Genome-wide linkage analysis of serum creatinine in three isolated European populations
2009; Elsevier BV; Volume: 76; Issue: 3 Linguagem: Inglês
10.1038/ki.2009.135
ISSN1523-1755
AutoresCristian Pattaro, Yurii S. Aulchenko, Aaron Isaacs, Véronique Vitart, Caroline Hayward, Christopher S. Franklin, Ozren Polašek, Ivana Kolčić, Zrinka Biloglav, Susan Campbell, Nick Hastie, Gordan Lauc, Thomas Meitinger, Ben A. Oostra, Ulf Gyllensten, James F. Wilson, Irene Pichler, Andrew A. Hicks, Harry Campbell, Alan F. Wright, Igor Rudan, Cornelia M. van Duijn, Peter Riegler, Fabio Marroni, Peter P. Pramstaller,
Tópico(s)Diabetes Treatment and Management
ResumoThere is increasing evidence for a role of genetic predisposition in the etiology of kidney disease, but linkage scans have been poorly replicated. Here we performed a genome-wide linkage analysis of serum creatinine on 2859 individuals from isolated villages in South Tyrol (Italy), Rucphen (The Netherlands) and Vis Island (Croatia), populations that have been stable and permanently resident in their region. Linkage of serum creatinine levels to loci on chromosomes 7p14, 9p21, 11p15, 15q15-21, 16p13, and 18p11 was successfully replicated in at least one discovery population or in the pooled analysis. A novel locus was found on chromosome 10p11. Linkage to chromosome 22q13, independent of diabetes and hypertension, was detected over a region containing the non-muscle myosin heavy chain type II isoform A (MYH9) gene (LOD score=3.52). In non-diabetic individuals, serum creatinine was associated with this gene in two of the three populations and in meta-analysis (SNP rs11089788, P-value=0.0089). In populations sharing a homogeneous environment and genetic background, heritability of serum creatinine was higher than in outbred populations, with consequent detection of a larger number of loci than reported before. Our finding of a replicated association of serum creatinine with the MYH9 gene, recently linked to pathological renal conditions in African Americans, suggests that this gene may also influence kidney function in healthy Europeans. There is increasing evidence for a role of genetic predisposition in the etiology of kidney disease, but linkage scans have been poorly replicated. Here we performed a genome-wide linkage analysis of serum creatinine on 2859 individuals from isolated villages in South Tyrol (Italy), Rucphen (The Netherlands) and Vis Island (Croatia), populations that have been stable and permanently resident in their region. Linkage of serum creatinine levels to loci on chromosomes 7p14, 9p21, 11p15, 15q15-21, 16p13, and 18p11 was successfully replicated in at least one discovery population or in the pooled analysis. A novel locus was found on chromosome 10p11. Linkage to chromosome 22q13, independent of diabetes and hypertension, was detected over a region containing the non-muscle myosin heavy chain type II isoform A (MYH9) gene (LOD score=3.52). In non-diabetic individuals, serum creatinine was associated with this gene in two of the three populations and in meta-analysis (SNP rs11089788, P-value=0.0089). In populations sharing a homogeneous environment and genetic background, heritability of serum creatinine was higher than in outbred populations, with consequent detection of a larger number of loci than reported before. Our finding of a replicated association of serum creatinine with the MYH9 gene, recently linked to pathological renal conditions in African Americans, suggests that this gene may also influence kidney function in healthy Europeans. It is well established that inherited factors play an important role in the etiology of renal disease.1.Freedman B.I. Satko S.G. Genes and renal disease.Curr Opin Nephrol Hypertens. 2000; 9: 273-277Crossref PubMed Scopus (25) Google Scholar Familial aggregation of both diabetic and IgA nephropathies has been extensively recognized,2.Chow K.M. Wong T.Y. Li P.K. Genetics of common progressive renal disease.Kidney Int Suppl. 