Evaluation of HLA typing content of next-generation sequencing datasets from family trios and individuals of arab ethnicity.

Introduction: HLA typing is a critical tool in both clinical and research applications at the individual and population levels. Benchmarking studies have indicated HLA-HD as the preferred tool for accurate and comprehensive HLA allele calling. The advent of next-generation sequencing (NGS) has revolutionized genetic analysis by providing high-throughput sequencing data. This study aims to evaluate, using the HLA-HD tool, the HLA typing content of whole exome, whole genome, and HLA-targeted panel sequence data from the consanguineous population of Arab ethnicity, which has been underrepresented in prior benchmarking studies. Methods: We utilized sequence data from family trios and individuals, sequenced on one or more of the whole exome, whole genome, and HLA-targeted panel sequencing technologies. The performance and resolution across various HLA genes were evaluated. We incorporated a comparative quality control analysis, assessing the results obtained from HLA-HD by comparing them with those from the HLA-Twin tool to authenticate the accuracy of the findings. Results: Our analysis found that alleles across 29 HLA loci can be successfully and consistently typed from NGS datasets. Clinical-grade whole exome sequencing datasets achieved the highest consistency rate at three-field resolution, followed by targeted HLA panel, research-grade whole exome, and whole genome datasets. Discussion: The study catalogues HLA typing consistency across NGS datasets for a large array of HLA genes and highlights assessments regarding the feasibility of utilizing available NGS datasets in HLA allele studies. These findings underscore the reliability of HLA-HD for HLA typing in underrepresented populations and demonstrate the utility of various NGS technologies in achieving accurate HLA allele calling.

Identification of potential regulatory mechanisms and therapeutic targets for lung cancer.

Lung cancer poses a significant health threat globally, especially in regions like India, with 5-year survival rates remain alarmingly low. Our study aimed to uncover key markers for effective treatment and early detection. We identified specific genes related to lung cancer using the BioXpress database and delved into their roles through DAVID enrichment analysis. By employing network theory, we explored the intricate interactions within lung cancer networks, identifying ASPM and MKI67 as crucial regulator genes. Predictions of microRNA and transcription factor interactions provided additional insights. Examining gene expression patterns using GEPIA and KM Plotter revealed the clinical relevance of these key genes. In our pursuit of targeted therapies, Drug Bank pointed to methotrexate as a potential drug for the identified key regulator genes. Confirming this, molecular docking studies through Swiss Dock showed promising binding interactions. To ensure stability, we conducted molecular dynamics simulations using the AMBER 16 suite. In summary, our study pinpoints ASPM and MKI67 as vital regulators in lung cancer networks. The identification of hub genes and functional pathways enhances our understanding of molecular processes, offering potential therapeutic targets. Importantly, methotrexate emerged as a promising drug candidate, supported by robust docking and simulation studies. These findings lay a solid foundation for further experimental validations and hold promise for advancing personalized therapeutic strategies in lung cancer.Communicated by Ramaswamy H. Sarma.

ONECUT1 variants beyond type 1 and type 2 diabetes: exploring clinical diversity and epigenetic associations in Arab cohorts.

ONECUT1 gene, encoding hepatocyte nuclear factor 6, is involved in pancreas and liver development. ONECUT1 mutations impair the function of pancreatic ß-cells and control a transcriptional/epigenetic machinery regulating endocrine development. Homozygous nonsense and missense mutations at ONECUT1_p.E231 and a homozygous frameshift mutation at ONECUT1_p.M289 were reported in neonatal diabetes individuals of French, Turkish, and Indian ethnicity, respectively. Additionally, heterozygous variants were observed in Northern European T2D patients, and Italian patients with neonatal diabetes and early-/late-onset T2D. Examining diverse populations, such as Arabs known for consanguinity, can generalize the ONECUT1 involvement in diabetes. Upon screening the cohorts of Kuwaiti T1D and MODY families, and of Kuwaiti and Qatari T2D individuals, we observed two homozygous variants-the deleterious missense rs202151356_p.H33Q in one MODY, one T1D, and two T2D individuals, and the synonymous rs61735385_p.P94P in two T2D individuals. Heterozygous variants were also observed. Examination of GTEx, NephQTL, mQTLdb and HaploReg highlighted the rs61735385_p.P94P variant as eQTL influencing the tissue-specific expression of ONECUT1, as mQTL influencing methylation at CpG sites in and around ONECUT1 with the nearest site at 677-bases 3' to rs61735385_p.P94P; as overlapping predicted binding sites for NF-kappaB and EBF on ONECUT1. DNA methylation profiles of peripheral blood from 19 MODY-X patients versus eight healthy individuals revealed significant hypomethylation at two CpG sites-one located 617-bases 3' to the p.P94P variant and 8,102 bases away from transcription start; and the other located 14,999 bases away from transcription start. Our study generalizes the association of ONECUT1 with clinical diversity in diabetes.

