Genetic testing for familial hypercholesterolaemia is essential in individuals with high LDL cholesterol: who does it in the world?

Familial hypercholesterolaemia (FH) with elevated LDL cholesterol is a dominantly inherited genetic disease (or disorder) that affects 50% of first-degree relatives in FH families. FH is the genetic disease that kills most individuals in the world, and a genetic disease requires a genetic diagnosis. Brown and Goldstein received the Nobel Prize in 1985 for showing the cause of FH, including how FH can be diagnosed genetically. It therefore seems a mystery why genetic testing for FH is not used universally, and only rarely in the USA where Brown and Goldstein still work. Many European countries use genetic testing for FH, because it makes sense. Less affluent countries do not use it, because of the expense, while some rich countries including Japan and the USA do not use genetic testing for FH, because it is not yet considered ‘standard of care’. We recently showed that FH is more common in the general population than originally thought: using a clinical diagnosis, FH was found in 1:200 individuals in the Danish general population. Several later studies have confirmed that FH is common, and in The Netherlands, Poland, the UK, the USA, and Denmark FH frequencies in the general population of 1:200 to 1:250 have been observed, using either a clinical or a genetic diagnosis. Compared with other genetic diseases found in children, FH is by far the most common. Recent studies have also documented that FH is both underdiagnosed and undertreated worldwide, with the exceptions being The Netherlands and Norway. In this issue of the journal, Tada and co-workers provide important data on FH in Japan, including the value of genetic diagnosis and the importance of clinical signs of FH for the prevalence of coronary heart disease. They used data from 20 453 LDL cholesterol measurements from a Japanese hospital population examined from 2000 to 2012, to select 636 individuals with LDL cholesterol >_4.7mmol/L (>_180 mg/dL) as recommended by the Japan Atherosclerosis Society for the diagnosis of FH; this threshold corresponds to the top 4% of the Japanese population distribution. Included individuals were divided into four groups: (i) a reference group of 76 individuals (12% of study sample) with mean LDL cholesterol of 6.1 mmol/L (235mg/dL), but without clinical signs (xanthomas and/or family history) and without an FH mutation; (ii) a group of 58 individuals (9%; 6.2 mmol/L = 239 mg/dL) with clinical signs, but without an FH mutation; (iii) a group of 78 individuals (12%; 7.0 mmol/L = 270 mg/dL) with an FH mutation, but no clinical signs; and (iv) a group of 424 individuals (67%; 7.0 mmol/L = 270 mg/dL) with both clinical signs and an FH mutation. The LDL cholesterol adjusted odds ratios for coronary artery disease were 4.6 [95% confidence interval (CI) 1.5–14.5] in individuals with clinical signs of FH, 3.4 (95% CI 1.0–10.9) in individuals with an FH mutation, and 11.6 (95% CI 4.4–30.2) in individuals with both clinical signs and an FH mutation, compared with individuals with high LDL cholesterol alone. Further, the presence of clinical signs and an FH mutation both contributed to a better prediction of coronary artery disease events, estimated by significant increases in area under the curve in C-statistics and by net reclassification improvement. Thus, these important findings from Japan highlight that a genetic diagnosis of FH identifies individuals at higher risk of coronary artery disease than solely judged by the LDL cholesterol level alone, probably because the genetic diagnosis indicates a lifelong effect. A recent US study reported that an FH phenotype of LDL cholesterol >_4.9 mmol/L (>_190 mg/dL) was associated with a five-fold risk