2005; 67: S41-S45Abstract Full Text Full Text PDF Google Scholar and several genetic factors contributing to chronic renal failure have been proposed.3.Freedman B.I. Susceptibility genes for hypertension and renal failure.J Am Soc Nephrol. 2003; 14: S192-S194Crossref PubMed Google Scholar The genetic heritability of serum creatinine (SCR), glomerular filtration rate (GFR), and creatinine clearance (CrCl) was shown to be significant and very high, irrespective of ethnicity and concomitant pathologies.4.Puppala S. Arya R. Thameem F. et al.Genotype by diabetes interaction effects on the detection of linkage of glomerular filtration rate to a region on chromosome 2q in Mexican Americans.Diabetes. 2007; 56: 2818-2828Crossref PubMed Scopus (33) Google Scholar, 5.Hunt S.C. Coon H. 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Coon H. et al.Linkage of creatinine clearance to chromosome 10 in Utah pedigrees replicates a locus for end-stage renal disease in humans and renal failure in the fawn-hooded rat.Kidney Int. 2002; 62: 1143-1148Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 10.Arar N.H. Voruganti V.S. Nath S.D. et al.A genome-wide search for linkage to chronic kidney disease in a community-based sample: the SAFHS.Nephrol Dial Transplant. 2008; 23: 3184-3191Crossref PubMed Scopus (34) Google Scholar, 11.Mottl A.K. Vupputuri S. Cole S.A. et al.Linkage analysis of glomerular filtration rate in American Indians.Kidney Int. 2008; 74: 1185-1191Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar Recently, several genome-wide linkage scans have been carried out in the attempt to detect loci explaining variability of quantitative renal phenotypes in individuals of different ethnicities,4.Puppala S. Arya R. Thameem F. et al.Genotype by diabetes interaction effects on the detection of linkage of glomerular filtration rate to a region on chromosome 2q in Mexican Americans.Diabetes. 2007; 56: 2818-2828Crossref PubMed Scopus (33) Google Scholar, 5.Hunt S.C. Coon H. Hasstedt S.J. et al.Linkage of serum creatinine and glomerular filtration rate to chromosome 2 in Utah pedigrees.Am J Hypertens. 2004; 17: 511-515Crossref PubMed Scopus (33) Google Scholar, 6.Placha G. Poznik G.D. Dunn J. et al.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. 2006; 55: 3358-3365Crossref PubMed Scopus (61) Google Scholar, 7.Turner S.T. Kardia S.L. Mosley T.H. et al.Influence of genomic loci on measures of chronic kidney disease in hypertensive sibships.J Am Soc Nephrol. 2006; 17: 2048-2055Crossref PubMed Scopus (36) Google Scholar, 10.Arar N.H. Voruganti V.S. Nath S.D. et al.A genome-wide search for linkage to chronic kidney disease in a community-based sample: the SAFHS.Nephrol Dial Transplant. 2008; 23: 3184-3191Crossref PubMed Scopus (34) Google Scholar, 11.Mottl A.K. Vupputuri S. Cole S.A. et al.Linkage analysis of glomerular filtration rate in American Indians.Kidney Int. 2008; 74: 1185-1191Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 12.DeWan A.T. Arnett D.K. Atwood L.D. et al.A genome scan for renal function among hypertensives: the HyperGEN study.Am J Hum Genet. 2001; 68: 136-144Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 13.DeWan A.T. Arnett D.K. Miller M.B. et al.Refined mapping of suggestive linkage to renal function in African Americans: the HyperGEN study.Am J Hum Genet. 2002; 71: 204-205Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar, 14.Chen G. Adeyemo A.A. Zhou J. et al.A genome-wide search for linkage to renal function phenotypes in West Africans with type 2 diabetes.Am J Kidney Dis. 2007; 49: 394-400Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, 15.Schelling J.R. Abboud H.E. Nicholas S.B. et al.Genome-wide scan for estimated glomerular filtration rate in multi-ethnic diabetic populations: the Family Investigation of Nephropathy and Diabetes (FIND).Diabetes. 2008; 57: 235-243Crossref PubMed Scopus (81) Google Scholar including extended pedigrees of diabetic4.Puppala S. Arya R. Thameem F. et al.Genotype by diabetes interaction effects on the detection of linkage of glomerular filtration rate to a region on chromosome 2q in Mexican Americans.Diabetes. 