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Exclusion of Polymorphisms in Carnosinase Genes (CNDP1 and CNDP2) As a Cause of Diabetic Nephropathy in Type 1 Diabetes

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Exclusion of Polymorphisms in Carnosinase Genes (CNDP1 and CNDP2) As a Cause of Diabetic Nephropathy in Type 1 Diabetes Exclusion of Polymorphisms in Carnosinase Genes (CNDP1 and CNDP2) as a Cause of Diabetic Nephropathy in Type 1 Diabetes The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Wanic, Krzysztof, Grzegorz Placha, Jonathon Dunn, Adam Smiles, James H. Warram, and Andrzej S. Krolewski. 2008. Exclusion of polymorphisms in carnosinase genes (CNDP1 and CNDP2) as a cause of diabetic nephropathy in type 1 diabetes. Diabetes 57(9): 2547-2551. Published Version doi:10.2337/db07-1303 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:4879178 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA BRIEF REPORT Exclusion of Polymorphisms in Carnosinase Genes (CNDP1 and CNDP2) as a Cause of Diabetic Nephropathy in Type 1 Diabetes Results of Large Case-Control and Follow-Up Studies Krzysztof Wanic,1,2 Grzegorz Placha,1,2,3 Jonathon Dunn,1 Adam Smiles,1 James H. Warram,1 and Andrzej S. Krolewski1,2 OBJECTIVES—Recently, an association was found between diabetic nephropathy and the D18S880 microsatellite, located in the carnosinase gene (CNDP1) on chromosome 18q. Alleles of iabetic nephropathy is the most severe compli- this microsatellite encode for a variable number of leucine cation resulting from type 1 diabetes. Approxi- residues (from four to seven) in the leader peptide of the mately 30 to 40% of type 1 diabetic patients carnosinase precursor. The frequency of subjects homozygous Ddevelop this complication, which leads to end- for the five leucines was higher in control subjects than in case stage renal disease (ESRD) and increases the risk of subjects in studies focusing on type 2 diabetic patients. To test cardiovascular morbidity and mortality (1–3). Epidemio- whether this finding can be extended to type 1 diabetic patients, logic and family studies have demonstrated that in addi- we carried out a comprehensive study on association between tion to levels of glycemic control, genetic factors play an diabetic nephropathy and the D18S880 microsatellite and 21 important role in the development of diabetic nephropathy additional SNPs that tagged the genomic region containing (4–6). Many groups have been searching for genes that CNDP1 and CNDP2. make individuals susceptible to diabetic nephropathy us- RESEARCH DESIGN AND METHODS—Overall, 1,269 Cauca- ing linkage studies or candidate gene approaches (7). sian patients with type 1 diabetes were included in the study, Recently, a family study conducted in 19 Turkish extended including 613 patients with normoalbuminuria and a long dura- families exhibiting type 2 diabetes showed evidence for tion of diabetes, 445 patients with persistent proteinuria, and 211 linkage between microalbuminuria and proteinuria and the patients with end-stage renal disease (ESRD). All patients were genomic region on chromosome 18q22.3–q23 (8). Following genotyped for selected polymorphisms, the associations with these findings, Janssen et al. (9) found an association be- 2 diabetic nephropathy were tested by a ␹ test, and odds ratios tween diabetic nephropathy and the common sequence vari- were calculated. ant in the carnosinase 1 gene (CNDP1) located in that region. RESULTS—We did not find any significant association between The case-control study, however, consisted of only 135 case diabetic nephropathy and any examined genetic markers. The and 107 control subjects (both groups consisted of type 1 and negative findings of the case-control study were supported type 2 diabetic individuals)selected from among patients in further by negative findings obtained from the 6-year follow-up four different countries. In that study, association was found study of 445 patients with persistent proteinuria, during which between microsatellite D18S880, a trinucleotide repeat in 135 patients developed ESRD. exon 2 of CNDP1, and diabetic nephropathy. Because this polymorphism lies in the 5Ј coding part of the transcript, CONCLUSIONS—Our large, comprehensive study did not find an association between the D18S880 microsatellite or any other the number of trinucleotide repeats is directly related to the polymorphisms in the CNDP2–CNDP1 genomic region and sus- number of leucine residues in the leader peptide of the ceptibility for diabetic nephropathy in type 1 diabetes. Diabetes carnosinase precursor: five, six, or seven leucines. The fre- 57:2547–2551, 