Analysis of the frequency and spectrum of mutations recognised to cause familial hypercholesterolaemia in routine clinical practice in a UK specialist hospital lipid clinic.
Analysis of the frequency and spectrum of mutations recognised to cause familial hypercholesterolaemia in routine clinical practice in a UK specialist hospital lipid clinic.
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DOI：
10.1016/j.atherosclerosis.2013.04.011
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发表时间：
2013-07
期刊：
影响因子：
5.3
通讯作者：
Humphries SE
中科院分区：
文献类型：
--
作者：
Futema M;Whittall RA;Kiley A;Steel LK;Cooper JA;Badmus E;Leigh SE;Karpe F;Neil HA;Simon Broome Register Group;Humphries SE
确定在牛津一家英国专科医院脂质诊所就诊的患者中引起家族性高胆固醇血症（FH）的突变频率和谱，并确定导致高突变检出率的特征。使用标准分子遗传学技术，在2年内对289例患者（272名先证者）进行LDLR、APOB和PCSK 9突变的连续筛查。采用Simon Broome（SB）临床诊断标准对患者进行分类，并采用409例FH患者的单独队列进行重复研究。在101例无关患者中发现了FH致突变（LDLR = 54种不同突变，APOB p.（Arg3527Gln）= 10，PCSK9 p.（Asp374Tyr）= 0）。在60例SB明确FH患者中，突变检出率为73%，而在142例可能FH患者中，突变检出率显著较低（27%，p < 0.0001），但与70例数据不足以进行临床诊断的患者相似（14%，p = 0.06）。突变检出率差异显著（p = 9.83 × 10−5）未处理的总胆固醇（TC）水平（<8.1 mmol/l者为25%，>10.0 mmol/l者为74%），以及甘油三酯水平（>2.16 mmol/l为20%，<1.0 mmol/l为60%（p = 0.0005）），两种效应均在重复样本中得到证实（趋势p = 0.0001，p = 1.8 × 10−6）。SB标准与荷兰脂质临床网络评分在识别突变携带者方面的特异性或灵敏度没有差异（AROC分别为0.73和0.72，p = 0.68）。在这个遗传异质性FH患者队列中，突变检出率显著依赖于治疗前TC和甘油三酯水平。在272名FH先证者队列中发现54种不同的LDLR突变。发现该队列具有遗传异质性，无特异性FH突变。突变检出率高度依赖于治疗前TC和TG水平。2种临床FH诊断方法之间的特异性/灵敏度无差异。LDL-C降低不足标志着需要更有效的降脂治疗。
To determine the frequency and spectrum of mutations causing Familial Hypercholesterolaemia (FH) in patients attending a single UK specialist hospital lipid clinic in Oxford and to identify characteristics contributing to a high mutation detection rate. 289 patients (272 probands) were screened sequentially over a 2-year period for mutations in LDLR, APOB and PCSK9 using standard molecular genetic techniques. The Simon Broome (SB) clinical diagnostic criteria were used to classify patients and a separate cohort of 409 FH patients was used for replication. An FH-causing mutation was found in 101 unrelated patients (LDLR = 54 different mutations, APOB p.(Arg3527Gln) = 10, PCSK9 p.(Asp374Tyr) = 0). In the 60 SB Definite FH patients the mutation detection rate was 73% while in the 142 with Possible FH the rate was significantly lower (27%, p < 0.0001), but similar (14%, p = 0.06) to the 70 in whom there was insufficient data to make a clinical diagnosis. The mutation detection rate varied significantly (p = 9.83 × 10−5) by untreated total cholesterol (TC) levels (25% in those <8.1 mmol/l and 74% in those >10.0 mmol/l), and by triglyceride levels (20% in those >2.16 mmol/l and 60% in those <1.0 mmol/l (p = 0.0005)), with both effects confirmed in the replication sample (p for trend = 0.0001 and p = 1.8 × 10−6 respectively). There was no difference in the specificity or sensitivity of the SB criteria versus the Dutch Lipid Clinic Network score in identifying mutation carriers (AROC respectively 0.73 and 0.72, p = 0.68). In this genetically heterogeneous cohort of FH patients the mutation detection rate was significantly dependent on pre-treatment TC and triglyceride levels. 54 different LDLR mutations found in a cohort of 272 FH probands. The cohort was found to be genetically heterogeneous with no specific FH mutation. Mutation detection rate was highly dependent on pre-treatment TC and TG levels. No difference in specificity/sensitivity between 2 clinical FH diagnosis approaches. Inadequate LDL-C reduction marks the need for more effective lipid-lowering therapy.
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影响因子：
1.9
作者：
Usifo, Ebele;Leigh, Sarah E. A.;Humphries, Steve E.
通讯作者：
Humphries, Steve E.
影响因子：
5.7
作者：
Neil, HAW;Seagroatt, V;Humphries, SE
通讯作者：
Humphries, SE
影响因子：
--
作者：
Neil, HAW;Hammond, T;Humphries, SE
通讯作者：
Humphries, SE
影响因子：
4
作者：
Lee, WK;Haddad, L;Dominiczak, AF
通讯作者：
Dominiczak, AF
DOI：
10.1161/atvbaha.111.226365
发表时间：
2011-08
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Johansen CT;Wang J;Lanktree MB;McIntyre AD;Ban MR;Martins RA;Kennedy BA;Hassell RG;Visser ME;Schwartz SM;Voight BF;Elosua R;Salomaa V;O'Donnell CJ;Dallinga-Thie GM;Anand SS;Yusuf S;Huff MW;Kathiresan S;Cao H;Hegele RA
通讯作者：
Hegele RA