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1.  Statin-associated muscle symptoms: impact on statin therapy—European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management 
European Heart Journal  2015;36(17):1012-1022.
Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. This European Atherosclerosis Society (EAS) Consensus Panel overviews current understanding of the pathophysiology of statin-associated myopathy, and provides guidance for diagnosis and management of SAMS. Statin-associated myopathy, with significant elevation of serum creatine kinase (CK), is a rare but serious side effect of statins, affecting 1 per 1000 to 1 per 10 000 people on standard statin doses. Statin-associated muscle symptoms cover a broader range of clinical presentations, usually with normal or minimally elevated CK levels, with a prevalence of 7–29% in registries and observational studies. Preclinical studies show that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, thereby providing a potential link between statins and muscle symptoms; controlled mechanistic and genetic studies in humans are necessary to further understanding. The Panel proposes to identify SAMS by symptoms typical of statin myalgia (i.e. muscle pain or aching) and their temporal association with discontinuation and response to repetitive statin re-challenge. In people with SAMS, the Panel recommends the use of a maximally tolerated statin dose combined with non-statin lipid-lowering therapies to attain recommended low-density lipoprotein cholesterol targets. The Panel recommends a structured work-up to identify individuals with clinically relevant SAMS generally to at least three different statins, so that they can be offered therapeutic regimens to satisfactorily address their cardiovascular risk. Further research into the underlying pathophysiological mechanisms may offer future therapeutic potential.
doi:10.1093/eurheartj/ehv043
PMCID: PMC4416140  PMID: 25694464
Statin; Muscle symptoms; Myalgia; Myopathy; Statin intolerance; Mitochondrial; Consensus statement; Lipids; Cholesterol
2.  Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society 
European Heart Journal  2014;35(32):2146-2157.
Aims
Homozygous familial hypercholesterolaemia (HoFH) is a rare life-threatening condition characterized by markedly elevated circulating levels of low-density lipoprotein cholesterol (LDL-C) and accelerated, premature atherosclerotic cardiovascular disease (ACVD). Given recent insights into the heterogeneity of genetic defects and clinical phenotype of HoFH, and the availability of new therapeutic options, this Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society (EAS) critically reviewed available data with the aim of providing clinical guidance for the recognition and management of HoFH.
Methods and results
Early diagnosis of HoFH and prompt initiation of diet and lipid-lowering therapy are critical. Genetic testing may provide a definitive diagnosis, but if unavailable, markedly elevated LDL-C levels together with cutaneous or tendon xanthomas before 10 years, or untreated elevated LDL-C levels consistent with heterozygous FH in both parents, are suggestive of HoFH. We recommend that patients with suspected HoFH are promptly referred to specialist centres for a comprehensive ACVD evaluation and clinical management. Lifestyle intervention and maximal statin therapy are the mainstays of treatment, ideally started in the first year of life or at an initial diagnosis, often with ezetimibe and other lipid-modifying therapy. As patients rarely achieve LDL-C targets, adjunctive lipoprotein apheresis is recommended where available, preferably started by age 5 and no later than 8 years. The number of therapeutic approaches has increased following approval of lomitapide and mipomersen for HoFH. Given the severity of ACVD, we recommend regular follow-up, including Doppler echocardiographic evaluation of the heart and aorta annually, stress testing and, if available, computed tomography coronary angiography every 5 years, or less if deemed necessary.
Conclusion
This EAS Consensus Panel highlights the need for early identification of HoFH patients, prompt referral to specialized centres, and early initiation of appropriate treatment. These recommendations offer guidance for a wide spectrum of clinicians who are often the first to identify patients with suspected HoFH.
doi:10.1093/eurheartj/ehu274
PMCID: PMC4139706  PMID: 25053660
Homozygous familial hypercholesterolaemia; Diagnosis; Genetics; Phenotypic heterogeneity; Statins; Ezetimibe; Lipoprotein apheresis; Lomitapide; Mipomersen
3.  A novel ICK mutation causes ciliary disruption and lethal endocrine-cerebro-osteodysplasia syndrome 
Cilia  2016;5:8.
Background
Endocrine-cerebro-osteodysplasia (ECO) syndrome [MIM:612651] caused by a recessive mutation (p.R272Q) in Intestinal cell kinase (ICK) shows significant clinical overlap with ciliary disorders. Similarities are strongest between ECO syndrome, the Majewski and Mohr-Majewski short-rib thoracic dysplasia (SRTD) with polydactyly syndromes, and hydrolethalus syndrome. In this study, we present a novel homozygous ICK mutation in a fetus with ECO syndrome and compare the effect of this mutation with the previously reported ICK variant on ciliogenesis and cilium morphology.
Results
Through homozygosity mapping and whole-exome sequencing, we identified a second variant (c.358G > T; p.G120C) in ICK in a Turkish fetus presenting with ECO syndrome. In vitro studies of wild-type and mutant mRFP-ICK (p.G120C and p.R272Q) revealed that, in contrast to the wild-type protein that localizes along the ciliary axoneme and/or is present in the ciliary base, mutant proteins rather enrich in the ciliary tip. In addition, immunocytochemistry revealed a decreased number of cilia in ICK p.R272Q-affected cells.