2008 quency of subjects homozygous for the five leucines was higher in control subjects compared with case subjects. The odds ratio (OR) of diabetic nephropathy for carriers of four, six, or seven leucines, in comparison with those homozygous for the five leucines, was 2.6 (95% CI 1.4–4.8). Interestingly, functional studies carried out by the same group provided From the 1Research Division, Joslin Diabetes Center, Harvard Medical School, some support for a biological explanation of the observed Boston, Massachusetts; the 2Department of Medicine, Harvard Medical School, Boston, Massachusetts; and the 3Department of Hypertension, association (9–11). Warsaw Medical University, Warsaw, Poland. Recently, Freedman et al. (12) published data from a Correspondingauthor:AndrzejS.Krolewski,[email protected]. case-control study in which the authors selected case edu. Received 12 September 2007 and accepted 31 May 2008. (patients with type 2 diabetes and ESRD) and control Published ahead of print at http://diabetes.diabetesjournals.org on 15 June (individuals with type 2 diabetes but without diabetic 2008. DOI: 10.2337/db07-1303. nephropathy) subjects from among Caucasians in North © 2008 by the American Diabetes Association. Readers may use this article as Carolina. The cases were ascertained through dialysis long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by centers, and the control subjects were recruited as volun- -nc-nd/3.0/ for details. teers for the Diabetes Heart Study. This study supported The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance Janssen et al.’s (5) findings that subjects with diabetes but with 18 U.S.C. Section 1734 solely to indicate this fact. without diabetic nephropathy were more frequently ho- DIABETES, VOL. 57, SEPTEMBER 2008 2547 CARNOSINASE POLYMORPHISMS AND NEPHROPATHY CNDP2 CNDP1 Rs12954438 (13) Rs11876158 (1) Rs7234384 (4) Rs8088885 (5) Rs17089361 (6) Rs3794950 (7) Rs17089368 (12) Rs890332 (14) Rs11151964 (15) Rs2114230 (2) Rs747175 (3) Rs2241509 (8) Rs735076 (9) Rs2241508 (10) Rs7577 (11) Rs12607796 (16) Rs4329999 (17) Rs12960862 (18) Rs4892247 (19) Rs11659237 (20) Rs2887 (21) D18S880 promoter promoter Exon: 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 A B C D E F Controls versus Proteinurics (P – value) SNP 1234567 8910 11 12 13 14 15 16 17 18 19 20 21 * 0.88 0.38 0.23 0.55 0.21 0.51 0.91 0.75 0.65 0.61 0.29 0.66 0.93 0.82 0.98 0.59 0.53 0.74 0.42 0.43 0.28 ** 0.74 0.43 0.09 0.50 0.83 0.40 0.76 0.85 0.98 0.64 0.43 0.42 0.87 0.80 0.88 0.31 0.26 0.69 0.19 0.20 0.11 Controls versus ESRD (P – value) SNP 123 4 5 6 7 8 910111213 14 15 16 17 18 19 20 21 * 0.90 0.66 0.41 0.60 0.83 0.07 0.50 0.50 0.10 0.36 0.33 0.27 0.04 0.03 0.06 0.79 0.02 0.86 0.82 0.54 0.58 ** 0.87 0.59 0.21 0.42 0.57 0.04 0.26 0.30 0.04 0.15 0.34 0.18 0.01 0.01 0.02 0.68 0.17 0.63 0.69 0.97 0.87 * 2 degree of freedom ** additive mode of inheritance FIG. 1. Approximate genomic location and P values for selected single SNP comparisons for the CNDP1 and CNDP2 genomic regions assuming additive mode of inheritance. Nominal P values for ␹2 tests with 2 d.f. are also provided. Haploblocks are shown schematically as gray rectangles. SNPs 1–12 are considered tagging SNPs for particular haplo- and interblocks. *2 d.f.; **additive mode of inheritance. mozygous for the five-leucine repeat genotype than those criteria have previously been described (14). At the time of enrollment, who had ESRD. Although both studies concluded that the patients were classified into the following study groups (detailed description five-leucine repeat was protecting against diabetic ne- of the criteria can be found in the online appendix): 1) Control subjects were considered to have normoalbuminuria if they had diabetes duration of Ն15 phropathy, the effect of duration of diabetes on frequency years and had persistent normoalbuminuria; 2) Case subjects were considered of this genotype in control and case subjects was not to have persistent microalbuminuria if they had diabetes duration Ն3 years examined in either study (13). and had persistent microalbuminuria; 3) Case subjects were considered to In this report, we attempted to extend the findings of have persistent proteinuria if they had diabetes Ն7 years and had persistent Janssen et al. and Freedman et al. (9,12) to patients with proteinuria; and 4) Case subjects were considered to have ESRD if they had type 1 diabetes. We examined the association between the begun dialysis or received a renal transplant as a result of diabetic nephrop- number of leucine repeats in CNDP1 and other tagging athy.
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