Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study

Talmud, Philippa J., Shah, Sonia, Whittall, Ros, Futema, Marta, Howard, Philip, Cooper, Jackie A., Harrison, Seamus C., Li, KaWah, Drenos, Fotios, Karpe, Frederik, Neil, H. Andrew W., Descamps, Olivier S., Langenberg, Claudia, Lench, Nicholas, Kivimaki, Mika, Whittaker, John, Hingorani, Aroon D., Kumari, Meena and Humphries, Steve E. (2013) Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study. Lancet, 381 9874: 1293-1301. doi:10.1016/S0140-6736(12)62127-8


Author Talmud, Philippa J.
Shah, Sonia
Whittall, Ros
Futema, Marta
Howard, Philip
Cooper, Jackie A.
Harrison, Seamus C.
Li, KaWah
Drenos, Fotios
Karpe, Frederik
Neil, H. Andrew W.
Descamps, Olivier S.
Langenberg, Claudia
Lench, Nicholas
Kivimaki, Mika
Whittaker, John
Hingorani, Aroon D.
Kumari, Meena
Humphries, Steve E.
Title Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study
Journal name Lancet   Check publisher's open access policy
ISSN 0140-6736
1474-547X
Publication date 2013-04-01
Year available 2013
Sub-type Article (original research)
DOI 10.1016/S0140-6736(12)62127-8
Open Access Status Not Open Access
Volume 381
Issue 9874
Start page 1293
End page 1301
Total pages 9
Place of publication London, United Kingdom
Publisher The Lancet Publishing Group
Language eng
Formatted abstract
Background
Familial hypercholesterolaemia is a common autosomal-dominant disorder caused by mutations in three known genes. DNA-based cascade testing is recommended by UK guidelines to identify affected relatives; however, about 60% of patients are mutation-negative. We assessed the hypothesis that familial hypercholesterolaemia can also be caused by an accumulation of common small-effect LDL-C-raising alleles.
Methods
In November, 2011, we assembled a sample of patients with familial hypercholesterolaemia from three UK-based sources and compared them with a healthy control sample from the UK Whitehall II (WHII) study. We also studied patients from a Belgian lipid clinic (Hôpital de Jolimont, Haine St-Paul, Belgium) for validation analyses. We genotyped participants for 12 common LDL-C-raising alleles identified by the Global Lipid Genetics Consortium and constructed a weighted LDL-C-raising gene score. We compared the gene score distribution among patients with familial hypercholesterolaemia with no confirmed mutation, those with an identified mutation, and controls from WHII.
Findings
We recruited 321 mutation-negative UK patients (451 Belgian), 319 mutation-positive UK patients (273 Belgian), and 3020 controls from WHII. The mean weighted LDL-C gene score of the WHII participants (0·90 [SD 0·23]) was strongly associated with LDL-C concentration (p=1·4 × 10−77; R2=0·11). Mutation-negative UK patients had a significantly higher mean weighted LDL-C score (1·0 [SD 0·21]) than did WHII controls (p=4·5 × 10−16), as did the mutation-negative Belgian patients (0·99 [0·19]; p=5·2 × 10−20). The score was also higher in UK (0·95 [0·20]; p=1·6 × 10−5) and Belgian (0·92 [0·20]; p=0·04) mutation-positive patients than in WHII controls. 167 (52%) of 321 mutation-negative UK patients had a score within the top three deciles of the WHII weighted LDL-C gene score distribution, and only 35 (11%) fell within the lowest three deciles.
Interpretation
In a substantial proportion of patients with familial hypercholesterolaemia without a known mutation, their raised LDL-C concentrations might have a polygenic cause, which could compromise the efficiency of cascade testing. In patients with a detected mutation, a substantial polygenic contribution might add to the variable penetrance of the disease.
Keyword Cascade testing project
Mutation detection rate
Coronary risk
Lipid-levels
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
School of Medicine Publications
 
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