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Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain.
Suri, P, Palmer, MR, Tsepilov, YA, Freidin, MB, Boer, CG, Yau, MS, Evans, DS, Gelemanovic, A, Bartz, TM, Nethander, M, et al
PLoS genetics. 2018;(9):e1007601
Abstract
Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. CBP cases were defined as those reporting back pain present for ≥3-6 months; non-cases were included as comparisons ("controls"). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p<5×10(-8). Suggestive (p<5×10(-7)) and genome-wide significant (p<5×10(-8)) variants were carried forward for replication or further investigation in the remaining UK Biobank participants not included in the discovery sample. The discovery sample comprised 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p = 7.2×10(-10)). This was subsequently replicated in 283,752 UK Biobank participants not included in the discovery sample, including 50,915 cases (OR 1.06, p = 5.3×10(-11)), and exceeded genome-wide significance in joint meta-analysis (OR 1.07, p = 4.5×10(-19)). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p = 4.4×10(-13)), and an intronic variant, rs4384683, in DCC (OR 0.97, p = 2.4×10(-10)). In this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC).
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Racial Variation in Total Knee Replacement in a Diverse Nationwide Clinical Trial.
MacFarlane, LA, Kim, E, Cook, NR, Lee, IM, Iversen, MD, Katz, JN, Costenbader, KH
Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases. 2018;(1):1-5
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Abstract
OBJECTIVE Racial variation in total knee replacement (TKR) utilization in the United States has been reported in administrative database studies. We investigated racial variation in TKR procedures in a diverse cohort with severe knee pain followed in an ongoing clinical trial. METHODS VITAL (VITamin D and OmegA-3 TriaL) is a nationwide, randomized controlled trial of 25,874 adults, 20% of whom are black. We identified a subgroup highly likely to have knee osteoarthritis based on severity of knee pain, physician-diagnosed knee osteoarthritis, and inability to walk 2 to 3 blocks without pain. Participants completed a modified Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at baseline and self-reported incident TKR annually in follow-up. Using Cox regression, we analyzed the association of black versus white race with TKR, adjusting for demographic and socioeconomic characteristics, comorbidities, and WOMAC pain and function. RESULTS Among 1070 participants who met the inclusion criteria, black participants reported worse baseline WOMAC pain (45 vs. 32, P < 0.001) and worse function (45 vs. 32, P < 0.001). During a median of 3.6 years (interquartile range, 3.2, 3.8 years) of follow-up, TKRs were reported by 180 participants. Black participants were less likely to undergo TKR (11% vs. 19%). After adjustment, the hazard ratio for TKR for black versus white participants was 0.51 (95% confidence interval, 0.32-0.81). Lower use of TKR among black participants was observed across all levels of income and education. CONCLUSIONS Despite worse baseline knee pain and function, black participants had much lower adjusted risk of having TKR than white participants, demonstrating persistent racial disparity in TKR utilization.
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The Association of Acylcarnitines and Amino Acids With Age in Dutch and South-Asian Surinamese Living in Amsterdam.
Muilwijk, M, Vaz, FM, Celis-Morales, C, Peters, RJG, van Valkengoed, IGM
The Journal of clinical endocrinology and metabolism. 2018;(10):3783-3791
Abstract
CONTEXT Type 2 diabetes and cardiovascular disease occur more frequently and at a younger age in South-Asians than Europeans. This may be related to differences in regulation of the fatty acid metabolism during aging. We compared age-related acylcarnitine and amino acid concentrations in Dutch and South-Asian Surinamese study participants. METHODS We measured types of acylcarnitine and amino acid concentrations in plasma (by tandem mass spectrometry) in a random subsample of 350 Dutch and 350 South-Asian Surinamese origin participants of the Healthy Life in an Urban Setting study (Amsterdam, Netherlands). We derived principal components (PCs) from the metabolites. Linear regression was used to assess differences in PCs and individual metabolite concentrations, and their age trends between the groups by sex. We adjusted for body mass index and intake of fat and total energy. RESULTS Mean age was 44.8 (SD, 13.3) years. Amino acid concentrations were higher among South-Asian Surinamese women compared with Dutch women; acylcarnitine and amino acid levels were higher among South-Asian Surinamese men than Dutch men. Metabolite levels increased similarly with age in both ethnic groups. Results remained similar after adjustment. CONCLUSION Ethnic differences in metabolite concentrations suggest that fatty acid and amino acid metabolism are more dysregulated among South-Asian Surinamese compared with Dutch from a young age. During adulthood, metabolites increase similarly in both ethnic groups.
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TG haplotype in the LRP8 is associated with myocardial infarction in south Indian population.
