Publications by authors named "Gudmundur I Eyjolfsson"

31 Publications

Lifelong Reduction in LDL (Low-Density Lipoprotein) Cholesterol due to a Gain-of-Function Mutation in .

Circ Genom Precis Med 2021 02 14;14(1):e003029. Epub 2020 Dec 14.

deCODE genetics/Amgen, Inc (E.B., K.G., G.H.H., A.S., G.A.A., H.J., G.S., S.G., A.H., G. Thorleifsson, J.S., I.J., O.T.M., G.M., H.S., D.F.G., G. Thorgeirsson, H.H., B.V.H., P.M., G.L.N., P.S., U.T., K.S.), University of Iceland.

Background: Loss-of-function mutations in the LDL (low-density lipoprotein) receptor gene () cause elevated levels of LDL cholesterol and premature cardiovascular disease. To date, a gain-of-function mutation in with a large effect on LDL cholesterol levels has not been described. Here, we searched for sequence variants in that have a large effect on LDL cholesterol levels.

Methods: We analyzed whole-genome sequencing data from 43 202 Icelanders. Single-nucleotide polymorphisms and structural variants including deletions, insertions, and duplications were genotyped using whole-genome sequencing-based data. LDL cholesterol associations were carried out in a sample of >100 000 Icelanders with genetic information (imputed or whole-genome sequencing). Molecular analyses were performed using RNA sequencing and protein expression assays in Epstein-Barr virus-transformed lymphocytes.

Results: We discovered a 2.5-kb deletion (del2.5) overlapping the 3' untranslated region of in 7 heterozygous carriers from a single family. Mean level of LDL cholesterol was 74% lower in del2.5 carriers than in 101 851 noncarriers, a difference of 2.48 mmol/L (96 mg/dL; =8.4×10). Del2.5 results in production of an alternative mRNA isoform with a truncated 3' untranslated region. The truncation leads to a loss of target sites for microRNAs known to repress translation of . In Epstein-Barr virus-transformed lymphocytes derived from del2.5 carriers, expression of alternative mRNA isoform was 1.84-fold higher than the wild-type isoform (=0.0013), and there was 1.79-fold higher surface expression of the LDL receptor than in noncarriers (=0.0086). We did not find a highly penetrant detrimental impact of lifelong very low levels of LDL cholesterol due to del2.5 on health of the carriers.

Conclusions: Del2.5 is the first reported gain-of-function mutation in causing a large reduction in LDL cholesterol. These data point to a role for alternative polyadenylation of mRNA as a potent regulator of LDL receptor expression in humans.
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http://dx.doi.org/10.1161/CIRCGEN.120.003029DOI Listing
February 2021

Eighty-eight variants highlight the role of T cell regulation and airway remodeling in asthma pathogenesis.

Nat Commun 2020 01 20;11(1):393. Epub 2020 Jan 20.

deCODE genetics/Amgen, Inc., Reykjavik, Iceland.

Asthma is one of the most common chronic diseases affecting both children and adults. We report a genome-wide association meta-analysis of 69,189 cases and 702,199 controls from Iceland and UK biobank. We find 88 asthma risk variants at 56 loci, 19 previously unreported, and evaluate their effect on other asthma and allergic phenotypes. Of special interest are two low frequency variants associated with protection against asthma; a missense variant in TNFRSF8 and 3' UTR variant in TGFBR1. Functional studies show that the TNFRSF8 variant reduces TNFRSF8 expression both on cell surface and in soluble form, acting as loss of function. eQTL analysis suggests that the TGFBR1 variant acts through gain of function and together with an intronic variant in a downstream gene, SMAD3, points to defective TGFβR1 signaling as one of the biological perturbations increasing asthma risk. Our results increase the number of asthma variants and implicate genes with known role in T cell regulation, inflammation and airway remodeling in asthma pathogenesis.
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http://dx.doi.org/10.1038/s41467-019-14144-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971247PMC
January 2020

Lipoprotein(a) Concentration and Risks of Cardiovascular Disease and Diabetes.

J Am Coll Cardiol 2019 12 9;74(24):2982-2994. Epub 2019 Dec 9.

deCODE genetics/Amgen, Reykjavik, Iceland; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.

Background: Lipoprotein(a) [Lp(a)] is a causal risk factor for cardiovascular diseases that has no established therapy. The attribute of Lp(a) that affects cardiovascular risk is not established. Low levels of Lp(a) have been associated with type 2 diabetes (T2D).

Objectives: This study investigated whether cardiovascular risk is conferred by Lp(a) molar concentration or apolipoprotein(a) [apo(a)] size, and whether the relationship between Lp(a) and T2D risk is causal.

Methods: This was a case-control study of 143,087 Icelanders with genetic information, including 17,715 with coronary artery disease (CAD) and 8,734 with T2D. This study used measured and genetically imputed Lp(a) molar concentration, kringle IV type 2 (KIV-2) repeats (which determine apo(a) size), and a splice variant in LPA associated with small apo(a) but low Lp(a) molar concentration to disentangle the relationship between Lp(a) and cardiovascular risk. Loss-of-function homozygotes and other subjects genetically predicted to have low Lp(a) levels were evaluated to assess the relationship between Lp(a) and T2D.

Results: Lp(a) molar concentration was associated dose-dependently with CAD risk, peripheral artery disease, aortic valve stenosis, heart failure, and lifespan. Lp(a) molar concentration fully explained the Lp(a) association with CAD, and there was no residual association with apo(a) size. Homozygous carriers of loss-of-function mutations had little or no Lp(a) and increased the risk of T2D.

Conclusions: Molar concentration is the attribute of Lp(a) that affects risk of cardiovascular diseases. Low Lp(a) concentration (bottom 10%) increases T2D risk. Pharmacologic reduction of Lp(a) concentration in the 20% of individuals with the greatest concentration down to the population median is predicted to decrease CAD risk without increasing T2D risk.
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http://dx.doi.org/10.1016/j.jacc.2019.10.019DOI Listing
December 2019

Common and Rare Sequence Variants Influencing Tumor Biomarkers in Blood.

