| 1. |
- Lunetta, Kathryn L., et al.
(författare)
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Rare coding variants and X-linked loci associated with age at menarche
- 2015
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only similar to 3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency proteincoding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 x 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P = 9.4 x 10(-13)) and FAAH2 (rs5914101, P = 4.9 x 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P = 2.8 x 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain similar to 0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.
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| 2. |
- Pearce, Neil E, et al.
(författare)
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IARC Monographs : 40 Years of Evaluating Carcinogenic Hazards to Humans
- 2015
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Ingår i: Journal of Environmental Health Perspectives. - : Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 123:6, s. 507-514
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Recently the International Agency for Research on Cancer (IARC) Programme for the Evaluation of Carcinogenic Risks to Humans has been criticized for several of its evaluations, and also the approach used to perform these evaluations. Some critics have claimed that IARC Working Groups' failures to recognize study weaknesses and biases of Working Group members have led to inappropriate classification of a number of agents as carcinogenic to humans.OBJECTIVES: The authors of this paper are scientists from various disciplines relevant to the identification and hazard evaluation of human carcinogens. We have examined here criticisms of the IARC classification process to determine the validity of these concerns. We review the history of IARC evaluations and describe how the IARC evaluations are performed.DISCUSSION: We conclude that these recent criticisms are unconvincing. The procedures employed by IARC to assemble Working Groups of scientists from the various discipline and the techniques followed to review the literature and perform hazard assessment of various agents provide a balanced evaluation and an appropriate indication of the weight of the evidence. Some disagreement by individual scientists to some evaluations is not evidence of process failure. The review process has been modified over time and will undoubtedly be altered in the future to improve the process. Any process can in theory be improved, and we would support continued review and improvement of the IARC processes. This does not mean, however, that the current procedures are flawed.CONCLUSIONS: The IARC Monographs have made, and continue to make, major contributions to the scientific underpinning for societal actions to improve the public's health.
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| 3. |
- Flannick, Jason, et al.
(författare)
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Data Descriptor : Sequence data and association statistics from 12,940 type 2 diabetes cases and controls
- 2017
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Ingår i: Scientific Data. - : Springer Science and Business Media LLC. - 2052-4463. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (> 80% of low-frequency coding variants in similar to ~82 K Europeans via the exome chip, and similar to ~90% of low-frequency non-coding variants in similar to ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.
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| 4. |
- Fuchsberger, Christian, et al.
(författare)
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The genetic architecture of type 2 diabetes
- 2016
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 536:7614, s. 41-47
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Tidskriftsartikel (refereegranskat)abstract
- The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
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| 5. |
- Kilpeläinen, Tuomas O, et al.
(författare)
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Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
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| 6. |
- Manning, Alisa, et al.
(författare)
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A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
- 2017
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Ingår i: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 66:7, s. 2019-2032
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Tidskriftsartikel (refereegranskat)abstract
- To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.
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| 7. |
- Marouli, Eirini, et al.
(författare)
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Rare and low-frequency coding variants alter human adult height
- 2017
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
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Tidskriftsartikel (refereegranskat)abstract
- Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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| 8. |
- Bauer, Ann Z., et al.
(författare)
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Paracetamol use during pregnancy - a call for precautionary action
- 2021
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Ingår i: Nature Reviews Endocrinology. - : Springer Nature. - 1759-5029 .- 1759-5037. ; 17, s. 757-766
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Tidskriftsartikel (refereegranskat)abstract
- Paracetamol (N-acetyl-p-aminophenol (APAP), otherwise known as acetaminophen) is the active ingredient in more than 600 medications used to relieve mild to moderate pain and reduce fever. APAP is widely used by pregnant women as governmental agencies, including the FDA and EMA, have long considered APAP appropriate for use during pregnancy when used as directed. However, increasing experimental and epidemiological research suggests that prenatal exposure to APAP might alter fetal development, which could increase the risks of some neurodevelopmental, reproductive and urogenital disorders. Here we summarize this evidence and call for precautionary action through a focused research effort and by increasing awareness among health professionals and pregnant women. APAP is an important medication and alternatives for treatment of high fever and severe pain are limited. We recommend that pregnant women should be cautioned at the beginning of pregnancy to: forego APAP unless its use is medically indicated; consult with a physician or pharmacist if they are uncertain whether use is indicated and before using on a long-term basis; and minimize exposure by using the lowest effective dose for the shortest possible time. We suggest specific actions to implement these recommendations. This Consensus Statement reflects our concerns and is currently supported by 91 scientists, clinicians and public health professionals from across the globe. A growing body of research suggests that prenatal exposure to paracetamol (APAP) might alter development and increase the risk of some reproductive, urogenital and neurodevelopmental disorders. This Consensus Statement calls for precautionary action, including a focused research effort, increasing awareness among health professionals and pregnant women and, whenever possible, minimizing use.
