Autori: Ahram D.F.1, Gillies C.2, Mitrotti A.1, Krithivasan P.1, Bodria M.3, Pontrelli P.4, Gesualdo L.4, Martino M.5, Giordano M.5, Gigante M.6, Allegri L.7 Pisani I.7, Amoroso A.8, Marasa M.1, Zhang J.1, Kil BH.1, Shril S.9, D’Agati V1., Appel G.1, Andrew Bomback1, Izzi C.10, Maringhini S.11, Conti G.12, Santoro D.12, Saraga M.13, Bonomini M.14, Zononi F.15, Peruzzi L.16, Zaza G.17, Magistroni R.18, Caliskan Y.19, Scolari F10, Gharavi A.G.1, Kiryluk K1, Ghiggeri G.M.3, Hildebrandt F.9, Sampson M.G.2, Sanna-Cherchi S.1
Affiliazioni: 1. Div. of Nephrology, Columbia University, New York, USA. 2. Div. of Pediatric Nephrology, University of Michigan, Ann Arbor, USA. 3. Div. of Nephrology, Giannina Gaslini Children’s Hospital, Genova, Italy. 4. Div. of Nephrology, University of Bari, Bari, Italy. 5. Pediatric Nephrology, University of Bari, Bari, Italy.6. Dept. of “Scienze Mediche e Chirurgiche”, University of Foggia, Foggia. 7. Div. of Nephrology, Parma University, Parma, Italy. 8. Dept. of Genetics, University of Torino, Torino, Italy. 9. Div. of Nephrology, Harvard University, Boston, USA. 10. Div. of Nephrology, University of Brescia, Brescia, Italy. 11. Pediatric Nephrology Unit, Children’s Hospital ‘G. Di Cristina’, Palermo, Italy. 12. Div. of Nephrology, University of Messina, Messina, Italy. 13. Pediatric Nephrology, University of Split, Split, Croatia. 14. Div. of Nephrology, University of Chieti-Pescara, Italy. 15. Div. of Nephrology, University of Milano, Milano, Italy 16. Pediatric Nephrology, University of Torino, Torino, Italy. 17. Div. of Nephrology, University of Verona, Verona, Italy. 18. Div. of Nephrology, University of Modena, Modena, Italy. 19. Div. of Nephrology, Istanbul University, Istanbul, Turkey.
Introduction
Primary idiopathic nephrotic syndrome (NS) caused by focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD) is a frequent cause of end-stage renal disease (ESRD). Despite the identification of several genetic causes, the etiologic basis of NS remains to be fully understood. We investigated the genetic basis of FSGS in a heterogeneous population of Caucasian descent.
Methods
We recruited a heterogeneous population of Caucasian descent ascertained for FSGS (88% of the cases) and MCD (12%), for a total of 1,153 cases. A set of independent and meta-analyzed case-control, genome-wide association studies (GWAS) were performed using an additive model with covariate-correction for population stratification in three cohorts of Caucasian descent (Western European: 301, Italian: 754, Turkish: 98), matched genetically with 2,393 controls. Quality control assessment was carried out according to standard practices.
Results
In a Meta-analysis of three, combined Caucasian cohorts (1153 cases, 2393 controls), a significant association was found for the SNP rs28383303 (OR=1.57, 95%CI: 1.29-1.67, P= 1.48×10-8). All three cohorts contributed to the signal without evidence for heterogeneity. The variant was identified in a 50kb haploblock on chromosome 6p21, which contains the gene encoding the HLA complex class II HLA-DQ alpha chain 1 (HLA-DQA1).
Conclusions
In line with previously reported findings implicating the HLA system in childhood-onset nephrotic syndrome and membranous nephropathy, our results indicate the association of HLA risk alleles with NS in individuals of Caucasian descent. Our findings allude to a role for HLA in modulating adaptive immunity and suggest a basis for understanding the complex genetic mechanisms of FSGS.
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