Conclusions
Through identification of a novel ICK mutation, we confirm that disruption of ICK causes ECO syndrome, which clinically overlaps with the spectrum of ciliopathies. Expression of ICK-mutated proteins result in an abnormal ciliary localization compared to wild-type protein. Primary fibroblasts derived from an individual with ECO syndrome display ciliogenesis defects. In aggregate, our findings are consistent with recent reports that show that ICK regulates ciliary biology in vitro and in mice, confirming that ECO syndrome is a severe ciliopathy.
Electronic supplementary material
The online version of this article (doi:10.1186/s13630-016-0029-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s13630-016-0029-1
PMCID: PMC4827216  PMID: 27069622
Endocrine-cerebro-osteodysplasia syndrome; ECO; Intestinal cell kinase; ICK; Short-rib thoracic dysplasia syndrome; SRTD; Ciliopathy; Ciliary defects
4.  Statin Safety in Chinese: A Population-Based Study of Older Adults 
PLoS ONE  2016;11(3):e0150990.
Background
Compared to Caucasians, Chinese achieve a higher blood concentration of statin for a given dose. It remains unknown whether this translates to increased risk of serious statin-associated adverse events amongst Chinese patients.
Methods
We conducted a population-based retrospective cohort study of older adults (mean age, 74 years) newly prescribed a statin in Ontario, Canada between 2002 and 2013, where 19,033 Chinese (assessed through a validated surname algorithm) were matched (1:3) by propensity score to 57,099 non-Chinese. This study used linked healthcare databases.
Findings
The follow-up observation period (mean 1.1, maximum 10.8 years) was similar between groups, as were the reasons for censoring the observation period (end of follow-up, death, or statin discontinuation). Forty-seven percent (47%) of Chinese were initiated on a higher than recommended statin dose. Compared to non-Chinese, Chinese ethnicity did not associate with any of the four serious statin-associated adverse events assessed in this study [rhabdomyolysis hazard ratio (HR) 0.61 (95% CI 0.28 to 1.34), incident diabetes HR 1.02 (95% CI 0.80 to 1.30), acute kidney injury HR 0.90 (95% CI 0.72 to 1.13), or all-cause mortality HR 0.88 (95% CI 0.74 to 1.05)]. Similar results were observed in subgroups defined by statin type and dose.
Conclusions
We observed no higher risk of serious statin toxicity in Chinese than matched non-Chinese older adults with similar indicators of baseline health. Regulatory agencies should review available data, including findings from our study, to decide if a change in their statin dosing recommendations for people of Chinese ethnicity is warranted.
doi:10.1371/journal.pone.0150990
PMCID: PMC4783028  PMID: 26954681
5.  An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes 
Wheway, Gabrielle | Schmidts, Miriam | Mans, Dorus A. | Szymanska, Katarzyna | Nguyen, Thanh-Minh T. | Racher, Hilary | Phelps, Ian G. | Toedt, Grischa | Kennedy, Julie | Wunderlich, Kirsten A. | Sorusch, Nasrin | Abdelhamed, Zakia A. | Natarajan, Subaashini | Herridge, Warren | van Reeuwijk, Jeroen | Horn, Nicola | Boldt, Karsten | Parry, David A. | Letteboer, Stef J.F. | Roosing, Susanne | Adams, Matthew | Bell, Sandra M. | Bond, Jacquelyn | Higgins, Julie | Morrison, Ewan E. | Tomlinson, Darren C. | Slaats, Gisela G. | van Dam, Teunis J. P. | Huang, Lijia | Kessler, Kristin | Giessl, Andreas | Logan, Clare V. | Boyle, Evan A. | Shendure, Jay | Anazi, Shamsa | Aldahmesh, Mohammed | Al Hazzaa, Selwa | Hegele, Robert A. | Ober, Carole | Frosk, Patrick | Mhanni, Aizeddin A. | Chodirker, Bernard N. | Chudley, Albert E. | Lamont, Ryan | Bernier, Francois P. | Beaulieu, Chandree L. | Gordon, Paul | Pon, Richard T. | Donahue, Clem | Barkovich, A. James | Wolf, Louis | Toomes, Carmel | Thiel, Christian T. | Boycott, Kym M. | McKibbin, Martin | Inglehearn, Chris F. | Stewart, Fiona | Omran, Heymut | Huynen, Martijn A. | Sergouniotis, Panagiotis I. | Alkuraya, Fowzan S. | Parboosingh, Jillian S. | Innes, A Micheil | Willoughby, Colin E. | Giles, Rachel H. | Webster, Andrew R. | Ueffing, Marius | Blacque, Oliver | Gleeson, Joseph G. | Wolfrum, Uwe | Beales, Philip L. | Gibson, Toby | Doherty, Dan | Mitchison, Hannah M. | Roepman, Ronald | Johnson, Colin A.
Nature cell biology  2015;17(8):1074-1087.
Defects in primary cilium biogenesis underlie the ciliopathies, a growing group of genetic disorders. We describe a whole genome siRNA-based reverse genetics screen for defects in biogenesis and/or maintenance of the primary cilium, obtaining a global resource. We identify 112 candidate ciliogenesis and ciliopathy genes, including 44 components of the ubiquitin-proteasome system, 12 G-protein-coupled receptors, and three pre-mRNA processing factors (PRPF6, PRPF8 and PRPF31) mutated in autosomal dominant retinitis pigmentosa. The PRPFs localise to the connecting cilium, and PRPF8- and PRPF31-mutated cells have ciliary defects. Combining the screen with exome sequencing data identified recessive mutations in PIBF1/CEP90 and C21orf2/LRRC76 as causes of the ciliopathies Joubert and Jeune syndromes. Biochemical approaches place C21orf2 within key ciliopathy-associated protein modules, offering an explanation for the skeletal and retinal involvement observed in individuals with C21orf2-variants. Our global, unbiased approaches provide insights into ciliogenesis complexity and identify roles for unanticipated pathways in human genetic disease.
doi:10.1038/ncb3201
PMCID: PMC4536769  PMID: 26167768
cilia; ciliopathies; reverse genetics; whole-genome siRNA screen; Jeune syndrome; Joubert syndrome
6.  A common hypofunctional genetic variant of GPER is associated with increased blood pressure in women 
Aims
Activation of vascular GPER has been linked to vasodepressor effects in animals. However, the significance of GPER regulation on chronic blood pressure control in humans is unknown.