Cancer Epidemiol Biomarkers Prev 2020 01 30;29(1):225-235. Epub 2019 Oct 30.

deCODE genetics/AMGEN, Reykjavik, Iceland.

Background: Alpha-fetoprotein (AFP), cancer antigens 15.3, 19.9, and 125, carcinoembryonic antigen, and alkaline phosphatase (ALP) are widely measured in attempts to detect cancer and to monitor treatment response. However, due to lack of sensitivity and specificity, their utility is debated. The serum levels of these markers are affected by a number of nonmalignant factors, including genotype. Thus, it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects.

Methods: We performed genome-wide association studies of serum levels of AFP ( = 22,686), carcinoembryonic antigen ( = 22,309), cancer antigens 15.3 ( = 7,107), 19.9 ( = 9,945), and 125 ( = 9,824), and ALP ( = 162,774). We also examined the correlations between levels of these biomarkers and the presence of cancer, using data from a nationwide cancer registry.

Results: We report a total of 84 associations of 79 sequence variants with levels of the six biomarkers, explaining between 2.3% and 42.3% of the phenotypic variance. Among the 79 variants, 22 are cis (in- or near the gene encoding the biomarker), 18 have minor allele frequency less than 1%, 31 are coding variants, and 7 are associated with gene expression in whole blood. We also find multiple conditions associated with higher biomarker levels.

Conclusions: Our results provide insights into the genetic contribution to diversity in concentration of tumor biomarkers in blood.

Impact: Genetic correction of biomarker values could improve prediction algorithms and decision-making based on these biomarkers.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-1060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954334PMC
January 2020

A loss-of-function variant in ALOX15 protects against nasal polyps and chronic rhinosinusitis.

Nat Genet 2019 02 14;51(2):267-276. Epub 2019 Jan 14.

deCODE genetics/Amgen Inc., Reykjavik, Iceland.

Nasal polyps (NP) are lesions on the nasal and paranasal sinus mucosa and are a risk factor for chronic rhinosinusitis (CRS). We performed genome-wide association studies on NP and CRS in Iceland and the UK (using UK Biobank data) with 4,366 NP cases, 5,608 CRS cases, and >700,000 controls. We found 10 markers associated with NP and 2 with CRS. We also tested 210 markers reported to associate with eosinophil count, yielding 17 additional NP associations. Of the 27 NP signals, 7 associate with CRS and 13 with asthma. Most notably, a missense variant in ALOX15 that causes a p.Thr560Met alteration in arachidonate 15-lipoxygenase (15-LO) confers large genome-wide significant protection against NP (P = 8.0 × 10, odds ratio = 0.32; 95% confidence interval = 0.26, 0.39) and CRS (P = 1.1 × 10, odds ratio = 0.64; 95% confidence interval = 0.55, 0.75). p.Thr560Met, carried by around 1 in 20 Europeans, was previously shown to cause near total loss of 15-LO enzymatic activity. Our findings identify 15-LO as a potential target for therapeutic intervention in NP and CRS.
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http://dx.doi.org/10.1038/s41588-018-0314-6DOI Listing
February 2019

Genome-wide association meta-analysis yields 20 loci associated with gallstone disease.

Nat Commun 2018 11 30;9(1):5101. Epub 2018 Nov 30.

deCODE Genetics/Amgen, Inc., Reykjavik, 101, Iceland.

Gallstones are responsible for one of the most common diseases in the Western world and are commonly treated with cholecystectomy. We perform a meta-analysis of two genome-wide association studies of gallstone disease in Iceland and the UK, totaling 27,174 cases and 736,838 controls, uncovering 21 novel gallstone-associated variants at 20 loci. Two distinct low frequency missense variants in SLC10A2, encoding the apical sodium-dependent bile acid transporter (ASBT), associate with an increased risk of gallstone disease (Pro290Ser: OR = 1.36 [1.25-1.49], P = 2.1 × 10, MAF = 1%; Val98Ile: OR = 1.15 [1.10-1.20], P = 1.8 × 10, MAF = 4%). We demonstrate that lower bile acid transport by ASBT is accompanied by greater risk of gallstone disease and highlight the role of the intestinal compartment of the enterohepatic circulation of bile acids in gallstone disease susceptibility. Additionally, two low frequency missense variants in SERPINA1 and HNF4A and 17 common variants represent novel associations with gallstone disease.
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http://dx.doi.org/10.1038/s41467-018-07460-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269469PMC
November 2018

Sequence variants associating with urinary biomarkers.

Hum Mol Genet 2019 04;28(7):1199-1211

Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

Urine dipstick tests are widely used in routine medical care to diagnose kidney and urinary tract and metabolic diseases. Several environmental factors are known to affect the test results, whereas the effects of genetic diversity are largely unknown. We tested 32.5 million sequence variants for association with urinary biomarkers in a set of 150 274 Icelanders with urine dipstick measurements. We detected 20 association signals, of which 14 are novel, associating with at least one of five clinical entities defined by the urine dipstick: glucosuria, ketonuria, proteinuria, hematuria and urine pH. These include three independent glucosuria variants at SLC5A2, the gene encoding the sodium-dependent glucose transporter (SGLT2), a protein targeted pharmacologically to increase urinary glucose excretion in the treatment of diabetes. Two variants associating with proteinuria are in LRP2 and CUBN, encoding the co-transporters megalin and cubilin, respectively, that mediate proximal tubule protein uptake. One of the hematuria-associated variants is a rare, previously unreported 2.5 kb exonic deletion in COL4A3. Of the four signals associated with urine pH, we note that the pH-increasing alleles of two variants (POU2AF1, WDR72) associate significantly with increased risk of kidney stones. Our results reveal that genetic factors affect variability in urinary biomarkers, in both a disease dependent and independent context.
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http://dx.doi.org/10.1093/hmg/ddy409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423415PMC
April 2019

Genome-wide associations for benign prostatic hyperplasia reveal a genetic correlation with serum levels of PSA.

