BMJ 2001;322:1019-1023 ( 28 April )

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Mortality over two centuries in large pedigree with familial hypercholesterolaemia: family tree mortality study

Eric J G Sijbrands, consultant, ^a Rudi G J Westendorp, professor, ^b Joep C Defesche, molecular biologist, ^a Paul H E M de Meier, consultant, ^c Augustinus H M Smelt, lecturer, ^c John J P Kastelein, lecturer. ^a

^a Department of Vascular Medicine and General Internal Medicine, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands, ^b Clinical Epidemiology, Leiden University Medical Centre, 2300RC Leiden, Netherlands, ^c Department of General Internal Medicine, Leiden University Medical Centre

Correspondence to: E J G Sijbrands nrexpert{at}euronet.nl

Objective: To estimate all cause mortality from untreated familial hypercholesterolaemia free from selection for coronary artery disease.
Design: Family tree mortality study.
Setting: Large pedigree in Netherlands traced back to a single pair of ancestors in the 19th century.
Subjects: All members of pedigree aged over 20 years with 0.5 probability of carrying a mutation for familial hypercholesterolaemia.
Main outcome measure: All cause mortality.
Results: A total of 70 deaths took place among 250 people analysed for 6950 person years. Mortality was not increased in carriers of the mutation during the 19th and early 20th century; it rose after 1915, reached its maximum between 1935 and 1964 (standardised mortality ratio 1.78, 95% confidence interval 1.13 to 2.76; P=0.003), and fell thereafter. Mortality differed significantly between two branches of the pedigree (relative risk 3.26, 95% confidence interval 1.74 to 6.11; P=0.001).
Conclusions: Risk of death varies significantly among patients with familial hypercholesterolaemia. This large variability over time and between branches of the pedigree points to a strong interaction with environmental factors. Future research is required to identify patients with familial hypercholesterolaemia who are at extreme risk and need early and vigorous preventive measures.

What is already known on this topic Familial hypercholesterolaemia is associated with excess mortality in families of patients who present with cardiovascular disease Population data are lacking What this study adds Many untreated patients with familial hypercholesterolaemia (about 40%) reach a normal life span Standardised mortality ratio was normal in the 19th century and rose to a peak in the 1930s to 1960s The variation in mortality suggests an interaction between genetic and environmental factors

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