Familial Aggregation of ESRD and Heritability of Variation in GFR

Familial aggregation of ESRD and the heritability of a variation in GFR have been examined in the same fashion as proteinuria and a variation in UAE; the summary of the studies is shown in Table 2.

The first study was by Pettitt et al. (23) who described the familial aggregation of impaired kidney function among diabetic parents and their diabetic offspring in Pima Indians with T2DM. Subsequently, Freedman et al. (24) reported that in families selected through an index case with ESRD caused by DN, there was an excess of relatives with ESRD in comparison with the risk of ESRD in the general population.

The heritability of GFR was examined in four studies conducted in families ascertained through an individual without diabetes. One analysis was performed in 539 monozygotic and 1208 dizygotic sets of female twins, all of them nondiabetics. The h2 of serum creatinine was 0.37 and the calculated creatinine clearance using the Cockcroft-Gault formula was 0.63 (9). The heritability of kidney function was computed in multi-generational families in Utah, enriched for the presence of premature cardiovascular disease (25). The examinations were performed three times during a 10-yr follow-up study. The h2 for serum creatinine varied between 0.25 and 0.31. For GFR estimated using the Modification of Diet in Renal Disease (MDRD) formula, the h2 ranged from 0.37 to 0.42. Recently, similar data were reported from the Framingham Heart Study, which included 1200 individuals from 330 nuclear families. In this study, the h2 for various estimates of GFR varied between 0.29 and 0.46 (26). In a more recent report, Langefeld et al. (21) examined the h2 of GFR estimated by the modified MDRD formula in 662 Caucasian individuals with T2DM from 310 families. The h2 of GFR was 0.75, the highest value in the literature.

In a recent study, we demonstrated that the concentration of serum cystatin C is an accurate estimate of renal function in individuals with T2DM (27). This method provides a more accurate estimate of GFR than other methods (including the MDRD equation), particularly in individuals with normal or elevated values of GFR. By measuring

Table 2

Summary of Studies on Familial Clustering of ESRD and Heritability of Variation of GFR

Authors

Population

Results of the study

Pettit et al., 1990 (23) Freedman et al., 1995 (24)

Langefeld et al., 2004 (21) Placha et al., 2005 (28)

Pima Indians, Arizona,

African-Americans, Southern US

Caucasians, UK

Caucasians, Utah

Caucasians, Framingham, MA

Caucasians, North Carolina

Caucasians, New England

Diabetic siblings and offspring of diabetic index cases with impaired kidney function had elevated serum creatinine.

Relatives of index cases with type 2 diabetes and ESRD had a risk of ESRD 8.1 times that of relatives of index cases with type 2 diabetes and without DN.

In a twin study of adult women, heritabilities of serum creatinine (h2 = 0.37), and calculated creatinine clearance (h2 = 0.63) were both significant.

In extended nondiabetic families ascertained for early cardiovascular disease, heritabilities of serum creatinine (h2 from 0.25 to 0.31) and estimated GFR (h2 from 0.37 to 0.42) were significant.

In mainly nondiabetic families in the Framingham Heart Study, heritabilities of serum creatinine (h2 = 0.29), estimated GFRa (h2 = 0.31) and calculated creatinine clearance (h2 = 0.56) were all significant.

In nuclear families consisting of at least two siblings with type 2 diabetes, heritability of GFRa (h2 = 0.75) was significant.

In extended families ascertained for type 2 diabetes, heritability of GFRb was significant in relatives with diabetes (h2 = 0.45) and in those without (h2 = 0.35).

aGFR was estimated using serum creatinine levels and the MDRD formula. ftGFR was estimated as the reciprocal of serum cystatin C concentration x 100.

families, 63 families out of 104 were included with typical T2DM diagnosed after age 35 yr. The example of the typical family with values of GFR estimated from serum cystatin C is shown in Fig. 1.

To study familial aggregation of variation in renal function, a variance components analysis was used to estimate the heritability for estimated GFR after adjustment for covariates such as sex and age. In our multigenerational families, the heritability (h2) of GFR estimated by serum cystatin C levels was 0.45 in diabetic relatives and 0.35 in nondiabetic relatives (28). Interestingly, when ACR was included in the variance components analysis as a covariate (in addition to sex and age), the heritability estimates in diabetics and nondiabetics increased slightly to 0.47 and 0.39, respectively. These findings provide very strong evidence that variation in renal function, as measured by estimated GFR, is controlled by genetic factors in individuals with and without diabetes, and they suggest that genes controlling variation in GFR are different from genes controlling ACR.

Table 3

Genetic and Environmental Correlations Between ACR and GFR in Diabetic and Nondiabetic Relatives in the Joslin Collection of Families With T2DM

Table 3

Genetic and Environmental Correlations Between ACR and GFR in Diabetic and Nondiabetic Relatives in the Joslin Collection of Families With T2DM

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