The association of genetic variants of type 2 diabetes with kidney function
2012; Elsevier BV; Volume: 82; Issue: 2 Linguagem: Inglês
10.1038/ki.2012.107
ISSN1523-1755
AutoresNora Franceschini, Nawar Shara, Hong Wang, V. Saroja Voruganti, Sandy Laston, Karin Haack, Elisa T. Lee, Lyle G. Best, Jean W. MacCluer, Barbara Cochran, Thomas D. Dyer, Barbara V. Howard, Shelley A. Cole, Kari E. North, Jason G. Umans,
Tópico(s)Liver Disease Diagnosis and Treatment
ResumoType 2 diabetes is highly prevalent and is the major cause of progressive chronic kidney disease in American Indians. Genome-wide association studies identified several loci associated with diabetes but their impact on susceptibility to diabetic complications is unknown. We studied the association of 18 type 2 diabetes genome-wide association single-nucleotide polymorphisms (SNPs) with estimated glomerular filtration rate (eGFR; MDRD equation) and urine albumin-to-creatinine ratio in 6958 Strong Heart Study family and cohort participants. Center-specific residuals of eGFR and log urine albumin-to-creatinine ratio, obtained from linear regression models adjusted for age, sex, and body mass index, were regressed onto SNP dosage using variance component models in family data and linear regression in unrelated individuals. Estimates were then combined across centers. Four diabetic loci were associated with eGFR and one locus with urine albumin-to-creatinine ratio. A SNP in the WFS1 gene (rs10010131) was associated with higher eGFR in younger individuals and with increased albuminuria. SNPs in the FTO, KCNJ11, and TCF7L2 genes were associated with lower eGFR, but not albuminuria, and were not significant in prospective analyses. Our findings suggest a shared genetic risk for type 2 diabetes and its kidney complications, and a potential role for WFS1 in early-onset diabetic nephropathy in American Indian populations. Type 2 diabetes is highly prevalent and is the major cause of progressive chronic kidney disease in American Indians. Genome-wide association studies identified several loci associated with diabetes but their impact on susceptibility to diabetic complications is unknown. We studied the association of 18 type 2 diabetes genome-wide association single-nucleotide polymorphisms (SNPs) with estimated glomerular filtration rate (eGFR; MDRD equation) and urine albumin-to-creatinine ratio in 6958 Strong Heart Study family and cohort participants. Center-specific residuals of eGFR and log urine albumin-to-creatinine ratio, obtained from linear regression models adjusted for age, sex, and body mass index, were regressed onto SNP dosage using variance component models in family data and linear regression in unrelated individuals. Estimates were then combined across centers. Four diabetic loci were associated with eGFR and one locus with urine albumin-to-creatinine ratio. A SNP in the WFS1 gene (rs10010131) was associated with higher eGFR in younger individuals and with increased albuminuria. SNPs in the FTO, KCNJ11, and TCF7L2 genes were associated with lower eGFR, but not albuminuria, and were not significant in prospective analyses. Our findings suggest a shared genetic risk for type 2 diabetes and its kidney complications, and a potential role for WFS1 in early-onset diabetic nephropathy in American Indian populations. American Indians have a high prevalence of obesity, type 2 diabetes (T2D), and metabolic syndrome.1.Kurella M. Lo J.C. Chertow G.M. Metabolic syndrome and the risk for chronic kidney disease among nondiabetic adults.J Am Soc Nephrol. 2005; 16: 2134-2140Crossref PubMed Scopus (562) Google Scholar,2.Lucove J. Vupputuri S. Heiss G. et al.Metabolic syndrome and the development of CKD in American Indians: the Strong Heart Study.Am J Kidney Dis. 2008; 51: 21-28Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar These conditions, together with hypertension, hyperlipidemia,3.Fried L.F. Orchard T.J. Kasiske B.L. Effect of lipid reduction on the progression of renal disease: a meta-analysis.Kidney Int. 2001; 59: 260-269Abstract Full Text Full Text PDF PubMed Scopus (641) Google Scholar,4.Fagot-Campagna A. Nelson R.G. Knowler W.C. et al.Plasma lipoproteins and the incidence of abnormal excretion of albumin in diabetic American Indians: the Strong Heart Study.Diabetologia. 1998; 41: 1002-1009Crossref PubMed Scopus (17) Google Scholar and smoking,5.Gambaro G. Verlato F. Budakovic A. et al.Renal impairment in chronic cigarette smokers.J Am Soc Nephrol. 