Association between alleles, haplotypes, and amino acid variations in HLA class II genes and type 1 diabetes in Kuwaiti children.

Type 1 diabetes (T1D) is a complex autoimmune disorder that is highly prevalent globally. The interactions between genetic and environmental factors may trigger T1D in susceptible individuals. HLA genes play a significant role in T1D pathogenesis, and specific haplotypes are associated with an increased risk of developing the disease. Identifying risk haplotypes can greatly improve the genetic scoring for early diagnosis of T1D in difficult to rank subgroups. This study employed next-generation sequencing to evaluate the association between HLA class II alleles, haplotypes, and amino acids and T1D, by recruiting 95 children with T1D and 150 controls in the Kuwaiti population. Significant associations were identified for alleles at the HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci, including DRB1*03:01:01, DQA1*05:01:01, and DQB1*02:01:01, which conferred high risk, and DRB1*11:04:01, DQA1*05:05:01, and DQB1*03:01:01, which were protective. The DRB1*03:01:01~DQA1*05:01:01~DQB1*02:01:01 haplotype was most strongly associated with the risk of developing T1D, while DRB1*11:04-DQA1*05:05-DQB1*03:01 was the only haplotype that rendered protection against T1D. We also identified 66 amino acid positions across the HLA-DRB1, HLA-DQA1, and HLA-DQB1 genes that were significantly associated with T1D, including novel associations. These results validate and extend our knowledge on the associations between HLA genes and T1D in Kuwaiti children. The identified risk alleles, haplotypes, and amino acid variations may influence disease development through effects on HLA structure and function and may allow early intervention via population-based screening efforts.

Disruption in the regulation of casein kinase 2 in circadian rhythm leads to pathological states: cancer, diabetes and neurodegenerative disorders.

Introduction: Circadian rhythm maintains the sleep-wake cycle in biological systems. Various biological activities are regulated and modulated by the circadian rhythm, disruption of which can result in onset of diseases. Robust rhythms of phosphorylation profiles and abundances of PERIOD (PER) proteins are thought to be the master keys that drive circadian clock functions. The role of casein kinase 2 (CK2) in circadian rhythm via its direct interactions with the PER protein has been extensively studied; however, the exact mechanism by which it affects circadian rhythms at the molecular level is not known. Methods: Here, we propose an extended circadian rhythm model in Drosophila that incorporates the crosstalk between the PER protein and CK2. We studied the regulatory role of CK2 in the dynamics of PER proteins involved in circadian rhythm using the stochastic simulation algorithm. Results: We observed that variations in the concentration of CK2 in the circadian rhythm model modulates the PER protein dynamics at different cellular states, namely, active, weakly active, and rhythmic death. These oscillatory states may correspond to distinct pathological cellular states of the living system. We find molecular noise at the expression level of CK2 to switch normal circadian rhythm to any of the three above-mentioned circadian oscillatory states. Our results suggest that the concentration levels of CK2 in the system has a strong impact on its dynamics, which is reflected in the time evolution of PER protein. Discussion: We believe that our findings can contribute towards understanding the molecular mechanisms of circadian dysregulation in pathways driven by the PER mutant genes and their pathological states, including cancer, obesity, diabetes, neurodegenerative disorders, and socio-psychological disease.

Signatures of purifying selection and site-specific positive selection on the mitochondrial DNA of dromedary camels (Camelus dromedarius).