Nat Commun 2018 11 8;9(1):4568. Epub 2018 Nov 8.

deCODE genetics/AMGEN, 101, Reykjavik, Iceland.

Benign prostatic hyperplasia and associated lower urinary tract symptoms (BPH/LUTS) are common conditions affecting the majority of elderly males. Here we report the results of a genome-wide association study of symptomatic BPH/LUTS in 20,621 patients and 280,541 controls of European ancestry, from Iceland and the UK. We discovered 23 genome-wide significant variants, located at 14 loci. There is little or no overlap between the BPH/LUTS variants and published prostate cancer risk variants. However, 15 of the variants reported here also associate with serum levels of prostate specific antigen (PSA) (at a Bonferroni corrected P < 0.0022). Furthermore, there is a strong genetic correlation, r = 0.77 (P = 2.6 × 10), between PSA and BPH/LUTS, and one standard deviation increase in a polygenic risk score (PRS) for BPH/LUTS increases PSA levels by 12.9% (P = 1.6×10). These results shed a light on the genetic background of BPH/LUTS and its substantial influence on PSA levels.
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http://dx.doi.org/10.1038/s41467-018-06920-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224563PMC
November 2018

A rare missense variant in associates with lower cholesterol levels.

Commun Biol 2018 8;1:14. Epub 2018 Feb 8.

deCODE Genetics/Amgen, Inc., Reykjavik, 101, Iceland.

Searching for novel sequence variants associated with cholesterol levels is of particular interest due to the causative role of non-HDL cholesterol levels in cardiovascular disease. Through whole-genome sequencing of 15,220 Icelanders and imputation of the variants identified, we discovered a rare missense variant in (R436H) associating with lower levels of total cholesterol (effect = -0.47 standard deviations or -0.55 mmol L,  = 4.21 × 10,  = 150,211). Importantly, R436H also associates with lower levels of non-HDL cholesterol and, consistent with this, protects against coronary artery disease. encodes FXR that regulates bile acid homeostasis, however, we do not detect a significant association between R436H and biological markers of liver function. Transcriptional profiling of hepatocytes carrying R436H shows that it is not a loss-of-function variant. Rather, we observe changes in gene expression compatible with effects on lipids. These findings highlight the role of FXR in regulation of cholesterol levels in humans.
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http://dx.doi.org/10.1038/s42003-018-0015-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123719PMC
February 2018

Rare SCARB1 mutations associate with high-density lipoprotein cholesterol but not with coronary artery disease.

Eur Heart J 2018 06;39(23):2172-2178

deCODE Genetics/Amgen, Inc., Sturlugata 8, 101 Reykjavik, Iceland.

Aims: Scavenger receptor Class B Type 1 (SR-BI) is a major receptor for high-density lipoprotein (HDL) that promotes hepatic uptake of cholesterol from HDL. A rare mutation p.P376L, in the gene encoding SR-BI, SCARB1, was recently reported to associate with elevated HDL cholesterol (HDL-C) and increased risk of coronary artery disease (CAD), suggesting that increased HDL-C caused by SR-BI impairment might be an independent marker of cardiovascular risk. We tested the hypothesis that alleles in or close to SCARB1 that associate with elevated levels of HDL-C also associate with increased risk of CAD in the relatively homogeneous population of Iceland.

Methods And Results: Using a large resource of whole-genome sequenced Icelanders, we identified thirteen SCARB1 coding mutations that we examined for association with HDL-C (n = 136 672). Three rare SCARB1 mutations, encoding p.G319V, p.V111M, and p.V32M (combined allelic frequency = 0.2%) associate with elevated levels of HDL-C (p.G319V: β = 11.1 mg/dL, P = 8.0 × 10-7; p.V111M: β = 8.3 mg/dL, P = 1.1 × 10-6; p.V32M: β = 10.2 mg/dL, P = 8.1 × 10-4). These mutations do not associate with CAD (36 886 cases/306 268 controls) (odds ratio = 0.90, 95% confidence interval 0.67-1.22, P = 0.49), despite effects on HDL-C comparable to that reported for p.P376L, both in terms of direction and magnitude. Furthermore, HDL-C raising alleles of three common SCARB1 non-coding variants, including one previously unreported (rs61941676-C: β = 1.25 mg/dL, P = 1.7 × 10-18), and of one low frequency coding variant (p.V135I) that independently associate with higher HDL-C, do not confer increased risk of CAD.

Conclusion: Elevated HDL-C due to genetically compromised SR-BI function is not a marker of CAD risk.
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http://dx.doi.org/10.1093/eurheartj/ehy169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6001888PMC
June 2018

Identification of sequence variants influencing immunoglobulin levels.

Nat Genet 2017 Aug 19;49(8):1182-1191. Epub 2017 Jun 19.

Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands.

Immunoglobulins are the effector molecules of the adaptive humoral immune system. In a genome-wide association study of 19,219 individuals, we found 38 new variants and replicated 5 known variants associating with IgA, IgG or IgM levels or with composite immunoglobulin traits, accounted for by 32 loci. Variants at these loci also affect the risk of autoimmune diseases and blood malignancies and influence blood cell development. Notable associations include a rare variant at RUNX3 decreasing IgA levels by shifting isoform proportions (rs188468174[C>T]: P = 8.3 × 10, β = -0.90 s.d.), a rare in-frame deletion in FCGR2B abolishing IgG binding to the encoded receptor (p.Asn106del: P = 4.2 × 10, β = 1.03 s.d.), four IGH locus variants influencing class switching, and ten new associations with the HLA region. Our results provide new insight into the regulation of humoral immunity.
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http://dx.doi.org/10.1038/ng.3897DOI Listing
August 2017

A rare splice donor mutation in the haptoglobin gene associates with blood lipid levels and coronary artery disease.