Asif, M, Bhat, S, Nizamuddin, S, Mustak, MS
Gene. 2018;:225-229
Abstract
Myocardial infarction (MI) is a complex multifactorial cardiovascular disease. India experiences a much greater burden of MI, also suggesting an experimental increase of this burden in the future. The absolute reasons for MI are context dependent and differ with different geographical settings. Several reports indicate that SNPs that are associated with certain diseases in other populations may not be associated with Indian population. It is, therefore, important to validate the association of SNPs. Low density lipoprotein receptor related protein 8 (LRP8) gene plays central role in human lipoprotein metabolism as it facilitates the clearance of bad cholesterol LDL, VLDL from plasma and is reported to be associated with MI in the western population. However, this gene has not been studied in the South Indian population. We aim to test the role of the LRP8 gene variants correlating with the lipid profile in MI patients in South Indian population. We sequenced regions of SNPs rs10788952, rs7546246, rs2297660 and rs5174 of LRP8 in 100 MI patients and 100 age-matched controls. Our result revealed a total of 4 variations. None of the SNPs were significantly associated with MI (p>0.973). Interestingly, haplotype based association analysis showed TG and CG of rs10788952 and rs7546246 significantly associated with MI (p<0.01 and p<0.00005) and in particular, haplotype TG was positively correlated with the risk of MI, as this increased the LDL and total cholesterol level in MI patients in south Indians. Our results suggest that haplotype TG is a risk factor for MI in South Indian population.
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Associations of coffee genetic risk scores with consumption of coffee, tea and other beverages in the UK Biobank.
Taylor, AE, Davey Smith, G, Munafò, MR
Addiction (Abingdon, England). 2018;(1):148-157
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Abstract
AIMS: To evaluate the utility of coffee-related genetic variants as proxies for coffee consumption in Mendelian randomization studies, by examining their association with non-alcoholic beverage consumption (including subtypes of coffee and tea) and a range of socio-demographic and life-style factors. DESIGN Observational study of the association of genetic risk scores for coffee consumption with different types of non-alcoholic beverage consumption. SETTING UK general population. PARTICIPANTS Individuals of European ancestry aged 40-73 years from the UK Biobank between 2006 and 2010 (n = 114 316). MEASUREMENTS Genetic risk scores were constructed using two, four and eight independent single nucleotide polymorphisms (SNPs) identified in genome-wide association studies (GWAS) of coffee consumption. Drinks were self-reported in a baseline questionnaire (all participants) and in detailed 24 dietary recall questionnaires in a subset (n = 48 692). FINDINGS Genetic risk scores explained up to 0.38, 0.19 and 0.76% of the variance in coffee, tea and combined coffee and tea consumption, respectively. Genetic risk scores demonstrated positive associations with both caffeinated and decaffeinated coffee and tea consumption, and with most subtypes of coffee consumption, but only with standard tea consumption. There was no clear evidence for positive associations with most other non-alcoholic beverages, but higher genetic risk for coffee consumption was associated with lower daily water consumption. The genetic risk scores were associated with increased alcohol consumption, but not consistently with other socio-demographic and life-style factors. CONCLUSIONS Coffee-related genetic risk scores could be used as instruments for combined coffee and tea consumption in Mendelian randomization studies. However, associations observed with alcohol consumption require further investigation to determine whether these are due to causal effects of coffee and tea consumption or biological pleiotropy.
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Low Prevalence of Colorectal Cancer in South Asians than White Population in UK: Probable Factors.
Tahir, MZ
Journal of the College of Physicians and Surgeons--Pakistan : JCPSP. 2018;(8):631-635
Abstract
Colorectal cancer is common in White population in UK, while rare among South Asians living in UK. The main aim of this study was to find out probable reasons for very low prevalence of colorectal cancer among South Asians living in UK than White population. PubMed was searched by using key words and 2,153 articles were found and reviewed to find out related information. Websites of WHO, Office of National Statistics UK, and Cancer Research UK were also searched for relevant information. Diet and lifestyle are important factors for low colorectal prevalence among South Asians in UK. Vegetable and fruit use, physical activity, alcohol abstention or low usage, less tobacco use, and fecal material time in large intestine are important factors for low colorectal cancer development. It was concluded that South Asians have very low colorectal cancer prevalence in the UK than White population, which may be related to their diet, dietary habit, and lifestyle.
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Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels.
Jiang, X, O'Reilly, PF, Aschard, H, Hsu, YH, Richards, JB, Dupuis, J, Ingelsson, E, Karasik, D, Pilz, S, Berry, D, et al
Nature communications. 2018;(1):260
Abstract
Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10-9 at rs8018720 in SEC23A, and P = 1.9×10-14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.
