Familial studies display that calcium excretion is correlated be­tween sib-pairs, brothers and sisters, parents and children, but not between spouses (Figure 2) that do not share a common genetic background. Thus, a great portion of calcium excretion variability appears to be explained by hereditary factors. The proportion of calcium excretion variance is indicated by the cor­relation coefficient in offspring-parents. In the considered families, approximately 50% of the calcium excretion variance is justified by additive effect of genes (r=0.474, n=63, p=0.0001, Figure 2). In human pedigrees, hypercalciuria can be detected at each generation, with a sex independent trans­mission and no concordance for hypercalciuria in wives and husbands. These familial studies considered urinary calci­um as a qualitative trait with hypercalciuria/normocalciuria as the only possible phenotypes. In these studies hypercalciuria inheritance was regarded as an autosomal dominant Mendelian trait with high penetrance. However, calcium excretion is a quantitative trait and its phenotypes are distrib­uted on a continuous scale. Variance of a quantitative trait is a multigenic parameter involving many alleles singularly ex­erting a small effect, and hypercalciuria has to be considered as a polygenic trait with a heterogeneous genetic substrate and complex pattern of hereditary transmission. we care about you health

The com­plexity of this picture is increased by gene-gene and gene-envi­ronment interactions with reciprocal influences, able to change substantially the effect of a gene on a phenotype. The search for genetics of hypercalciuria has been aimed to identify both candidate genes and genetic polymorphisms underlying the genetic susceptibility for this disorder. Although it cannot be excluded that polymorphisms in a single gene may be sufficient to cause hypercalciuria, it is more likely that PH arises when predisposing alleles, at different loci, together concur to regu­late urinary calcium excretion. The number of involved loci and the effect size of alleles may vary according to the role of can­didate genes in calcium metabolism, to the activity of their dif­ferent variants and to the gene/s-gene/s interactions. A different genetic substrate may be present in the two subpopula- tions of stone formers identified by the analysis of calcium ex­cretion distribution: they may be distinguished by the presence of allele variants at one locus or, more likely, at few loci having remarkable effects on the phenotype, shifting the mean of the calcium excretion distribution curve toward higher values. Genetic causes of PH have been approached with different strategies.

A strain of spontaneously hypercalciuric rats has been ob­tained, but the gene/s responsible for the defect has not been yet found. Furthermore, at least three strains of knockout rats have been selected, respectively not expressing sodium- phosphate co-transporter, paracellin or caveolin 1, and they are under investigation. In humans, familial studies un- revealed the association between polymorphisms of soluble adenilate-cyclase (sAC) gene, located onto chromosome 1q23.3-q24, and hypercalciuria and low bone mass, while the study of calcium sensing receptor (C a S R) gene exhibited conflictual results. Moreover, other genes have been taken into account, like those of epithelial calcium channel (EcaC1) or vitamin D receptor (VDR) gene, but no signif­icant association with hypercalciuria has been observed. All these genetic studies tested a single gene and, due to this limi­tation, their results cannot be considered definitive in the pre­sence/absence of a genotype-phenotype correlation. Posi­tive or negative results have to be reconsidered in function of gene-gene and gene-environment interactions.

Figure 2 - Positive correlation between calcium excretion in parents and offspring (upper part) and absence of correlation between spouses (lower part) in 48 families living in Milan and villages near Milan.

Figure 2 – Positive correlation between calcium excretion in parents and offspring (upper part) and absence of correlation between spouses (lower part) in 48 families living in Milan and villages near Milan.

Several genes accounting for Mendelian forms of PH, with or without nephrocalcinosis, have been identified, such as Dent’s disease, Bartter’s syndrome, familial hypomagnesaemia hypocalciuria, familial hypocalcaemia hypercalciuria, familial hypercalcaemia hypercalciuria, and some hypophosphatemic syndromes. Unfortunately, their role in the pathogenesis of sporadic forms of PH has to be clearly elucidated.