Hum Mol Genet 2017 06;26(12):2364-2376

deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.

Common sequence variants at the haptoglobin gene (HP) have been associated with blood lipid levels. Through whole-genome sequencing of 8,453 Icelanders, we discovered a splice donor founder mutation in HP (NM_001126102.1:c.190 + 1G > C, minor allele frequency = 0.56%). This mutation occurs on the HP1 allele of the common copy number variant in HP and leads to a loss of function of HP1. It associates with lower levels of haptoglobin (P = 2.1 × 10-54), higher levels of non-high density lipoprotein cholesterol (β = 0.26 mmol/l, P = 2.6 × 10-9) and greater risk of coronary artery disease (odds ratio = 1.30, 95% confidence interval: 1.10-1.54, P = 0.0024). Through haplotype analysis and with RNA sequencing, we provide evidence of a causal relationship between one of the two haptoglobin isoforms, namely Hp1, and lower levels of non-HDL cholesterol. Furthermore, we show that the HP1 allele associates with various other quantitative biological traits.
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http://dx.doi.org/10.1093/hmg/ddx123DOI Listing
June 2017

A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma.

PLoS Genet 2017 03 8;13(3):e1006659. Epub 2017 Mar 8.

Department of Respiratory Medicine, Bispebjerg University Hospital, Copenhagen University, Copenhagen, Denmark.

IL-33 is a tissue-derived cytokine that induces and amplifies eosinophilic inflammation and has emerged as a promising new drug target for asthma and allergic disease. Common variants at IL33 and IL1RL1, encoding the IL-33 receptor ST2, associate with eosinophil counts and asthma. Through whole-genome sequencing and imputation into the Icelandic population, we found a rare variant in IL33 (NM_001199640:exon7:c.487-1G>C (rs146597587-C), allele frequency = 0.65%) that disrupts a canonical splice acceptor site before the last coding exon. It is also found at low frequency in European populations. rs146597587-C associates with lower eosinophil counts (β = -0.21 SD, P = 2.5×10-16, N = 103,104), and reduced risk of asthma in Europeans (OR = 0.47; 95%CI: 0.32, 0.70, P = 1.8×10-4, N cases = 6,465, N controls = 302,977). Heterozygotes have about 40% lower total IL33 mRNA expression than non-carriers and allele-specific analysis based on RNA sequencing and phased genotypes shows that only 20% of the total expression is from the mutated chromosome. In half of those transcripts the mutation causes retention of the last intron, predicted to result in a premature stop codon that leads to truncation of 66 amino acids. The truncated IL-33 has normal intracellular localization but neither binds IL-33R/ST2 nor activates ST2-expressing cells. Together these data demonstrate that rs146597587-C is a loss of function mutation and support the hypothesis that IL-33 haploinsufficiency protects against asthma.
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http://dx.doi.org/10.1371/journal.pgen.1006659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5362243PMC
March 2017

A genome-wide association study yields five novel thyroid cancer risk loci.

Nat Commun 2017 02 14;8:14517. Epub 2017 Feb 14.

Division of Endocrinology, Department of Internal Medicine, Radboud University Medical Centre, Radboud Institute for Health Sciences, 6500HB Nijmegen, The Netherlands.

The great majority of thyroid cancers are of the non-medullary type. Here we report findings from a genome-wide association study of non-medullary thyroid cancer, including in total 3,001 patients and 287,550 controls from five study groups of European descent. Our results yield five novel loci (all with P<3 × 10): 1q42.2 (rs12129938 in PCNXL2), 3q26.2 (rs6793295 a missense mutation in LRCC34 near TERC), 5q22.1 (rs73227498 between NREP and EPB41L4A), 10q24.33 (rs7902587 near OBFC1), and two independently associated variants at 15q22.33 (rs2289261 and rs56062135; both in SMAD3). We also confirm recently published association results from a Chinese study of a variant on 5p15.33 (rs2736100 near the TERT gene) and present a stronger association result for a moderately correlated variant (rs10069690; OR=1.20, P=3.2 × 10) based on our study of individuals of European ancestry. In combination, these results raise several opportunities for future studies of the pathogenesis of thyroid cancer.
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http://dx.doi.org/10.1038/ncomms14517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5316879PMC
February 2017

Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease.

N Engl J Med 2016 Jun 18;374(22):2131-41. Epub 2016 May 18.

From deCODE Genetics-Amgen (P.N., A.S., G. Thorleifsson, H. Helgason, A.B.A., G.L.N., A.H., A.M., A.J., S.G., I.J., V.S., T.R., G.M., H. Holm, D.G., P.S., U.T., K.S.), Faculty of Medicine (A.H., I.J., G. Thorgeirsson, U.T., K.S.) and School of Engineering and Natural Sciences (H. Helgason, D.G.), University of Iceland, the Laboratory in Mjodd (G.I.E.), and the Department of Clinical Biochemistry (I.O.) and Division of Cardiology, Department of Internal Medicine (G. Thorgeirsson, H. Holm), Landspitali, National University Hospital of Iceland, Reykjavik, and the Department of Clinical Biochemistry, Akureyri Hospital, Akureyri (O.S.) - all in Iceland; Radboud Institute for Molecular Life Sciences, Department of Laboratory Medicine (D.W.S.), Radboud Institute for Health Sciences (T.E.G., L.A.K.), and the Department of Health Evidence (L.A.K.), Radboud University Medical Center Nijmegen, Nijmegen, the Netherlands; Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics (N.G., H.V., T.H., N.T.K., O.P.), and Institute of Public Health, Faculty of Health and Medical Science (T.J., A.L.), University of Copenhagen, and Research Center for Prevention and Health, Capital Region of Denmark (T.J., A.L.), Copenhagen, Faculty of Medicine, University of Aalborg, Aalborg (T.J.), Faculty of Health Sciences, University of Southern Denmark, Odense (T.H.), Department of Public Health, Section of General Practice, University of Aarhus, Aarhus (T.L.), Department of Clinical Experimental Research, Rigshospitalet, Glostrup (A.L.), Department of Clinical Biochemistry, University Hospital of Copenhagen at Hvidovre, Hvidovre (M.F.), Department of Cardiology, Gentofte University Hospital, Hellerup (U.A., P.R.H., A.M.G.), and Department of Cardiology, Roskilde Hospital, Roskilde (A.M.G.) - all in Denmark; Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany (N.F.); Department of Cardiovascular Sciences, Uni

