Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9

Cohen, Jonathan C.; Pertsemlidis, Alexander; Kotowski, Ingrid K.; Graham, Randall B.; Garcia, Christine Kim; Hobbs, Helen H.

doi:10.1038/ng1509

Cited by 1,256 publications

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“…The use of a multiethnic population for resequencing capitalizes on genetic variation that arises from ethnic differences in population history. Previously, in the Dallas Heart Study we found highly informative sequence variants in PCSK9 and NPC1L1 that were largely confined to African Americans [18][19][20] . In contrast, the ANGPTL4 variants identified in this study were more informative in European Americans.…”

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Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL

et al. 2007

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Resequencing genes provides the opportunity to assess the full spectrum of variants that influence complex traits. Here we report the first application of resequencing to a large population (n = 3,551) to examine the role of the adipokine ANGPTL4 in lipid metabolism. Nonsynonymous variants in ANGPTL4 were more prevalent in individuals with triglyceride levels in the lowest quartile than in individuals with levels in the highest quartile (P = 0.016). One variant (E40K), present in ~3% of European Americans, was associated with significantly lower plasma levels of triglyceride and higher levels of high-density lipoprotein cholesterol in European Americans from the Atherosclerosis Risk in Communities Study and in Danes from the Copenhagen City Heart Study. The ratio of nonsynonymous to synonymous variants was higher in European Americans than in African Americans (4:1 versus 1.3:1), suggesting population-specific relaxation of purifying selection. Thus, resequencing of ANGPTL4 in a multiethnic population allowed analysis of the phenotypic effects of both rare and common variants while taking advantage of genetic variation arising from ethnic differences in population history.Adipocytes secrete a variety of proteins that regulate glucose and lipid metabolism 1 . The metabolic effects of these proteins have been largely deduced from studies in mice; less is Correspondence should be addressed to H.H. (helen.hobbs@utsouthwestern.edu) or J.C.C. (jonathan.cohen@utsouthwestern.edu). 7 These authors contributed equally to this work.Note: Supplementary information is available on the Nature Genetics website.Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. , most of which were rare: more than half (n = 49) were found only in one subject, and 86% (n = 80) had a minor allele frequency below 3% (Supplementary Fig. 1 and Supplementary Table 2 online). NIH Public AccessTo examine the phenotypic effects of sequence variation in ANGPTL4, we stratified the population by race, sex and trait level and then compared the number of nonsynonymous variants in the top and bottom quartiles of the distribution. We excluded variants found in both quartiles. The first trait we examined was fasting levels of plasma triglyceride. Individuals with factors known to affect triglyceride levels (lipid-lowering drugs, diabetes mellitus and heavy alcohol use) were excluded from the analyses. After these exclusions, the number of individuals with nonsynonymous sequence variants in the bottom quartile (n = 13) was significantly greater than the number in the highest quartile (n = 2; P = 0.016) (Fig. 1); we found all sequence variations in separate individuals except R336C, which was present in three European Americans in the lowest quartile of triglycerides. Although European Americans comprised less than one-third of the sample (1,045 out of 3,551), 10 of the 13 individuals with a nonsynonymou...

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Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL

et al. 2007

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“…[13][14][15] Missense mutations of PCSK9 associated with hypercholesterolemia in humans would increase the capacity of PCSK9 to limit the number of LDL-r, thus representing gain of function mutations. In sharp contrast, mice with targeted inactivation of PCSK9 gene (pcsk9 Ϫ/Ϫ ) have an increased number of LDL-r in the liver, increased removal of plasma LDL, and reduced plasma LDL-C. 16 In 2005 Cohen et al 17 found that 2 inactivating mutations of PCSK9 (Y142X and C679X), present in 2% to 2.6% of blacks of the Dallas Heart Study, were associated with 30% to 40% reduction of plasma LDL-C. They proposed the concept that in human loss of function mutations of PCSK9 would increase the number of liver LDL-r and the receptor mediated uptake and catabolism of plasma LDL, as observed in pcsk9 Ϫ/Ϫ mice.…”

