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Genome-Wide Association of CKD Progression: the Chronic Renal Insufficiency Cohort Study

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Genome-Wide Association of CKD Progression: the Chronic Renal Insufficiency Cohort Study CLINICAL EPIDEMIOLOGY www.jasn.org Genome-Wide Association of CKD Progression: The Chronic Renal Insufficiency Cohort Study † ‡ | Afshin Parsa,* Peter A. Kanetsky, Rui Xiao,§ Jayanta Gupta, Nandita Mitra,§ †† ‡‡ Sophie Limou,¶ Dawei Xie,§ Huichun Xu,** Amanda Hyre Anderson, Akinlolu Ojo, || †††‡‡‡ John W. Kusek,§§ Claudia M. Lora, L. Lee Hamm,¶¶ Jiang He,¶¶ Niina Sandholm,*** ||| Janina Jeff,§§§ Dominic E. Raj, Carsten A. Böger,¶¶¶ Erwin Bottinger,§§§ †††† ‡‡‡‡ Shabnam Salimi,**** Rulan S. Parekh, Sharon G. Adler, Carl D. Langefeld,§§§§ |||| †††‡‡‡ Donald W. Bowden, the FIND Consortium, Per-Henrik Groop,*** †††‡‡‡ Carol Forsblom,*** Barry I. Freedman,¶¶¶¶ Michael Lipkowitz,***** ††††† †† Caroline S. Fox, Cheryl A. Winkler,§ and Harold I. Feldman, and the Chronic Renal Insufficiency Cohort (CRIC) Study Investigators Due to the number of contributing authors, the affiliations are listed at the end of this article. ABSTRACT The rate of decline of renal function varies significantly among individuals with CKD. To understand better the contribution of genetics to CKD progression, we performed a genome–wide association study among partic- ipants in the Chronic Renal Insufficiency Cohort Study. Our outcome of interest was CKD progression measured as change in eGFR over time among 1331 blacks and 1476 whites with CKD. We stratified all analyses by race and subsequently, diabetes status. Single-nucleotide polymorphisms (SNPs) that surpassed a significance threshold 2 of P,1310 6 for association with eGFR slope were selected as candidates for follow-up and secondarily tested for association with proteinuria and time to ESRD. We identified 12 such SNPs among black patients and six such SNPs among white patients. We were able to conduct follow-up analyses of three candidate SNPs in similar (replication) cohorts and eight candidate SNPs in phenotype-related (validation) cohorts. Among blacks without diabetes, rs653747 in LINC00923 replicated in the African American Study of Kidney Disease and Hypertension 2 2 cohort (discovery P=5.42310 7;replicationP=0.039; combined P=7.42310 9). This SNP also associated with 2 ESRD (hazard ratio, 2.0 (95% confidence interval, 1.5 to 2.7); P=4.90310 6). Similarly, rs931891 in LINC00923 2 associated with eGFR decline (P=1.44310 4) in white patients without diabetes. In summary, SNPs in LINC00923, an RNA gene expressed in the kidney, significantly associated with CKD progression in individuals with nondiabetic CKD. However, the lack of equivalent cohorts hampered replication for most discovery loci. Further replication of our findings in comparable study populations is warranted. J Am Soc Nephrol 28: ccc–ccc, 2016. doi: 10.1681/ASN.2015101152 It is well established that progression of CKD varies Received October 20, 2015. Accepted August 25, 2016. substantially among individuals, despite similar disease A.P. and P.A.K. contributed equally to this work. R.X., J.G., and etiologies, BP,and/or glycemic control.1,2 However, our N.M. contributed equally to this work. fl understanding of factors in uencing rates of CKD pro- Published online ahead of print. Publication date available at gression is limited, with known clinical factors account- www.jasn.org. 2 ing for less than one half of the observed variability. Correspondence: Dr.AfshinParsa,UniversityofMaryland Various studies have implicated a common pathway School of Medicine, 685 West Baltimore Street, MSTF 357, Bal- for CKD progression, and results strongly suggest that timore, MD 21201. Email: [email protected] the genetic basis for progression of renal disease is, in Copyright © 2016 by the American Society of Nephrology J Am Soc Nephrol 28: ccc–ccc, 2016 ISSN : 1046-6673/2803-ccc 1 CLINICAL EPIDEMIOLOGY www.jasn.org part, distinct from the underlying genetic determinants of CKD Graphic summaries of eGFR decline by race and diabetes status onset.3–5 Inherited variation in apolipoprotein L1 (APOL1)has are shown in Supplemental Figure 1. Mean follow-up for the been shown to explain a significant proportion of the observed various strata ranged between 4.0 and 4.2 years. racial differences in CKD progression among blacks and com- pared with whites, irrespective of initial CKD etiology6; however, Genotype Associations and Replication more comprehensive data on genetic associations across the ge- Among blacks, we report 12 single-nucleotide polymorphisms nome are still lacking. Several large population–based genome– (SNPs) with minor allele frequency (MAF) .0.03 in distinct 2 wide association studies (GWASs) have identified variants gene regions that were independently associated (P#1310 6) associated with measures of eGFR, leading to the recognition with eGFR slope (Table 2), of which four met the genome-wide 2 of novel biologic pathways related to level of renal function.7– threshold for significance of P#5310 8 (Supplemental Figure 2). 