1998; 9: 562-567PubMed Google Scholar,6.Pinto-Sietsma S.J. Mulder J. Janssen W.M. et al.Smoking is related to albuminuria and abnormal renal function in nondiabetic persons.Ann Intern Med. 2000; 133: 585-591Crossref PubMed Scopus (244) Google Scholar may contribute to an increased burden of chronic kidney disease (CKD), defined either by increased albuminuria or by decreased glomerular filtration rate (GFR).7.Robbins D.C. Knowler W.C. Lee E.T. et al.Regional differences in albuminuria among American Indians: an epidemic of renal disease.Kidney Int. 1996; 49: 557-563Abstract Full Text PDF PubMed Scopus (55) Google Scholar, 8.Scavini M. Stidley C.A. Paine S.S. et al.The burden of chronic kidney disease among the Zuni Indians: the Zuni kidney project.Clin J Am Soc Nephrol. 2007; 2: 509-516Crossref PubMed Scopus (22) Google Scholar, 9.Luo F. Wang Y. Wang X. et al.A functional variant of NEDD4L is associated with hypertension, antihypertensive response, and orthostatic hypotension.Hypertension. 2009; 54: 796-801Crossref PubMed Scopus (60) Google Scholar CKD is associated with increased cardiovascular disease events and death in American Indians.10.Shara N.M. Resnick H.E. Lu L. et al.Decreased GFR estimated by MDRD or Cockcroft-Gault equation predicts incident CVD: the Strong Heart Study.J Nephrol. 2009; 22: 373-380PubMed Google Scholar,11.Shara N.M. Wang H. Valaitis E. et al.Comparison of estimated glomerular filtration rates and albuminuria in predicting risk of coronary heart disease in a population with high prevalence of diabetes mellitus and renal disease.Am J Cardiol. 2011; 107: 399-405Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Therefore, understanding the pathways leading to CKD is relevant to public health. T2D is one of the most common conditions associated with CKD and kidney failure in Western populations.12.US renal data system: excerpts from the USRDS 2006 annual data report.Am J Kidney Dis. 2006; 49: S1-S296Google Scholar Diabetic nephropathy most typically progresses through an early phase in which microalbuminuria, detected by a spot urine albumin-to-creatinine ratio (UACR) ≥30mg/g, is associated with supranormal GFR, i.e., glomerular hyperfiltration.13.Silveiro S.P. Friedman R. de Azevedo M.J. et al.Five-year prospective study of glomerular filtration rate and albumin excretion rate in normofiltering and hyperfiltering normoalbuminuric NIDDM patients.Diabetes Care. 1996; 19: 171-174Crossref PubMed Scopus (72) Google Scholar, 14.Pruijm M. Wuerzner G. Maillard M. et al.Glomerular hyperfiltration and increased proximal sodium reabsorption in subjects with type 2 diabetes or impaired fasting glucose in a population of the African region.Nephrol Dial Transplant. 2010; 25: 2225-2231Crossref PubMed Scopus (48) Google Scholar, 15.Brenner B.M. Lawler E.V. Mackenzie H.S. The hyperfiltration theory: a paradigm shift in nephrology.Kidney Int. 1996; 49: 1774-1777Abstract Full Text PDF PubMed Scopus (664) Google Scholar These initial abnormalities may be reversible, but then may progress to macroalbuminuria (UACR ≥300mg/g) and an irreversible decline in GFR. Alternatively, in some T2D individuals, impaired GFR can occur without substantial albuminuria.16.Kramer H.J. Nguyen Q.D. Curhan G. et al.Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus.JAMA. 2003; 289: 3273-3277Crossref PubMed Scopus (481) Google Scholar In the Strong Heart Study (SHS), American Indians with T2D often have microalbuminuria or macroalbuminuria associated with decreased GFR.17.Franceschini N. Voruganti V.S. Haack K. et al.The association of the MYH9 gene and kidney outcomes in American Indians: the strong heart family study.Hum Genet. 2010; 127: 295-301Crossref PubMed Scopus (15) Google Scholar Similarly, young Pima Indians with T2D, aged 5–19 years, frequently have microalbuminuria, which is a strong predictor of macroalbuminuria at follow-up.18.Kim N.H. Pavkov M.E. Knowler W.C. et al.Predictive value of albuminuria in American Indian youth with or without type 2 diabetes.Pediatrics. 2010; 125: e844-e851Crossref PubMed Scopus (21) Google Scholar Diabetic nephropathy occurs more often among family members,19.Bleyer A.J. Sedor J.R. Freedman B.I. et al.Risk factors for development and progression of diabetic kidney disease and treatment patterns among diabetic siblings of patients with diabetic kidney disease.Am J Kidney Dis. 2008; 51: 29-37Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar suggesting a genetic susceptibility to this complication. The heritability of kidney traits in American Indians has been documented for estimated GFR (eGFR) and UACR, a marker of kidney damage.20.Imperatore G. Knowler W.C. Nelson R.G. et al.Genetics of diabetic nephropathy in the Pima Indians.Curr Diab Rep. 2001; 1: 275-281Crossref PubMed Scopus (41) Google Scholar, 21.MacCluer J.W. Scavini M. Shah V.O. et al.Heritability of measures of kidney disease among Zuni Indians: the Zuni kidney project.Am J Kidney Dis. 2010; 56: 289-302Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 22.Mottl A.K. Vupputuri S. Cole S.A. et al.Linkage analysis of albuminuria.J Am Soc Nephrol. 