Homozygous familial hypercholesterolaemia in China: a genotype-phenotype analysis of cross-sectional data.

BACKGROUND: Homozygous familial hypercholesterolaemia is a rare life-threatening disease characterised by markedly elevated LDL cholesterol concentrations and accelerated atherosclerosis. Few studies have focused specifically on this group of patients, especially in China. We set out to investigate the phenotypical characteristics and the genotype-phenotype correlations of homozygous familial hypercholesterolaemia in China.

METHODS: In this analysis of cross-sectional data, we collected data from patients with suspected homozygous familial hypercholesterolaemia from ten clinical hospitals in mainland China from 2003 to 2015. Inclusion criteria included total cholesterol greater than 10 mmol/L, presence of xanthomas, and a family history of premature coronary heart disease. Clinical data and DNA sequence of LDLR, APOB, and PCSK9 were obtained in all patients. All participants gave written informed consent using consent forms approved by the research ethics committee of Beijing Anzhen Hospital, China.

FINDINGS: We collected data from 64 probands with suspected unrelated homozygous familial hypercholesterolaemia (mean age 13 years [range 2-37]). Molecular diagnosis showed that 15 had homozygous familial hypercholesterolaemia, 34 had compound heterozygous disease, nine had heterozygous disease, and six were mutation-negative. 66 LDLR mutations were found, and no APOB or PCSK9 mutations were found. Of the LDLR mutations, 26 were novel, and the most common mutation, occurring in 11 (17%) of 64 patients, was Trp462X (c1448G→A). The mean total cholesterol concentration was 16·6 mmol/L (SD 3·84; range 10·4-25·9), and the mean LDL cholesterol concentration was 13·86 mmol/L (SD 3·50; range 7·1-23·5). Total cholesterol and LDL cholesterol concentrations did not significantly differ between patients with homozygous familial hypercholesterolaemia, compound heterozygous familial hypercholesterolaemia, heterozygous familial hypercholesterolaemia, or those who were mutation-negative.

INTERPRETATION: This research provides important clinical and genetic information about suspected homozygous familial hypercholesterolaemia in mainland China. Our data suggest that diagnostic criteria need to be developed to screen patients with potential homozygous familial hypercholesterolaemia.

FUNDING: National Natural Science Foundation of China (number 81471098).