Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk

Humphries, Steve E.; Whittall, Ros; Hubbart, Christina; Maplebeck, S; Cooper, Jackie A.; Soutar, Anne K.; Naoumova, R.P.; Thompson, G. R.; Seed, Mary; Durrington, Paul N.; Miller, J P; Betteridge, D. J.; Neil, H. A. W.

doi:10.1136/jmg.2006.038356

Cited by 253 publications

(203 citation statements)

References 36 publications

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“…ApoA-I in fact can directly inactivate bacterial endotoxin by protein-protein interaction (Emancipator et al 1992), being the C-terminal half of apoA-I the main domain responsible for LPS neutralization (Henning et al 2011), but also inhibits LPS-induced cytokine release from human monocytes (Flegel et al 1993); in addition, apoA-I reduces TNF-α levels during LPS challenge in rats and increases the survival rates (Humphries et al 2006), suggesting that apoA-I might inhibit LPS binding to macrophages thus inhibiting the production of inflammatory cytokines that are related to sepsis. In mice, the overexpression of apoA-I (that results in an increased serum level of both apoA-I and HDL) attenuates LPS-induced acute injury in lung and kidney (Li et al 2008); LPS-induced proinflammatory cytokines decrease, as well as CD14 expression in liver and lung, resulting in a protective effect against systemic inflammation and multiple organ damage (Li et al 2008).…”

Section: Interaction Of Hdl With Lps and Gram-negative Bacteriamentioning

confidence: 99%

HDL in Infectious Diseases and Sepsis

Pirillo

Catapano

Norata

2014

Handbook of Experimental Pharmacology

180

163

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Section: Interaction Of Hdl With Lps and Gram-negative Bacteriamentioning

confidence: 99%

HDL in Infectious Diseases and Sepsis

Pirillo

Catapano

Norata

2014

Handbook of Experimental Pharmacology

180

163

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“…In UK FH patients where a monogenic cause can be found, approximately 93% carry a mutation in the LDLR gene, 5% in APOB and 2% in PCSK9 [11]. Although other novel genes have been proposed [12], none have yet been independently confirmed.…”

Section: Introductionmentioning

confidence: 99%

“…Mutations in three genes, the LDL-receptor gene (LDLR), the gene coding for apolipoprotein B (APOB) and the gene encoding protein convertase subtilisin/kexin 9 (PCSK9), are known to cause FH [11]. In UK FH patients where a monogenic cause can be found, approximately 93% carry a mutation in the LDLR gene, 5% in APOB and 2% in PCSK9 [11].…”

Section: Introductionmentioning

confidence: 99%

Coronary heart disease mortality in treated Familial Hypercholesterolaemia: Update of the UK Simon Broome FH Register

Humphries¹,

Cooper²,

Seed

et al. 2017

Atherosclerosis Supplements

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a b s t r a c tBackground and aims: Patients with familial hypercholesterolaemia (FH) have an elevated risk of coronary heart disease (CHD). Here we compare changes in CHD mortality in patients with heterozygous (FH) pre 1992, before lipid-lowering therapy with statins was used routinely, and in the periods 1992e2008 and 2008e2016. Methods: 1903 Definite (DFH) and 1650 Possible (PFH) patients (51% women) aged 20e79 years, recruited from 21 lipid clinics in the United Kingdom and followed prospectively between 1980 and 2016 for 67,060 person-years. The CHD standardised mortality ratio (SMR) compared to the population in England and Wales was calculated (with 95% Confidence intervals). Results: There were 585 deaths, including 252 from CHD. Overall, the observed 2.4-fold excess coronary mortality for treated DFH post-1991 was significantly higher than the 1.78 excess for PFH (35% 95% CI 3% e76%). In patients with DFH and established coronary disease, there was a significant excess coronary mortality in all time periods, but in men it was reduced from a 4.83-fold excess (2.32e8.89) pre-1992 to 4.66 (3.46e6.14) in 1992e2008 and 2.51 (1.01e5.17) post-2008, while in women the corresponding values were 7.23 (2.65e15.73), 4.42 (2.70e6.82) and 6.34 (2.06e14.81). Primary prevention in men with DFH resulted in a progressive reduction in coronary mortality over the three time-periods, with no excess mortality evident post-2008 (0.89 (0.29e2.08)), although in women the excess persisted (post-2008 3.65 (1.75e6.72)). Conclusions:The results confirm the benefit of statin treatment in reducing CHD mortality, but suggest that FH patients with pre-existing CHD and women with FH may not be treated adequately.

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“…In carriers of the mutant APOB, p.(R3527Q), the affinity of LDL-R for R3527Q-LDL is markedly reduced, resulting in the FH phenotype and increased risk of CHD. [6] This mutation explains ~5% of cases of FH in many European countries, [6] but has not been found in subjects of African origin. PCSK9 encodes an enzyme that is involved in the post-translational regulation of LDLR by degrading the LDLR in the lysosome of the cell, preventing its recycling.…”

Section: Researchmentioning

confidence: 99%