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Cardiovascular risk profile in a patient with a novel splice site ABCA1 mutation (HDL Chelsea–Modena)
Abstracts / Atherosclerosis 218 (2011) e1–e12
The first ninety families diagnosed with mutation positive familial hypercholesterolaemia in two lipid clinics in a Scottish Health Board area R.M. Finnie 1,2,∗ , S. Walker 2 , W.G. Simpson 3 , Z. Miedzybrodzka 4 1
St John’s Hospital, Livingston, United Kingdom Royal Infirmary of Edinburgh, Edinburgh, United Kingdom 3 Clinical Biochemistry and Medical Genetics, United Kingdom 4 Aberdeen Royal Infirmary, Aberdeen, United Kingdom 2
The publication of the NICE Guideline on Identification and Management of Familial Hypercholesterolaemia (FH) in 2008, served as a catalyst for the Scottish Lipid Forum to implement a system of genetic and cascade screening for familial heterozygous hypercholesterolaemia (FH) in Scotland. We describe the first ninety mutation positive families identified in one Health Board area where the prevalence is estimated at 1000 cases. There are two designated Lipid Clinics and also a two further clinics that deal with Lipid problems. These two designated Lipid clinics amalgamated their databases in 2010 and the mutations of these first ninety families identified as genetically positive for familial hypercholesterolaemia are described. The positive pickup rate from all samples sent was 34% similar to other studies. When there was a possible family connection between two probands only one was included. Unclassified variants were also included. Sixty-five families were identified at one centre and twenty-five at the other. The male:female ratio of probands was not significantly different. There were no reports of the PCSK9 (Arg374Tyr) mutation, ten unclassified variants were found and seven Apo B 3500 (c.1058G>A; p.Arg3527Gln) mutations. LDLR MPLA showed evidence of four duplications of exons 11–12, three deletions of exon 1, a single deletion involving 2–6, a single deletion involving exons 3–6 and also a single deletion of exons 11–12.LDL sequencing yielded seven c.660delC; p.Asp221Trhfx44 mutations, five c.1444G>A; p.Asp482Asn, five c.682G>T; p.Glu228X, four c.2054C>T; p.Pro685Leu, three c.933delA; p.Glu312SerfsX58, and two c.313+1G>A mutations with a further 37 different point mutations being identified. Of particular note is that commercially available kits would only have picked up 34% (FH20) or 57% (FH48) of these mutations. Conclusion: Gene sequencing is necessary for all possible new cases of FH in small geographical areas. doi:10.1016/j.atherosclerosis.2011.07.064 Cardiovascular risk profile in a patient with a novel splice site ABCA1 mutation (HDL Chelsea–Modena) B. Jones 1,∗ , T. Fasano 2 , P. Zanoni 2 , G. Ball 1 , S. Calandra 2 , M.D. Feher 1 1
The Lipid Clinic, Chelsea and Westminster Hospital NHS Trust, London, United Kingdom 2 University of Modena and Reggio Emilia, Modena, Italy
Presentation: A 37 year old man was found to have a very low HDL (0.14 mmol/L), total cholesterol 4.1 mmol/L and fasting hypertriglyceridaemia (4.4–13.3 mmol/L) after a lipid check due to a family history of low HDL. Other vascular risk markers included Lp(a) 484 mg/L (RR < 300) and homocysteine 29.3 mol/L (RR < 15.0) Molecular genetics: Sequencing of ABCA1 revealed a heterozygous G>A transition at the 3 end of intron 10, with all coding regions intact. In silico analysis predicted alternative splice site formation due to the mutation causing partial incorporation of intron 10 into mRNA and subsequent aberrant ABCA1 gene product forma-
e3
tion. This effect was confirmed in vitro using a minigene approach. No other genetic cause of abnormal HDL metabolism or of hypertriglyceridaemia was identified. Discussion: ABCA1 transporter defects are a rare cause of very low HDL. The majority of reported cases are genetic variants in coding regions, whereas in our case the mutation was in a noncoding region, but resulting in significant effect on expression. Additionally, the lipid profile was not typical of heterozygous ABCA1 transporter defects. The extremely low HDL in our patient is similar to that of homozygous patients, e.g. Tangier disease, and hypertriglyceridaemia is not usually seen. Evidence regarding increased vascular risk in ABCA1-variant heterozygotes is conflicting, but additional factors in our patient including extremely low HDL, hypertriglyceridaemia, and elevated Lp(a) and homocysteine, are all associated with elevated risk. Therapy has been directed at lowering triglycerides to influence atherogenic particle composition due to the lack of effect by lipid-modifying drugs on raising the very low HDL. doi:10.1016/j.atherosclerosis.2011.07.065 Apolipoprotein C3 gene variants are not related to isolated low HDL cholesterol in South Asians: The Ethnic-Echocardiographic Heart of England Screening study (E-ECHOES) J. Chackathayil 1,∗ , J.V. Patel 1 , P.S. Gill 2 , E.A. Hughes 1 , G.Y.H. Lip 1 1 2
