Heritability of serum sodium concentration: evidence for sex- and ethnic-specific effects

Abstract

Serum sodium concentration is the clinical index of systemic water balance. Although disordered water balance is common and morbid, little is known about genetic effects on serum sodium concentration at the population level. Prior studies addressed only participants of European descent and either failed to demonstrate significant heritability or showed only modest effect. We investigated heritability of serum sodium concentration in large cohorts reflecting a range of races/ethnicities, including the Framingham Heart Study (FHS, non-Hispanic Caucasian), the Heredity and Phenotype Intervention Heart Study (HAPI, Amish Caucasian), the Jackson Heart Study (JHS, African American), the Strong Heart Family Study (SHFS, American Indian), and the Genetics of Kidney Disease in Zuni Indians Study (GKDZI, American Indian). Serum sodium was transformed for the osmotic effect of glucose, and participants with markedly elevated glucose or reduced estimated glomerular filtration rate (eGFR) were excluded. Using a standard variance components method, incorporating covariates of age, glucose, and eGFR, we found heritability to be high in African American and American Indian populations and much more modest in non-Hispanic Caucasian populations. Estimates among females increased after stratification on sex and were suggestive among female participants in FHS (0.18 ± 0.12, P = 0.057) and male participants in JHS (0.24 ± 0.16, P = 0.067) and statistically significant among female participants in JHS (0.44 ± 0.09, P = 1 × 10 ⁻⁷), SHFS (0.59 ± 0.05, P = 9.4 × 10⁻⁴⁶), and GKDZI (0.46 ± 0.15, P = 1.7 × 10⁻⁴), and male participants in HAPI (0.18 ± 0.12, P = 0.03) and SHFS (0.67 ± 0.07, P = 5.4 × 10⁻²⁶). Exclusion of diuretic users increased heritability among females and was significant in all cohorts where data were available. In aggregate, these data strongly support the heritability of systemic water balance and underscore sex and ethnicity-specific effects.

Individuality of the plasma sodium concentration

“…In contrast, in our heritabiity study, differential heritability in men versus women was seen across some races and/or ethnicities (46). As was the case for race-specific data, these findings suggest that the sex-specific differences in the heritability of sodium concentration are not caused by differences in the individuality of the phenotype.…”

“…We have previously observed a stronger heritability of sodium concentration among AfricanAmericans than among Caucasians (46). Although the present study does not address heritability, it has implications for the interpretation of our earlier heritability data on this phenotype.…”

“…In our earlier investigations unrelated to this study, the heritability of sodium concentration among African-Americans generally exceeded that among Caucasians (46). Although there is likely a genetic or environmental basis for this distinction, it is conceivable that greater individuality of the sodium concentration may create the appearance of increased heritability.…”

“…We have previously observed differences in heritability (and in genetic association on sodium concentration) among men and women (39,46). We hypothesized that differences in the individuality of sodium concentration could account for these observed effects.…”

“…1B). We also inferred individuality of the plasma sodium concentration from our recent demonstration of the heritability of the serum sodium concentration across various ethnicities (46) and from a functional genetic polymorphism in a putative water balance gene that associated with the plasma sodium concentration on a population-wide basis (39). Specifically, were there to be no individuality of the plasma sodium concentration, it would not have been possible for us to observe either heritability or genetic association.…”