The two species of the Old World Camelini tribe, dromedary and Bactrian camels, show superior adaptability to the different environmental conditions they populate, e.g. desert, mountains and coastal areas, which might be associated with adaptive variations on their mitochondrial DNA. Here, we investigate signatures of natural selection in the 13-mitochondrial protein-coding genes of different dromedary camel populations from the Arabian Peninsula, Africa and southwest Asia. The full mitogenome sequences of 42 dromedaries, 38 domestic Bactrian, 29 wild Bactrian camels and 31 samples representing the New World Lamini tribe reveal species-wise genetic distinction among Camelidae family species, with no evidence of geographic distinction among dromedary camels. We observe gene-wide signals of adaptive divergence between the Old World and New World camels, with evidence of purifying selection among Old World camel species. Upon comparing the different Camelidae tribes, 27 amino acid substitutions across ten mtDNA protein-coding genes were found to be under positive selection, in which, 24 codons were defined to be under positive adaptive divergence between Old World and New World camels. Seven codons belonging to three genes demonstrated positive selection in dromedary lineage. A total of 89 codons were found to be under positive selection in Camelidae family based on investigating the impact of amino acid replacement on the physiochemical properties of proteins, including equilibrium constant and surrounding hydrophobicity. These mtDNA variants under positive selection in the Camelidae family might be associated with their adaptation to their contrasting environments.

Frequency of functional exonic single-nucleotide polymorphisms and haplotype distribution in the SLCO1B1 gene across genetic ancestry groups in the Qatari population.

Organic anion transporting polypeptides (OATP), which are encoded by SLCO genes, participate in the hepatic elimination of drugs and xenobiotics. SLCO1B1 is an important pharmacogenomic gene (encoding OATP1B1) associated with response to the uptake of endogenous compounds, such as statin and bilirubin. Ethnicity of the patient modulates the response to these drugs; the frequency and haplotype data for SLCO1B1 genetic variants in the Arab population is lacking. Therefore, we determined the frequencies of two well-characterized SLCO1B1 single nucleotide polymorphisms (SNP) and haplotypes that affect the OATP1B1 drugs transportation activity in Qatari population. Genotyping data for two SLCO1B1 SNPs (c.388A > G, c.521 T > C) were extracted from whole exome data of 1050 Qatari individuals, who were divided into three ancestry groups, namely Bedouins, Persians/South Asians, and Africans. By way of using Fisher's exact and Chi-square tests, we evaluated the differences in minor allele frequency (MAF) of the two functional SNPs and haplotype frequencies (HF) among the three ancestry groups. The OATP1B1 phenotypes were assigned according to their function by following the guidelines from the Clinical Pharmacogenetics Implementation Consortium for SLCO1B1 and Simvastatin-Induced Myopathy.The MAF of SLCO1B1:c.388A > G was higher compared to that of SLCO1B1:c.521 T > C in the study cohort. It was significantly high in the African ancestry group compared with the other two groups, whereas SLCO1B1:c.521 T > C was significantly low in the African ancestry group compared with the other two groups. The SLCO1B1 *15 haplotype had the highest HF, followed by *1b, *1a, and *5. Only the SLCO1B1 *5 haplotype showed no significant difference in frequency across the three ancestry groups. Furthermore, we observed that the OATP1B1 normal function phenotype accounted for 58% of the Qatari individuals, the intermediate function phenotype accounted for 35% with significant differences across the ancestry groups, and the low function phenotype accounted for 6% of the total Qatari individuals with a higher trend observed in the Bedouin group.The results indicate that the phenotype frequencies of the OATP1B1 intermediate and low function in the Qatari population appear at the higher end of the frequency range seen worldwide. Thus, a pharmacogenetic screening program for SLCO1B1 variants may be necessary for the Qatari population.

Distribution of HLA-B Alleles and Haplotypes in Qatari: Recommendation for Establishing Pharmacogenomic Markers Screening for Drug Hypersensitivity.

Human leukocyte antigen (HLA) proteins are present at the cellular surface of antigen-presenting cells and play a crucial role in the adaptive immune response. Class I genes, specifically certain HLA-B alleles, are associated with adverse drug reactions (ADRs) and are used as pharmacogenetic markers. Although ADRs are a common causes of hospitalization and mortality, the data on the prevalence of HLA-B pharmacogenetics markers in Arab countries are scarce. In this study, we investigated the frequencies of major HLA-B pharmacogenomics markers in the Qatari population. Next-generation sequencing data from 1,098 Qatari individuals were employed for HLA-B typing using HLA-HD version 1.4.0 and IPD-IMGT/HLA database. In addition, HLA-B pharmacogenetics markers were obtained from the HLA Adverse Drug Reaction Database. In total, 469 major HLA-B pharmacogenetic markers were identified, with HLA-B*51:01 being the most frequent pharmacogenetic marker (26.67%) in the Qatari population. Moreover, HLA-B*51:01 is associated with phenytoin- and clindamycin-induced ADRs. The second most frequent pharmacogenetic marker was the HLA-B*58:01 allele (6.56%), which is associated with allopurinol-induced ADRs. The third most frequent pharmacogenetic marker was the HLA-B*44:03 allele, which is associated with phenytoin-induced ADRs. The establishment of a pharmacogenetics screening program in Qatar for cost effective interventions aimed at preventing drug-induced hypersensitivity can be aided by the highly prevalent HLA-B pharmacogenetic markers detected here.