Sandwell and West Birmingham Hospitals, United Kingdom University of Birmingham, United Kingdom
Low levels of HDL cholesterol (HDL-c) in the absence of other lipid abnormalities are associated with an increased risk of CHD, and this trait is highly prevalent in South Asian populations. APOC3 gene variants are associated with variations in triglyceride and HDL cholesterol. We determined the contribution of APOC3 promoter region mutations (482 C/T and 455 T/C) to variations of HDL-c in South Asians. Lipids and genetic variants were analysed in 944 South Asians (56.0% men, mean age 57.4 years), of whom 144 (15.3%) had CHD. Low levels of HDL-c were defined as (HDL-c <1.0 mmol/L in males and <1.2 mmol/L in women) and ‘normal’ triglycerides <2.26 mmol/L, LDL-c <4.14 mmol/L, cholesterol <5.18 mmol/L. The APOC3 −455 T/C and −482 C/T SNPs were analysed by taqman PCR. Study participants were recruited as part of a population based epidemiological study, the EthnicEchocardiographic Heart of England Screening study (E-ECHOES). Results: Mean (SD) levels of HDL-c were 0.97(0.32) mmol/L and 1.11(0.38) mmol/L in men and women respectively (P < 0.001). Low HDLc was seen amongst 59% (95% CI, 54.8–63.2) men (36% smokers) and 62% (95% CI, 57.3–66.7) women (2% smokers). The prevalence of isolated low HDL in the presence of normal TG, cholesterol and LDLc was 30% (95% CI, 25.3–34.7) in men and 36.4% (95% CI, 30.9–41.9) in women. The allelic frequency for APOC3 −455 T/C and −482 C/T was 0.42 and 0.52, higher than those reported in non-Asian populations. Genotypes were unrelated to isolated low HDL, HDL-c levels, other lipid measurements nor a clinical history of CHD.Conclusion: Isolated low HDL-c is common in South Asians, with a prevalence of 22.4% compared to 14.5% in other ethnic groups, but the APOC3 promoter variants do not account for this susceptibility to low HDLc in South Asians. Other genetic predisposing factors to low HDL-c merit further study. doi:10.1016/j.atherosclerosis.2011.07.066
The first ninety families diagnosed with mutation positive familial hypercholesterolaemia in two lipid clinics in a Scottish Health Board area R.M. Finnie 1,2,∗ , S. Walker 2 , W.G. Simpson 3 , Z. Miedzybrodzka 4 1
St John’s Hospital, Livingston, United Kingdom Royal Infirmary of Edinburgh, Edinburgh, United Kingdom 3 Clinical Biochemistry and Medical Genetics, United Kingdom 4 Aberdeen Royal Infirmary, Aberdeen, United Kingdom 2
The publication of the NICE Guideline on Identification and Management of Familial Hypercholesterolaemia (FH) in 2008, served as a catalyst for the Scottish Lipid Forum to implement a system of genetic and cascade screening for familial heterozygous hypercholesterolaemia (FH) in Scotland. We describe the first ninety mutation positive families identified in one Health Board area where the prevalence is estimated at 1000 cases. There are two designated Lipid Clinics and also a two further clinics that deal with Lipid problems. These two designated Lipid clinics amalgamated their databases in 2010 and the mutations of these first ninety families identified as genetically positive for familial hypercholesterolaemia are described. The positive pickup rate from all samples sent was 34% similar to other studies. When there was a possible family connection between two probands only one was included. Unclassified variants were also included. Sixty-five families were identified at one centre and twenty-five at the other. The male:female ratio of probands was not significantly different. There were no reports of the PCSK9 (Arg374Tyr) mutation, ten unclassified variants were found and seven Apo B 3500 (c.1058G>A; p.Arg3527Gln) mutations. LDLR MPLA showed evidence of four duplications of exons 11–12, three deletions of exon 1, a single deletion involving 2–6, a single deletion involving exons 3–6 and also a single deletion of exons 11–12.LDL sequencing yielded seven c.660delC; p.Asp221Trhfx44 mutations, five c.1444G>A; p.Asp482Asn, five c.682G>T; p.Glu228X, four c.2054C>T; p.Pro685Leu, three c.933delA; p.Glu312SerfsX58, and two c.313+1G>A mutations with a further 37 different point mutations being identified. Of particular note is that commercially available kits would only have picked up 34% (FH20) or 57% (FH48) of these mutations. Conclusion: Gene sequencing is necessary for all possible new cases of FH in small geographical areas. doi:10.1016/j.atherosclerosis.2011.07.064 Cardiovascular risk profile in a patient with a novel splice site ABCA1 mutation (HDL Chelsea–Modena) B. Jones 1,∗ , T. Fasano 2 , P. Zanoni 2 , G. Ball 1 , S. Calandra 2 , M.D. Feher 1 1
