The Second Highest Prevalence of Celiac Disease Worldwide: Genetic and Metabolic Insights in Southern Brazilian Mennonites

Abstract

Celiac disease (CD), despite its high morbidity, is an often-underdiagnosed autoimmune enteropathy. Using a modified version of the Brazilian questionnaire of the 2013 National Health Survey, we interviewed 604 Mennonites of Frisian/Flemish origin that have been isolated for 25 generations. A subgroup of 576 participants were screened for IgA autoantibodies in serum, and 391 participants were screened for HLA-DQ2.5/DQ8 subtypes. CD seroprevalence was 1:29 (3.48%, 95% CI = 2.16–5.27%) and biopsy-confirmed CD was 1:75 (1.32%, 95% CI = 0.57–2.59%), which is superior to the highest reported global prevalence (1:100). Half (10/21) of the patients did not suspect the disease. HLA-DQ2.5/DQ8 increased CD susceptibility (OR = 12.13 [95% CI = 1.56–94.20], p = 0.003). The HLA-DQ2.5 carrier frequency was higher in Mennonites than in Brazilians (p = 7 × 10−6). HLA-DQ8 but not HLA-DQ2.5 carrier frequency differed among settlements (p = 0.007) and was higher than in Belgians, a Mennonite ancestral population (p = 1.8 × 10−6), and higher than in Euro-Brazilians (p = 6.5 × 10−6). The glutathione pathway, which prevents reactive oxygen species-causing bowel damage, was altered within the metabolic profiles of untreated CD patients. Those with lower serological positivity clustered with controls presenting close relatives with CD or rheumatoid arthritis. In conclusion, Mennonites have a high CD prevalence with a strong genetic component and altered glutathione metabolism that calls for urgent action to alleviate the burden of comorbidities due to late diagnosis.

Glucocorticoid Receptor Gene (NR3C1) Polymorphisms and Metabolic Syndrome: Insights from the Mennonite Population

“…The investigation of genetically isolated populations sharing the environment and demographic history for several generations benefits from the reduced variability and similar long-term exposure to confounding risk factors. The Mennonite population presents almost 500 years of isolation and three historical demographic bottlenecks (promoted by migrations mostly due to political–religious persecution), which increases the frequencies of uncommon alleles and allows for the use of smaller sample sizes for the identification of the loci associated with phenotypes [ 5 , 6 ], providing a unique opportunity to investigate the association of MetS with several parameters, like age, diet, physical activity, and paternal warmth in childhood.…”