Methods
To examine this question we determined the functional significance of expression of a common missense single nucleotide variant of GPER, P16L in vascular smooth muscle cells, and its association with blood pressure in humans. Further, to validate the importance of carrying GPER P16L in the development of hypertension we assessed allele frequency in a cohort of hard-to-treat hypertensive patients referred to a tertiary care clinic.
Results
Expression of the GPER P16L variant (V) vs. wild type (WT) in rat aortic vascular smooth muscle cells, was associated with a significant decrease in G1 (1 μm, a GPER agonist)-mediated ERK phosphorylation (slope of the function of G1-stimulated ERK phosphorylation: GPER content WT: 16.2, 95% CI 9.9, 22.6; V: 5.0, 95% CI 1.0, 9.0; P < 0.005) and apoptosis (slope of the function of G1-stimulated apoptosis: GPER content: WT: 4.4, 95% CI: 3.4, 5.4; V: 2.5, 95% CI 1.6, 2.3 P < 0.005). Normotensive female subjects, but not male subjects, carrying this hypofunctional variant (allele frequency 22%) have increased blood pressure [mean arterial pressure: P16/P16: 80 ± 1 mmHg (n = 204) vs. P16L carriers: 82 ± 1 mmHg (n = 127), 95% CI for difference: 0.6, 4.0 mmHg, P < 0.05], [systolic blood pressure: P16/P16: 105 ± 1 mmHg vs. P16L carriers: 108 ± 1 mmHg, 95% CI for difference:1.0, 5.1 mmHg, P < 0.05], [diastolic blood pressure: P16/P16: 66 ± 0.5 mmHg vs. P16L carriers 68 ± 0.7, 95% CI for difference: 0.2, 3.6 mmHg, P < 0.05]. Further, the P16L allele frequency was almost two-fold higher in female vs. male hypertensive patients (31% vs. 16%, allele ratio 0.5, 95% CI 0.32, 0.76, P < 0.05).
Conclusions
The common genetic variant, GPER P16L, is hypofunctional and female carriers of this allele have increased blood pressure. There was an increased prevalence in a population of hard-to-treat hypertensive female patients. Cumulatively, these data suggest that in females, impaired GPER function might be associated with increased blood pressure and risk of hypertension.
doi:10.1111/bcp.12471
PMCID: PMC4256633  PMID: 25039431
GPER; hypertension
7.  HDL Deficiency due to a New Insertion Mutation (ApoA-INashua) and Review of the Literature 
Journal of clinical lipidology  2012;7(2):169-173.
A 61 year old Caucasian male of European ancestry with significant coronary heart disease (CHD) since age 42 years and marked high density lipoprotein (HDL) deficiency (HDL cholesterol 1 mg/dl) was evaluated. His fasting low density lipoprotein (LDL) cholesterol (C) level was 42 mg/dl, and his triglycerides were 417 mg/dl on therapy with rosuvastatin 40 mg/day, ezetimibe 10 mg/day, fenofibrate 145 mg/day, and extended release niacin 2 g/day. Further analysis of his plasma revealed an apolipoprotein (apo) A-I level of 23.5 mg/dl (about 20% of normal), and the absence of small alpha-4 HDL, medium alpha-3 HDL, and very large alpha-1 HDL, with only very small pre-beta-1 HDL and large alpha-2 HDL being present. ApoA-I gene sequencing revealed a novel heterozygous in-frame insertion mutation with duplication of nucleotides 1535 through 1552 inserted at position 1553, causing a new amino acid glycine at codon 157 and a duplication of amino acids alanine, arginine, alanine, histidine, and leucine at codons 158 – 162. This novel apoA-I mutation results in the formation of apoA-I that appears to have abnormal lipid binding properties, resulting in impaired reverse cholesterol transport, probable enhanced clearance, and premature CHD.
doi:10.1016/j.jacl.2012.10.011
PMCID: PMC4565164  PMID: 23415437
8.  Severe Hypertriglyceridemia due to a novel p.Q240H mutation in the Lipoprotein Lipase gene 
Background
Lipoprotein Lipase (LPL) deficiency is a rare autosomal recessive disorder with a heterogeneous clinical presentation. Several mutations in the LPL gene have been identified to cause decreased activity of the enzyme.
Findings
An 11-week-old, exclusively breastfed male presented with coffee-ground emesis, melena, xanthomas, lipemia retinalis and chylomicronemia. Genomic DNA analysis identified lipoprotein lipase deficiency due to compound heterozygosity including a novel p.Q240H mutation in exon 5 of the lipoprotein lipase (LPL) gene. His severe hypertriglyceridemia, including xanthomas, resolved with dietary long-chain fat restriction.