The Lipid Clinic, Chelsea and Westminster Hospital NHS Trust, London, United Kingdom 2 University of Modena and Reggio Emilia, Modena, Italy
Presentation: A 37 year old man was found to have a very low HDL (0.14 mmol/L), total cholesterol 4.1 mmol/L and fasting hypertriglyceridaemia (4.4–13.3 mmol/L) after a lipid check due to a family history of low HDL. Other vascular risk markers included Lp(a) 484 mg/L (RR < 300) and homocysteine 29.3 mol/L (RR < 15.0) Molecular genetics: Sequencing of ABCA1 revealed a heterozygous G>A transition at the 3 end of intron 10, with all coding regions intact. In silico analysis predicted alternative splice site formation due to the mutation causing partial incorporation of intron 10 into mRNA and subsequent aberrant ABCA1 gene product forma-
e3
tion. This effect was confirmed in vitro using a minigene approach. No other genetic cause of abnormal HDL metabolism or of hypertriglyceridaemia was identified. Discussion: ABCA1 transporter defects are a rare cause of very low HDL. The majority of reported cases are genetic variants in coding regions, whereas in our case the mutation was in a noncoding region, but resulting in significant effect on expression. Additionally, the lipid profile was not typical of heterozygous ABCA1 transporter defects. The extremely low HDL in our patient is similar to that of homozygous patients, e.g. Tangier disease, and hypertriglyceridaemia is not usually seen. Evidence regarding increased vascular risk in ABCA1-variant heterozygotes is conflicting, but additional factors in our patient including extremely low HDL, hypertriglyceridaemia, and elevated Lp(a) and homocysteine, are all associated with elevated risk. Therapy has been directed at lowering triglycerides to influence atherogenic particle composition due to the lack of effect by lipid-modifying drugs on raising the very low HDL. doi:10.1016/j.atherosclerosis.2011.07.065 Apolipoprotein C3 gene variants are not related to isolated low HDL cholesterol in South Asians: The Ethnic-Echocardiographic Heart of England Screening study (E-ECHOES) J. Chackathayil 1,∗ , J.V. Patel 1 , P.S. Gill 2 , E.A. Hughes 1 , G.Y.H. Lip 1 1 2
Sandwell and West Birmingham Hospitals, United Kingdom University of Birmingham, United Kingdom
Low levels of HDL cholesterol (HDL-c) in the absence of other lipid abnormalities are associated with an increased risk of CHD, and this trait is highly prevalent in South Asian populations. APOC3 gene variants are associated with variations in triglyceride and HDL cholesterol. We determined the contribution of APOC3 promoter region mutations (482 C/T and 455 T/C) to variations of HDL-c in South Asians. Lipids and genetic variants were analysed in 944 South Asians (56.0% men, mean age 57.4 years), of whom 144 (15.3%) had CHD. Low levels of HDL-c were defined as (HDL-c <1.0 mmol/L in males and <1.2 mmol/L in women) and ‘normal’ triglycerides <2.26 mmol/L, LDL-c <4.14 mmol/L, cholesterol <5.18 mmol/L. The APOC3 −455 T/C and −482 C/T SNPs were analysed by taqman PCR. Study participants were recruited as part of a population based epidemiological study, the EthnicEchocardiographic Heart of England Screening study (E-ECHOES). Results: Mean (SD) levels of HDL-c were 0.97(0.32) mmol/L and 1.11(0.38) mmol/L in men and women respectively (P < 0.001). Low HDLc was seen amongst 59% (95% CI, 54.8–63.2) men (36% smokers) and 62% (95% CI, 57.3–66.7) women (2% smokers). The prevalence of isolated low HDL in the presence of normal TG, cholesterol and LDLc was 30% (95% CI, 25.3–34.7) in men and 36.4% (95% CI, 30.9–41.9) in women. The allelic frequency for APOC3 −455 T/C and −482 C/T was 0.42 and 0.52, higher than those reported in non-Asian populations. Genotypes were unrelated to isolated low HDL, HDL-c levels, other lipid measurements nor a clinical history of CHD.Conclusion: Isolated low HDL-c is common in South Asians, with a prevalence of 22.4% compared to 14.5% in other ethnic groups, but the APOC3 promoter variants do not account for this susceptibility to low HDLc in South Asians. Other genetic predisposing factors to low HDL-c merit further study. doi:10.1016/j.atherosclerosis.2011.07.066