2007; 56: 2818-2828Crossref PubMed Scopus (33) Google Scholar, 14.Chen G. Adeyemo A.A. Zhou J. et al.A genome-wide search for linkage to renal function phenotypes in West Africans with type 2 diabetes.Am J Kidney Dis. 2007; 49: 394-400Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, 15.Schelling J.R. Abboud H.E. Nicholas S.B. et al.Genome-wide scan for estimated glomerular filtration rate in multi-ethnic diabetic populations: the Family Investigation of Nephropathy and Diabetes (FIND).Diabetes. 2008; 57: 235-243Crossref PubMed Scopus (81) Google Scholar and hypertensive6.Placha G. Poznik G.D. Dunn J. et al.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. 2006; 55: 3358-3365Crossref PubMed Scopus (61) Google Scholar, 7.Turner S.T. Kardia S.L. Mosley T.H. et al.Influence of genomic loci on measures of chronic kidney disease in hypertensive sibships.J Am Soc Nephrol. 2006; 17: 2048-2055Crossref PubMed Scopus (36) Google Scholar, 12.DeWan A.T. Arnett D.K. Atwood L.D. et al.A genome scan for renal function among hypertensives: the HyperGEN study.Am J Hum Genet. 2001; 68: 136-144Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 13.DeWan A.T. Arnett D.K. Miller M.B. et al.Refined mapping of suggestive linkage to renal function in African Americans: the HyperGEN study.Am J Hum Genet. 2002; 71: 204-205Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar individuals. Some of these studies assessed linkage of GFR or CrCl, estimated by means of common SCR-based equations.16.Stevens L.A. Coresh J. Greene T. et al.Assessing kidney function—measured and estimated glomerular filtration rate.N Engl J Med. 2006; 354: 2473-2483Crossref PubMed Scopus (2300) Google Scholar However, it is worth noting that, when age, sex, and other factors used for estimation of these quantities are included in regression models, there is no meaningful difference between the analysis of estimated GFR (CrCl) and SCR. In this study, we investigated the genetics of SCR in three genetically isolated populations living in Europe and participating in the European Special Population Research Network (EUROSPAN). Isolated populations can play an important role in dissecting complex traits.17.Peltonen L. Palotie A. Lange K. Use of population isolates for mapping complex traits.Nat Rev Genet. 2000; 1: 182-190Crossref PubMed Scopus (310) Google Scholar,18.Shifman S. Darvasi A. The value of isolated populations.Nat Genet. 2001; 28: 309-310Crossref PubMed Scopus (129) Google Scholar One advantage over outbred populations is related to the greater homogeneity of lifestyle and environmental factors, as empirically shown in South Tyrolean isolates.19.Marroni F. Grazio D. Pattaro C. et al.Estimates of genetic and environmental contribution to 43 quantitative traits support sharing of a homogeneous environment in an isolated population from South Tyrol, Italy.Hum Hered. 2008; 65: 175-182Crossref PubMed Scopus (30) Google Scholar Population isolates are characterized by a reduced number of recombination events, typical of pedigrees generated from a small group of founders. Thus, the study of small isolates could facilitate the search for causal loci involved in both monogenic and polygenic disorders.20.Sheffield V.C. Stone E.M. Carmi R. Use of isolated inbred human populations for identification of disease genes.Trends Genet. 1998; 14: 391-396Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar, 21.Escamilla M.A. Population isolates: their special value for locating genes for bipolar disorder.Bipolar Disord. 