Differentially methylated and expressed genes in familial type 1 diabetes.

There has recently been a growing interest in examining the role of epigenetic modifications, such as DNA methylation, in the etiology of type 1 diabetes (T1D). This study aimed to delineate differences in methylation patterns between T1D-affected and healthy individuals by examining the genome-wide methylation of individuals from three Arab families from Kuwait with T1D-affected mono-/dizygotic twins and non-twinned siblings. Bisulfite sequencing of DNA from the peripheral blood of the affected and healthy individuals from each of the three families was performed. Methylation profiles of the affected individuals were compared to those of the healthy individuals Principal component analysis on the observed methylation profiling based on base-pair resolution clustered the T1D-affected twins together family-wide. The sites/regions that were differentially methylated between the T1D and healthy samples harbored 84 genes, of which 18 were known to be differentially methylated in T1D individuals compared to healthy individuals in publicly available gene expression data resources. We further validated two of the 18 genes-namely ICA1 and DRAM1 that were hypermethylated in T1D samples compared to healthy samples-for upregulation in T1D samples from an extended study cohort of familial T1D. The study confirmed that the ICA1 and DRAM1 genes are differentially expressed in T1D samples compared to healthy samples.

Delineation of Mitochondrial DNA Variants From Exome Sequencing Data and Association of Haplogroups With Obesity in Kuwait.

BACKGROUND/OBJECTIVES: Whole-exome sequencing is a valuable tool to determine genetic variations that are associated with rare and common health conditions. A limited number of studies demonstrated that mitochondrial DNA can be captured using whole-exome sequencing. Previous studies have suggested that mitochondrial DNA variants and haplogroup lineages are associated with obesity. Therefore, we investigated the role of mitochondrial variants and haplogroups contributing to the risk of obesity in Arabs in Kuwait using exome sequencing data. SUBJECTS/METHODS: Indirect mitochondrial genomes were extracted from exome sequencing data from 288 unrelated native Arab individuals from Kuwait. The cohort was divided into obese [body mass index (BMI) ≥ 30 kg/m2] and non-obese (BMI < 30 kg/m2) groups. Mitochondrial variants were identified, and haplogroups were classified and compared with other sequencing technologies. Statistical analysis was performed to determine associations and identify mitochondrial variants and haplogroups affecting obesity. RESULTS: Haplogroup R showed a protective effect on obesity [odds ratio (OR) = 0.311; P = 0.006], whereas haplogroup L individuals were at high risk of obesity (OR = 2.285; P = 0.046). Significant differences in mitochondrial variants between the obese and non-obese groups were mainly haplogroup-defining mutations and were involved in processes in energy generation. The majority of mitochondrial variants and haplogroups extracted from exome were in agreement with technical replica from Sanger and whole-genome sequencing. CONCLUSIONS: This is the first to utilize whole-exome data to extract entire mitochondrial haplogroups to study its association with obesity in an Arab population.

Mitochondrial haplogroup J associated with higher risk of obesity in the Qatari population.

Obesity, a major risk factor for metabolic disorders, is highly prevalent in Qatari population. Maternal transmission of obesity traits can be significant; for example, X haplogroup is known to be associated with lower BMI and body fat mass in Northern Europeans and T haplogroup which is a sister haplogroup of J is known to be associated with obesity in Caucasian subjects from Austria and Southern Italy. We aimed to delineate the mitochondrial haplogroups and variants associated with obesity in Qatari population. Mitochondrial genomes of 864 Qatari individuals were extracted from whole exome sequencing data with an average coverage of 77X. We distributed the participants into 2 sub-cohorts: obese (BMI ≥ 30) and non-obese (BMI < 30); the mean value of BMI from these two groups were 36.5 ± 5.7 and 26.5 ± 2.6, respectively. Mitochondrial haplogroup profiling followed by uni- and multivariant association tests adjusted for covariates were performed. Qatari individuals with mitochondrial haplogroup J had an increased (twofold) risk of obesity (odds ratio [OR] 1.925; 95% CI 1.234-3.002; P = 0.0038; the Bonferroni adjusted P value threshold is 0.0041), whereas the individuals with haplogroup X were at low risk of obesity (OR 0.387; 95% CI 0.175-0.857; P = 0.019). Further, a set of 38 mitochondrial variants were found to be associated (at P ≤ 0.05) with obesity in models adjusted for age, sex and haplogroup.