Background: Several sequence variants are known to have effects on serum levels of non-high-density lipoprotein (HDL) cholesterol that alter the risk of coronary artery disease.

Methods: We sequenced the genomes of 2636 Icelanders and found variants that we then imputed into the genomes of approximately 398,000 Icelanders. We tested for association between these imputed variants and non-HDL cholesterol levels in 119,146 samples. We then performed replication testing in two populations of European descent. We assessed the effects of an implicated loss-of-function variant on the risk of coronary artery disease in 42,524 case patients and 249,414 controls from five European ancestry populations. An augmented set of genomes was screened for additional loss-of-function variants in a target gene. We evaluated the effect of an implicated variant on protein stability.

Results: We found a rare noncoding 12-base-pair (bp) deletion (del12) in intron 4 of ASGR1, which encodes a subunit of the asialoglycoprotein receptor, a lectin that plays a role in the homeostasis of circulating glycoproteins. The del12 mutation activates a cryptic splice site, leading to a frameshift mutation and a premature stop codon that renders a truncated protein prone to degradation. Heterozygous carriers of the mutation (1 in 120 persons in our study population) had a lower level of non-HDL cholesterol than noncarriers, a difference of 15.3 mg per deciliter (0.40 mmol per liter) (P=1.0×10(-16)), and a lower risk of coronary artery disease (by 34%; 95% confidence interval, 21 to 45; P=4.0×10(-6)). In a larger set of sequenced samples from Icelanders, we found another loss-of-function ASGR1 variant (p.W158X, carried by 1 in 1850 persons) that was also associated with lower levels of non-HDL cholesterol (P=1.8×10(-3)).

Conclusions: ASGR1 haploinsufficiency was associated with reduced levels of non-HDL cholesterol and a reduced risk of coronary artery disease. (Funded by the National Institutes of Health and others.).
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http://dx.doi.org/10.1056/NEJMoa1508419DOI Listing
June 2016

Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease.

Nat Genet 2016 06 2;48(6):634-9. Epub 2016 May 2.

deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.

Sequence variants affecting blood lipids and coronary artery disease (CAD) may enhance understanding of the atherogenicity of lipid fractions. Using a large resource of whole-genome sequence data, we examined rare and low-frequency variants for association with non-HDL cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides in up to 119,146 Icelanders. We discovered 13 variants with large effects (within ANGPTL3, APOB, ABCA1, NR1H3, APOA1, LIPC, CETP, LDLR, and APOC1) and replicated 14 variants. Five variants within PCSK9, APOA1, ANGPTL4, and LDLR associate with CAD (33,090 cases and 236,254 controls). We used genetic risk scores for the lipid fractions to examine their causal relationship with CAD. The non-HDL cholesterol genetic risk score associates most strongly with CAD (P = 2.7 × 10(-28)), and no other genetic risk score associates with CAD after accounting for non-HDL cholesterol. The genetic risk score for non-HDL cholesterol confers CAD risk beyond that of LDL cholesterol (P = 5.5 × 10(-8)), suggesting that targeting atherogenic remnant cholesterol may reduce cardiovascular risk.
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http://dx.doi.org/10.1038/ng.3561DOI Listing
June 2016

Common and rare variants associating with serum levels of creatine kinase and lactate dehydrogenase.

Nat Commun 2016 Feb 3;7:10572. Epub 2016 Feb 3.

deCODE genetics/Amgen, Inc., 101 Reykjavik, Iceland.

Creatine kinase (CK) and lactate dehydrogenase (LDH) are widely used markers of tissue damage. To search for sequence variants influencing serum levels of CK and LDH, 28.3 million sequence variants identified through whole-genome sequencing of 2,636 Icelanders were imputed into 63,159 and 98,585 people with CK and LDH measurements, respectively. Here we describe 13 variants associating with serum CK and 16 with LDH levels, including four that associate with both. Among those, 15 are non-synonymous variants and 12 have a minor allele frequency below 5%. We report sequence variants in genes encoding the enzymes being measured (CKM and LDHA), as well as in genes linked to muscular (ANO5) and immune/inflammatory function (CD163/CD163L1, CSF1, CFH, HLA-DQB1, LILRB5, NINJ1 and STAB1). A number of the genes are linked to the mononuclear/phagocyte system and clearance of enzymes from the serum. This highlights the variety in the sources of normal diversity in serum levels of enzymes.
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http://dx.doi.org/10.1038/ncomms10572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742860PMC
February 2016

Common and rare variants associated with kidney stones and biochemical traits.

Nat Commun 2015 Aug 14;6:7975. Epub 2015 Aug 14.

1] deCODE genetics/Amgen, Inc., Reykjavik 101, Iceland [2] Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland.

