BACKGROUND: Pernicious anemia (PA) is an autoimmune disease (AID) which is caused by lack of vitamin B12 (cobalamin) due to its impaired uptake. PA is a multifactorial disease which is associated with a number of other AID comorbidities and which is manifested as part of autoimmune polyglandular syndrome. Due to the shortage of family studies on PA, we planned to address the problem by assessing familial risks for concordant PA between family members and for discordant PA in families of other AID patients. METHODS: We collected data on patients diagnosed with AIDs from the Swedish hospitals and family data from a population register. We calculated standardized incidence ratios (SIRs) in families for concordant and discordant risks. RESULTS: The number of PA patients in the offspring generation (for which the familial risk was calculated) was 7701; 278 (3.6%) patients had a family history of PA. The population prevalence of PA was 0.9/1000. The familial risk for PA was 3.88 when any first-degree relative was the proband, equal for men and women. The familial risk was two times higher between siblings than between offspring and parents which may be due to complex genetic background. Associations of PA with 14 discordant AIDs were significant; these included some AIDs that have previously been described as comorbidities in PA patients and several yet unreported associations, including rheumatoid arthritis and other AIDs. CONCLUSIONS: The familial risks for PA were high suggesting multifactorial genetic etiology. The results call for further population-level studies to unravel mechanisms of familial PA which may help to understand the etiology of this disease.

Center for Community based Healthcare Research and Education Department of Functional Pathology School of Medicine Shimane University Matsue Japan

Center for Primary Health Care Research Lund University Malmö Sweden

Department of Family Medicine and Community Health Department of Population Health Science and Policy Icahn School of Medicine at Mount Sinai New York USA

Division of Cancer Epidemiology German Cancer Research Centre 69120 Heidelberg Germany

Division of Molecular Genetic Epidemiology German Cancer Research Center 69120 Heidelberg Germany

Division of Pediatric Neurooncology German Cancer Research Center Heidelberg Germany

Faculty of Medicine and Biomedical Center in Pilsen Charles University Prague 30605 Pilsen Czech Republic

Genewerk GmbH Heidelberg Germany

Hopp Children's Cancer Center Heidelberg Germany

Zobrazit více v PubMed

Oo T. H. Diagnostic difficulties in pernicious anemia. Discovery Medicine. 2019;28(155):247–253. PubMed

Rodriguez N. M., Shackelford K. Pernicious Anemia. Treasure Island, FL, USA: StatPearls; 2020.

Bunn H. F. Vitamin B12 and pernicious anemia—the dawn of molecular medicine. New England Journal of Medicine. 2014;370(8):773–776. doi: 10.1056/nejmcibr1315544. PubMed DOI

Hayter S. M., Cook M. C. Updated assessment of the prevalence, spectrum and case definition of autoimmune disease. Autoimmunity Reviews. 2012;11(10):754–765. doi: 10.1016/j.autrev.2012.02.001. PubMed DOI

Oo T. H., Rojas-Hernandez C. M. Challenging clinical presentations of pernicious anemia. Discovery Medicine. 2017;24(131):107–115. PubMed

Hemminki K., Li X., Sundquist J., Sundquist K. The epidemiology of Graves’ disease: evidence of a genetic and an environmental contribution. Journal of Autoimmunity. 2010;34(3):J307–J313. doi: 10.1016/j.jaut.2009.11.019. PubMed DOI

Bliddal S., Nielsen C. H., Feldt-Rasmussen U. Recent advances in understanding autoimmune thyroid disease: the tallest tree in the forest of polyautoimmunity. F1000Res. 2017;6 doi: 10.12688/f1000research.11535.1.1776 PubMed DOI PMC

Husebye E. S., Anderson M. S., Kämpe O. Autoimmune polyendocrine syndromes. New England Journal of Medicine. 2018;378(12):1132–1141. doi: 10.1056/nejmra1713301. PubMed DOI PMC