2001; 3: 299-317Crossref PubMed Scopus (39) Google Scholar, 22.Sheffield V.C. Use of isolated populations in the study of a human obesity syndrome, the Bardet–Biedl syndrome.Pediatr Res. 2004; 55: 908-911Crossref PubMed Scopus (20) Google Scholar The study involved 2859 participants from the MICROS study (Italy), the Erasmus Rucphen Family (ERF) study (the Netherlands), and from the island of Vis (Croatia). Characteristics of participants are reported in Table 1. Overall, women were slightly more in number than were men, and Vis participants were 7–9 years older than other participants. Body mass index was higher in ERF and Vis study participants than in the MICROS study participants. ERF had a higher prevalence of ever smokers, diabetes, hypertension, and higher systolic blood pressure. Distribution of renal function indicators suggested a better renal condition in MICROS and ERF than in Vis participants.Table 1Characteristics of study participantsaReported data are mean (s.d.) or N (%), depending on the type of study variable.StudyMICROSERFVisP-valuebUnadjusted homogeneity χ2 test for categorical variables. Kruskal–Wallis test for continuous variables.No. of participants8911388580Determinants of renal function Age (years)47 (16.6)49 (14.6)56 (16.2)<0.00001 Sex (F)487 (54.7)785 (56.6)330 (56.9)0.60232 BMI (kg/m2)26 (4.5)27 (4.6)27 (4.1)<0.00001 Ever smoked (yes)365 (41.1)963 (70.3)294 (50.8)<0.00001 Diabetes (yes)32 (3.7)63 (7.4)35 (6.1)0.00273 Under anti-hypertensive treatment (yes)76 (8.5)284 (34.0)149 (25.8)<0.00001 SBP (mm Hg)133 (20.8)140 (19.8)137 (23.7)<0.00001 DBP (mm Hg)80 (11.2)80 (9.7)80 (11.4)0.69550 MAP (mm Hg)98 (13.5)100 (11.8)99 (14.1)0.00007Renal function Males SCR0.96 (0.175)0.97 (0.181)1.09 (0.22)<0.00001 eGFRceGFR: glomerular filtration rate as estimated with the updated 4-variable modification of diet in renal disease (MDRD) formula.2386 (17.2)86 (17.9)75 (17.5)<0.00001 Females SCR0.80 (0.175)0.79 (0.181)0.91 (0.218)<0.00001 eGFRceGFR: glomerular filtration rate as estimated with the updated 4-variable modification of diet in renal disease (MDRD) formula.2381 (17.2)81 (17.9)67 (17.5)<0.00001BMI, body mass index; DBP, diastolic blood pressure; GFR, glomerular filtration rate; MAP, mean arterial pressure; SCR, serum creatinine; SBP, systolic blood pressure.a Reported data are mean (s.d.) or N (%), depending on the type of study variable.b Unadjusted homogeneity χ2 test for categorical variables. Kruskal–Wallis test for continuous variables.c eGFR: glomerular filtration rate as estimated with the updated 4-variable modification of diet in renal disease (MDRD) formula.23.Levey A.S. Coresh J. Greene T. et al.Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate.Ann Intern Med. 2006; 145: 247-254Crossref PubMed Scopus (4112) Google Scholar Open table in a new tab BMI, body mass index; DBP, diastolic blood pressure; GFR, glomerular filtration rate; MAP, mean arterial pressure; SCR, serum creatinine; SBP, systolic blood pressure. After pedigree splitting, singletons and individuals with missing information on covariates were eliminated, and finally, 856, 822, and 561 individuals from MICROS, ERF, and Vis, respectively, were retained in the analysis. They were subdivided into 121 (MICROS), 138 (ERF), and 156 (Vis) smaller pedigrees with a median size of 18 individuals (range: 3–27) in MICROS, 19 (12–28) in ERF, and 5.5 (3–25) in Vis. The distribution of relative pairs according to study and genetic relationship is reported in the Supplementary Information File 1. Given a hypothesized total heritability of 40%, the pooled sample showed 76% power to detect a logarithm of odds (LOD) score ≥1.9 for a quantitative trait locus with specific heritability of 18%. The pedigrees from MICROS and ERF cohorts showed substantial power as well. Most likely because of the small size of split pedigrees, the power was much reduced in Vis (an overview of power estimates is given in the Supplementary Information File 2). Download .doc (.06 MB) Help with doc files Supplementary Figures 1–2 Download .doc (.06 MB) Help with doc files Supplementary Table S1 As depicted in Table 2, genetic heritability (h2) of SCR was 0.44 in the pooled sample (P-value=1.09 × 10−31), with a minimum in Vis (h2=0.24, P-value=0.0073) and a maximum in MICROS (h2=0.53, P-value=1.22 × 10–17). The exclusion of diabetics did not affect the estimates. In MICROS, ERF, and in the pooled sample, h2 increased when excluding individuals on anti-hypertensive