doktorska disertacija
Špela Šalamon (Avtor), Uroš Potočnik (Mentor), Sebastjan Bevc (Komentor)

Povzetek

Kronično ledvično bolezen (KLB) še vedno pogosto obravnavamo kot samo eno izmed pridruženih bolezni pri multimorbidnih bolnikih. Ker je bolezen do poznih faz tipično klinično nema, je mnogokrat ne odkrijemo in zdravimo pravočasno. Pri nekaterih bolnikih hitro napreduje do končne ledvične odpovedi, tako da postanejo odvisni od nadomestnega zdravljenja. To prinaša za bolnike zaplete in slabšo kvaliteto življenja, za zdravstvene sisteme in svojce pa obremenitve in stroške. Ker se bolezen pojavlja pretežno pri starejših bolnikih, jih ob počasnem poteku velika večina umre iz drugih razlogov, preden bi prišlo do končne odpovedi ledvic. Bolezen napreduje z zelo različno hitrostjo, tudi pri bolnikih, ki imajo sicer podobne demografske in klinične značilnosti. Dejavnike, ki vplivajo na hitrost napredovanja bolezni, poznamo in razumemo samo delno. Posebej malo vemo o genetskih vplivih na napredovanje bolezni, čeprav že imamo veliko informacij o genetski predispoziciji za nivo glomerulne filtracije (kreatininska oGF) v splošni populaciji ocenjene na osnovi kreatinina. V naši raziskavi smo poskušali ugotoviti, kateri klinični in genetski dejavniki vplivajo na hitrost upada ledvične funkcije. To smo naredili na dva načina: prvič s primerjavo sicer demografsko in klinično podobnih bolnikov, ki potrebujejo ali ne potrebujejo dialize, in drugič z večletnim opazovanjem poteka bolezni pri bolnikih, ki v začetku niso potrebovali dialize. Polimorfizme posameznega nukleotida (angl. SNP za Single Nucleotide Polymorphism), ki so v splošni populaciji najbolj značilno povezani s kreatininsko oGF, smo analizirali za povezavo s hitrostjo napredovanja bolezni pri bolnikih s KLB. Preverjali smo tudi povezave polimorfizmov SNP z drugimi kliničnimi in laboratorijskimi dejavniki, vključno z izražanjem kandidatnih genov. Tako pri v začetku dializno odvisnih bolnikih v primerjavi z dializno neodvisnimi (p = 0,002) kot pri v začetku dializno neodvisnih bolnikih s hitrejšim potekom bolezni v primerjavi s tistimi s počasnejšim (p < 0,001), smo zabeležili veliko višje nivoje albuminurije, kar je skladno z dosedanjimi ugotovitvami. Polimorfizem SNP rs2453533 v genu GATM, ki ima iz splošne populacije znano povezavo alela A z znižano kreatininsko oGF, smo prvič povezali s klinično izraženo KLB v asociacijski analizi med bolniki in zdravimi posamezniki. Frekvenca alela A je bila povišana pri dializno neodvisnih (Bonferroni p = 0,02), ne pa tudi pri dializno odvisnih bolnikih. Uspešno smo replicirali tudi znano povezavo alela C polimorfizma rs4293393 v področju genov UMOD/PDILT z od dialize neodvisno, ne pa z od dialize odvisno KLB (Bonferroni p = 0,04). Ugotovili smo, da je nivo serumskega vitamina D značilno nižji med bolniki, ki so v času raziskave umrli, kot med preživelimi bolniki (p = 0,002). Preživeli bolniki so imeli povprečno vrednost 51,0 ng/mL - bistveno višje od trenutno priporočene minimalne vrednosti 30 ng/mL. Razlika je bila posebej izrazita med dializno odvisnimi bolniki, ni pa bilo povezave med nobenim izmed izbranih polimorfizmov in nivojem serumskega vitamina D. Uspešno smo potrdili povezavo med alelom A polimorfizma rs2453533 in znižanim izražanjem gena GATM v perifernih limfocitih bolnikov s KLB (p = 0,01). Poudariti želimo vlogo spremljanja vrednosti albuminurije in zagotavljanja zadostnih vrednosti vitamina D pri bolnikih s KLB in opozoriti, da lahko nekateri genetski dejavniki (npr. genotip polimorfizma rs2453533) vplivajo na kreatininsko oGF. Pri nosilcih alela A polimorfizma rs2453533 lahko namreč tudi v odsotnosti ledvične okvare pride do višjih vrednosti serumskega kreatinina.