Leptin rs7799039 polymorphism is associated with multiple sclerosis risk in Kuwait.

BACKGROUND: Leptin association with Multiple sclerosis (MS) pathogenesis and MS related clinical characteristics is inconsistent. Here, we investigated whether two common variants in leptin (LEP) and leptin receptor (LEPR) genes influence MS risk and leptin levels in MS patients. METHODS: In a case-control study including 169 MS patients and 100 controls we examined the association of leptin in MS. Blood samples were used for DNA extraction and plasma retrieval. Taqman genotyping assays were used for LEP rs7799039 and LEPR rs1137101 genotyping, and enzyme-linked immunosorbent assay for plasma leptin level. RESULTS: Leptin levels were significantly lower in MS patients compared to controls (ß = 0.157, 95%CI: 0.033-0.26, p = 0.012). LEP rs7799039AA associated with MS risk (OR: 2.52; 95%CI: 1.35-4.67, p = 0.003). None of the assessed markers associated with MS disability, severity or response to treatment. CONCLUSION: LEP rs7799039AA is a risk factor for MS in our Kuwaiti population, and leptin levels are lower in MS patients compared to healthy controls. Our findings suggest future studies must consider all factors influencing leptin levels to resolve its controversial involvement in MS pathogenesis or progression.

A novel LPL intronic variant: g.18704C>A identified by re-sequencing Kuwaiti Arab samples is associated with high-density lipoprotein, very low-density lipoprotein and triglyceride lipid levels.

The role interethnic genetic differences play in plasma lipid level variation across populations is a global health concern. Several genes involved in lipid metabolism and transport are strong candidates for the genetic association with lipid level variation especially lipoprotein lipase (LPL). The objective of this study was to re-sequence the full LPL gene in Kuwaiti Arabs, analyse the sequence variation and identify variants that could attribute to variation in plasma lipid levels for further genetic association. Samples (n = 100) of an Arab ethnic group from Kuwait were analysed for sequence variation by Sanger sequencing across the 30 Kb LPL gene and its flanking sequences. A total of 293 variants including 252 single nucleotide polymorphisms (SNPs) and 39 insertions/deletions (InDels) were identified among which 47 variants (32 SNPs and 15 InDels) were novel to Kuwaiti Arabs. This study is the first to report sequence data and analysis of frequencies of variants at the LPL gene locus in an Arab ethnic group with a novel "rare" variant (LPL:g.18704C>A) significantly associated to HDL (B = -0.181; 95% CI (-0.357, -0.006); p = 0.043), TG (B = 0.134; 95% CI (0.004-0.263); p = 0.044) and VLDL (B = 0.131; 95% CI (-0.001-0.263); p = 0.043) levels. Sequence variation in Kuwaiti Arabs was compared to other populations and was found to be similar with regards to the number of SNPs, InDels and distribution of the number of variants across the LPL gene locus and minor allele frequency (MAF). Moreover, comparison of the identified variants and their MAF with other reports provided a list of 46 potential variants across the LPL gene to be considered for future genetic association studies. The findings warrant further investigation into the association of g.18704C>A with lipid levels in other ethnic groups and with clinical manifestations of dyslipidemia.

Dissecting the genetic components of a quantitative trait locus for blood pressure and renal pathology on rat chromosome 3.

