טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentTzur Shay
SubjectA Population Genetics Approach to End Stage Kidney Disease
Susceptibility
DepartmentDepartment of Medicine
Supervisor Professor Karl Skorecki
Full Thesis textFull thesis text - English Version


Abstract

Clinical epidemiological observations in the United States have shown a consistent disparity between populations of African and European ancestry in the risk for chronic kidney disease. These observations strongly suggest the presence of a responsible genetic locus. Using an admixture mapping approach, DNA variants in the gene MYH9 located within a genomic region on chromosome 22 were identified, which were highly associated with non-diabetic end stage kidney disease (ESKD) in African Americans. In our first study, we used fine mapping to identify additional variants in MYH9 gene that are even highly associated with ESKD and extended the study to Hispanic Americans. Since, these MYH9 variants were intronic, without an evident predicted effect on MYH9 protein function, we hypothesized that MYH9 risk variants are in linkage disequilibrium with and tag causal variants at another genetic locus in the region. Accordingly, we searched for other functional candidate variants using publicly available complete genome sequences, and found the highest association with ESKD for non-synonymous variants in the adjacent APOL1 gene. In a similar contemporaneous study by Genovese et al., the same APOL1 variants were identified and designated as G1 and G2. We also suggested that these APOL1 variants might protect carriers from having a specific form of African sleeping sickness caused by Trypanosoma brucei rhodesiensa, an effect that was subsequently demonstrated to occur. The association of ESKD with G1 and G2 mutations is strongest under an inheritance model of association of disease with the two APOL1 risk allele genotype (G1:G1 or G2:G2 or G1:G2). The highest associations were with particular etiologies of kidney disease (odds ratio of 29 for HIVAN, 16 for SGS, and 7.3 for hypertension attributed kidney disease). This is the most striking effect described for a common variant in a common disease with non-Mendelian inheritance. In addition, we demonstrated that dialysis patients with two APOL1 risk alleles initiated dialysis 9 years earlier than for patients with zero risk alleles.

Hence, the population genetic approaches that were used to study the genetics of ESKD in African ancestry Americans led to the identification of common genetic variants that confer a selective advantage against a lethal parasitic pathogen, but at the same time, confer a powerful risk for common forms of kidney disease. These APOL1 risk variants comprise a distinct category of wide spread non-diabetic kidney diseases that manifest at younger ages in African ancestry populations.