2009; 20: 1597-1606Crossref PubMed Scopus (20) Google Scholar, 23.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 Genome-wide association studies have identified several loci associated with T2D (reviewed in Wolfs et al.24.Wolfs M.G. Hofker M.H. Wijmenga C. et al.Type 2 diabetes mellitus: new genetic insights will lead to new therapeutics.Curr Genomics. 2009; 10: 110-118Crossref PubMed Scopus (28) Google Scholar). There is some evidence for associations of T2D loci with diabetic nephropathy including reported variants in PPARG in Chinese25.Liu L. Zheng T. Wang F. et al.Pro12Ala polymorphism in the PPARG gene contributes to the development of diabetic nephropathy in Chinese type 2 diabetic patients.Diabetes Care. 2010; 33: 144-149Crossref PubMed Scopus (46) Google Scholar and KCNQ1 in Japanese individuals.26.Ohshige T. Tanaka Y. Araki S. et al.A single nucleotide polymorphism in KCNQ1 is associated with susceptibility to diabetic nephropathy in Japanese subjects with type 2 diabetes.Diabetes Care. 2010; 33: 842-846Crossref PubMed Scopus (21) Google Scholar In addition, TCF7L2 has been associated with diabetic nephropathy in individuals with early-onset T2D27.Buraczynska M. Swatowski A. Markowska-Gosik D. et al.Transcription factor 7-like 2 (TCF7L2) gene polymorphism and complication/comorbidity profile in type 2 diabetes patients.Diabetes Res Clin Pract. 2011; 93: 390-395Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar and among middle-aged individuals.28.Kottgen A. Hwang S.J. Rampersaud E. et al.TCF7L2 variants associate with CKD progression and renal function in population-based cohorts.J Am Soc Nephrol. 2008; 19: 1989-1999Crossref PubMed Scopus (41) Google Scholar Given the large number of newly identified loci for T2D, the effects of genes associated with T2D on kidney function and damage merit exploration in American Indian populations. We recently genotyped several genome-wide association study-validated single-nucleotide polymorphisms (SNPs) in American Indians in the Genetic Epidemiology of Causal Variants Across the Life Course (CALiCo) Consortium as part of the Population Architecture using Genomics and Epidemiology study.29.Matise T.C. Ambite J. Buyske S. et al.Population architecture using genetics and epidemiology.Am J Epidemiol. 2011; 174: 849-859Crossref PubMed Scopus (120) Google Scholar We studied associations of T2D SNPs with prevalent eGFR and UACR in over 6900 American Indians from the Strong Heart Family Study (SHFS) and SHS cohort. We also explored the evidence for SNP associations with incident CKD and new-onset microalbuminuria using longitudinal data from the SHS participants. Baseline characteristics of the SHFS and SHS cohort American Indian samples are displayed in Table 1. By design, the mean age of SHFS participants was lower than that of the SHS cohort participants. The prevalence of T2D and impaired fasting glucose varied across centers, but the mean body mass index (BMI) was similar when comparing the cohort with family members for the same recruiting center. Cohort participants had lower mean eGFR and higher median UACR than family study participants. A total of 18 SNPs representing 15 loci were examined. Minor allele frequencies per center are shown in Supplementary Table S1 online. Two SNPs in each of the FTO and the TCF7L2 genes were highly correlated in American Indians (r2>0.95 in the overall sample and within each center).Table 1Baseline characteristics of American Indians of the Strong Heart Family Study (1998–2003) and Strong Heart Study (1989–1991)Strong Heart Family StudyStrong Heart StudyDakotaArizonaOklahomaDakotaArizonaOklahomaNumber117611651167118811471115Mean age (s.d.), years38.4 (16.8)36.2 (15.5)43.4 (17.3)56.3 (8.1)55.8 (7.9)56.8 (8.4)Female sex, %58.762.159.356.863.857.9Type 2 diabetes, %13.431.419.833.163.736.1Impaired fasting glucose, %7.98.16.214.710.714.5Mean BMI (s.d.), kg/m230.1 (6.8)35.5 (8.8)31.1 (6.9)29.3 (5.5)32.5 (7.1)30.7 (6.0)Mean eGFR (s.d.), ml/min per 1.73 m2aeGFR was estimated using the Modified Diet and Renal Disease equation.96.6 (23.8)114.5 (28.9)93.6 (22.9)81.3 (20.3)86.1 (23.6)78.6 (17.5)Median UACR (25–75%), mg/g7.1 (1.7–7805.9)10.4 (1.7–9756.1)7.1 (1.1–9645.7)7.5 (0.1–7493)27.1 (0.1–65,000.0)8.5 (0.04–12,419.8)Abbreviations: BMI, body mass index; eGFR, estimated glomerular filtration rate; UACR, urine albumin-to-creatinine ratio.a eGFR was estimated using the Modified Diet and Renal Disease equation. Open