{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T06:32:39Z","timestamp":1768458759333,"version":"3.49.0"},"reference-count":31,"publisher":"American Diabetes Association","issue":"9","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2008,9,1]]},"abstract":"<jats:p>OBJECTIVE\u2014 Epidemiological and family studies have demonstrated that susceptibility genes play an important role in the etiology of diabetic nephropathy, defined as persistent proteinuria or end-stage renal disease (ESRD) in type 1 diabetes.<\/jats:p>\n               <jats:p>RESEARCH DESIGN AND METHODS\u2014 To efficiently search for genomic regions harboring diabetic nephropathy genes, we conducted a scan using 5,382 informative single nucleotide polymorphisms on 100 sibpairs concordant for type 1 diabetes but discordant for diabetic nephropathy. In addition to being powerful for detecting linkage to diabetic nephropathy, this design allows linkage analysis on type 1 diabetes via traditional affected sibpair (ASP) analysis. In weighing the evidence for linkage, we considered maximum logarithm of odds score (maximum likelihood score [MLS]) values and corresponding allelic sharing patterns, calculated and viewed graphically using the software package SPLAT.<\/jats:p>\n               <jats:p>RESULTS\u2014 Our primary finding for diabetic nephropathy, broadly defined, is on chromosome 19q (MLS = 3.1), and a secondary peak exists on chromosome 2q (MLS = 2.1). Stratification of discordant sibpairs based on whether disease had progressed to ESRD suggested four tertiary peaks on chromosome 1q (ESRD only), chromosome 20p (proteinuria only), and chromosome 3q (two loci 58 cm apart, one for ESRD only and another for proteinuria only). Additionally, analysis of 130 ASPs for type 1 diabetes confirmed the linkage to the HLA region on chromosome 6p (MLS = 9.2) and IDDM15 on chromosome 6q (MLS = 3.1).<\/jats:p>\n               <jats:p>CONCLUSIONS\u2014 This study identified several novel loci as candidates for diabetic nephropathy, none of which appear to be the sole genetic determinant of diabetic nephropathy in type 1 diabetes. In addition, this study confirms two previously reported type 1 diabetes loci.<\/jats:p>","DOI":"10.2337\/db07-1086","type":"journal-article","created":{"date-parts":[[2008,6,17]],"date-time":"2008-06-17T00:58:47Z","timestamp":1213664327000},"page":"2519-2526","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":46,"title":["High-Density Single Nucleotide Polymorphism Genome-Wide Linkage Scan for Susceptibility Genes for Diabetic Nephropathy in Type 1 Diabetes"],"prefix":"10.2337","volume":"57","author":[{"given":"John J.","family":"Rogus","sequence":"first","affiliation":[{"name":"Research Division, Joslin Diabetes Center, Boston, Massachusetts"},{"name":"Department of Medicine, Harvard Medical School, Boston, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G. David","family":"Poznik","sequence":"additional","affiliation":[{"name":"Research Division, Joslin Diabetes Center, Boston, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcus G.","family":"Pezzolesi","sequence":"additional","affiliation":[{"name":"Research Division, Joslin Diabetes Center, Boston, Massachusetts"},{"name":"Department of Medicine, Harvard Medical School, Boston, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam M.","family":"Smiles","sequence":"additional","affiliation":[{"name":"Research Division, Joslin Diabetes Center, Boston, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathon","family":"Dunn","sequence":"additional","affiliation":[{"name":"Research Division, Joslin Diabetes Center, Boston, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William","family":"Walker","sequence":"additional","affiliation":[{"name":"Research Division, Joslin Diabetes Center, Boston, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Krzysztof","family":"Wanic","sequence":"additional","affiliation":[{"name":"Research Division, Joslin Diabetes Center, Boston, Massachusetts"},{"name":"Department of Medicine, Harvard Medical School, Boston, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dariusz","family":"Moczulski","sequence":"additional","affiliation":[{"name":"Research