Conclusions
We describe a novel mutation of the LPL gene causing severe hypertriglyceridemia and report the response to treatment. A review of the current literature regarding LPL deficiency syndrome reveals a few potential new therapies under investigation.
doi:10.1186/s12944-015-0107-1
PMCID: PMC4559337  PMID: 26337181
Chylomicronemia; Triglyceride; Lipoprotein lipase deficiency
9.  The common LDLR p.G116S variant has a large effect on plasma LDL cholesterol in circumpolar Inuit populations 
Background
Inuit are considered to be vulnerable to cardiovascular disease (CVD) as their lifestyles become more Westernized. During sequence analysis of Inuit individuals at extremes of lipid traits, we identified two nonsynonymous variants in LDLR encoding the low-density lipoprotein (LDL) receptor, namely p.G116S and p.R730W.
Methods and Results
Genotyping these variants in 3,324 Inuit from Alaska, Canada and Greenland showed they were common, with allele frequencies 10–15%. Only p.G116S was associated with dyslipidemia: the increase in LDL cholesterol was 0.54 mmol/L (20.9 mg/dL) per allele (P = 5.6 × 10−49), which was >3-times larger than the largest effect sizes seen with common variants in other populations. Carriers of p.G116S had a 3.02-fold increased risk of hypercholesterolemia (CI 2.34 – 3.90, P = 1.7 × 10−17), but did not have classical familial hypercholesterolemia. In vitro, p.G116S showed 60% reduced ligand binding activity compared to wild-type receptor. In contrast, p.R730W was associated with neither LDL cholesterol nor altered in vitro activity.
Conclusions
LDLR p.G116S is thus unique: a common dysfunctional variant in Inuit whose large effect on LDL cholesterol may have public health implications.
doi:10.1161/CIRCGENETICS.114.000646
PMCID: PMC4560235  PMID: 25414273
lipoprotein; indigenous population; cardiovascular risk; DNA polymorphism; low-density lipoprotein receptor; familial hypercholesterolemia
10.  Multiple rare alleles at LDLR and APOA5 confer risk for early-onset myocardial infarction 
Do, Ron | Stitziel, Nathan O. | Won, Hong-Hee | Jørgensen, Anders Berg | Duga, Stefano | Merlini, Pier Angelica | Kiezun, Adam | Farrall, Martin | Goel, Anuj | Zuk, Or | Guella, Illaria | Asselta, Rosanna | Lange, Leslie A. | Peloso, Gina M. | Auer, Paul L. | Girelli, Domenico | Martinelli, Nicola | Farlow, Deborah N. | DePristo, Mark A. | Roberts, Robert | Stewart, Alexander F.R. | Saleheen, Danish | Danesh, John | Epstein, Stephen E. | Sivapalaratnam, Suthesh | Hovingh, G. Kees | Kastelein, John J. | Samani, Nilesh J. | Schunkert, Heribert | Erdmann, Jeanette | Shah, Svati H. | Kraus, William E. | Davies, Robert | Nikpay, Majid | Johansen, Christopher T. | Wang, Jian | Hegele, Robert A. | Hechter, Eliana | Marz, Winfried | Kleber, Marcus E. | Huang, Jie | Johnson, Andrew D. | Li, Mingyao | Burke, Greg L. | Gross, Myron | Liu, Yongmei | Assimes, Themistocles L. | Heiss, Gerardo | Lange, Ethan M. | Folsom, Aaron R. | Taylor, Herman A. | Olivieri, Oliviero | Hamsten, Anders | Clarke, Robert | Reilly, Dermot F. | Yin, Wu | Rivas, Manuel A. | Donnelly, Peter | Rossouw, Jacques E. | Psaty, Bruce M. | Herrington, David M. | Wilson, James G. | Rich, Stephen S. | Bamshad, Michael J. | Tracy, Russell P. | Cupples, L. Adrienne | Rader, Daniel J. | Reilly, Muredach P. | Spertus, John A. | Cresci, Sharon | Hartiala, Jaana | Tang, W.H. Wilson | Hazen, Stanley L. | Allayee, Hooman | Reiner, Alex P. | Carlson, Christopher S. | Kooperberg, Charles | Jackson, Rebecca D. | Boerwinkle, Eric | Lander, Eric S. | Schwartz, Stephen M. | Siscovick, David S. | McPherson, Ruth | Tybjaerg-Hansen, Anne | Abecasis, Goncalo R. | Watkins, Hugh | Nickerson, Deborah A. | Ardissino, Diego | Sunyaev, Shamil R. | O’Donnell, Christopher J. | Altshuler, David | Gabriel, Stacey | Kathiresan, Sekar
Nature  2014;518(7537):102-106.