table in a new tab Download .doc (.13 MB) Help with doc files Supplementary Tables Abbreviations: BMI, body mass index; eGFR, estimated glomerular filtration rate; UACR, urine albumin-to-creatinine ratio. We identified significant associations of SNPs in FTO, TCF7L2, and KCNJ11 with eGFR (P 45 years) SHS participants (Table 2 footnote). We thus hypothesized age-specific effects on eGFR. We then performed analyses using age categories (<45, 45 to 59 and 60 years or more). The magnitude of effect of WFS1 rs10010131 G allele on eGFR was larger in American Indians 0.95 in the overall sample and within each center.FTOAC–0.0780.02530.00268350.13↑BMI and T2Drs9939609aFTO variants (rs8050136 and rs9939609) and TCF7L2 variants (rs7901695 and rs7903146) are in linkage disequilibrium: r2>0.95 in the overall sample and within each center.FTOAT–0.07510.02520.00368020.18↑BMI and T2Drs5219KCNJ11TC–0.05430.01780.00268070.91↑T2Drs7901695aFTO variants (rs8050136 and rs9939609) and TCF7L2 variants (rs7901695 and rs7903146) are in linkage disequilibrium: r2>0.95 in the overall sample and within each center.TCF7L2CT–0.08840.02650.000868340.24↑T2Drs7903146aFTO variants (rs8050136 and rs9939609) and TCF7L2 variants (rs7901695 and rs7903146) are in linkage disequilibrium: r2>0.95 in the overall sample and within each center.TCF7L2TC–0.07580.02690.00568370.17↑T2Drs10010131bEstimates for the family study are: β (s.e.)=0.12 (0.04), P=0.0008, and for cohort study β (s.e.)=–0.02 (0.04), P=0.63.WFS1GA0.07040.02520.00568370.07↑T2DUACRrs10010131WFS1GA0.06840.02630.00967840.34↑T2DAbbreviations: BMI, body mass index; eGFR, estimated glomerular filtration rate; log UACR, urine albumin-to-creatinine ratio; SNP, single nucleotide polymorphism; T2D, type 2 diabetes.a FTO variants (rs8050136 and rs9939609) and TCF7L2 variants (rs7901695 and rs7903146) are in linkage disequilibrium: r2>0.95 in the overall sample and within each center.b Estimates for the family study are: β (s.e.)=0.12 (0.04), P=0.0008, and for cohort study β (s.e.)=–0.02 (0.04), P=0.63. Open table in a new tab Abbreviations: BMI, body mass index; eGFR, estimated glomerular filtration rate; log UACR, urine albumin-to-creatinine ratio; SNP, single nucleotide polymorphism; T2D, type 2 diabetes. To examine whether the significant findings were mediated by diabetes, we also performed diabetes-stratified analyses (Supplementary Table S3 online) and analyses adjusting for T2D. Interestingly, TCF7L2 SNP association with eGFR was unchanged when adjusting for T2D. The overall T2D-adjusted associations of WFS1 (P=0.08), KCNJ11 (P=0.72), and FTO (P=0.03) with eGFR were no longer significant, but the age-specific association with eGFR for the WFS1 SNP was mostly unchanged (P=0.0003 to 0.0008, n=2249, for association among individuals 45 years or younger). The association of rs10010131 with UACR was no longer significant when adjusting for T2D. In prospective data of SHS participants, incident (stage 3) CKD events were defined by the new occurrence of an eGFR of 60ml/min per 1.73m2 or lower, or by self-report of maintenance dialysis or kidney transplantation among individuals with an eGFR >60ml/min per 1.73m2 at baseline visit. Approximately 477 CKD events occurred among 3160 individuals at a median follow-up of 8 years. Of the 3918 SHS participants with baseline eGFR ≥60ml/min per 1.73m2, 1035 with albuminuria at baseline were excluded for the analysis of incident albuminuria (~499 events). A FTO SNP (rs9939609) was significantly associated with incident CKD in the Dakotas but not in the analyses of all three centers (Supplementary Table S4 online), and none of the loci was associated with new-onset microalbuminuria (Supplementary Table S5 online). However, the direction of the effect of the association with microalbuminuria was consistent with the findings for continuous prevalent UACR. CKD affects minorities disproportionally, who also progress more often to end-stage renal disease than individuals of European ancestry.8.Scavini M. Stidley C.A. Paine S.S. et al.The burden of chronic kidney disease among the Zuni Indians: the Zuni kidney project.Clin J Am Soc Nephrol. 2007; 2: 509-516Crossref PubMed Scopus (22) Google Scholar,9.Luo F. Wang Y. Wang X. et al.A functional variant of NEDD4L is associated with hypertension, antihypertensive response, and orthostatic hypotension.Hypertension. 2009; 54: 796-801Crossref PubMed Scopus (60) Google Scholar American Indians have a high prevalence of obesity and T2D, which contribute to the large burden of cardiovascular and kidney diseases in this population.7.Robbins D.C. Knowler W.C. Lee E.T. et al.Regional differences in albuminuria among American Indians: an epidemic of renal disease.Kidney Int. 1996; 49: 557-563Abstract Full Text PDF PubMed Scopus (55) Google Scholar, 8.Scavini M. Stidley C.A. Paine S.S. et al.The burden of chronic kidney disease among the Zuni Indians: the Zuni kidney project.Clin J Am Soc Nephrol. 