Familial Aggregation Of Phenotypes Of Diabetic Nephropathy

Proteinuria and kidney function impairment are two phenotypes that are the major hallmarks of DN. Several studies demonstrated that both aggregate in families of diabetic as well as nondiabetic individuals as heritable traits. Before we discuss these results, a few comments are necessary about the ways the studies were designed.

Two different but complementary study designs are used to examine familial aggregation of complex diseases such as DN. Usually, conventional epidemiological designs and methods are used to explore first whether the disease in question clusters in families (8). More formally, the notion of familial clustering or aggregation implies a higher prevalence of disease in family members of cases (index cases) than in the general population or in family members of unaffected individuals (index controls). It should be noted that a disease having no genetic etiology may aggregate or cluster in families owing to a shared environment, such as an infectious agent or a culturally transmitted risk factor such as smoking or dietary preferences.

The relative contributions of heredity and shared environment to the familial aggregation of a disease have been tested historically by comparing the occurrence of the disease in monozygotic and dizygotic twin pairs (9), an impractical approach in T2DM patients with nephropathy. Alternatively, the hereditary and environmental components of familial aggregation can be partitioned on the basis of the pattern of covariance between pairs of relatives within families. Recent developments in statistical genetic analysis now enable the assessment of heritability (h2) (the proportion of total pheno-typic variance owing to additive genetic effects) and the genetic correlation between traits in extended families, taking into account the presence of environmental covari-ates (10). The proportion of total phenotypic variance owing to additive genetic effects may vary between h2 = 0, i.e., no genetic effect and h2 = 1, i.e., all variance is as a result of genetic effect. This approach has been employed to assess the genetic contributions to variation in urinary albumin excretion (UAE) and glomerular filtration rate (GFR) and has been extended to the mapping of genes for these traits.

Familial Aggregation

Fig. 1. Example of an extended family from the Joslin Collection of Families with T2DM. Circles indicate women and squares indicate men. Empty symbols indicate the absence of diabetes and filled ones indicate diabetes. Values in italics are the urinary albumin to creatinine ratio (ACR). Underlined values are the GFR estimated from serum cystatin C concentration. (Adapted from ref. 18.)

Fig. 1. Example of an extended family from the Joslin Collection of Families with T2DM. Circles indicate women and squares indicate men. Empty symbols indicate the absence of diabetes and filled ones indicate diabetes. Values in italics are the urinary albumin to creatinine ratio (ACR). Underlined values are the GFR estimated from serum cystatin C concentration. (Adapted from ref. 18.)

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