Abstract
The ectodysplasin receptor (EDAR) is a tumor necrosis factor receptor (TNF) superfamily member. A substitution in an exon of EDAR at position 370 (EDARV370A) creates a gain of function mutant present at high frequencies in Asian and Indigenous American populations but absent in others. Its frequency is intermediate in populations of Mexican ancestry. EDAR regulates the development of ectodermal tissues, including mammary ducts. Obesity and type 2 diabetes mellitus are prevalent in people with Indigenous and Latino ancestry. Latino patients also have altered prevalence and presentation of breast cancer. It is unknown whether EDARV370A might connect these phenomena. The goals of this study were to determine 1) whether EDARV370A is associated with metabolic phenotypes and 2) if there is altered breast anatomy in women carrying EDARV370A. Participants were from two Latino cohorts, the Arizona Insulin Resistance (AIR) registry and Sangre por Salud (SPS) biobank. The frequency of EDARV370A was 47% in the Latino cohorts. In the AIR registry, carriers of EDARV370A (GG homozygous) had significantly (p < 0.05) higher plasma triglycerides, VLDL, ALT, 2-hour post-challenge glucose, and a higher prevalence of prediabetes/diabetes. In a subset of the AIR registry, serum levels of ectodysplasin A2 (EDA-A2) also were associated with HbA1c and prediabetes (p < 0.05). For the SPS biobank, participants that were carriers of EDARV370A had lower breast density and higher HbA1c (both p < 0.05). The significant associations with measures of glycemia remained when the cohorts were combined. We conclude that EDARV370A is associated with characteristics of the metabolic syndrome and breast density in Latinos.
Highlights
Ectodysplasin is a member of the tumor necrosis family (TNF) superfamily, and its receptor, the ectodysplasin receptor (EDAR), is a member of the TNF family of receptors [1]
The purposes of the present study were to determine whether the EDARV370A variant present in Latinos is associated 1) with phenotypic characteristics suggesting a connection between the variant and obesity, hyperglycemia, and other traits associated with the metabolic syndrome and 2) with alterations in breast characteristics as determined by mammography
EDARV370A was associated with various metabolic syndrome measures in two independent Latino cohorts and was significantly and inversely associated with breast density in women from the Sangre por Salud (SPS) biobank
Summary
Ectodysplasin is a member of the tumor necrosis family (TNF) superfamily, and its receptor, the ectodysplasin receptor (EDAR), is a member of the TNF family of receptors [1]. Individuals carrying at least one EDARV370A allele have a higher probability of having straight hair, more eccrine sweat glands, and shoveling of upper incisors [6,7,8,9,10,11,12,13,14]. Genomic analysis indicates that EDAR and the surrounding region have undergone a high degree of natural selection in favor of EDARV370A over the last approximately 30,000 years [4, 15]. One speculation regarding this selection is that a higher number of sweat glands may have been adaptive in Asian hunter-gatherers [6]
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