The exact cause of sarcoidosis is not known. The current working hypothesis is, in genetically susceptible individuals, sarcoidosis is caused through alteration to the immune response after exposure to an environmental, occupational, or infectious agent. Some cases may be caused by treatment with TNF inhibitors like etanercept.

The heritability of sarcoidosis varies according to ethnicity. About 20% of African Americans with sarcoidosis have a family member with the condition, whereas the same figure for European Americans is about 5%. Additionally, in African Americans, who seem to experience more severe and chronic disease, siblings and parents of sarcoidosis cases have about a 2.5-fold increased risk for developing the disease. Investigations of genetic susceptibility yielded many candidate genes, but only few were confirmed by further investigations and no reliable genetic markers are known. Currently, the most interesting candidate gene is "BTNL2"; several "HLA-DR" risk alleles are also being investigated. In persistent sarcoidosis, the HLA haplotype "HLA-B7-DR15" are either cooperating in disease or another gene between these two loci is associated. In nonpersistent disease, there is a strong genetic association with HLA DR3-DQ2. Cardiac sarcoid has been connected to TNFA variants.

In medicine, an enthesopathy refers to a disorder involving the attachment of a tendon or ligament to a bone. This site of attachment is known as the entheses.

If the condition is known to be inflammatory, it can more precisely be called an enthesitis.

Enthesopathies may take the form of spondyloarthropathies (joint diseases of the spine) such as ankylosing spondylitis, plantar fasciitis, and Achilles tendinitis. Enthesopathy can occur at the elbow, wrist, carpus, hip, knee, ankle, tarsus, or heel bone, among other regions. Further examples include:

- Adhesive capsulitis of shoulder

- Rotator cuff syndrome of shoulder and allied disorders

- Periarthritis of shoulder

- Scapulohumeral fibrositis

- Synovitis of hand or wrist

- Periarthritis of wrist

- Gluteal tendinitis

- Iliac crest spur

- Psoas tendinitis

- Trochanteric tendinitis

Perinatal and infantile hypophosphatasia are inherited as autosomal recessive traits with homozygosity or compound heterozygosity for two defective TNSALP alleles. The mode of inheritance for childhood, adult, and odonto forms of hypophosphatasia can be either autosomal dominant or recessive. Autosomal transmission accounts for the fact that the disease affects males and females with equal frequency. Genetic counseling is complicated by the disease’s variable inheritance pattern, and by incomplete penetration of the trait.

Hypophosphatasia is a rare disease that has been reported worldwide and appears to affect individuals of all ethnicities. The prevalence of severe hypophosphatasia is estimated to be 1:100,000 in a population of largely Anglo-Saxon origin. The frequency of mild hypophosphatasia is more challenging to assess because the symptoms may escape notice or be misdiagnosed. The highest incidence of hypophosphatasia has been reported in the Mennonite population in Manitoba, Canada where one in every 25 individuals are considered carriers and one in every 2,500 newborns exhibits severe disease. Hypophosphatasia is considered particularly rare in people of African ancestry in the U.S.

All clinical sub-types of hypophosphatasia have been traced to genetic mutations in the gene encoding TNSALP, which is localized on chromosome 1p36.1-34 in humans (ALPL; OMIM#171760). Approximately 204 distinct mutations have been described in the TNSALP gene. An up-to-date list of mutations is available online at The Tissue Nonspecific Alkaline Phosphatase Gene Mutations Database. About 80% of the mutations are missense mutations. The number and diversity of mutations results in highly variable phenotypic expression, and there appears to be a correlation between genotype and phenotype in hypophosphatasia”. Mutation analysis is possible and available in 3 laboratories.