Summary
Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance1,2. When MI occurs early in life, the role of inheritance is substantially greater1. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families3–8 whereas common variants at more than 45 loci have been associated with MI risk in the population9–15. Here, we evaluate the contribution of rare mutations to MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes where rare coding-sequence mutations were more frequent in cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare, damaging mutations (3.1% of cases versus 1.3% of controls) were at 2.4-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). This sequence-based estimate of the proportion of early MI cases due to LDLR mutations is remarkably similar to an estimate made more than 40 years ago using total cholesterol16. At apolipoprotein A-V (APOA5), carriers of rare nonsynonymous mutations (1.4% of cases versus 0.6% of controls) were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase15,17 and apolipoprotein C318,19. When combined, these observations suggest that, beyond LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.
doi:10.1038/nature13917
PMCID: PMC4319990  PMID: 25487149
11.  The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management 
Plasma triglyceride concentration is a biomarker for circulating triglyceride-rich lipoproteins and their metabolic remnants. Common mild-to-moderate hypertriglyceridaemia is typically multigenic, and results from the cumulative burden of common and rare variants in more than 30 genes, as quantified by genetic risk scores. Rare autosomal recessive monogenic hypertriglyceridaemia can result from large-effect mutations in six different genes. Hypertriglyceridaemia is exacerbated by non-genetic factors. On the basis of recent genetic data, we redefine the disorder into two states: severe (triglyceride concentration >10 mmol/L), which is more likely to have a monogenic cause; and mild-to-moderate (triglyceride concentration 2–10 mmol/L). Because of clustering of susceptibility alleles and secondary factors in families, biochemical screening and counselling for family members is essential, but routine genetic testing is not warranted. Treatment includes management of lifestyle and secondary factors, and pharmacotherapy. In severe hypertriglyceridaemia, intervention is indicated because of pancreatitis risk; in mild-to-moderate hypertriglyceridaemia, intervention can be indicated to prevent cardiovascular disease, dependent on triglyceride concentration, concomitant lipoprotein disturbances, and overall cardiovascular risk.
doi:10.1016/S2213-8587(13)70191-8
PMCID: PMC4201123  PMID: 24731657
12.  A novel MC4R mutation associated with childhood-onset obesity: A case report 
Paediatrics & Child Health  2014;19(10):515-518.
The melanocortin-4-receptor gene (MC4R) is a key regulator of energy homeostasis, food intake and body weight. MC4R gene mutations are associated with early-onset severe obesity. Most patients are heterozygotes, with some reports of homozygotes and compound heterozygotes. The authors report a case involving an eight-year-old girl with progressive weight gain from infancy, body mass index 44 kg/m2 (>97th percentile), hyperphagia, hyperinsulinemia and increased linear growth. There was no phenotype of morbid obesity in the parents or sibling. Coding regions and intron-exon boundaries of the genes encoding leptin, leptin receptor, pro-opiomelanocortin and MC4R were analyzed. Two heterozygous coding mutations in the MCR4 gene (S94N and C293R) were detected, of which the second has not been previously reported. The mutations were on opposite chromosomes, confirming compound heterozygosity. The molecular findings and clinical features associated with this novel MC4R mutation are described. The authors emphasize that rare mutations can be found in some patients with severe childhood-onset obesity.
PMCID: PMC4276379  PMID: 25587224
MC4R; Melanocortin; Obesity
13.  Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment 
European Heart Journal  2015;36(36):2425-2437.
Familial hypercholesterolaemia (FH) is a common genetic cause of premature coronary heart disease (CHD). Globally, one baby is born with FH every minute. If diagnosed and treated early in childhood, individuals with FH can have normal life expectancy. This consensus paper aims to improve awareness of the need for early detection and management of FH children. Familial hypercholesterolaemia is diagnosed either on phenotypic criteria, i.e. an elevated low-density lipoprotein cholesterol (LDL-C) level plus a family history of elevated LDL-C, premature coronary artery disease and/or genetic diagnosis, or positive genetic testing. Childhood is the optimal period for discrimination between FH and non-FH using LDL-C screening. An LDL-C ≥5 mmol/L (190 mg/dL), or an LDL-C ≥4 mmol/L (160 mg/dL) with family history of premature CHD and/or high baseline cholesterol in one parent, make the phenotypic diagnosis. If a parent has a genetic defect, the LDL-C cut-off for the child is ≥3.5 mmol/L (130 mg/dL). We recommend cascade screening of families using a combined phenotypic and genotypic strategy. In children, testing is recommended from age 5 years, or earlier if homozygous FH is suspected. A healthy lifestyle and statin treatment (from age 8 to 10 years) are the cornerstones of management of heterozygous FH. Target LDL-C is <3.5 mmol/L (130 mg/dL) if >10 years, or ideally 50% reduction from baseline if 8–10 years, especially with very high LDL-C, elevated lipoprotein(a), a family history of premature CHD or other cardiovascular risk factors, balanced against the long-term risk of treatment side effects. Identifying FH early and optimally lowering LDL-C over the lifespan reduces cumulative LDL-C burden and offers health and socioeconomic benefits. To drive policy change for timely detection and management, we call for further studies in the young. Increased awareness, early identification, and optimal treatment from childhood are critical to adding decades of healthy life for children and adolescents with FH.