Division, Joslin Diabetes Center, Boston, Massachusetts"},{"name":"Department of Medicine, Harvard Medical School, Boston, Massachusetts"},{"name":"Department of Internal Medicine, Nephrology and Dialysis, Medical University of Lodz, Lodz, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luis","family":"Canani","sequence":"additional","affiliation":[{"name":"Research Division, Joslin Diabetes Center, Boston, Massachusetts"},{"name":"Department of Medicine, Harvard Medical School, Boston, Massachusetts"},{"name":"Department of Endocrinology, Universidade Federal do Rio Grande Do Sul, Porto Alegre, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinichi","family":"Araki","sequence":"additional","affiliation":[{"name":"Research Division, Joslin Diabetes Center, Boston, Massachusetts"},{"name":"Department of Medicine, Harvard Medical School, Boston, Massachusetts"},{"name":"Department of Internal Medicine, Shiga University of Medical Science, Otsu, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuichiro","family":"Makita","sequence":"additional","affiliation":[{"name":"Research Division, Joslin Diabetes Center, Boston, Massachusetts"},{"name":"Department of Medicine, Harvard Medical School, Boston, Massachusetts"},{"name":"Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James H.","family":"Warram","sequence":"additional","affiliation":[{"name":"Research Division, Joslin Diabetes Center, Boston, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrzej S.","family":"Krolewski","sequence":"additional","affiliation":[{"name":"Research Division, Joslin Diabetes Center, Boston, Massachusetts"},{"name":"Department of Medicine, Harvard Medical School, Boston, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1167","reference":[{"key":"2022031210132358300_R1","unstructured":"Parving HH, Mauer M, Ritz E: Diabetic nephropathy. In Brenner and Rector's The Kidney. 7th ed. Brenner BM, Ed. Philadelphia, Elsevier,2004, p. 1777\u20131818"},{"key":"2022031210132358300_R2","doi-asserted-by":"crossref","unstructured":"Seaquist ER, Goetz FC, Rich S, Barbosa J: Familial clustering of diabetic kidney disease: evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med\u2008320: 1161\u20131165,1989","DOI":"10.1056\/NEJM198905043201801"},{"key":"2022031210132358300_R3","doi-asserted-by":"crossref","unstructured":"Borch-Johnsen K, Norgaard K, Hommel E, Mathiesen ER, Jensen JS, Deckert T, Parving HH: Is diabetic nephropathy and inherited complication?Kidney Int\u200841: 719\u2013722,1992","DOI":"10.1038\/ki.1992.112"},{"key":"2022031210132358300_R4","doi-asserted-by":"crossref","unstructured":"Quinn M, Angelico MC, Warram JH, Krolewski AS: Familial factors determine the development of diabetic nephropathy in patients with IDDM. Diabetologia\u200839: 940\u2013945,1996","DOI":"10.1007\/BF00403913"},{"key":"2022031210132358300_R5","doi-asserted-by":"crossref","unstructured":"The Diabetes Control and Complications Trial Research Group: Clustering of long-term complications in families with diabetes in the Diabetes Control and Complications Trial. Diabetes\u200846: 1829\u20131839,1997","DOI":"10.2337\/diabetes.46.11.1829"},{"key":"2022031210132358300_R6","doi-asserted-by":"crossref","unstructured":"Harjutsalo V, Katoh S, Sarti C, Tajima N, Tuomilehto J: Population-based assessment of familial clustering of diabetic nephropathy in type 1 diabetes. Diabetes\u200853: 2449\u20132454,2004","DOI":"10.2337\/diabetes.53.9.2449"},{"key":"2022031210132358300_R7","unstructured":"Rogus JJ, Krolewski AS: Using discordant sib pairs to map loci for qualitative traits with high sibling recurrence risk. Am J Hum Genet\u200859: 1376\u20131381,1996"},{"key":"2022031210132358300_R8","doi-asserted-by":"crossref","unstructured":"Moczulski DK, Rogus JJ, Antonellis A, Warram JH, Krolewski AS: Major susceptibility locus for nephropathy in type 1 diabetes on chromosome 3q: results of novel discordant sibpair analysis. Diabetes\u200847: 1164\u20131169,1998","DOI":"10.2337\/diabetes.47.7.1164"},{"key":"2022031210132358300_R9","doi-asserted-by":"crossref","unstructured":"Warram