Israeli study identifies country of origin with genetic variants in Familial Mediterranean fever

Familial Mediterranean fever (FMF) is the most common hereditary autoinflammatory disease, mostly affecting people of Middle Eastern or Mediterranean origin.

In some populations, including the Armenian, Turkish, Arabic, and North African Jewish populations, its prevalence is high, an estimated 1 in 200.

FMF is caused by a gene defect in the immune system protein pyrin, which helps regulate inflammation in the body. FMF involves recurrent bouts of fever, accompanied by pain in the chest, joints and abdomen. Untreated cases can develop amyloidosis, a buildup of amyloid protein in the kidney or other organs that can cause them not to function properly.

The specific gene involved is MEFV, which has 300 variants, but the majority of FMF cases are caused by only five of these variants.

FMF is an autosomal recessive disease, which means that two copies of the defective gene, one from the mother and one from the father, must be passed on for FMF to affect the child. If the child has only one copy of the gene, he/she is a carrier and can pass the genetic defect to his or her child, but is unlikely to suffer from the disease.

Ethnicity and MEFV variants

In Israel, where FMF is endemic, a group of medical scientists used a novel approach with a machine learning algorithm to predict the particular genetic mutation of FMF patients based on where their parents or grandparents were born.

Their research appears in Scientific Reports, Sept. 8.

Because Israel's Jewish population has diverse ancestry, the researchers note, "A growing number of familial Mediterranean fever patients do not have a single country of origin for all four grandparents." Thus, establishing an association between different combinations of grandparent origins and FMF variants requires a complex statistical analysis.

The authors state in the introduction that there is a ". . . correlation between the p.Met694Val variant and Jewish Moroccan ethnicity as well as with a severe disease phenotype. However, associations between other countries of origin and FMF variants have been only partially established. Such knowledge is important to understand the epidemiology of FMF."

Study results

The study population consisted of 1,781 individuals from the Chaim Sheba Medical Center, a referral center for genetic testing of FMF patients.

The machine learning program designed by the researchers analyzed the most common MEFV mutation variants for each of the individuals, correlated with the countries of origin of the FMF patients' grandparents.

The program was able to identify particular countries of origin for the three most common variants. 

Specifically, the researchers report, "Our results showed that the p.Met694Val variant was the most prevalent among the study population, identified in 72% of studied subjects. Referrals whose parents or grandparents came to Israel from Tunisia, Libya, Algeria or Morocco were most likely to carry this specific variant. 

"The second most common mutation, p.Glu148Gln, was observed in 23% of the cohort; the most common countries of origin were Iran, Yemen, India, and Ukraine," they added. "The p.Val726Ala variant was the third most common, found in 19% of subjects. The countries of origin that mostly contributed to the existence of this variant are Lebanon, Romania, Hungary and Poland." 

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Orit Adato et al. "Determining the origin of different variants associated with familial mediterranean fever by machine learning." Scientific Reports, Sept. 8, 2022.

DOI: https://doi.org/10.1038/s41598-022-19538-1