doi:10.1093/eurheartj/ehv157
PMCID: PMC4576143  PMID: 26009596
Familial hypercholesterolaemia; Children; Adolescents; LDL cholesterol; Diagnosis; Treatment; Statin; Ezetimibe; PCSK9 inhibitor; Consensus statement
14.  Gene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations 
Yoneyama, Sachiko | Guo, Yiran | Lanktree, Matthew B. | Barnes, Michael R. | Elbers, Clara C. | Karczewski, Konrad J | Padmanabhan, Sandosh | Bauer, Florianne | Baumert, Jens | Beitelshees, Amber | Berenson, Gerald S. | Boer, Jolanda M.A. | Burke, Gregory | Cade, Brian | Chen, Wei | Cooper-Dehoff, Rhonda M. | Gaunt, Tom R. | Gieger, Christian | Gong, Yan | Gorski, Mathias | Heard-Costa, Nancy | Johnson, Toby | Lamonte, Michael J. | Mcdonough, Caitrin | Monda, Keri L. | Onland-Moret, N. Charlotte | Nelson, Christopher P. | O'Connell, Jeffrey R. | Ordovas, Jose | Peter, Inga | Peters, Annette | Shaffer, Jonathan | Shen, Haiqinq | Smith, Erin | Speilotes, Liz | Thomas, Fridtjof | Thorand, Barbara | Monique Verschuren, W. M. | Anand, Sonia S. | Dominiczak, Anna | Davidson, Karina W. | Hegele, Robert A. | Heid, Iris | Hofker, Marten H. | Huggins, Gordon S. | Illig, Thomas | Johnson, Julie A. | Kirkland, Susan | König, Wolfgang | Langaee, Taimour Y. | Mccaffery, Jeanne | Melander, Olle | Mitchell, Braxton D. | Munroe, Patricia | Murray, Sarah S. | Papanicolaou, George | Redline, Susan | Reilly, Muredach | Samani, Nilesh J. | Schork, Nicholas J. | Van Der Schouw, Yvonne T. | Shimbo, Daichi | Shuldiner, Alan R. | Tobin, Martin D. | Wijmenga, Cisca | Yusuf, Salim | Hakonarson, Hakon | Lange, Leslie A. | Demerath, Ellen W | Fox, Caroline S. | North, Kari E | Reiner, Alex P. | Keating, Brendan | Taylor, Kira C.
Human Molecular Genetics  2013;23(9):2498-2510.
Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBI's Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20–80 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes ∼50 000 cosmopolitan tagged SNPs across ∼2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P < 2.4 × 10−6). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (β ± SE, 0.048 ± 0.008, P = 7.7 × 10−9) as was rs7302703-G in HOXC10 (β = 0.044 ± 0.008, P = 2.9 × 10−7) and rs936108-C in PEMT (β = 0.035 ± 0.007, P = 1.9 × 10−6). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 (β = 0.10 ± 0.02, P = 1.9 × 10−6) and rs1037575-A in ATBDB4 (β = 0.046 ± 0.01, P = 2.2 × 10−6), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue.
doi:10.1093/hmg/ddt626
PMCID: PMC3988452  PMID: 24345515
15.  Congenital sucrase–isomaltase deficiency: identification of a common Inuit founder mutation 
Background:
Congenital sucrase–isomaltase deficiency is a rare hereditary cause of chronic diarrhea in children. People with this condition lack the intestinal brush-border enzyme required for digestion of di- and oligosaccharides, including sucrose and isomaltose, leading to malabsorption. Although the condition is known to be highly prevalent (about 5%–10%) in several Inuit populations, the genetic basis for this has not been described. We sought to identify a common mutation for congenital sucrase–isomaltase deficiency in the Inuit population.
Methods:
We sequenced the sucrase–isomaltase gene, SI, in a single Inuit proband with congenital sucrase–isomaltase deficiency who had severe fermentative diarrhea and failure to thrive. We then genotyped a further 128 anonymized Inuit controls from a variety of locales in the Canadian Arctic to assess for a possible founder effect.
Results:
In the proband, we identified a novel, homozygous frameshift mutation, c.273_274delAG (p.Gly92Leufs*8), predicted to result in complete absence of a functional protein product. This change was very common among the Inuit controls, with an observed allele frequency of 17.2% (95% confidence interval [CI] 12.6%–21.8%). The predicted Hardy–Weinberg prevalence of congenital sucrase–isomaltase deficiency in Inuit people, based on this single founder allele, is 3.0% (95% CI 1.4%–4.5%), which is comparable with previous estimates.
Interpretation:
We found a common mutation, SI c.273_274delAG, to be responsible for the high prevalence of congenital sucrase–isomaltase deficiency among Inuit people. Targeted mutation testing for this allele should afford a simple and minimally invasive means of diagnosing this condition in Inuit patients with chronic diarrhea.
doi:10.1503/cmaj.140657
PMCID: PMC4312148  PMID: 25452324
16.  A Shared Founder Mutation Underlies Restrictive Dermopathy in Old Colony (Dutch-German) Mennonite and Hutterite Patients in North America 
doi:10.1002/ajmg.a.35302
PMCID: PMC4247856  PMID: 22495976
restrictive dermopathy; tight skin contracture syndrome; laminopathy; lethal; Hutterite; Mennonite; ZMPSTE24
17.  Clinical and Pharmacogenetic Predictors of Circulating Atorvastatin and Rosuvastatin Concentration in Routine Clinical Care 
Background
A barrier to statin therapy is myopathy associated with elevated systemic drug exposure. Our objective was to examine the association between clinical and pharmacogenetic variables and statin concentrations in patients.
Methods and Results
In total, 299 patients taking atorvastatin or rosuvastatin were prospectively recruited at an outpatient referral center. The contribution of clinical variables and transporter gene polymorphisms to statin concentration was assessed using multiple linear regression. We observed 45-fold variation in statin concentration among patients taking the same dose. After adjustment for gender, age, body mass index, ethnicity, dose, and time from last dose, SLCO1B1 c.521T>C (p < 0.001) and ABCG2 c.421C>A (p < 0.01) were important to rosuvastatin concentration (adjusted R2 = 0.56 for the final model). Atorvastatin concentration was associated with SLCO1B1 c.388A>G (p < 0.01) and c.521T>C (p < 0.05), and 4β-hydroxycholesterol, a CYP3A activity marker (adjusted R2 = 0.47). A second cohort of 579 patients from primary and specialty care databases were retrospectively genotyped. In this cohort, genotypes associated with statin concentration were not differently distributed among dosing groups, implying providers had not yet optimized each patient's risk-benefit ratio. Nearly 50% of patients in routine practice taking the highest doses were predicted to have statin concentrations greater than the 90th percentile.
