymorphisms (SNPs; n = 31) in four key Wnt pathway genes (CTNNB1, AXIN2, LRP5 and LRP6) for association with diabetic nephropathy using a case-control design.
SNPs were genotyped using Sequenom or Taqman technologies in 1351 individuals with type 1 diabetes (651 cases with nephropathy and 700 controls without nephropathy). Cases and controls were white and recruited from the UK and Ireland. Association analyses were performed using PLINK, to compare allele and haplotype frequencies in cases and controls. Adjustment for multiple testing was performed by permutation testing.
Following logistic regression analysis adjusted by collection centre, duration of T1D, and average HbA1c as covariates, a single SNP in LRP6 (rs1337791) was significantly associated with DN (OR = 0.74; CI: 0.57–0.97; P = 0.028), although this was not maintained following correction for multiple testing. Three additional SNPs (rs2075241 in LRP6; rs3736228 and rs491347 both in LRP5) were marginally associated with diabetic nephropathy, but none of the associations were replicated in an independent dataset. Haplotype and subgroup analysis (according to duration of diabetes, and end-stage renal disease) also failed to reveal an association with diabetic nephropathy.
Our results suggest that analysed common variants in CTNNB1, AXIN2, LRP5 and LRP6 are not strongly associated with diabetic nephropathy in type 1 diabetes among white individuals. Our findings, however, cannot entirely exclude these genes or other members of the Wnt pathway, from involvement in the pathogenesis of diabetic nephropathy as our study had limited power to detect variants with small effect size.
PMCID: PMC3158097  PMID: 21876774
16.  Elevated soluble cellular adhesion molecules are associated with increased mortality in a prospective cohort of renal transplant recipients 
BMC Nephrology  2011;12:23.
Increased plasma levels of cellular adhesion molecules (CAMs) have been shown to be predictors of all cause mortality in individuals with chronic renal failure [1,2] and patients with end-stage renal disease receiving haemodialysis [3]. In renal transplant recipients the predictive value of CAMs has not been well characterised. The aim of this study was to assess the relationship between CAMs and all-cause mortality during prospective follow-up of a renal transplant cohort.
A total of 378 renal transplant recipients were recruited between June 2000 and December 2002. Soluble vascular CAM-1 (VCAM) and soluble intercellular CAM-1 (ICAM) were measured at baseline and prospective follow-up data was collected at a median of 2441 days after enrolment.
In univariate survival analysis the renal transplant recipients with a VCAM or ICAM concentration in the lowest third were significantly more likely to have survived at follow-up (p < 0.001 and p = 0.009 respectively). In multivariate survival analysis VCAM and ICAM remained significant independent predictors of mortality following adjustment for traditional cardiovascular risk factors, hsCRP and estimated GFR (p = 0.030 and p = 0.037 respectively).
The results of this prospective study are the first to show that the CAMs, ICAM and particularly VCAM, are significant independent predictors of mortality in patients with a renal transplant.
PMCID: PMC3120748  PMID: 21600046
17.  Targeted genome-wide investigation identifies novel SNPs associated with diabetic nephropathy 
The HUGO Journal  2010;3(1-4):77-82.
Loci contributing to complex disease have been identified by focusing on genome-wide scans utilising non-synonymous single nucleotide polymorphisms (nsSNPs). We employed Illumina’s HNS12 BeadChip (13,917 high-value SNPs) which was specifically designed to capture nsSNPs and ideally complements more dense genome-wide association studies that fail to consider many of these putatively functional variants. The HNS12 panel also includes 870 tag SNPs covering the major histocompatibility region. All individuals genotyped in this study were Caucasians with (cases) and without (controls) diabetic nephropathy. About 449 individuals with type 2 diabetes (203 cases, 246 controls) were genotyped in the initial study. 1,467 individuals with type 1 diabetes (718 cases, 749 controls) were genotyped in the follow up study. 11,152 SNPs were successfully analysed and ranked for association with diabetic nephropathy based on significance (P) values. The top ranked 32 SNPs were subsequently genotyped using MassARRAY iPLEX™ and TaqMan technologies to investigate association of these polymorphisms with nephropathy in individuals with type 1 diabetes. The top ranked nsSNP, rs1543547 (P = 10−5), is located in RAET1L, a major histocompatibility class I-related gene at 6q25.1. Of particular interest, multiple nsSNPs within the top ranked (0.2%) SNPs are within several plausible candidate genes for nephropathy on 3q21.3 and 6p21.3.
PMCID: PMC2882642  PMID: 21119753
nsSNP; MHC; Genetic predisposition; Diabetic nephropathy
18.  Genome-wide DNA methylation analysis for diabetic nephropathy in type 1 diabetes mellitus 
BMC Medical Genomics  2010;3:33.
Diabetic nephropathy is a serious complication of diabetes mellitus and is associated with considerable morbidity and high mortality. There is increasing evidence to suggest that dysregulation of the epigenome is involved in diabetic nephropathy. We assessed whether epigenetic modification of DNA methylation is associated with diabetic nephropathy in a case-control study of 192 Irish patients with type 1 diabetes mellitus (T1D). Cases had T1D and nephropathy whereas controls had T1D but no evidence of renal disease.
We performed DNA methylation profiling in bisulphite converted DNA from cases and controls using the recently developed Illumina Infinium® HumanMethylation27 BeadChip, that enables the direct investigation of 27,578 individual cytosines at CpG loci throughout the genome, which are focused on the promoter regions of 14,495 genes.
Singular Value Decomposition (SVD) analysis indicated that significant components of DNA methylation variation correlated with patient age, time to onset of diabetic nephropathy, and sex. Adjusting for confounding factors using multivariate Cox-regression analyses, and with a false discovery rate (FDR) of 0.05, we observed 19 CpG sites that demonstrated correlations with time to development of diabetic nephropathy. Of note, this included one CpG site located 18 bp upstream of the transcription start site of UNC13B, a gene in which the first intronic SNP rs13293564 has recently been reported to be associated with diabetic nephropathy.
This high throughput platform was able to successfully interrogate the methylation state of individual cytosines and identified 19 prospective CpG sites associated with risk of diabetic nephropathy. These differences in DNA methylation are worthy of further follow-up in replication studies using larger cohorts of diabetic patients with and without nephropathy.
PMCID: PMC2924253  PMID: 20687937

Results 1-18 (18)