JH, Gearin G, Laffel L, Krolewski AS: Effect of duration of IDDM on the prevalence of stages of diabetic nephropathy defined by urinary albumin\/creatinine ratio. J Am Soc Nephrol\u20087: 930\u2013937,1996","DOI":"10.1681\/ASN.V76930"},{"key":"2022031210132358300_R10","doi-asserted-by":"crossref","unstructured":"McPeek S: Statistical tests for detection of misspecified relationships by use of genome-screen data. Am J Hum Genet\u200866: 1076\u20131094,2000","DOI":"10.1086\/302800"},{"key":"2022031210132358300_R11","doi-asserted-by":"crossref","unstructured":"O'Connell JR, Weeks DE: PedCheck: a program for identifying genotype incompatibilities in linkage analysis. Am J Hum Genet\u200863: 259\u2013266,1998","DOI":"10.1086\/301904"},{"key":"2022031210132358300_R12","doi-asserted-by":"crossref","unstructured":"Abecasis GR, Cherny SS, Cookson WO, Cardon LR: Merlin-rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet\u200830: 97\u2013101,2002","DOI":"10.1038\/ng786"},{"key":"2022031210132358300_R13","doi-asserted-by":"crossref","unstructured":"Huang Q, Shete S, Amos CI: Ignoring linkage disequilibrium among tightly linked markers induces false-positive evidence of linkage for affected sib pair analysis. Am J Hum Genet\u200875: 1106\u20131112,2004","DOI":"10.1086\/426000"},{"key":"2022031210132358300_R14","doi-asserted-by":"crossref","unstructured":"Abecasis GR, Wigginton JE: Handling marker-marker linkage disequilibrium: pedigree analysis with clustered markers. Am J Hum Genet\u200877: 754\u2013767,2005","DOI":"10.1086\/497345"},{"key":"2022031210132358300_R15","doi-asserted-by":"crossref","unstructured":"Boyles AL, Scott WK, Martin ER, Schmidt S, Li YJ, Ashley-Koch A, Bass MP, Schmidt M, Pericak-Vance MA, Speer MC, Hauser ER: Linkage disequilibrium inflates type I error rates in multipoint linkage analysis when parental genotypes are missing. Hum Hered\u200859: 220\u2013227,2005","DOI":"10.1159\/000087122"},{"key":"2022031210132358300_R16","doi-asserted-by":"crossref","unstructured":"Poznik GD, Adamska K, Xu X, Krolewski AS, Rogus JJ: A novel framework for sib pair linkage analysis. Am J Hum Genet\u200878: 222\u2013230,2006","DOI":"10.1086\/499827"},{"key":"2022031210132358300_R17","doi-asserted-by":"crossref","unstructured":"Lander E, Kruglyak L: Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet\u200811: 241\u2013247,1995","DOI":"10.1038\/ng1195-241"},{"key":"2022031210132358300_R18","doi-asserted-by":"crossref","unstructured":"Lunetta KL, Rogus JJ: Strategy for mapping minor histocompatibility genes involved in graft-versus-host disease: a novel application of discordant sib pair methodology. Genet Epidemiol\u200815: 595\u2013607,1998","DOI":"10.1002\/(SICI)1098-2272(1998)15:6<595::AID-GEPI4>3.0.CO;2-4"},{"key":"2022031210132358300_R19","unstructured":"Holmans P: Asymptotic properties of affected-sib-pair linkage analysis. Am J Hum Genet\u200852: 362\u2013374,1993"},{"key":"2022031210132358300_R20","doi-asserted-by":"crossref","unstructured":"Osterholm AM, He B, Pitkaniemi J, Albinsson L, Berg T, Sarti C, Tuomilehto J, Tryggvason K: Genome-wide scan for type 1 diabetic nephropathy in the Finnish population reveals suggestive linkage to a single locus on chromosome 3q. Kidney Int\u200871: 140\u2013145,2007","DOI":"10.1038\/sj.ki.5001933"},{"key":"2022031210132358300_R21","doi-asserted-by":"crossref","unstructured":"Krolewski AS, Poznik DG, Placha GP, Canani L, Dunn J, Walker W, Smiles A, Krolewski B, Fogarty D, Moczulski D, Araki S, Makita Y, Ng DPK, Rogus JJ, Duggirala R, Rich SS, Warram JH: A genome-wide linkage scan for genes controlling variation in urinary albumin excretion in type 2 diabetes. Kidney Int\u200869: 129\u2013136,2006","DOI":"10.1038\/sj.ki.5000023"},{"key":"2022031210132358300_R22","doi-asserted-by":"crossref","unstructured":"Placha G, Poznik GD, Dunn J, Smiles A, Krolewski B, Glew T, Puppala S, Schneider J, Rogus JJ, Rich SS, Duggirala R, Warram JH, Krolewski AS: A genome-wide linkage scan for genes controlling variation in renal function estimated by serum cystatin C levels in extended families with type 2 diabetes. Diabetes\u200855: 