Kidney stone disease is a complex disorder with a strong genetic component. We conducted a genome-wide association study of 28.3 million sequence variants detected through whole-genome sequencing of 2,636 Icelanders that were imputed into 5,419 kidney stone cases, including 2,172 cases with a history of recurrent kidney stones, and 279,870 controls. We identify sequence variants associating with kidney stones at ALPL (rs1256328[T], odds ratio (OR)=1.21, P=5.8 × 10(-10)) and a suggestive association at CASR (rs7627468[A], OR=1.16, P=2.0 × 10(-8)). Focusing our analysis on coding sequence variants in 63 genes with preferential kidney expression we identify two rare missense variants SLC34A1 p.Tyr489Cys (OR=2.38, P=2.8 × 10(-5)) and TRPV5 p.Leu530Arg (OR=3.62, P=4.1 × 10(-5)) associating with recurrent kidney stones. We also observe associations of the identified kidney stone variants with biochemical traits in a large population set, indicating potential biological mechanism.
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http://dx.doi.org/10.1038/ncomms8975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4557269PMC
August 2015

Large-scale whole-genome sequencing of the Icelandic population.

Nat Genet 2015 May 25;47(5):435-44. Epub 2015 Mar 25.

Department of Internal Medicine, Division of Gastroenterology and Hepatology, Landspitali University Hospital, Reykjavik, Iceland.

Here we describe the insights gained from sequencing the whole genomes of 2,636 Icelanders to a median depth of 20×. We found 20 million SNPs and 1.5 million insertions-deletions (indels). We describe the density and frequency spectra of sequence variants in relation to their functional annotation, gene position, pathway and conservation score. We demonstrate an excess of homozygosity and rare protein-coding variants in Iceland. We imputed these variants into 104,220 individuals down to a minor allele frequency of 0.1% and found a recessive frameshift mutation in MYL4 that causes early-onset atrial fibrillation, several mutations in ABCB4 that increase risk of liver diseases and an intronic variant in GNAS associating with increased thyroid-stimulating hormone levels when maternally inherited. These data provide a study design that can be used to determine how variation in the sequence of the human genome gives rise to human diversity.
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http://dx.doi.org/10.1038/ng.3247DOI Listing
May 2015

Genetic architecture of vitamin B12 and folate levels uncovered applying deeply sequenced large datasets.

PLoS Genet 2013 Jun 6;9(6):e1003530. Epub 2013 Jun 6.

The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Genome-wide association studies have mainly relied on common HapMap sequence variations. Recently, sequencing approaches have allowed analysis of low frequency and rare variants in conjunction with common variants, thereby improving the search for functional variants and thus the understanding of the underlying biology of human traits and diseases. Here, we used a large Icelandic whole genome sequence dataset combined with Danish exome sequence data to gain insight into the genetic architecture of serum levels of vitamin B(12) (B12) and folate. Up to 22.9 million sequence variants were analyzed in combined samples of 45,576 and 37,341 individuals with serum B(12) and folate measurements, respectively. We found six novel loci associating with serum B(12) (CD320, TCN2, ABCD4, MMAA, MMACHC) or folate levels (FOLR3) and confirmed seven loci for these traits (TCN1, FUT6, FUT2, CUBN, CLYBL, MUT, MTHFR). Conditional analyses established that four loci contain additional independent signals. Interestingly, 13 of the 18 identified variants were coding and 11 of the 13 target genes have known functions related to B(12) and folate pathways. Contrary to epidemiological studies we did not find consistent association of the variants with cardiovascular diseases, cancers or Alzheimer's disease although some variants demonstrated pleiotropic effects. Although to some degree impeded by low statistical power for some of these conditions, these data suggest that sequence variants that contribute to the population diversity in serum B(12) or folate levels do not modify the risk of developing these conditions. Yet, the study demonstrates the value of combining whole genome and exome sequencing approaches to ascertain the genetic and molecular architectures underlying quantitative trait associations.
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http://dx.doi.org/10.1371/journal.pgen.1003530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674994PMC
June 2013

Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits.

Nature 2013 May 5;497(7450):517-20. Epub 2013 May 5.

deCODE Genetics/Amgen, 101 Reykjavik, Iceland.

Low bone mineral density (BMD) is used as a parameter of osteoporosis. Genome-wide association studies of BMD have hitherto focused on BMD as a quantitative trait, yielding common variants of small effects that contribute to the population diversity in BMD. Here we use BMD as a dichotomous trait, searching for variants that may have a direct effect on the risk of pathologically low BMD rather than on the regulation of BMD in the healthy population. Through whole-genome sequencing of Icelandic individuals, we found a rare nonsense mutation within the leucine-rich-repeat-containing G-protein-coupled receptor 4 (LGR4) gene (c.376C>T) that is strongly associated with low BMD, and with osteoporotic fractures. This mutation leads to termination of LGR4 at position 126 and fully disrupts its function. The c.376C>T mutation is also associated with electrolyte imbalance, late onset of menarche and reduced testosterone levels, as well as an increased risk of squamous cell carcinoma of the skin and biliary tract cancer. Interestingly, the phenotype of carriers of the c.376C>T mutation overlaps that of Lgr4 mutant mice.
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http://dx.doi.org/10.1038/nature12124DOI Listing
May 2013

Discovery of common variants associated with low TSH levels and thyroid cancer risk.

Nat Genet 2012 Jan 22;44(3):319-22. Epub 2012 Jan 22.

deCODE Genetics, Reykjavik, Iceland.

To search for sequence variants conferring risk of nonmedullary thyroid cancer, we focused our analysis on 22 SNPs with a P < 5 × 10(-8) in a genome-wide association study on levels of thyroid stimulating hormone (TSH) in 27,758 Icelanders. Of those, rs965513 has previously been shown to associate with thyroid cancer. The remaining 21 SNPs were genotyped in 561 Icelandic individuals with thyroid cancer (cases) and up to 40,013 controls. Variants suggestively associated with thyroid cancer (P < 0.05) were genotyped in an additional 595 non-Icelandic cases and 2,604 controls. After combining the results, three variants were shown to associate with thyroid cancer: rs966423 on 2q35 (OR = 1.34; P(combined) = 1.3 × 10(-9)), rs2439302 on 8p12 (OR = 1.36; P(combined) = 2.0 × 10(-9)) and rs116909374 on 14q13.3 (OR = 2.09; P(combined) = 4.6 × 10(-11)), a region previously reported to contain an uncorrelated variant conferring risk of thyroid cancer. A strong association (P = 9.1 × 10(-91)) was observed between rs2439302 on 8p12 and expression of NRG1, which encodes the signaling protein neuregulin 1, in blood.
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http://dx.doi.org/10.1038/ng.1046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3655412PMC
January 2012

Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma.