Conclusions
Interindividual variability in statin exposure in patients is associated with uptake and efflux transporter polymorphisms. An algorithm incorporating genomic and clinical variables to avoid high atorvastatin and rosuvastatin levels is described; further study will determine if this approach reduces incidence of statin-myopathy.
doi:10.1161/CIRCGENETICS.113.000099
PMCID: PMC3922121  PMID: 23876492
statin therapy; pharmacogenetics; pharmacokinetics; drug transporters
18.  Inheritance of rare functional GCKR variants and their contribution to triglyceride levels in families 
Human Molecular Genetics  2014;23(20):5570-5578.
Significant resources have been invested in sequencing studies to investigate the role of rare variants in complex disease etiology. However, the diagnostic interpretation of individual rare variants remains a major challenge, and may require accurate variant functional classification and the collection of large numbers of variant carriers. Utilizing sequence data from 458 individuals with hypertriglyceridemia and 333 controls with normal plasma triglyceride levels, we investigated these issues using GCKR, encoding glucokinase regulatory protein. Eighteen rare non-synonymous GCKR variants identified in these 791 individuals were comprehensively characterized by a range of biochemical and cell biological assays, including a novel high-throughput-screening-based approach capable of measuring all variant proteins simultaneously. Functionally deleterious variants were collectively associated with hypertriglyceridemia, but a range of in silico prediction algorithms showed little consistency between algorithms and poor agreement with functional data. We extended our study by obtaining sequence data on family members; however, functional variants did not co-segregate with triglyceride levels. Therefore, despite evidence for their collective functional and clinical relevance, our results emphasize the low predictive value of rare GCKR variants in individuals and the complex heritability of lipid traits.
doi:10.1093/hmg/ddu269
PMCID: PMC4168830  PMID: 24879641
19.  LipidSeq: a next-generation clinical resequencing panel for monogenic dyslipidemias[S] 
Journal of Lipid Research  2014;55(4):765-772.
We report the design of a targeted resequencing panel for monogenic dyslipidemias, LipidSeq, for the purpose of replacing Sanger sequencing in the clinical detection of dyslipidemia-causing variants. We also evaluate the performance of the LipidSeq approach versus Sanger sequencing in 84 patients with a range of phenotypes including extreme blood lipid concentrations as well as additional dyslipidemias and related metabolic disorders. The panel performs well, with high concordance (95.2%) in samples with known mutations based on Sanger sequencing and a high detection rate (57.9%) of mutations likely to be causative for disease in samples not previously sequenced. Clinical implementation of LipidSeq has the potential to aid in the molecular diagnosis of patients with monogenic dyslipidemias with a high degree of speed and accuracy and at lower cost than either Sanger sequencing or whole exome sequencing. Furthermore, LipidSeq will help to provide a more focused picture of monogenic and polygenic contributors that underlie dyslipidemia while excluding the discovery of incidental pathogenic clinically actionable variants in nonmetabolism-related genes, such as oncogenes, that would otherwise be identified by a whole exome approach, thus minimizing potential ethical issues.
doi:10.1194/jlr.D045963
PMCID: PMC3966710  PMID: 24503134
next generation sequencing; DNA diagnosis; familial dyslipidemia; Sanger sequencing; mutations; genetic risk score; polygenic dyslipidemia
20.  Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients with severe hypertriglyceridaemia 
Journal of internal medicine  2012;272(2):185-196.
Objective
The severe forms of hypertriglyceridaemia (HTG) are caused by mutations in genes that lead to loss of function of lipoprotein lipase (LPL). In most patients with severe HTG (TG >10 mmol/L) it is a challenge to define the underlying cause. We investigated the molecular basis of severe HTG in patients referred to the Lipid Clinic at the Academic Medical Center Amsterdam.
Methods
The coding regions of LPL, APOC2, APOA5 and two novel genes, lipase maturation factor 1 (LMF1) and GPI-anchored HDL-binding protein 1 (GPIHBP1), were sequenced in 86 patients with type 1 and type 5 HTG and 327 controls.
Results
In 46 patients (54%) rare DNA sequence variants were identified, comprising variants in LPL (n=19), APOC2 (n=1), APOA5 (n=2), GPIHBP1 (n=3) and LMF1 (n=8). In 22 patients (26%) only common variants in LPL (p.Asp36Asn, p.Asn318Ser and p.Ser474Ter) and APOA5 (p.Ser19Trp) could be identified, whereas no mutations were found in 18 patients (21%). In vitro validation revealed that the mutations in LMF1 were not associated with compromised LPL function. Consistent with this, five of the eight LMF1 variants were also found in controls and therefore cannot account for the observed phenotype.