treatment. In all populations, h2 was higher in non-diabetics not treated for hypertension. The results were similar under the multivariable model (data not shown).Table 2Genetic heritability of serum creatinineMODELAll subjectsSubjects not on anti-hypertensive treatmentNon-diabetics onlySubjects without diabetes and not on anti-hypertensive treatmentStudyh2(s.e.)P-valueh2(s.e.)P-valueh2(s.e.)P-valueh2(s.e.)P-valueERF0.44(0.06)7.00 × 10−170.47(0.09)3.48 × 10−080.41(0.06)4.46 × 10−140.48(0.09)2.97 × 10−08Vis0.24(0.10)0.00730.21(0.18)0.11240.25(0.11)0.00940.31(0.19)0.0505MICROS0.53(0.07)1.22 × 10−170.79(0.09)2.15 × 10−170.52(0.07)1.10 × 10−150.76(0.10)3.32 × 10−16Total0.44(0.04)1.09 × 10−310.53(0.06)1.03 × 10−190.42(0.04)1.74 × 10−270.54(0.06)1.32 × 10−19Estimates (h2), s.e., and P-value are reported by study population (ERF, Vis, MICROS, and pooled), and model (all subjects included; subjects not on anti-hypertensive treatment; non-diabetics only; subjects without diabetes and not on anti-hypertensive treatment).Polygenic models were adjusted for sex, age, and age2. Open table in a new tab Estimates (h2), s.e., and P-value are reported by study population (ERF, Vis, MICROS, and pooled), and model (all subjects included; subjects not on anti-hypertensive treatment; non-diabetics only; subjects without diabetes and not on anti-hypertensive treatment). Polygenic models were adjusted for sex, age, and age2. Linkage regions corresponding to a LOD score ≥1.9 (suggestive linkage) or ≥3.3 (significant linkage) are reported in Table 3. A linkage peak was detected in MICROS on chromosome 7p14 (multivariable LOD score=2.25). Two peaks (at 46 and 49 cM) were observed on chromosome 9p21 in the pooled analysis (Figure 1). The first peak was slightly higher when excluding individuals on anti-hypertensive treatment (multivariable LOD score=2.09). Linkage was more pronounced in the multivariable analysis than in the sex- and age-adjusted one. On chromosome 10p11, suggestive linkage was detected in ERF in individuals not treated for hypertension. Much smaller values were observed when these individuals were included. In the pooled analysis, we detected linkage on chromosome 11p15 in individuals not on anti-hypertensive medication (Figure 1). The signal was similar when diabetics were also removed. On chromosome 15p15, suggestive linkage was observed in the ERF sample under both models, and in all subgroup analyses.Table 3Chromosomal regions corresponding to a LOD score ≥1.9 (suggestive linkageaUnder Lander and Kruglyak's guidelines.28)ChromosomebNCBI Build 36.3, region where the closest marker is located.cMClosest markerscGiven that the three populations had three different maps and the deCODE map was taken as the reference, these are the markers from the deCODE map that are the closest ones to the location of the maximum LOD score.LOD-1 interval (bp)PopulationGroupdALL, no subjects excluded; –AHT, subjects on anti-hypertensive treatment excluded; –DM, subjects with diabetes excluded; –AHT and DM, subjects on anti-hypertensive treatment and diabetics excluded.LOD scoreeNominal and empirical LOD scores estimated under sex- and age-adjusted model (S-A) and multivariable model (M); see the Methods section for details.Previous evidence (linkage)NominalEmpiricalS-AMS-AM7p1457D7S2250-D7S220930,080,312–46,082,813MICROSAll1.952.251.771.86Linkage to the logarithm of SCR in hypertensive sibships of black individuals7.Turner S.T. Kardia S.L. Mosley T.H. et al.Influence of genomic loci on measures of chronic kidney disease in hypertensive sibships.J Am Soc Nephrol. 2006; 17: 2048-2055Crossref PubMed Scopus (36) Google Scholar and to eGFR in the Framingham Heart Study8.Fox C.S. Yang Q. Cupples L.A. et al.Genomewide linkage analysis to serum creatinine, GFR, and creatinine clearance in a community-based population: the Framingham Heart Study.J Am Soc Nephrol. 