Nat Genet 2011 Oct 16;43(11):1131-8. Epub 2011 Oct 16.

Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London, UK.

Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10(-8) to P = 10(-190)). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function.
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http://dx.doi.org/10.1038/ng.970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482372PMC
October 2011

Identification of low-frequency variants associated with gout and serum uric acid levels.

Nat Genet 2011 Oct 9;43(11):1127-30. Epub 2011 Oct 9.

deCODE genetics, Reykjavik, Iceland.

We tested 16 million SNPs, identified through whole-genome sequencing of 457 Icelanders, for association with gout and serum uric acid levels. Genotypes were imputed into 41,675 chip-genotyped Icelanders and their relatives, for effective sample sizes of 968 individuals with gout and 15,506 individuals for whom serum uric acid measurements were available. We identified a low-frequency missense variant (c.1580C>G) in ALDH16A1 associated with gout (OR = 3.12, P = 1.5 × 10(-16), at-risk allele frequency = 0.019) and serum uric acid levels (effect = 0.36 s.d., P = 4.5 × 10(-21)). We confirmed the association with gout by performing Sanger sequencing on 6,017 Icelanders. The association with gout was stronger in males relative to females. We also found a second variant on chromosome 1 associated with gout (OR = 1.92, P = 0.046, at-risk allele frequency = 0.986) and serum uric acid levels (effect = 0.48 s.d., P = 4.5 × 10(-16)). This variant is close to a common variant previously associated with serum uric acid levels. This work illustrates how whole-genome sequencing data allow the detection of associations between low-frequency variants and complex traits.
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http://dx.doi.org/10.1038/ng.972DOI Listing
October 2011

Genetic correction of PSA values using sequence variants associated with PSA levels.

Sci Transl Med 2010 Dec;2(62):62ra92

deCODE genetics, IS-101 Reykjavik, Iceland.

Measuring serum levels of the prostate-specific antigen (PSA) is the most common screening method for prostate cancer. However, PSA levels are affected by a number of factors apart from neoplasia. Notably, around 40% of the variability of PSA levels in the general population is accounted for by inherited factors, suggesting that it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects. To search for sequence variants that associate with PSA levels, we performed a genome-wide association study and follow-up analysis using PSA information from 15,757 Icelandic and 454 British men not diagnosed with prostate cancer. Overall, we detected a genome-wide significant association between PSA levels and single-nucleotide polymorphisms (SNPs) at six loci: 5p15.33 (rs2736098), 10q11 (rs10993994), 10q26 (rs10788160), 12q24 (rs11067228), 17q12 (rs4430796), and 19q13.33 [rs17632542 (KLK3: I179T)], each with P(combined) <3 × 10(-10). Among 3834 men who underwent a biopsy of the prostate, the 10q26, 12q24, and 19q13.33 alleles that associate with high PSA levels are associated with higher probability of a negative biopsy (odds ratio between 1.15 and 1.27). Assessment of association between the six loci and prostate cancer risk in 5325 cases and 41,417 controls from Iceland, the Netherlands, Spain, Romania, and the United States showed that the SNPs at 10q26 and 12q24 were exclusively associated with PSA levels, whereas the other four loci also were associated with prostate cancer risk. We propose that a personalized PSA cutoff value, based on genotype, should be used when deciding to perform a prostate biopsy.
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http://dx.doi.org/10.1126/scitranslmed.3001513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3564581PMC
December 2010

Association of variants at UMOD with chronic kidney disease and kidney stones-role of age and comorbid diseases.

PLoS Genet 2010 Jul 29;6(7):e1001039. Epub 2010 Jul 29.

deCODE genetics, Reykjavik, Iceland.

Chronic kidney disease (CKD) is a worldwide public health problem that is associated with substantial morbidity and mortality. To search for sequence variants that associate with CKD, we conducted a genome-wide association study (GWAS) that included a total of 3,203 Icelandic cases and 38,782 controls. We observed an association between CKD and a variant with 80% population frequency, rs4293393-T, positioned next to the UMOD gene (GeneID: 7369) on chromosome 16p12 (OR = 1.25, P = 4.1x10(-10)). This gene encodes uromodulin (Tamm-Horsfall protein), the most abundant protein in mammalian urine. The variant also associates significantly with serum creatinine concentration (SCr) in Icelandic subjects (N = 24,635, P = 1.3 x 10(-23)) but not in a smaller set of healthy Dutch controls (N = 1,819, P = 0.39). Our findings validate the association between the UMOD variant and both CKD and SCr recently discovered in a large GWAS. In the Icelandic dataset, we demonstrate that the effect on SCr increases substantially with both age (P = 3.0 x 10(-17)) and number of comorbid diseases (P = 0.008). The association with CKD is also stronger in the older age groups. These results suggest that the UMOD variant may influence the adaptation of the kidney to age-related risk factors of kidney disease such as hypertension and diabetes. The variant also associates with serum urea (P = 1.0 x 10(-6)), uric acid (P = 0.0064), and suggestively with gout. In contrast to CKD, the UMOD variant confers protection against kidney stones when studied in 3,617 Icelandic and Dutch kidney stone cases and 43,201 controls (OR = 0.88, P = 5.7 x 10(-5)).
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http://dx.doi.org/10.1371/journal.pgen.1001039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2912386PMC
July 2010

Genome-wide meta-analysis for serum calcium identifies significantly associated SNPs near the calcium-sensing receptor (CASR) gene.