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| 9. |
- Bauer, Ann Z., et al.
(författare)
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Paracetamol Use During Pregnancy-A Call for Precautionary Action
- 2022
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Ingår i: Obstetrical and Gynecological Survey. - : Lippincott Williams & Wilkins. - 0029-7828 .- 1533-9866. ; 77:3, s. 133-134
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Tidskriftsartikel (refereegranskat)abstract
- Paracetamol, otherwise known as acetaminophen, is the active ingredient in over 600 prescription and nonprescription analgesic and antipyretic medications. Worldwide and in the United States, more than 50% and 65% of pregnant women use acetaminophen, respectively. Currently, acetaminophen is considered to be of minimal risk and appropriate for use during pregnancy by the US Food and Drug Administration and European Medicines Agency. Despite this, there exists concern that environmental exposure to pharmaceuticals including acetaminophen during fetal life may contribute to the increased rates of neurological, urogenital, and reproductive disorders.This consensus statement aimed to provide an evidence-based summary of the literature relating to neurological, urogenital, and reproductive outcomes that have been associated with maternal and perinatal use of acetaminophen. This consensus statement was created by an international multidisciplinary group consisting of experts in neurology, obstetrics/gynecologists, pediatrics, epidemiology, toxicology, endocrinology, reproductive medicine, and neurodevelopment. A literature review was conducted for studies published between 1995 and 2020, including only those with acetaminophen as an independent exposure. There is a limitation in the existing epidemiological literature addressing these questions, and future efforts are required.This consensus statement and systematic review finds evidence of significant neurodevelopmental and reproductive adverse effects of acetaminophen prenatal exposure, particularly with long-term use. It is recommended by this document that acetaminophen be used by pregnant women cautiously at the lowest effective dose for the shortest possible time and longer or higher-dose use be discussed with a health professional. It is also advised that packaging display warning labels related to the evidence discussed here.
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| 10. |
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| 11. |
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| 12. |
- Bustamante, Mariona, et al.
(författare)
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A genome-wide association meta-analysis of diarrhoeal disease in young children identifies FUT2 locus and provides plausible biological pathways.
- 2016
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Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 25:18, s. 4127-4142
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Tidskriftsartikel (refereegranskat)abstract
- More than a million childhood diarrhoeal episodes occur worldwide each year, and in developed countries a considerable part of them are caused by viral infections. In this study, we aimed to search for genetic variants associated with diarrhoeal disease in young children by meta-analyzing genome-wide association studies, and to elucidate plausible biological mechanisms. The study was conducted in the context of the Early Genetics and Lifecourse Epidemiology (EAGLE) consortium. Data about diarrhoeal disease in two time windows (around 1 year of age and around 2 years of age) was obtained via parental questionnaires, doctor interviews or medical records. Standard quality control and statistical tests were applied to the 1000 Genomes imputed genotypic data. The meta-analysis (N=5758) followed by replication (N=3784) identified a genome-wide significant association between rs8111874 and diarrhoea at age 1 year. Conditional analysis suggested that the causal variant could be rs601338 (W154X) in the FUT2 gene. Children with the A allele, which results in a truncated FUT2 protein, had lower risk of diarrhoea. FUT2 participates in the production of histo-blood group antigens and has previously been implicated in the susceptibility to infections, including Rotavirus and Norovirus Gene-set enrichment analysis suggested pathways related to the histo-blood group antigen production, and the regulation of ion transport and blood pressure. Among others, the gastrointestinal tract, and the immune and neuro-secretory systems were detected as relevant organs. In summary, this genome-wide association meta-analysis suggests the implication of the FUT2 gene in diarrhoeal disease in young children from the general population.