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Vitamin D receptor rs2228570 polymorphism and susceptibility to ovarian cancer: An updated meta-analysis.
Chen, H, Zhu, J
The journal of obstetrics and gynaecology research. 2018;(3):556-565
Abstract
AIM: The FokI polymorphism (C>T, rs2228570) of the vitamin D receptor gene is a coding nonsynonymous single nucleotide polymorphism in the translational initiation codon reported to have functional significance. Although the role of rs2228570 in the risk of ovarian cancer has been widely researched, the association is still unclear. We performed an updated meta-analysis to clarify this issue. METHODS Eligible studies were retrieved from electronic databases for the period 2007-2016. The association was measured by unadjusted odds ratio combined with 95% confidence intervals (CIs). Random-effect or fixed-effect models were used according to the heterogeneity of the studies. We further appreciated the strength of evidence according to Venice guidance. RESULTS Fourteen studies (4448 cases and 7242 controls) were included in the meta-analysis. Studies were predominantly conducted in Caucasian populations (4152 cases and 6693 controls). A dominant genetic model was determined to be the most appropriate genetic model. Overall meta-analysis showed a fixed-effect odds ratio of 1.14 (95% CI 1.05-1.23) under a dominant model. The fixed-effect odds ratios were 1.12 (95% CI 1.03-1.21) and 1.49 (95% CI 1.06-2.09) in Caucasian and Asian populations, respectively. The strength of the evidence was moderate. CONCLUSION The rs2228570 polymorphism increased the risk of ovarian cancer in Caucasian populations in a dominant genetic model. The role of this polymorphism in the risk of ovarian cancer in Asian populations should be further studied.
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Benefits for African American and white low-income 7-10-year-old children and their parents taught together in a community-based weight management program in the rural southeastern United States.
Berry, DC, McMurray, RG, Schwartz, TA, Adatorwovor, R
BMC public health. 2018;(1):1107
Abstract
BACKGROUND Low-income children and parents are at increased risk for developing overweight and obesity. Therefore, the purpose of this exploratory study was to compare whether African American and white children and parents benefitted equally from a community-based weight management intervention delivered in two rural counties in southeastern North Carolina (N.C.). METHODS We compared the efficacy of the Family Partners for Health intervention for African American and white children and their parents by testing the three-way interaction of the intervention group according to visit and race. RESULTS African American children in the intervention group weighed significantly (P = 0.027) less than those in the control group, while white children in the intervention group weighed less than those in the control group, but the difference did not reach statistical significance. African American and white parents in the intervention group weighed less than their respective control groups across all three data collections, but the difference was only significant in the group of white parents (P = 0.010) at the completion of the study. At the completion of the study, African American children in the intervention group received significantly (P = 0.003) more support for physical activity than African American children in the control group. At both time points, white children in the intervention group were not significantly different from those in the control group. African American parents in the intervention group scored slightly worse in the stress management assessment compared to those in the control group, while white parents in the intervention group showed a significantly (P = 0.041) better level of stress management than those in the control group. At the completion of the study, African American parents in the intervention group scored somewhat worse in emotional eating self-efficacy compared to the scores of the African American parents in the control group, while white parents in the intervention group scored significantly (P < 0.001) better than those in the control group. CONCLUSIONS We were successful in affecting some outcomes in both African American and white children and parents using the same intervention. TRIAL REGISTRATION NCT01378806 Registered June 22, 2011.
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Identification and characterization of two functional variants in the human longevity gene FOXO3.
Flachsbart, F, Dose, J, Gentschew, L, Geismann, C, Caliebe, A, Knecht, C, Nygaard, M, Badarinarayan, N, ElSharawy, A, May, S, et al
Nature communications. 2017;(1):2063
Abstract
FOXO3 is consistently annotated as a human longevity gene. However, functional variants and underlying mechanisms for the association remain unknown. Here, we perform resequencing of the FOXO3 locus and single-nucleotide variant (SNV) genotyping in three European populations. We find two FOXO3 SNVs, rs12206094 and rs4946935, to be most significantly associated with longevity and further characterize them functionally. We experimentally validate the in silico predicted allele-dependent binding of transcription factors (CTCF, SRF) to the SNVs. Specifically, in luciferase reporter assays, the longevity alleles of both variants show considerable enhancer activities that are reversed by IGF-1 treatment. An eQTL database search reveals that the alleles are also associated with higher FOXO3 mRNA expression in various human tissues, which is in line with observations in long-lived model organisms. In summary, we present experimental evidence for a functional link between common intronic variants in FOXO3 and human longevity.