PLoS Genet 2010 Jul 22;6(7):e1001035. Epub 2010 Jul 22.

Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.

Calcium has a pivotal role in biological functions, and serum calcium levels have been associated with numerous disorders of bone and mineral metabolism, as well as with cardiovascular mortality. Here we report results from a genome-wide association study of serum calcium, integrating data from four independent cohorts including a total of 12,865 individuals of European and Indian Asian descent. Our meta-analysis shows that serum calcium is associated with SNPs in or near the calcium-sensing receptor (CASR) gene on 3q13. The top hit with a p-value of 6.3 x 10(-37) is rs1801725, a missense variant, explaining 1.26% of the variance in serum calcium. This SNP had the strongest association in individuals of European descent, while for individuals of Indian Asian descent the top hit was rs17251221 (p = 1.1 x 10(-21)), a SNP in strong linkage disequilibrium with rs1801725. The strongest locus in CASR was shown to replicate in an independent Icelandic cohort of 4,126 individuals (p = 1.02 x 10(-4)). This genome-wide meta-analysis shows that common CASR variants modulate serum calcium levels in the adult general population, which confirms previous results in some candidate gene studies of the CASR locus. This study highlights the key role of CASR in calcium regulation.
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http://dx.doi.org/10.1371/journal.pgen.1001035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2908705PMC
July 2010

Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations.

Nat Genet 2009 Apr 6;41(4):460-4. Epub 2009 Feb 6.

deCODE Genetics, Sturlugata 8, Reykjavik, Iceland.

In order to search for sequence variants conferring risk of thyroid cancer we conducted a genome-wide association study in 192 and 37,196 Icelandic cases and controls, respectively, followed by a replication study in individuals of European descent. Here we show that two common variants, located on 9q22.33 and 14q13.3, are associated with the disease. Overall, the strongest association signals were observed for rs965513 on 9q22.33 (OR = 1.75; P = 1.7 x 10(-27)) and rs944289 on 14q13.3 (OR = 1.37; P = 2.0 x 10(-9)). The gene nearest to the 9q22.33 locus is FOXE1 (TTF2) and NKX2-1 (TTF1) is among the genes located at the 14q13.3 locus. Both variants contribute to an increased risk of both papillary and follicular thyroid cancer. Approximately 3.7% of individuals are homozygous for both variants, and their estimated risk of thyroid cancer is 5.7-fold greater than that of noncarriers. In a study on a large sample set from the general population, both risk alleles are associated with low concentrations of thyroid stimulating hormone (TSH), and the 9q22.33 allele is associated with low concentration of thyroxin (T(4)) and high concentration of triiodothyronine (T(3)).
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http://dx.doi.org/10.1038/ng.339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3664837PMC
April 2009

Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction.

Nat Genet 2009 Mar 8;41(3):342-7. Epub 2009 Feb 8.

deCODE Genetics, Sturlugata 8, 101 Reykjavik, Iceland.

Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of inflammatory responses and thus have important roles in the pathogenesis of inflammatory diseases. Here we describe a genome-wide association scan for sequence variants affecting eosinophil counts in blood of 9,392 Icelanders. The most significant SNPs were studied further in 12,118 Europeans and 5,212 East Asians. SNPs at 2q12 (rs1420101), 2q13 (rs12619285), 3q21 (rs4857855), 5q31 (rs4143832) and 12q24 (rs3184504) reached genome-wide significance (P = 5.3 x 10(-14), 5.4 x 10(-10), 8.6 x 10(-17), 1.2 x 10(-10) and 6.5 x 10(-19), respectively). A SNP at IL1RL1 associated with asthma (P = 5.5 x 10(-12)) in a collection of ten different populations (7,996 cases and 44,890 controls). SNPs at WDR36, IL33 and MYB that showed suggestive association with eosinophil counts were also associated with atopic asthma (P = 4.2 x 10(-6), 2.2 x 10(-5) and 2.4 x 10(-4), respectively). We also found that a nonsynonymous SNP at 12q24, in SH2B3, associated significantly (P = 8.6 x 10(-8)) with myocardial infarction in six different populations (6,650 cases and 40,621 controls).
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http://dx.doi.org/10.1038/ng.323DOI Listing
March 2009

[Myeloma in an archaeological skeleton from Hofstadir in Mývatnssveit].

Laeknabladid 2005 Jun;91(6):505-9

The Icelandic Archaeological Institute, Bárugata 3, 101 Reykjavík, Iceland.

Archaeological investigations have been ongoing in the cemetery at Hofstadir in Mývatnssveit since the summer of 1999. To date, the remains of two chapels as well as 78 skeletons have been excavated, dated to between the 11th and 15th century. A skeleton was excavated in the summer of 2003 which showed pathological changes indicative of a malignant disease. Palaeopathological cases of malignancies are very rare, and it is therefore important to report on each case. Skeleton HST-027 was a female, aged 45-50 years at the time of death. Standard osteological methods were used to determine the sex, age and stature. Macroscopic analysis was carried out on the skeleton and all pathological changes on each bone described. The cranium, ribs, left os coxa and all left long bones were then radiographed to aid in the diagnosis. The analysis showed lytic lesions in all the flat bones, as well as the vertebrae, ribs and the proximal end of the left femur, all changes indicative of multiple myeloma. Palaeopathologically myeloma and metastatic cancer (then usually due to breast cancer in the case of women) are often difficult to distinguish. However there is no new bone formation surrounding the lesions, which means that metastatic cancer is unlikely to be the cause. Skeleton HST-027 from Hofstadir is the first published case of malignant disease in Iceland, and one of the clearer cases of myeloma in an archaeological specimen, but to date, approximately twenty cases have been reported world-wide.
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June 2005
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