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| 13. |
- Farioli, Andrea, et al.
(författare)
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Occupational lifting and rhegmatogenous retinal detachment : a follow-up study of Swedish conscripts
- 2017
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Ingår i: Occupational and Environmental Medicine. - : BMJ. - 1351-0711 .- 1470-7926. ; 74:7, s. 489-495
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Tidskriftsartikel (refereegranskat)abstract
- Objectives To investigate the association between occupational lifting and the risk of rhegmatogenous retinal detachment (RRD) using data from a large population of men.Methods We used data from a national cohort of 49 321 Swedish men conscripted for compulsory military service in 1969–1970. We collected information on surgically treated RRD from the National Patient Register and we followed up the cohort between 1991 and 2009 at ages 40–60 years. Exposure to occupational lifting was assessed by applying a job exposure matrix to occupational data from the 1990 census. Incidence rate ratios (IRRs) and 95% CIs were estimated through Poisson regression models adjusted by degree of myopia, income and education level.Results We observed 217 cases of RRD in 7 80 166 person-years. In univariate analyses we did not observe an association between occupational lifting and RRD. However, after adjustment for myopia and socioeconomic factors, we found an increased risk of RRD (IRR 2.38, 95% CI 1.15 to 4.93) for subjects in the highest category of exposure compared with those in the lowest one. The incidence rate of RRD among subjects lifting heavy loads at least twice per week, aged between 50 years and 59 years, and affected by severe myopia was as high as 7.9 cases per 1000 person-years, compared with an overall rate of 0.28.Conclusions Our study supports the hypothesis that heavy occupational lifting is a risk factor for RRD. Information on myopia degree and socioeconomic status is necessary when studying the association between occupational lifting and RRD.
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| 14. |
- Farioli, Andrea, et al.
(författare)
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Vascular risk factors and rhegmatogenous retinal detachment : a follow-up of a national cohort of Swedish men
- 2016
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Ingår i: British Journal of Ophthalmology. - : BMJ. - 0007-1161 .- 1468-2079. ; 100:7, s. 907-913
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Tidskriftsartikel (refereegranskat)abstract
- Background We aimed to investigate the role of vascular risk factors in the genesis of rhegmatogenous retinal detachment (RRD) using data from a large cohort of Swedish conscripts. Methods We used data from a nationwide cohort of 49 321 Swedish men born during 1949-1951, conscripted for compulsory military service in 19691970 with nearly complete follow-up to 2009. Information on surgically treated RRD between 1973 and 2009 was collected from the National Patient Register. We fitted Cox regression models stratified on myopia degree and including blood pressure levels, body mass index and cigarette smoking. Population attributable fractions of RRD were estimated through maximum likelihood methods. Results We observed 262 cases of RRD in 1 725 770 person-years. At multivariate analysis, the number of cigarettes per day showed a reverse association with the risk of RRD (p for trend 0.01). Conscripts with obesity presented a higher risk compared with normal subjects (adjusted HR 2.51, 95% CI 1.02 to 6.13). We found weak evidence of an association between blood pressure and RRD (HR for men with hypertension compared with normotension 1.41, 95% CI 0.93 to 2.13). All the observed associations were stronger when the analysis was restricted to non-myopic conscripts. In particular, the HR for hypertension was 2.33 (95% CI 1.30 to 4.19) compared with normotension. If this association is causal, we estimated that 42.0% of RRD cases (95% CI 11.5% to 62.0%) occurring among non-myopics are attributable to elevated blood pressure. Conclusions Vascular risk factors may be important determinants of RRD, particularly among non-myopics. Further investigations on the role of hypertension and obesity are needed.
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| 15. |
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| 16. |
- Hemmingsson, Tomas, et al.