2007; 2: 509-516Crossref PubMed Scopus (22) Google Scholar, 9.Luo F. Wang Y. Wang X. et al.A functional variant of NEDD4L is associated with hypertension, antihypertensive response, and orthostatic hypotension.Hypertension. 2009; 54: 796-801Crossref PubMed Scopus (60) Google Scholar, 30.Howard B.V. Lee E.T. Cowan L.D. et al.Coronary heart disease prevalence and its relation to risk factors in American Indians. The Strong Heart Study.Am J Epidemiol. 1995; 142: 254-268PubMed Google Scholar We investigated the genetic contribution of recently discovered T2D genetic variants to kidney function and markers of kidney damage in American Indians. The selected SNPs were initially identified in European and Asian ancestry studies, and some of these variants have also been replicated for T2D associations in American Indian participants of the SHS (Haiman et al., Diabetes, in press). Several loci (FTO, KCNJ11, TCF7L2, and WFS1) were associated with eGFR, and a SNP in WFS1 was associated with albuminuria. WFS1 product is a transmembrane protein localized to the endoplasmic reticulum,31.Takeda K. Inoue H. Tanizawa Y. et al.WFS1 (Wolfram syndrome 1) gene product: predominant subcellular localization to endoplasmic reticulum in cultured cells and neuronal expression in rat brain.Hum Mol Genet. 2001; 10: 477-484Crossref PubMed Scopus (265) Google Scholar which is involved in endoplasmic reticulum stress signaling pathways.32.Ueda K. Kawano J. Takeda K. et al.Endoplasmic reticulum stress induces Wfs1 gene expression in pancreatic beta-cells via transcriptional activation.Eur J Endocrinol. 2005; 153: 167-176Crossref PubMed Scopus (69) Google Scholar The WFS1 SNP T2D risk allele was associated with increased albuminuria and eGFR, with a large effect on eGFR in American Indians younger than 45 years compared with those 45 to 59 years old or older than 60 years, for whom the SNP effect was greatly attenuated. In analyses adjusted for both BMI and T2D, the association with eGFR was slightly changed in the younger age category and it was no longer significant for UACR. These are interesting findings as American Indians develop diabetic nephropathy at earlier ages than individuals of other ancestry.33.Knowler W.C. Pettitt D.J. Saad M.F. et al.Diabetes mellitus in the Pima Indians: incidence, risk factors and pathogenesis.Diabetes Metab Rev. 1990; 6: 1-27Crossref PubMed Scopus (515) Google Scholar Early stages in the pathogenesis of the diabetic nephropathy are characterized by microalbuminuria and hyperfiltration. Our findings of increasing eGFR and albuminuria for WFS1, although modest, are consistent with the early development of nephropathy and suggest that the genetic effect is partially mediated by diabetes. These findings will require further confirmation in American Indians and other populations, and in studies using direct measures of kidney function to detect higher ranges of GFR. In contrast, the alleles associated with T2D risk for FTO, KCNJ11, and TCF7L2 were associated with reduced eGFR in American Indians and were not associated with albuminuria. FTO is known to confer risk for T2D through its association with obesity34.Frayling T.M. Timpson N.J. Weedon M.N. et al.A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity.Science. 2007; 316: 889-894Crossref PubMed Scopus (3353) Google Scholar in both children and adults.34.Frayling T.M. Timpson N.J. Weedon M.N. et al.A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity.Science. 2007; 316: 889-894Crossref PubMed Scopus (3353) Google Scholar,35.Elks C.E. Loos R.J. Sharp S.J. et al.Genetic markers of adult obesity risk are associated with greater early infancy weight gain and growth.PLoS Med. 2010; 7: e1000284Crossref PubMed Scopus (150) Google Scholar Variants in this gene have been recently reported to be associated with end-stage renal disease in two case–control studies.36.Hubacek J.A. Viklicky O. Dlouha D. et al.The FTO gene polymorphism is associated with end-stage renal disease: two large independent case-control studies in a general population.Nephrol Dial Transplant. 2012; 27: 1030-1035Crossref PubMed Google Scholar It is interesting to note that the associations with low eGFR in American Indians occurred in models adjusting for BMI, suggesting an effect independent of body size, although the mean BMI in American Indians in our study was high and in the range of overweight to obese. The KCNJ11 gene was identified in T2D associations in individuals of European and Asian ancestry.37.Zeggini E. Weedon M.N. Lindgren C.M. et al.Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes.Science. 2007; 316: 1336-1341Crossref PubMed Scopus (1830) Google Scholar, 38.Omori S. Tanaka Y. Takahashi A. et al.Association of CDKAL1, IGF2BP2, CDKN2A/B, HHEX, SLC30A8, and KCNJ11 with susceptibility to type 2 diabetes in a Japanese population.Diabetes. 2008; 57: 791-795Crossref PubMed Scopus (240) Google Scholar, 39.Wang F. Han X.Y. Ren Q. et al.Effect of genetic variants in KCNJ11, ABCC8, PPARG and HNF4A loci on the susceptibility of type 2 diabetes in Chinese Han population.Chin Med J (Engl). 2009; 122: 2477-2482PubMed Google Scholar The gene product impairs glucose-induced insulin release, and its variants has also been associated with increased BMI.40.Nielsen E.M. Hansen L. Carstensen B. et al.The E23K variant of Kir6.2 associates with impaired post-OGTT serum insulin response and increased risk of type 2 diabetes.Diabetes. 2003; 52: 573-577Crossref PubMed Scopus (239) Google Scholar,41.Yang L. Zhou X. Luo Y. et al.Association between KCNJ11 gene polymorphisms and risk of type 2 diabetes mellitus in East Asian populations: a meta-analysis in 42,573 individuals.Mol Biol Rep. 2012; 39: 645-659Crossref PubMed Scopus (23) Google Scholar It is intriguing that variants in both these genes are associated with lower eGFR in the context of obesity, which is a risk factor for CKD.42.Hsu C.Y. McCulloch C.E. Iribarren C. et al.Body mass index and risk for end-stage renal disease.Ann Intern Med. 2006; 144: 21-28Crossref PubMed Scopus (1036) Google Scholar However, for both genes, the associations seem to be mediated by diabetes, as they are no longer significant in analyses adjusted for T2D. TCF7L2 has shown consistent associations with T2D across ancestry groups43.Grant S.F. Thorleifsson G. Reynisdottir I. et al.Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes.Nat Genet. 2006; 38: 320-323Crossref PubMed Scopus (1749) Google Scholar,44.Palmer N.D. Hester J.M. An S.S. et al.Resequencing and analysis of variation in the TCF7L2 gene in African Americans suggests that SNP rs7903146 is the causal diabetes susceptibility variant.Diabetes. 2011; 60: 662-668Crossref PubMed Scopus (61) Google Scholar and, in American Indians, it has been associated with glucose homeostasis traits (unpublished data). TCF7L2 product is a key component of the Wnt signaling pathway involved in the regulation of pancreatic β-cell proliferation, differentiation, and insulin secretion,45.Pearson E.R. Translating TCF7L2: from gene to function.Diabetologia. 2009; 52: 1227-1230Crossref PubMed Scopus (39) Google Scholar but is also important in kidney embryogenesis and disease.46.Lancaster M.A. Gleeson J.G. Cystic kidney disease: the role of Wnt signaling.Trends Mol Med. 2010; 16: 349-360Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar The rs7903146 T allele was significantly associated with lower eGFR in American Indians but not with incident CKD, which is in contrast to a previous report in a population-based study of middle-aged individuals.28.Kottgen A. Hwang S.J. Rampersaud E. et al.TCF7L2 variants associate with CKD progression and renal function in population-based cohorts.J Am Soc Nephrol. 2008; 19: 1989-1999Crossref PubMed Scopus (41) Google Scholar Interestingly, a recent large study of T2D showed association of the rs7903146 T allele with diabetic nephropathy, with larger effect in individuals with early-onset T2D.27.Buraczynska M. Swatowski A. Markowska-Gosik D. et al.Transcription factor 7-like 2 (TCF7L2) gene polymorphism and complication/comorbidity profile in type 2 diabetes patients.Diabetes Res Clin Pract. 2011; 93: 390-395Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar In our study, this genetic variant shows no evidence of heterogeneity across age categories. In addition, the association was slightly attenuated when adjusting for diabetes. In summary, our findings suggest that at least four T2D loci are associated with kidney traits in American Indians, of which two may have effects that are partially independent of diabetes. These findings may have important implications in prevention efforts for CKD in this population. Our prospective associations with incident CKD and new-onset albuminuria were restricted to the SHS cohort study, which has long-term longitudinal data. Although we noted significant associations for the FTO rs9939609 A allele in the Dakotas, our samples were limited. In addition, we did not identify associations with new-onset albuminuria for tested SNPs. This study used kidney function estimates from an equation derived from CKD