3358\u20133365,2006","DOI":"10.2337\/db06-0781"},{"key":"2022031210132358300_R23","doi-asserted-by":"crossref","unstructured":"Iyengar SK, Abboud He, Goddard KA, Saad MF, Adler SG, Arar NH, Bowden DW, Duggirala R, Elston RC, Hanson RL, Ipp E, Kao WH, Kimmel PL, Klag MJ, Knowler WC, Meoni LA, Nelson RG, Nicholas SB, Pahl MV, Parekh RS, Quade SR, Rich SS, Rotter JI, Scavini M, Schelling JR, Sedor JR, Sehgal AR, Shah VO, Smith MW, Taylor KD, Winkler CA, Zager PG, Freedman BI: Genome-wide scans for diabetic nephropathy and albuminuria in multiethnic populations: the Family Investigation of Nephropathy and Diabetes (FIND). Diabetes\u200856: 1577\u20131585,2007","DOI":"10.2337\/db06-1154"},{"key":"2022031210132358300_R24","doi-asserted-by":"crossref","unstructured":"Imperatore G, Hanson RL, Pettitt DJ, Kobes S, Bennett PH, Knowler WC: Sib-pair linkage analysis for susceptibility genes for microvascular complications among Pima Indians with type 2 diabetes: Pima Diabetes Genes Group. Diabetes\u200847: 821\u2013830,1998","DOI":"10.2337\/diabetes.47.5.821"},{"key":"2022031210132358300_R25","doi-asserted-by":"crossref","unstructured":"Bowden DW, Colicigno CJ, Langefeld CD, Sale MM, Williams A, Anderson PJ, Rich SS, Freedman BI: A genome scan for diabetic nephropathy in African Americans. Kidney Int\u200866: 1517\u20131526,2004","DOI":"10.1111\/j.1523-1755.2004.00915.x"},{"key":"2022031210132358300_R26","doi-asserted-by":"crossref","unstructured":"Chen G, Adeyemo AA, Zhou J, Chen Y, Doumatey A, Lashley K, Huang H, Amoah A, Agyenim-Boateng K, Eghan BA, Okafor G, Acheampong J, Oli J, Fasanmade O, Johnson T, Rotimi C: A genome-wide search for linkage to renal function phenotypes in West Africans with type 2 diabetes. Am J Kidney Dis\u200849: 394\u2013400,2007","DOI":"10.1053\/j.ajkd.2006.12.011"},{"key":"2022031210132358300_R27","doi-asserted-by":"crossref","unstructured":"Rogus JJ, Warram JH, Krolewski AS: Genetics studies of late diabetic complications: the overlooked importance of diabetes duration before complication onset. Diabetes\u200851: 1655\u20131662,2002","DOI":"10.2337\/diabetes.51.6.1655"},{"key":"2022031210132358300_R28","doi-asserted-by":"crossref","unstructured":"Shih PY, Wang T, Xing C, Sinha M, Song Y, Elston RC: Linkage analysis of alcohol dependence using both affected and discordant sib pairs. BMC Genet\u20086 (Suppl. 1): S36,2005","DOI":"10.1186\/1471-2156-6-S1-S36"},{"key":"2022031210132358300_R29","doi-asserted-by":"crossref","unstructured":"Xing C, Sinha R, Xing G, Lu Q, Elston RC: The affected-\/discordant-sib-pair design can guarantee validity of multipoint model-free linkage analysis of incomplete pedigrees when there is marker-marker disequilibrium. Am J Hum Genet\u200879: 396\u2013401,2006","DOI":"10.1086\/506331"},{"key":"2022031210132358300_R30","doi-asserted-by":"crossref","unstructured":"Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR: Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int\u200863: 225\u2013232,2003","DOI":"10.1046\/j.1523-1755.2003.00712.x"},{"key":"2022031210132358300_R31","doi-asserted-by":"crossref","unstructured":"Mueller PM, Rogus JJ, Cleary PA, Zhao Y, Smiles AM, Steffes MW, Bucksa J, Gibson TB, Cordovado SK, Krolewski AS, Nierras CR, Warram JH: The Genetics of Kidneys in Diabetes (GoKinD) Study: a genetics collection available for identifying the genetic susceptibility factors for diabetic nephropathy in type 1 diabetes mellitus. J Am Soc Neph\u200817: 1782\u20131790,2006","DOI":"10.1681\/ASN.2005080822"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/57\/9\/2519\/508070\/zdb00908002519.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/57\/9\/2519\/508070\/zdb00908002519.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:12:51Z","timestamp":1667405571000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/57\/9\/2519\/15510\/High-Density-Single-Nucleotide-Polymorphism-Genome"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,9,1]]},"references-count":31,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2008,9,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db07-1086","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,9,1]]}}}