(författare)
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How does IQ affect onset of smoking and cessation of smoking - Linking the Swedish 1969 conscription cohort to the Swedish survey of living conditions
- 2008
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Ingår i: Psychosomatic Medicine. - 0033-3174 .- 1534-7796. ; 70:7, s. 805-810
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To examine the association between intelligence quotient (IQ) measured at ages 18 to 20 and onset of smoking, and the association between IQ and smoking cessation. Methods: Data on IQ, smoking, mental health, and social background among 49.321 Swedish men born 1949 to 51, collected at conscription for military service in 1969, were used. The association between IQ and smoking cessation was investigated among those 694 members of the full cohort also interviewed in the Swedish Level of Living Conditions study 1981 to 2002, Results: Lower IQ measured at ages 18 to 20 was weakly associated with increased prevalence of smoking, independently of indicators of mental illness and social misbehavior measured in late adolescence, By contrast, smoking cessation later in life among those who smoked at ages 18 to 20 was not associated with IQ. Among smokers, lower IQ was significantly associated with a lower level of smoking after adjusting for other factors. Conclusion: Low IQ was associated with an increased prevalence of smoking in adolescence. However, the main part of this association disappeared after adjustment for measures of mental health and social function in early life. IQ was not associated with likelihood of quitting smoking.
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| 17. |
- Mahajan, Anubha, et al.
(författare)
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Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation
- 2022
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:5, s. 560-572
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Tidskriftsartikel (refereegranskat)abstract
- We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 x 10(-9)), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background. Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.
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| 18. |
- Schott, Kevin D., et al.
(författare)
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A cohort study of retinal detachment among Swedish construction workers
- 2023
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Ingår i: Scandinavian Journal of Work, Environment and Health. - : Nordic Association of Occupational Safety and Health. - 0355-3140 .- 1795-990X. ; 49:7, s. 518-525
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Retinal detachment (RD) has been associated with exposure to heavy lifting. Many occupations within the construction industry are likely to involve lifting tasks. We investigated the association between occupational heavy lifting and rhegmatogenous RD in a retrospective cohort study of Swedish construction workers.Methods: We studied Swedish construction workers who participated in an industry-wide health and safety program from 1971 to 1993. Individual occupation codes were linked to a job exposure matrix, assigning intensity of exposure to heavy lifting to each worker. The Swedish National Patient Register was used to identify cases of RD that occurred during follow-up through the end of 2012. We used Poisson regression modeling to calculate incidence rates of RD associated with heavy lifting, age and other covariates. A subcohort of those age ≤25 years at enrollment was studied to reduce bias from missing exposure information from work prior to enrollment.Results: Of 256 241 construction workers, 17% were classified with high exposure to heavy lifting in their occupation. Within the cohort, 1588 cases of RD were identified. Average exposure intensity of heavy lifting was not associated with risk of RD. However, RD risk increased with increasing cumulative exposure to heavy lifting, both in the full cohort and subcohort of those who were ≤25 years old at entry into the construction-worker cohort.Conclusion: Construction workers' risk of RD appeared to increase with time spent exposed to heavy lifting.
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| 19. |
- Spracklen, Cassandra N., et al.
(författare)
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Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology
- 2019
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Ingår i: American Journal of Human Genetics. - : CELL PRESS. - 0002-9297 .- 1537-6605. ; 105:1, s. 15-28
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Tidskriftsartikel (refereegranskat)abstract
- Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p < 2 x 10(-7)). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r(2) > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 x 10(-4)) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.
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| 20. |
- Stitziel, Nathan O., et al.
(författare)
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Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease
- 2016
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 374:12, s. 1134-1144
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets. METHODS Through DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes. RESULTS We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P = 4.2x10(-10)) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P = 4.0x10(-8)), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P = 0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P = 0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P = 2.0x10(-4)) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P = 2.5x10(-7)). CONCLUSIONS We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease.
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| 21. |
- Yaghootkar, Hanieh, et al.
(författare)
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Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity
- 2020
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 69:12, s. 2806-2818
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Tidskriftsartikel (refereegranskat)abstract
- Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.
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