Conclusion
The prevalence of mutations in LPL was 34% and mostly restricted to patients with type 1 HTG. Mutations in GPIHBP1 (n=3), APOC2 (n=1) and APOA5 (n=2) were rare but the associated clinical phenotype was severe. Routine sequencing of candidate genes in severe HTG has improved our understanding of the molecular basis of this phenotype associated with acute pancreatitis, and may help to guide future individualized therapeutic strategies.
doi:10.1111/j.1365-2796.2012.02516.x
PMCID: PMC3940136  PMID: 22239554
triglycerides; lipoprotein lipase; APOC2; APOA5; LMF1; GPIHBP1
21.  Exome sequencing identifies NFS1 deficiency in a novel Fe-S cluster disease, infantile mitochondrial complex II/III deficiency 
Iron-sulfur (Fe-S) clusters are a class of highly conserved and ubiquitous prosthetic groups with unique chemical properties that allow the proteins that contain them, Fe-S proteins, to assist in various key biochemical pathways. Mutations in Fe-S proteins often disrupt Fe-S cluster assembly leading to a spectrum of severe disorders such as Friedreich's ataxia or iron-sulfur cluster assembly enzyme (ISCU) myopathy. Herein, we describe infantile mitochondrial complex II/III deficiency, a novel autosomal recessive mitochondrial disease characterized by lactic acidemia, hypotonia, respiratory chain complex II and III deficiency, multisystem organ failure and abnormal mitochondria. Through autozygosity mapping, exome sequencing, in silico analyses, population studies and functional tests, we identified c.215G>A, p.Arg72Gln in NFS1 as the likely causative mutation. We describe the first disease in man likely caused by deficiency in NFS1, a cysteine desulfurase that is implicated in respiratory chain function and iron maintenance by initiating Fe-S cluster biosynthesis. Our results further demonstrate the importance of sufficient NFS1 expression in human physiology.
doi:10.1002/mgg3.46
PMCID: PMC3907916  PMID: 24498631
Autozygosity mapping; Fe-S proteins; mitochondrial complex deficiency; NFS1; whole-exome sequencing.
22.  A mutation in the serine protease TMPRSS4 in a novel pediatric neurodegenerative disorder 
Background
To elucidate the genetic basis of a novel neurodegenerative disorder in an Old Order Amish pedigree by combining homozygosity mapping with exome sequencing.
Methods and results
We identified four individuals with an autosomal recessive condition affecting the central nervous system (CNS). Neuroimaging studies identified progressive global CNS tissue loss presenting early in life, associated with microcephaly, seizures, and psychomotor retardation; based on this, we named the condition Autosomal Recessive Cerebral Atrophy (ARCA). Using two unbiased genetic approaches, homozygosity mapping and exome sequencing, we narrowed the candidate region to chromosome 11q and identified the c.995C > T (p.Thr332Met) mutation in the TMPRSS4 gene. Sanger sequencing of additional relatives confirmed that the c.995C > T genotype segregates with the ARCA phenotype. Residue Thr332 is conserved across species and among various ethnic groups. The mutation is predicted to be deleterious, most likely due to a protein structure alteration as demonstrated with protein modelling.
Conclusions
This novel disease is the first to demonstrate a neurological role for a transmembrane serine proteases family member. This study demonstrates a proof-of-concept whereby combining exome sequencing with homozygosity mapping can find the genetic cause of a rare disease and acquire better understanding of a poorly described protein in human development.
doi:10.1186/1750-1172-8-126
PMCID: PMC3765793  PMID: 23957953
Autosomal recessive cerebral atrophy (ARCA) syndrome; Neurodegeneration; Trypsin-like serine protease; Homozygosity; Microarray; Exome sequencing; Autosomal recessive inheritance; Old Order Amish
23.  Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease  
European Heart Journal  2013;34(45):3478-3490.
Aims
The first aim was to critically evaluate the extent to which familial hypercholesterolaemia (FH) is underdiagnosed and undertreated. The second aim was to provide guidance for screening and treatment of FH, in order to prevent coronary heart disease (CHD).
Methods and results
Of the theoretical estimated prevalence of 1/500 for heterozygous FH, <1% are diagnosed in most countries. Recently, direct screening in a Northern European general population diagnosed approximately 1/200 with heterozygous FH. All reported studies document failure to achieve recommended LDL cholesterol targets in a large proportion of individuals with FH, and up to 13-fold increased risk of CHD. Based on prevalences between 1/500 and 1/200, between 14 and 34 million individuals worldwide have FH. We recommend that children, adults, and families should be screened for FH if a person or family member presents with FH, a plasma cholesterol level in an adult ≥8 mmol/L(≥310 mg/dL) or a child ≥6 mmol/L(≥230 mg/dL), premature CHD, tendon xanthomas, or sudden premature cardiac death. In FH, low-density lipoprotein cholesterol targets are <3.5 mmol/L(<135 mg/dL) for children, <2.5 mmol/L(<100 mg/dL) for adults, and <1.8 mmol/L(<70 mg/dL) for adults with known CHD or diabetes. In addition to lifestyle and dietary counselling, treatment priorities are (i) in children, statins, ezetimibe, and bile acid binding resins, and (ii) in adults, maximal potent statin dose, ezetimibe, and bile acid binding resins. Lipoprotein apheresis can be offered in homozygotes and in treatment-resistant heterozygotes with CHD.
Conclusion
Owing to severe underdiagnosis and undertreatment of FH, there is an urgent worldwide need for diagnostic screening together with early and aggressive treatment of this extremely high-risk condition.
doi:10.1093/eurheartj/eht273
PMCID: PMC3844152  PMID: 23956253
Cholesterol; Low-density lipoprotein; Atherosclerosis; Coronary heart disease; Cardiovascular disease

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