individuals. Calibrated serum creatinine concentrations are currently not available in the SHS. The SNPs investigated were identified in individuals of European ancestry. However, the FTO, WFS1, and TCF7L2 SNP associations have been replicated in American Indians for T2D or glycemic traits. In summary, we identified four T2D loci associated with kidney function in American Indians, including two previously reported associations with kidney traits in individuals of European ancestry. The WFS1 variant was associated with increased albuminuria and eGFR, and it showed age-specific effects on eGFR. These findings suggest shared genetic risk factors for T2D and its kidney complications in this population. The SHS is a population-based cohort study funded by the National Heart, Lung, and Blood Institute (NHLBI) of 4549 American Indian men and women, aged 45–74 years and recruited from 13 tribes located in Arizona, North and South Dakota, and Oklahoma, who underwent a baseline (1989–1991) and then two follow-up (1993–1995 and 1996–1999) examinations.47.Lee E.T. Welty T.K. Fabsitz R. et al.The Strong Heart Study. a study of cardiovascular disease in American Indians: design and methods.Am J Epidemiol. 1990; 132: 1141-1155PubMed Google Scholar The SHFS started in 1998 to study the genetics of cardiovascular disease among American Indian populations, and it recruited family members from the original cohort study.48.North K.E. Howard B.V. Welty T.K. et al.Genetic and environmental contributions to cardiovascular disease risk in American Indians: the Strong Heart Family Study.Am J Epidemiol. 2003; 157: 303-314Crossref PubMed Scopus (161) Google Scholar Over 3600 American Indians aged 14–93 years and in 94 multigenerational families were examined, of whom 540 also are SHS cohort members (and were included in the family data only for analyses). The SHS and SHFS protocols were approved by the Indian Health Service Institutional Review Board, by the Institutional Review Boards of the participating Institutions, and by the Indian tribes participating in these studies.47.Lee E.T. Welty T.K. Fabsitz R. et al.The Strong Heart Study. a study of cardiovascular disease in American Indians: design and methods.Am J Epidemiol. 1990; 132: 1141-1155PubMed Google Scholar,48.North K.E. Howard B.V. Welty T.K. et al.Genetic and environmental contributions to cardiovascular disease risk in American Indians: the Strong Heart Family Study.Am J Epidemiol. 2003; 157: 303-314Crossref PubMed Scopus (161) Google Scholar All participants gave informed consent for genetic testing. Demographic data and medical history were obtained by means of a personal interview during a clinical examination. Anthropometric measures of body weight (kg) and height (m) were used to estimate BMI (kg/m2). Blood was collected after an overnight fast, and plasma or serum samples were stored at –80°C until analyzed. T2D was defined as a fasting blood glucose level of 126mg/dl or higher, history of diabetes, or the use of diabetic medications.49.Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.Diabetes Care. 1997; 20: 1183-1197Crossref PubMed Scopus (7547) Google Scholar Impaired fasting glucose and impaired glucose tolerance were defined by the World Health Organization criteria based on fasting plasma glucose and 75g oral glucose tolerance test results. Serum and urine creatinine were assayed by a kinetic alkaline picrate method and urine albumin by a sensitive nephelometric method, both on the Hitachi 717 platform (Roche Diagnostics, Indianapolis, IN). Urine albumin excretion was estimated as the UACR (mg/g), and eGFR was calculated using the Modified Diet and Renal Disease (MDRD) equation.50.Levey A.S. Bosch J.P. Lewis J.B. et al.A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group.Ann Intern Med. 1999; 130: 461-470Crossref PubMed Scopus (13030) Google Scholar In prospective data of SHS participants, incident (stage 3) CKD events were defined by the new occurrence of an eGFR of 60ml/min per 1.73m2 or lower, or by self-report of maintenance dialysis or kidney transplantation. CKD events included events that occurred during a median of 8 years follow-up between the baseline and visit 3 examinations in individuals without a prior history of CKD (n=516 with CKD at baseline were excluded). New-onset albuminuria was defined as follows: 1. UACR ≥30mg/g at follow-up among individuals with UACR <30mg/g at baseline, or as 2. UACR ≥30mg/g at follow-up among individuals with UACR 95%), concordance of blinded replicates (>98%), and deviation from Hardy–Weinberg equilibrium among founders (P<0.01). Individuals with more than 10% of missing genotypes (n=64) were excluded. Eighteen SNPs