Hemminki K., Li X., Sundquist J., Sundquist K. Familial associations of rheumatoid arthritis with autoimmune diseases and related conditions. Arthritis & Rheumatism. 2009;60(3):661–668. doi: 10.1002/art.24328. PubMed DOI

Hemminki K., Li X., Sundquist J., Sundquist K. Familial association between type 1 diabetes and other autoimmune and related diseases. Diabetologia. 2009;52(9):1820–1828. doi: 10.1007/s00125-009-1427-3. PubMed DOI

Kahaly G. J., Hansen M. P. Type 1 diabetes associated autoimmunity. Autoimmunity Reviews. 2016;15(7):644–648. doi: 10.1016/j.autrev.2016.02.017. PubMed DOI

Skov J., Eriksson D., Kuja-Halkola R., et al. Co-aggregation and heritability of organ-specific autoimmunity: a population-based twin study. European Journal of Endocrinology. 2020;182(5):473–480. doi: 10.1530/eje-20-0049. PubMed DOI PMC

Ye W., Nyrén O. Risk of cancers of the oesophagus and stomach by histology or subsite in patients hospitalised for pernicious anaemia. Gut. 2003;52(7):938–941. doi: 10.1136/gut.52.7.938. PubMed DOI PMC

Landgren O., Engels E. A., Caporaso N. E., et al. Patterns of autoimmunity and subsequent chronic lymphocytic leukemia in Nordic countries. Blood. 2006;108(1):292–296. doi: 10.1182/blood-2005-11-4620. PubMed DOI PMC

Venerito M., Link A., Rokkas T., Malfertheiner P. Gastric cancer—clinical and epidemiological aspects. Helicobacter. 2016;21(1):39–44. doi: 10.1111/hel.12339. PubMed DOI

Fallah M., Liu X., Ji J., Försti A., Sundquist K., Hemminki K. Autoimmune diseases associated with non-Hodgkin lymphoma: a nationwide cohort study. Annals of Oncology. 2014;25(10):2025–2030. doi: 10.1093/annonc/mdu365. PubMed DOI

Hemminki K., Liu X., Ji J., Sundquist J., Sundquist K. Autoimmune disease and subsequent digestive tract cancer by histology. Annals of Oncology. 2012;23(4):927–933. doi: 10.1093/annonc/mdr333. PubMed DOI

Landgren O., Engels E. A., Pfeiffer R. M., et al. Autoimmunity and susceptibility to Hodgkin lymphoma: a population-based case-control study in Scandinavia. JNCI: Journal of the National Cancer Institute. 2006;98(18):1321–1330. doi: 10.1093/jnci/djj361. PubMed DOI

De Block C. E. M., De Leeuw I. H., Van Gaal L. F. Autoimmune gastritis in type 1 diabetes: a clinically oriented review. The Journal of Clinical Endocrinology & Metabolism. 2008;93(2):363–371. doi: 10.1210/jc.2007-2134. PubMed DOI

Hemminki K., Ji J., Brandt A., Mousavi S. M., Sundquist J. The Swedish family-cancer database 2009: prospects for histology-specific and immigrant studies. International Journal of Cancer. 2010;126(10):2259–2267. doi: 10.1002/ijc.24795. PubMed DOI

Lin X., Lu D., Gao Y., et al. Genome-wide association study identifies novel loci associated with serum level of vitamin B12 in Chinese men. Human Molecular Genetics. 2012;21(11):2610–2617. doi: 10.1093/hmg/dds062. PubMed DOI

Ungar B., Mathews J. D., Tait B. D., Cowling D. C. HLA-DR patterns in pernicious anaemia. BMJ. 1981;282(6266):768–770. doi: 10.1136/bmj.282.6266.768. PubMed DOI PMC

Thomsen H., Li X., Sundquist K., Sundquist J., Försti A., Hemminki K. Familial risks between Graves disease and Hashimoto thyroiditis and other autoimmune diseases in the population of Sweden. Journal of Translational Autoimmunity. 2020;3 doi: 10.1016/j.jtauto.2020.100058.100058 PubMed DOI PMC