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A Novel Loss of Function Mutation of PCSK9 Gene in White Subjects With Low-Plasma Low-Density Lipoprotein Cholesterol

Fasano

Cefalù

Leo

et al. 2007

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Objectives-The PCSK9 gene, encoding a pro-protein convertase involved in posttranslational degradation of low-density lipoprotein receptor, has emerged as a key regulator of plasma low-density lipoprotein cholesterol. In AfricanAmericans two nonsense mutations resulting in loss of function of PCSK9 are associated with a 30% to 40% reduction of plasma low-density lipoprotein cholesterol. The aim of this study was to assess whether loss of function mutations of PCSK9 were a cause of familial hypobetalipoproteinemia and a determinant of low-plasma low-density lipoprotein cholesterol in whites. Methods and Results-We sequenced PCSK9 gene in 18 familial hypobetalipoproteinemia subjects and in 102 hypocholesterolemic blood donors who were negative for APOB gene mutations known to cause familial hypobetalipoproteinemia. The PCSK9 gene variants found in these 2 groups were screened in 42 subjects in the lowest (Ͻ5 th ) percentile, 44 in the highest (Ͼ95 th ) percentile, and 100 with the average plasma cholesterol derived from general population. In one familial hypobetalipoproteinemia kindred and in 2 hypocholesterolemic blood donors we found a novel PCSK9 mutation in exon 1 (c.202delG) resulting in a truncated peptide (Ala68fsLeu82X). Two familial hypobetalipoproteinemia subjects and 4 hypocholesterolemic blood donors were carriers of the R46L substitution previously reported to be associated with reduced low-density lipoprotein cholesterol as well as other rare amino acid changes (T77I, V114A, A522T and P616L) not found in the other groups examined. Conclusions-We discovered a novel inactivating mutation as well as some rare nonconservative amino acid substitutions of PCSK9 in white hypocholesterolemic individuals.

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“…20 In addition, PCSK9 mutation has been linked to accelerated ApoB production, 21 and can worsen the phenotype of heterozygous FH. 22 One of the PCSK9 variants we found in this patient was previously, though not definitively, linked to alterations in cholesterol levels; it was initially associated with elevated cholesterol, but a subsequent, larger study in African Americans linked it with both unusually high and unusually low LDL cholesterol values.…”

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LDLR promoter variant and exon 14 mutation on the same chromosome are associated with an unusually severe FH phenotype and treatment resistance

et al. 2008

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Familial hypercholesterolemia (FH) is the most common form of autosomal-dominant hypercholesterolemia, and is caused by mutations in the low-density lipoprotein receptor (LDLR) gene. Heterozygous FH is characterized by elevated low-density lipoprotein (LDL) cholesterol and early-onset cardiovascular disease, whereas homozygous FH results in more severe LDL cholesterol elevation with death by 20 years of age. We present here the case of an African-American female FH patient presenting with a myocardial infarction at the age of 48, recurrent angina pectoris and numerous coronary artery stents. Her pretreated LDL cholesterol levels were more typical of a homozygous FH pattern and she was resistant to conventional lipid-lowering treatment, yet her other clinical parameters were not necessarily consistent with homozygous FH. Genetic testing revealed two LDLR variants on the same chromosome: one a novel missense mutation in exon 14 (Cys681Gly) and the other a promoter variant (IVS1-217C4T) previously shown to result in increased LDLR transcription. Disease-associated PCSK9 or APOB mutations were not identified in this individual. Overall, her genetic and clinical profile suggests that enhanced expression of the mutant LDLR allele resulted in a severe phenotype with characteristics of both heterozygous and homozygous FH.

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Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9

Cited by 1,256 publications

References 19 publications

Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL

Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL

A Novel Loss of Function Mutation of PCSK9 Gene in White Subjects With Low-Plasma Low-Density Lipoprotein Cholesterol

LDLR promoter variant and exon 14 mutation on the same chromosome are associated with an unusually severe FH phenotype and treatment resistance

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