Concept and design of a genome-wide association genotyping array tailored for transplantation-specific studies

Background: In addition to HLA genetic incompatibility, non-HLA difference between donor and recipients of transplantation leading to allograft rejection are now becoming evident. We aimed to create a unique genome-wide platform to facilitate genomic research studies in transplant-related studies. We designed a genome-wide genotyping tool based on the most recent human genomic reference datasets, and included customization for known and potentially relevant metabolic and pharmacological loci relevant to transplantation. Methods: We describe here the design and implementation of a customized genome-wide genotyping array, the ‘TxArray’, comprising approximately 782,000 markers with tailored content for deeper capture of variants across HLA, KIR, pharmacogenomic, and metabolic loci important in transplantation. To test concordance and genotyping quality, we genotyped 85 HapMap samples on the array, including eight trios. Results: We show low Mendelian error rates and high concordance rates for HapMap samples (average parent-parent-child heritability of 0.997, and concordance of 0.996). We performed genotype imputation across autosomal regions, masking directly genotyped SNPs to assess imputation accuracy and report an accuracy of >0.962 for directly genotyped SNPs. We demonstrate much higher capture of the natural killer cell immunoglobulin-like receptor (KIR) region versus comparable platforms. Overall, we show that the genotyping quality and coverage of the TxArray is very high when compared to reference samples and to other genome-wide genotyping platforms. Conclusions: We have designed a comprehensive genome-wide genotyping tool which enables accurate association testing and imputation of ungenotyped SNPs, facilitating powerful and cost-effective large-scale genotyping of transplant-related studies. Electronic supplementary material The online version of this article (doi:10.1186/s13073-015-0211-x) contains supplementary material, which is available to authorized users

End-stage renal disease in patients with sickle cell disease

Sickle cell nephropathy is a severe complication of sickle cell disease (SCD) that has a wide range of manifestations, from asymptomatic microalbuminuria to end-stage renal disease (ESRD). The data on patients with SCD who develop ESRD are scarce. The aim of this study was to explore the course of patients with SCD who developed ESRD and received renal replacement therapy (RRT). The course of patients with SCD who developed ESRD and started dialysis at two centers in the Eastern Province of Saudi Arabia was retrospectively analyzed. Parameters included age at initiation of dialysis, survival until death or kidney transplantation, hospitalization due to pain crisis, disease-related parameters, and requirement for blood transfusion. Sixteen patients with SCD developed ESRD and started RRT with either hemodialysis or peritoneal dialysis. The mean age at initiation of dialysis was 46.6 years. The majority of patients (10 out of 16) were resistant to erythropoiesis-stimulating agents (ESA) and required blood transfusion repeatedly. Pain crises were infrequently encountered. Median survival was 54 months. Four patients received kidney transplantation with good outcome. In conclusion, most patients with SCD who developed ESRD were resistant to ESA and required repeated blood transfusion. The rate of hospitalization due to pain crisis was relatively low. Survival on dialysis was comparable to that of patients with no SCD, and the post-transplant course was relatively benign

Assessing known chronic kidney disease associated genetic variants in Saudi Arabian populations

Abstract Background Genome wide association studies of patients with European descent have identified common variants associated with risk of reduced estimated glomerular filtration rate (eGFR). A panel of eight variants were selected to evaluate their association and prevalence in a Saudi Arabian patient cohort with chronic kidney disease (CKD). Methods Eight genetic variants in four genes (SHROOM3, MYH9, SLC7A9, and CST3) were genotyped in 160 CKD patients and 189 ethnicity-matched healthy controls. Genetic variants were tested for association with the development of CKD (eGFR < 60 ml/min/1.73m2) and effects were compared with results obtained from 133,413 participants in the CKD genetics consortium. Multivariable regression was used to evaluate the role of these eight variants in improving prediction of CKD development. Results All eight variants were present in Saudi populations with minor allele frequency ranging from 16 to 46%. The risk variant in all four genes demonstrated the same direction of effect as observed in European populations. One variant, rs4821480, in MYH9 was significantly associated with increased risk of development of CKD (OR = 1.69, 95% CI 1.22–2.36, P = 0.002), but the additional variants were not statistically significant given our modest sample size. Conclusions CKD risk variants identified in European populations are present in Saudis. We did not find evidence to suggest heterogeneity of effect size compared to previously published estimates in European populations. Multivariable logistic regression analysis showed a statistically significant improvement in predicting the CKD using models with either FGF23 and vitamin D or FGF23, vitamin D level, and MYH9 genotypes (AUC = 0.93, 95% CI 0.90–0.95, P <  0.0001)

Additional file 1: of Assessing known chronic kidney disease associated genetic variants in Saudi Arabian populations

Table S1. One-way ANOVA comparing the various Biochemical parameters in patients stratified for ESRD, T2D and HTN. Table S2. Correlation of biochemical parameters stratified by CKD, Type 2 Diabetes and Hypertension status. (DOCX 21 kb

Additional file 1: Table S1. of Concept and design of a genome-wide association genotyping array tailored for transplantation-specific studies

Tagging and coverage of MHC region markers. Table S2: Tagging and coverage of Tx-specific genes. Table S3: Untranslated regions (UTRs) considered in the TxArray design. Table S4: Loss-of-function variants included in the TxArray. Table S5: Copy number polymorphisms (CNPs) and variations (CNVs) included in the TxArray. (DOCX 54 kb