BACKGROUND: We have previously confirmed the importance of rat chromosome 3 (RNO3) genetic loci on blood pressure elevation, pulse pressure (PP) variability and renal pathology during salt challenge in the stroke-prone spontaneously hypertensive (SHRSP) rat. The aims of this study were to generate a panel of RNO3 congenic sub-strains to genetically dissect the implicated loci and identify positional candidate genes by microarray expression profiling and analysis of next-generation sequencing data. METHOD AND RESULTS: A panel of congenic sub-strains were generated containing Wistar-Kyoto (WKY)-introgressed segments of varying size on the SHRSP genetic background, focused within the first 50 Mbp of RNO3. Haemodynamic profiling during salt challenge demonstrated significantly reduced systolic blood pressure, diastolic blood pressure and PP variability in SP.WKYGla3a, SP.WKYGla3c, SP.WKYGla3d and SP.WKYGla3e sub-strains. Only SBP and DBP were significantly reduced during salt challenge in SP.WKYGla3b and SP.WKYGla3f sub-strains, whereas SP.WKYGla3g rats did not differ in haemodynamic response to SHRSP. Those sub-strains demonstrating significantly reduced PP variability during salt challenge also demonstrated significantly reduced renal pathology and proteinuria. Microarray expression profiling prioritized two candidate genes for blood pressure regulation (Dnm1, Tor1b), localized within the common congenic interval shared by SP.WKYGla3d and SP.WKYGla3f strains, and one candidate gene for salt-induced PP variability and renal pathology (Rabgap1), located within the region unique to the SP.WKYGla3d strain. Comparison of next-generation sequencing data identified variants within additional positional genes that are likely to affect protein function. CONCLUSION: This study has identified distinct intervals on RNO3-containing genes that may be important for blood pressure regulation and renal pathology during salt challenge.

Identification of a rare germline NBN gene mutation by whole exome sequencing in a lung-cancer survivor from a large family with various types of cancer.

Nijmegen breakage syndrome is an autosomal recessive disorder caused by biallelic mutation in NBN gene. It is characterized by microcephaly, growth retardation, immuno-deficiency and cancer predisposition. The monoallelic carriers of NBN gene are also reported to be at increased risk of developing various types of malignancy. We have investigated an individual with lung cancer from an extended family segregating different types of hereditary cancer over several generations, including lung, breast, ovarian, colon, prostate and renal cancers. By using next generation whole exome sequencing approach, we identified a rare heterozygous frameshift mutation in NBN gene; c.93_94delTG (Ala32HisfsTer4), which is predicted to be pathogenic together with 3 other variants; 2 being in the BRCA1 gene, c.1648A > C (p.Asn550His) and c.536A > G (p.Tyr179Cys), and one in RAD50 gene, c.3539G > A (p.Arg1180Gln). Some of the variants were also found in six out of eight clinically normal relatives, but in different combinations. To our knowledge, this is the first report of NBN gene mutation in an individual with lung cancer in the Arab world. Reporting such findings may aid in variants' risk classification and clinical decision in the future.

Identification of a common molecular pathway in hypertensive renal damage: comparison of rat and human gene expression profiles.

BACKGROUND: There is a common structural progression in hypertensive renal damage with early arterial damage and fibrosis in the juxtamedullary cortex. METHOD: The present investigation identifies a common pathway using three-gene expression profiles from hypertensive rat models: 60-week-old spontaneously hypertensive rat (SHR), salt-loaded stroke-prone SHR (SHRSP), and the non-clipped kidney after 24 weeks of two-kidney, one-clip hypertension (2K1C). Kidney damage was scored using a specialized system. Gene-expression profiles were determined using microarrays and validated using a panel of 47 genes by quantitative real-time PCR. RESULTS: All groups showed kidney damage (SHRs: 0.32 ±â€Š0.09 vs. Wistar-Kyoto rats: 0.06 ±â€Š0.03; 2K1C: 0.27 ±â€Š0.13 vs. pooled controls: 0.01 ±â€Š0.01; SHRSP: 1.13 ±â€Š0.14 vs. WKY: 0.04 ±â€Š0.03; all P < 0.05). A total of 1614 genes were changed in the SHR experiment, 1323 in the SHRSP, and 576 in the 2K1C. Eighty-eight genes were similarly regulated in all three models. Gene ontology enrichment analysis identified 59 ontologies that were enriched in all three datasets. These included over-representation to extracellular matrix, response to oxidative stress, and immune system processes. Out of the 88 in-common genes, 40 could be connected in a common pathway that was compared to two gene-expression profiles from human kidneys with histologically verified fibrosis to identify a highly significant number of in-common genes that were also represented in the common genetic pathway. CONCLUSION: There is a common pathway during the development of hypertensive kidney damage in rats irrespective of model. Interestingly, large parts of this common pathway are conserved in human kidney damage, which may indicate a broader importance in the development of chronic kidney disease.