Urinary metabolites along with common and rare genetic variations are associated with incident chronic kidney disease

被引:42
作者
McMahon, Gearoid M. [1 ,2 ]
Hwang, Shih-Jen [1 ]
Clish, Clary B. [3 ]
Tin, Adrienne [4 ]
Yang, Qiong [5 ]
Larson, Martin G. [1 ,6 ]
Rhee, Eugene P. [7 ]
Li, Man [4 ,8 ,9 ]
Levy, Daniel [1 ,10 ]
O'Donnell, Christopher J. [1 ]
Coresh, Josef [4 ]
Young, J. Hunter [4 ,11 ]
Gerszten, Robert E. [3 ,12 ]
Fox, Caroline S. [1 ,13 ]
机构
[1] NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA
[2] Brigham & Womens Hosp, Div Nephrol, Boston, MA 02115 USA
[3] Broad Inst, Cambridge, MA USA
[4] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA
[5] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA
[6] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA
[7] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA
[8] Univ Utah, Div Nephrol, Salt Lake City, UT USA
[9] Univ Utah, Dept Human Genet, Salt Lake City, UT USA
[10] NHLBI, NIH, Populat Sci Branch, Div Intramural Res, Bethesda, MD USA
[11] Johns Hopkins Sch Med, Dept Med, Baltimore, MD USA
[12] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA
[13] Brigham & Womens Hosp, Div Endocrinol & Metab, Boston, MA 02115 USA
关键词
chronic kidney disease; epidemiology; genetics; proximal tubule; GLOMERULAR-FILTRATION-RATE; GENOME-WIDE ASSOCIATION; OXIDATIVE STRESS; SERUM CREATININE; HISTIDINE; GLYCINE; INDEX; INFLAMMATION; ALBUMINURIA; MORTALITY;
D O I
10.1016/j.kint.2017.01.007
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
We assessed the association between urinary metabolites, genetic variants, and incident chronic kidney disease (CKD) in the Framingham Offspring cohort. Among the participants, 193 individuals developed CKD (estimated glomerular filtration rate under 60 ml/min/1.73m(2)) between cohort examinations 6 (1995-1998) and 8 (2005-2008, mean follow-up 9.7 years). They were age- and sex-matched to 193 control individuals free of CKD. A total of 154 urinary metabolites were measured using mass spectrometry, and the association between metabolites and CKD was examined using logistic regression. Next, we tested the genetic associations of each metabolite with an Illumina exome chip. Urinary glycine and histidine were associated with a lower risk of incident CKD with an odds ratio of 0.59 (95% confidence interval [CI] 0.43-0.80) and 0.65 (0.50-0.85) respectively, per one standard deviation increase in metabolite concentration. Follow-up in the Atherosclerosis Risk in Communities cohort confirmed the association of urinary glycine with CKD. In exome chip analyses, 36 single nucleotide polymorphisms at 30 loci were significantly associated with 31 metabolites. We surveyed exome chip findings for associations with known renal function loci such as rs8101881 in SLC7A9 coding for an amino acid transporter, which has been associated with a lower risk of CKD. We found this polymorphism was significantly associated with higher levels of lysine and NG-monomethyl-L-arginine (NMMA). Increased urinary lysine and NMMA were associated with a lower risk of CKD (0.73 [0.50-0.90] and 0.66 [0.53-0.83], respectively) in the univariate model. Thus, low urinary glycine and histidine are associated with incident CKD. Furthermore, genomic association of urinary metabolomics identified lysine and NMMA as being linked with CKD and provided additional evidence for the association of SLC7A9 with kidney disease.
引用
收藏
页码:1426 / 1435
页数:10
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