Ključne besede

KLB;GWA;eQTL;rs2453533;kreatinin;cistatin C;Bolezni izločal;Disertacije;Kronična ledvična bolezen;Molekularna genetika;Genetski polimorfizem;Kandidatni geni;

Podatki

Jezik: Slovenski jezik
Leto izida:
Tipologija: 2.08 - Doktorska disertacija
Organizacija: UM MF - Medicinska fakulteta
Založnik: [Š. Šalamon]
UDK: 616.61-008.6:577.21(043.3)
COBISS: 82823171 Povezava se bo odprla v novem oknu
Št. ogledov: 346
Št. prenosov: 45
Ocena: 0 (0 glasov)
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Ostali podatki

Sekundarni jezik: Angleški jezik
Sekundarni naslov: Genetic polymorphisms and candidate gene expression in chronic kidney disease patients
Sekundarni povzetek: Chronic kidney disease (CKD) is still often treated as just one among the comorbidities in multimorbid patients. Because the disease is usually asymptomatic until later stages, that is often when it is diagnosed and treated. In some cases, it quickly progresses to end stage kidney failure, making patients dependent on replacement therapy. This causes complications and a lower quality of life for patients, and puts pressure on healthcare systems and families. Because chronic kidney disease predominantly affects the elderly, patients often die from other causes before reaching terminal kidney failure. Factors that affect the rate of chronic kidney disease progression are only partially known, and especially little is known about the genetic factors. Genetic associations with creatinine-based glomerular filtration rate variability in the general population have been well studied. However, the course of chronic kidney disease and the rate of its progression are still among the seldom investigated phenotypes. In our study, we investigate the differences between patients with fast and slow disease course. We did this in two ways: by comparing demographically and clinically similar patients who were dependent on or independent of dialysis, and by observing the kidney function reduction over the course of several years in patients who had not required dialysis at the beginning of the study. We interrogated known glomerular filtration rate loci in the general population for associations with the rate of kidney function loss and other disease properties in chronic kidney disease patients. We also investigated the correlations of other clinical and laboratory parameters, including candidate gene expression, with the course of chronic kidney disease. We identified higher albuminuria levels in patients who required dialysis at study baseline (p = 0.002), as well as in initially dialysis-independent patients with faster kidney function decline (p < 0.001). This is in accordance with prior finds. We associated the SNP rs2453533 in the GATM gene region, which was previously linked to creatinine based estimated glomerular filtration rate, with clinically manifest CKD. The frequency of this allele was increased among dialysis-independent (Bonferroni p = 0.02), but not in dialysis-dependent CKD patients. In addition, we independently replicated the known association of allele C of the SNP rs4293393 in the UMOD/PDILT gene region with dialysis-independent (Bonferroni p = 0.04), but not dialysis-dependent CKD. We found significantly lower levels of vitamin D among patients who died during the study (p = 0.002). Surviving patients had mean values of serum vitamin D 51.0 ng/mL, which is significantly higher than the current recommended minimum of 30 ng/ml. The difference was especially marked among dialysis-dependent patients. Further, we successfully replicated the association between allele A of SNP rs2453533 in the GATM gene region and the expression of the GATM gene (p = 0.01), which was previously known for other tissues, but not peripheral lymphocytes (or specifically in CKD patients), to our knowledge. We wish to stress the importance of albuminuria monitoring and ensuring sufficient vitamin D levels in CKD patients. We also wish to draw attention to the association between certain genetic markers (in our case SNP rs2453533) and serum creatinine, which means clinicians may benefit from genetic information when performing CKD diagnostics.
Sekundarne ključne besede: CKD;GWA;eQTL;rs2453533;creatinine;cistatin C;Ledvične bolezni;Molekularna genetika;Univerzitetna in visokošolska dela;
Vrsta dela (COBISS): Doktorska disertacija
Komentar na gradivo: Univ. v Mariboru, Medicinska fak.
Strani: X, 150 str.
ID: 12079434