ESPE Abstracts (2018) 89 P-P1-004

Carriers of CYP21A2 Mutations have Decreased Mortality in Infectious Diseases, Anational Population Registry Study

Anna Nordenströma,b, Johan Svenssona, Svetlana Lajica, Louise Frisénc, Agneta Nordenskjölda, Christina Norrbyd, Catarina Almqvist Malmrosd & Henrik Falhammare

aDepartment of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden; bDepartment of Paediatric Endocrinology, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden; cDepartment of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; dDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; eDepartment of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden

Background: Congenital adrenal hyperplasia (CAH) is a relatively common monogenic recessive disorder with an incidence of 1/15 000 in most populations. It has been suggested that CYP21A2 deficiency is relatively common because it may confer a survival advantage to be a carrier. Carriers of CYP21A2 mutations typically do not have clinical symptoms but have a defined phenotype. The cortisol response to ACTH stimulation has been shown to be both more prompt and increased compared to healthy, non-carrier, controls. We have previously shown that carriers are less vulnerable to psychological stress. In this study, we investigated the mortality, and cause of mortality in carriers compared to population controls.

Method: A total of 1143 (561 men, 582 women) obligate carriers of a CYP21A2 mutation, were identified using the Swedish National CAH Registry encompassing more than 700 CAH patients and the Multigeneration Registry. Controls, matched for year of birth and sex, were identified from the general population, 100 controls per study subject. The mortality and cause of death was identified through the Swedish Cause of Death Registry. The Hazard Ration (HR) was calculated.

Results: The overall mortality was lower in carriers of one of the classic CYP21A2 mutations compared to the general population, for women (P=0.05), but not for the whole cohort (P=0.12). Infection as the cause of death was significant with HR 0.651 (CI 95%, 0.485–0.874; P=0.0043). In particular, a lower mortality in pneumonia was seen HR 0.220 (CI 95%, 0.055–0.881; P=0.03). There was no difference in mortality due to cancer. The generally observed lower overall mortality among women compared to men was confirmed in our study, both among the carriers and the controls.

Conclusion: Obligate CYP21A2 carriers had a reduced mortality, and specifically a reduced mortality due to pneumonia. The increased capacity to synthesize cortisol in acute situations could be the explanation for an evolutionary advantage of being a carrier of a CYP21A2 mutation. Our results suggest a better ability to cope with the somatic stress of severe infections among heterozygous carriers of severe CYP21A2 mutations. This may contribute to the apparent survival advantage since infectious diseases represent a common cause of death, especially in a historical perspective and in the history of mankind.

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