Dados do Trabalho

Title

FOUNDER EFFECT FOR RHEUMATOID ARTHRITIS IN SOUTH BRAZILIAN MENNONITES REVEALED BY A WHOLE-EXOME EPIDEMIOLOGICAL FIELD STUDY

Background

Mennonites belong to the Anabaptist population that originated in Central Europe about 500 years ago. They remained relatively isolated since and established their first communities in southern Brazil in 1930, suffering before, at least three bottleneck effects that reduced their genetic diversity. There are no studies in the Mennonite population addressing rheumatoid arthritis (RA), which has a strong genetic component.

Materials and methods

Information regarding the diagnosis of RA, family members with the disease and risk factors were collected from 469 Mennonites of three Southern Brazilian communities (109 from Curitiba-PR, 150 from Witmarsum-PR and 210 from Colônia Nova-RS), with a questionnaire adapted from the National Health Survey 2013 (approved by the local ethics committee CAAEE: 55297916.6.0000.0102). Whole-exome sequencing data, obtained with combinatorial probe-anchor ligation, was available for 98 participants (10 of those, with a history of rheumatoid arthritis). We selected the variants with Polyphen-2 score≥0.80 and CADD≥20, passing Hardy–Weinberg equilibrium (p<10-6) and call rates >99%) and evaluated them with multivariate logistic regression (PLINK v1.09). Epidemiological data were also evaluated with logistic multivariate regression (STATA).

Results

We found 41 cases of RA, of which 33 were women (80,5%, 8 female:2 male), with a prevalence of 8.74%. Affected relatives in the family increased the odds for being diagnosed to the disease (OR=4.09, P<0.0001), as well as age (OR=1.05, P<0.0001), whereas weekly practice of aerobic exercises were protective (OR=0.19, P<0.0001), being each factor, independent of each other. We found 12 variants associated with the disease, two of them, described for the first time in this study (P<0.01). These two and another eight polymorphisms were associated with a dominant susceptibility effect, increasing at least 10 times the odds for the disease. Another two were more common (minor allele frequency > 15%) and presented a recessive susceptibility effect. Of the 12 genes, six have been already associated with arthritis or autoimmune reactions in the literature or in genome-wide association studies (THADA, RGPD8, BST1, ADAMTS15, BICD1 and ZFC3H1). The role of the other six genes (if any) should be further investigated (PCDHB5, ALDH1B1, PTF1A, UTP14C, ZDHHC1 and CCDC105). Six polymorphisms were not previously identified in the Brazilian population (AbraOM database).

Conclusions

The prevalence of rheumatoid arthritis in the Mennonite population is 8.7 times higher than the reported in Neo-Brazilians. This is possibly the result of a founder effect, which should be further investigated with increasing sample size and functional studies.