on 15 loci passed quality control and were included in these analyses (Supplementary Table S1 online). SNPs that failed genotyping were rs4430796 (HNF1b), rs2074196 (KCNQ1), and rs1326634 (SLC30A8). We estimated the linkage disequilibrium between SNPs in the same loci using Haploview. Quantitative traits with non-normal distribution were natural log-transformed for analysis. We obtained center-specific residuals of eGFR and log UACR (LACR) using linear regression models adjusted for age, age2, sex, age and sex interactions, and BMI. These residuals were then regressed onto SNP dosage using variance component models for family data to account for family relatedness and population history51.Boerwinkle E. Chakraborty R. Sing C.F. The use of measured genotype information in the analysis of quantitative phenotypes in man. I. Models and analytical methods.Ann Hum Genet. 1986; 50: 181-194Crossref PubMed Scopus (250) Google Scholar and by using linear regression for analysis of unrelated individuals (SHS). For SHS analyses, we also adjusted for self-reported blood quantum to account for ancestry. To account for age-specific effects, analyses were performed within categories of age (<45, 45 to 59, and 60 years or older). We performed a quantitative transmission disequilibrium test52.Havill L.M. Dyer T.D. Richardson D.K. et al.The quantitative trait linkage disequilibrium test: a more powerful alternative to the quantitative transmission disequilibrium test for use in the absence of population stratification.BMC Genet. 2005; 6: S91Crossref PubMed Scopus (55) Google Scholar in the SHFS and found no evidence of population substructure within centers but significant evidence of population stratification when combining centers. Therefore, analyses were stratified by center. Summary estimates were combined across age categories and centers using a weighted average of point estimate meta-analyses. We also tested for evidence of between-study heterogeneity53.Ioannidis J.P. Patsopoulos N.A. Evangelou E. Heterogeneity in meta-analyses of genome-wide association investigations.PLoS One. 2007; 2: e841Crossref PubMed Scopus (257) Google Scholar for age and center estimates by estimating the between-study variance and the I2 metric, which is a measure of the percentage of the total variation across strata due to heterogeneity rather than chance.54.Higgins J.P. Thompson S.G. Deeks J.J. et al.Measuring inconsistency in meta-analyses.Br Med J. 2003; 327: 557-560Crossref PubMed Scopus (40066) Google Scholar Unadjusted P-values are reported. A Bonferroni correction for multiple testing P=0.003 (α=0.05/15 independent tests) was considered significant. In sensitivity analyses, we excluded 333 individuals younger than 18 years of age (ranging from 15 to 17 years) from eGFR analyses, and age-specific results were unchanged. We also performed analyses adjusting for T2D and stratified analyses by diabetes. For significant SNP associations in cross-sectional analysis, we evaluated associations with incident CKD and increased albuminuria in the SHS using center-stratified logistic regression models adjusted for age, age2, sex, and BMI. Odds ratio and 95% confidence intervals are reported. A Bonferroni correction for multiple testing P=0.01 (α=0.05/4 independent tests) was considered significant. The Population Architecture Using Genomics and Epidemiology program is funded by the National Human Genome Research Institute (NHGRI), supported by U01HG004803 (Causal Variants Across the Life Course), U01HG004798 (EAGLE), U01HG004802 (MEC), U01HG004790 (WHI), and U01HG004801 (Coordinating Center). The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. The complete list of PAGE members can be found at http://www.pagestudy.org. The Strong Heart Study is supported by NHLBI grants U01 HL65520, U01 HL41642, U01 HL41652, U01 HL41654, and U01 HL65521. The opinions expressed in this paper are those of the author(s) and do not necessarily reflect the views of the Indian Health Service. Table S1. Type 2 diabetes-related SNPs, minor allele frequencies for SHS and SHFS across centers and meta-analyses P-values for eGFR and LACR. Table S2. Meta-analyses results of age-specific effects of rs10010131 (WFS1 gene) on eGFR. Table S3. Association results from diabetes-specific strata. Table S4. Center-specific and meta-analyses of SNP associations with incident chronic kidney disease for SHS participants. Table S5. Center-specific and meta-analyses results of SNP associations with incident microalbuminuria for SHS participants. Supplementary material is linked to the online version of the paper at http://www.nature.com/ki
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