11 However, whether these gene regions are related to differ- Among whites, we discovered six SNPs in distinct gene 2 ential progression of CKD remains to be elucidated.12 regions that were associated (P#1310 6)witheGFRslope To better understand the contribution of inherited genes to (Table 3), which did not reach the threshold for genome- CKD progression, we performed a GWAS of eGFR change over wide significance (Supplemental Figure 3). time among participants with established CKD enrolled in a Of the 18 total candidate SNPs across both groups, seven were prospective, observational cohort study: the Chronic Renal not readily available from either observed or imputed genotypes Insufficiency Cohort (CRIC) Study. in the replication studies (Figure 1), and appropriate proxy SNPs in strong linkage disequilibrium (LD) with our discovery SNPs could not be identified. Reasons for unavailability of existing RESULTS genotyped SNPs in the replication studies were either that the discovery SNP was specific to our genotype platform (i.e.,not Study Participants available in the HapMap database) or unavailable imputed data Table 1 summarizes selected demographic and clinical informa- in some of the black replication cohorts, limiting the number of tion overall and in persons with and without diabetes for the 3074 available markers. We were able to attempt replication for three CRIC Study participants who were genotyped and included in our SNPs associated with progression in the CRIC Study black non- analyses; 49% were of African descent, and 46% had diabetes. As diabetic subcohort in the African American Study of Kidney expected, many of the baseline characteristics were different be- Disease and Hypertension (AASK), also consisting of nondia- tween black and white participants overall as well as within strata betic blacks with repeated eGFR measures over time, and vali- defined by diabetes status. Our eGFR slopes (Table 1) were on the dation of another eight SNPs in cohorts with related phenotypes basis of standardized annual measures, with a median number of and/or populations (Figure 1). six measures and interquartile ranges of five to eight and four to One of the three SNPs for which we had access to a similar seven measures in our white and black cohorts, respectively. population and outcome measure (i.e., the AASK), rs653747, Table 1. Baseline demographics in whites and blacks combined and stratified by baseline diabetes status Reported Combined Diabetes Nondiabetes Characteristic Variable White, n=1581 Black, n=1493 White, n=632 Black, n=771 White, n=949 Black, n=722 Age, yr Mean (SD) 59.0 (11.0) 58.0 (10.7) 59.5 (10.0) 59.8 (9.4) 58.7 (11.6) 56.1 (11.6) Sex Men 945 (59.8) 726 (48.6) 416 (65.8) 359 (46.6) 529 (55.7) 367 (50.8) eGFR, ml/min per 1.73 m2 Mean (SD) 43.8 (12.8) 43.7 (14.0) 41.8 (12.2) 42.0 (13.3) 45.1 (13.1) 45.6 (14.5) eGFR slope Mean (SD) 20.8 (3.4) 22.2 (4.7) 21.3 (4.3) 22.9 (5.0) 20.5 (2.6) 21.4 (4.3) Follow-up period, yr Mean (SD) 4.1 (1.2) 4.1 (1.2) 4.0 (1.2) 4.0 (1.2) 4.1 (1.1) 4.2 (1.2) Current smoker Yes 148 (9.4) 285 (19.1) 55 (8.7) 128 (16.6) 93 (9.8) 157 (21.7) Hypertension Yes 1250 (79.1) 1387 (92.9) 556 (88.0) 733 (95.1) 694 (73.1) 654 (90.6) Systolic BP, mmHg Mean (SD) 121.8 (18.5) 132.9 (23.2) 125.5 (19.2) 136.2 (23.5) 119.4 (17.6) 129.3 (22.4) Diastolic BP, mmHg Mean (SD) 69.0 (11.4) 73.8 (13.9) 66.8 (11.3) 71.4 (13.5) 70.4 (11.2) 76.4 (14.0) ACE-I or ARB Yes 1053 (67.0) 1063 (71.8) 510 (81.2) 619 (80.8) 543 (57.6) 444 (62.1) BMI, kg/m2 Mean (SD) 31.2 (7.5) 33.5 (8.4) 33.8 (8.2) 35.2 (8.2) 29.4 (6.3) 31.7 (8.1) LDL, mg/dl Mean (SD) 99.2 (32.2) 106.2 (37.2) 89.1 (29.9) 102.4 (38.1) 106.0 (31.9) 110.2 (35.8) Triglycerides, mg/dl Mean (SD) 163.8 (119.0) 140.2 (111.0) 182.6 (135.9) 152.7 (133.1) 151.3 (104.5) 126.8 (78.7) Lipid-lowering drugs Yes 995 (63.3) 830 (56.0) 508 (80.9) 540 (70.5) 487 (51.6) 290 (40.6) Hemoglobin, g/dl Mean (SD) 13.2 (1.6) 12.2 (1.7) 12.6 (1.6) 11.8 (1.6) 13.5 (1.5) 12.6 (1.7) Hemoglobin A1C, % Mean (SD) 6.4 (1.4) 6.9 (1.7) 7.5 (1.5) 7.9 (1.8) 5.6 (0.5) 5.8 (0.6) Uric acid, mg/dl Mean (SD) 7.0 (1.9) 7.7 (1.9) 7.3 (1.9) 7.9 (1.9) 6.9 (1.8) 7.6 (1.8) 24-h Urine protein, g Mean (SD) 0.7 (1.9) 1.1 (2.3) 1.1 (2.6) 1.5 (2.8) 0.4 (1.1) 0.6 (1.3) Proteinuria is indicated by 24-hour urine collection.
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