2004; 15: 2457-2461Crossref PubMed Scopus (138) Google Scholar7p1457D7S2250-D7S220930,080,312–46,082,813MICROS–DM1.982.271.811.939p2146D9S171-D9S167920,347,873–33,163,684Pooled–AHT1.882.291.692.09Overlap with a linkage peak for ESRD in black families enriched for nondiabetic nephropathy24.Freedman B.I. Langefeld C.D. Rich S.S. et al.A genome scan for ESRD in black families enriched for nondiabetic nephropathy.J Am Soc Nephrol. 2004; 15: 2719-2727Crossref PubMed Scopus (42) Google Scholar9p2146D9S171-D9S167920,347,873–33,163,684Pooled–AHT and DM1.842.101.651.949p2149D9S2154-D9S16920,347,873–33,163,684Pooled–AHT and DM1.722.141.551.9810p1161D10S1654-D10S121719,599,223–42,338,905ERF–AHT2.151.982.142.0510p1161D10S1654-D10S121718,880,109–42,338,905ERF–AHT and DM1.911.742.011.6911p1533D11S4106-D11S92815,494,428–23,559,409Pooled–AHT1.911.621.721.45Within the LOD-1 supporting region for linkage to eGFRMDRD in African Americans and in a multiethnic population15.Schelling J.R. Abboud H.E. Nicholas S.B. et al.Genome-wide scan for estimated glomerular filtration rate in multi-ethnic diabetic populations: the Family Investigation of Nephropathy and Diabetes (FIND).Diabetes. 2008; 57: 235-243Crossref PubMed Scopus (81) Google Scholar15q1544D15S537-D15S65934,024,135–53,542,801ERFALL1.941.991.851.86Within the LOD-1 supporting interval for linkage to SCR in West African pedigrees with type II diabetes.14.Chen G. Adeyemo A.A. Zhou J. et al.A genome-wide search for linkage to renal function phenotypes in West Africans with type 2 diabetes.Am J Kidney Dis. 2007; 49: 394-400Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar,25.Lichter-Konecki U. Broman K.W. Blau E.B. et al.Genetic and physical mapping of the locus for autosomal dominant renal Fanconi syndrome, on chromosome 15q15.3.Am J Hum Genet. 2001; 68: 264-268Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Linkage to autosomal-dominant renotubular Fanconi syndrome,25.Lichter-Konecki U. Broman K.W. Blau E.B. et al.Genetic and physical mapping of the locus for autosomal dominant renal Fanconi syndrome, on chromosome 15q15.3.Am J Hum Genet. 2001; 68: 264-268Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar which can be related to muscle weakness26.Smith R. Lindenbaum R.H. Walton R.J. Hypophosphataemic osteomalacia and Fanconi syndrome of adult onset with dominant inheritance. Possible relationship with diabetes mellitus.Q J Med. 1976; 45: 387-400PubMed Google Scholar15q1544D15S537-D15S65933,171,231–53,542,801ERF–DM1.981.921.821.8215q1544D15S537-D15S65936,794,835–53,542,801ERF–AHT1.881.861.881.9215q2147D15S123-D15S19633,171,231–53,542,801ERF–DM1.811.941.661.8415q2148D15S1028-D15S11936,794,835–53,542,801ERF–AHT2.041.802.031.8715q2148D15S1028-D15S11936,794,835–53,542,801ERF–AHT and DM2.111.932.211.8816p1315D16S423-D16S33924,274,729–8,392,753MICROS–AHT2.442.482.132.00Linkage to early onset ESRD in black families enriched for nondiabetic nephropathy;24.Freedman B.I. Langefeld C.D. Rich S.S. et al.A genome scan for ESRD in black families enriched for nondiabetic nephropathy.J Am Soc Nephrol. 2004; 15: 2719-2727Crossref PubMed Scopus (42) Google Scholar LOD score of 2.0 in a genome-wide scan of UACR in a diabetic, multiethnic population, in majority of Caucasians27.Krolewski A.S. Poznik G.D. Placha G. et al.A genome-wide linkage scan for genes controlling variation in urinary albumin excretion in type II diabetes.Kidney Int. 2006; 69: 129-136Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar16p1316D16S423-D16S33924,274,729–10,848,100MICROS–AHT and DM2.352.261.951.8818p1127D18S1163-D18S8434,609,789–9,951,551ERFALL2.462.592.352.42Linkage to GFR estimated by cystatin C in type II diabetic relative pairs (D18S843)6.Placha G. Poznik G.D. Dunn J. et al.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. 