Variants in the plasmacytoma variant translocation gene (PVT1) are associated with end-stage renal disease attributed to type 1 diabetes.
OBJECTIVE
End-stage renal disease (ESRD) attributed to diabetes is strongly dependent on genetic factors. We previously reported association between variants in the plasmacytoma variant translocation gene (PVT1) and ESRD attributed to type 2 diabetes in Pima Indians. The objective of this study was to evaluate the extent to which these variants mediate susceptibility in other populations.


METHODS
We genotyped 24 markers showing the strongest evidence for association in Pima Indians in unrelated Caucasians with type 1 diabetes from the Genetics of Kidneys in Diabetes (GoKinD) study. The study sample was comprised of 531 case subjects with ESRD and 564 control subjects with diabetes duration >20 years and a maximum urinary albumin-to-creatinine ratio <150 mg/g.


RESULTS
Markers rs13447075 (odds ratio [OR] 1.47 [95% CI 1.14-1.89] per copy of A allele; P = 0.003) and rs2648862 (2.66 [1.19-5.92] per copy of C allele; P = 0.008) were strongly associated with ESRD in analyses adjusting for age(2), age(3), duration of diabetes, and smoking status. We further identified a common haplotype containing the C allele at rs10808565 and the A allele at rs13447075 that was associated with ESRD (P = 0.003). PVT1 gene expression yields several isoforms, and rs13447075 is located within the coding region of one of these transcript variants. We identified expression of this isoform in four major human kidney cell types, including mesangial, cortical epithelial, epithelial, and proximal tubule cells.


CONCLUSIONS
These results are the first to provide confirmatory evidence supporting a role for PVT1 in mediating susceptibility to ESRD attributable to diabetes.
Millis
Meredith P
MP
Translational Genomics Research Institute, 445 North Fifth St., Phoenix, AZ 85004, USA.
Bowen
Danielle
D
Kingsley
Christopher
C
Watanabe
Richard M
RM
Wolford
Johanna K
JK
D000328:Adult; D001130:Arizona; D015992:Body Mass Index; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000235:genetics*; D003930:Diabetic Retinopathy / Q000235:genetics; D005260:Female; D005819:Genetic Markers; D014644:Genetic Variation; D006801:Humans; D007198:Indians, North American / Q000235:genetics; D007676:Kidney Failure, Chronic / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011506:Proteins / Q000235:genetics*; D062085:RNA, Long Noncoding; D012907:Smoking / Q000453:epidemiology
D005819:Genetic Markers; C521123:PVT1 long-non-coding RNA, human; D011506:Proteins; D062085:RNA, Long Noncoding