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Genomewide Linkage Analysis to Serum Creatinine, GFR, and Creatinine Clearance in a Community-Based Population: The Framingham Heart Study

Caroline S. Fox^*,,, Qiong Yang^,||, L. Adrienne Cupples, Chao-Yu Guo, Martin G. Larson^*,, Eric P. Leip^*,, Peter W.F. Wilson^*,¶ and Daniel Levy^*,,¶

*National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, Massachusetts; Department of Endocrinology, Diabetes, and Hypertension, the Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts; ^||Department of Neurology, Boston University School of Medicine, Boston, Massachusetts; ^¶Boston University School of Medicine, Boston, Massachusetts; and the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland

Correspondence to Dr. Caroline S. Fox, 73 Mt. Wayte Avenue, Suite #2, Framingham, MA 01702. Phone: 508-935-3447; Fax: 508-626-1262; E-mail: foxca{at}nhlbi.nih.gov

ABSTRACT. Kidney disease is a risk factor for the development of cardiovascular disease, all-cause mortality, and ESRD. It is not known to what extent genetic factors play a role in the development of kidney disease in the general population. Multipoint variance components linkage analysis was performed using Genehunter on 330 families from the Framingham Heart Study offspring cohort, using a 10-cM genomewide scan for serum creatinine, GFR, and creatinine clearance (CRCL) measured from 1998 to 2001. GFR was estimated using the simplified Modification of Diet in Renal Disease Study equation, and CRCL was estimated using the Cockcroft-Gault equation. Covariates in the adjustment included age, gender, body mass index, diabetes, systolic BP, hypertension treatment, tobacco use, and HDL cholesterol. Overall, 1224 subjects (52% women), mean age 59, were available for analysis. Mean creatinine was 0.87 mg/dl, mean GFR was 87 ml/min per 1.73 m², and mean creatinine clearance was 100 ml/min. The multivariable-adjusted heritability estimates for creatinine, GFR, and CRCL were 0.29, 0.33, and 0.46, respectively. The peak log of the odds ratio (LOD) scores for serum creatinine, GFR, and CRCL were 2.28 at 176 cM on chromosome 4, 2.19 at 78 cM on chromosome 4, and 1.91 at 103 cM on chromosome 3, respectively. In a community-based sample, measures of serum creatinine, GFR, and CRCL are heritable, suggesting an underlying genetic component. These results also provide suggestive evidence for linkage to measures of kidney function. Further research is necessary to identify the genes involved in the development of kidney disease and to understand their roles in this complex process.

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