2006; 55: 3358-3365Crossref PubMed Scopus (61) Google Scholar18p1127D18S1163-D18S8434,609,789–9,951,551ERF–DM2.692.662.472.5322q1345D22S1045-D22S44534,736,599–47,788,230MICROS–AHT2.493.012.222.42Overlap with the LOD-1 supporting interval for linkage to UACR in a diabetic, multiethnic population, in majority of Caucasians27.Krolewski A.S. Poznik G.D. Placha G. et al.A genome-wide linkage scan for genes controlling variation in urinary albumin excretion in type II diabetes.Kidney Int. 2006; 69: 129-136Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar22q1345D22S1045-D22S44532,925,593–47,788,230MICROS–AHT and DM2.763.162.282.6322q1356D22S1171-D22S116837,415,838–47,556,879PooledALL1.921.891.841.8022q1356D22S1171-D22S116841,383,475–47,556,879Pooled–AHT1.891.931.701.7622q1356D22S1171-D22S116841,383,475–47,556,879Pooled–AHT and DM2.172.141.951.9822q1361D22S532-D22S92235,593,050–47,788,230MICROSALL2.683.432.442.8422q1362D22S532-D22S92235,593,050–47,788,230MICROS–DM2.853.522.613.0022q1362D22S532-D22S92234,736,599–47,788,230MICROS–AHT2.552.982.222.4022q1362D22S532-D22S92232,925,593–47,788,230MICROS–AHT and DM2.863.162.372.63eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; LOD, logarithm of odds; SCR, serum creatinine; UACR, urinary albumin-to-creatinine ratio.a Under Lander and Kruglyak's guidelines.28.Lander E. Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results.Nat Genet. 1995; 11: 241-247Crossref PubMed Scopus (4471) Google Scholarb NCBI Build 36.3, region where the closest marker is located.c Given that the three populations had three different maps and the deCODE map was taken as the reference, these are the markers from the deCODE map that are the closest ones to the location of the maximum LOD score.d ALL, no subjects excluded; –AHT, subjects on anti-hypertensive treatment excluded; –DM, subjects with diabetes excluded; –AHT and DM, subjects on anti-hypertensive treatment and diabetics excluded.e Nominal and empirical LOD scores estimated under sex- and age-adjusted model (S-A) and multivariable model (M); see the Methods section for details. Open table in a new tab eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; LOD, logarithm of odds; SCR, serum creatinine; UACR, urinary albumin-to-creatinine ratio. Suggestive linkage to a quantitative trait locus located on chromosome 16p13 was detected in the MICROS sample when excluding individuals on anti-hypertensive treatment, independently of diabetic status (Figure 2). On chromosome 18p11, the sex- and age-adjusted LOD score was 2.46 in the ERF cohort. The signal was higher when excluding diabetics (LOD score=2.69), but disappeared when removing individuals on anti-hypertensive treatment. Similar results were observed with the multivariable analysis. The highest LOD scores were detected on chromosome 22q13 in the MICROS cohort (Figure 2). The first peak, at 45 cM, was observed especially when excluding individuals treated for hypertension and diabetics (multivariable LOD score=3.16). The second peak was observed between 61 and 62 cM. The highest LOD score was obtained when omitting diabetics (LOD score=3.52). Results were consistent and similar across all subgroup analyses, but signals were smaller when adjusting for age and sex only. In the same region, the pooled analysis detected a suggestive linkage peak at 56 cM, where the signal was of similar magnitude regardless of the considered subgroup of individuals and the adjustment applied to the regression model. To assess the consistency of our results with that which was earlier described, we carried out a review of the literature, identifying over 30 articles reporting linkage on SCR, SCR-derived traits, urinary albumin-to-creatinine ratio, and renal disease. For our most prominent findings, the comparison with the literature is reported in Table 3. Apart from the region on chromosome 10p11 and a part of the large region on chromosome 22q13, in all other cases, we confirmed many results reported earlier, and often our findings were supported by more than one earlier study. When extending the comparison to all LOD scores ≥1, the amount of replication was much larger. Of the 54 detected regions, 38 have been reported earlier. This extensive list is provided in the Supplementary Information File 3, together with annotated references to earlier findings. Download .doc (.68 MB)
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