Association between Vitamin D Genetic Risk Score and Cancer Risk in a Large Cohort of U.S. Women.
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SUBMITTER: Chandler PD
PROVIDER: S-EPMC5793283 | biostudies-literature | 2018 Jan
REPOSITORIES: biostudies-literature
Publications
Association between Vitamin D Genetic Risk Score and Cancer Risk in a Large Cohort of U.S. Women.
Chandler Paulette D PD Tobias Deirdre K DK Wang Lu L Smith-Warner Stephanie A SA Chasman Daniel I DI Rose Lynda L Giovannucci Edward L EL Buring Julie E JE Ridker Paul M PM Cook Nancy R NR Manson JoAnn E JE Sesso Howard D HD
Nutrients 20180109 1
Some observational studies suggest an inverse association between circulating 25-hydroxyvitamin D (25OHD) and cancer incidence and mortality. We conducted a Mendelian randomization analysis of the relationship between a vitamin D genetic risk score (GRS, range 0-10), comprised of five single nucleotide polymorphisms (SNPs) of vitamin D status in the DHCR7, CYP2R1 and GC genes and cancer risk among women. Analysis was performed in the Women's Genome Health Study (WGHS), including 23,294 women of ...[more]
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Project description:While multiple genetic markers associated with cardiovascular disease have been identified by genome-wide association studies, their aggregate effect on risk beyond traditional factors is uncertain, particularly among women.To test the predictive ability of a literature-based genetic risk score for cardiovascular disease.Prospective cohort of 19,313 initially healthy white women in the Women's Genome Health Study followed up over a median of 12.3 years (interquartile range, 11.6-12.8 years). Genetic risk scores were constructed from the National Human Genome Research Institute's catalog of genome-wide association study results published between 2005 and June 2009.Incident myocardial infarction, stroke, arterial revascularization, and cardiovascular death.A total of 101 single nucleotide polymorphisms reported to be associated with cardiovascular disease or at least 1 intermediate cardiovascular disease phenotype at a published P value of less than 10(-7) were identified and risk alleles were added to create a genetic risk score. During follow-up, 777 cardiovascular disease events occurred (199 myocardial infarctions, 203 strokes, 63 cardiovascular deaths, 312 revascularizations). After adjustment for age, the genetic risk score had a hazard ratio (HR) for cardiovascular disease of 1.02 per risk allele (95% confidence interval [CI], 1.00-1.03/risk allele; P = .006). This corresponds to an absolute cardiovascular disease risk of 3% over 10 years in the lowest tertile of genetic risk (73-99 risk alleles) and 3.7% in the highest tertile (106-125 risk alleles). However, after adjustment for traditional factors, the genetic risk score did not improve discrimination or reclassification (change in c index from Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults [ATP III] risk score, 0; net reclassification improvement, 0.5%; [P = .24]). The genetic risk score was not associated with cardiovascular disease risk (ATP III-adjusted HR/allele, 1.00; 95% CI, 0.99-1.01). In contrast, self-reported family history remained significantly associated with cardiovascular disease in multivariable models.After adjustment for traditional cardiovascular risk factors, a genetic risk score comprising 101 single nucleotide polymorphisms was not significantly associated with the incidence of total cardiovascular disease.
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Project description:Genetic risk of low BMD in African American women remains unclear. Based on SNPs discovered from a predominantly Caucasian sample, genetic profile was summarized and was found to be significantly associated with BMD variation in African American women.IntroductionOsteoporosis is largely under-recognized and undertreated in African-American women, the post-fracture morbidity and mortality rates in this racial group is rather high. Since BMD was proved to be highly heritable, based on a comprehensive genome-wide meta-analysis that reported 63 BMD-related single nucleotide polymorphisms (SNPs), we aim to unravel the overall genetic risk for decreased BMD and osteoporosis in African-American women.MethodsGenotype data of 842 African American women in a Women's Health Initiative cohort were analyzed. Comprehensive genotype imputation was conducted at the Sanger Imputation Server. Multi-locus genetic risk scores (GRSs) based on 62 BMD-related single-nucleotide polymorphisms (SNPs) were calculated. The association between GRS and BMD was assessed by regression analysis. Longitudinal data was further analyzed using a generalized estimating equation, which helps achieve more efficient and unbiased regression parameters by accounting for the within-subject correlation of responses on dependent variables.ResultsAfter adjusting for age, body weight, hormone use, and previous fracture, for every unit increase of GRS.FN and GRS.LS, BMD at hip and lumbar spine decreased 0.124 g/cm2 and 0.086 g/cm2, respectively. Collectively, the model accounted for 34.95% of the femoral neck BMD variation and 25.79% of lumbar spine BMD variation. Notably, GRS.FN and GRS.LS accounted for 2.03% and 2.39% of the total explained variance, respectively. The proportion of BMD variation can be explained by GRSs increasing as participants aged.ConclusionsGenetic risk score was significantly associated with lower BMD in the current study, suggesting that SNPs discovered from prior meta-analysis based on primarily Caucasian population can also explain a considerable proportion of BMD variation in African Americans.
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Project description:Metabolic diseases have been shown to be associated with low vitamin D status; however, the findings have been inconsistent. Hence, the objective of our study was to investigate the relationship between vitamin D status and metabolic disease-related traits in healthy Southeast Asian women and examine whether this relationship was modified by dietary factors using a nutrigenetic study. The study included 110 Minangkabau women (age: 25-60 years) from Padang, Indonesia. Genetic risk scores (GRS) were constructed based on five vitamin D-related single nucleotide polymorphisms (SNPs) (vitamin D-GRS) and ten metabolic disease-associated SNPs (metabolic-GRS). The metabolic-GRS was significantly associated with lower 25-hydroxyvitamin D (25(OH)D) concentrations (p = 0.009) and higher body mass index (BMI) (p = 0.016). Even though the vitamin D-GRS had no effect on metabolic traits (p > 0.12), an interaction was observed between the vitamin D-GRS and carbohydrate intake (g) on body fat percentage (BFP) (pinteraction = 0.049), where those individuals who consumed a high carbohydrate diet (mean ± SD: 319 g/d ± 46) and carried >2 vitamin D-lowering risk alleles had significantly higher BFP (p = 0.016). In summary, we have replicated the association of metabolic-GRS with higher BMI and lower 25(OH)D concentrations and identified a novel interaction between vitamin D-GRS and carbohydrate intake on body fat composition.
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Project description:To date, the utility of single genetic markers to improve disease risk assessment still explains only a small proportion of genetic variance for many complex diseases. This missing heritability may be explained by additional variants with weak effects. To discover and incorporate these additional genetic factors, statistical and computational methods must be evaluated and developed. We develop a multi-locus genetic risk score (GRS) based approach to analyze genes in NADPH oxidase complex which may result in susceptibility to development of inflammatory bowel disease (IBD). We find the complex is highly associated with IBD (P = 7.86 × 10(-14)) using the GRS-based association method. Similar results are also shown in permutation analysis (P = 6.65 × 10(-11)). Likelihood ratio test shows that the single nucleotide polymorphisms (SNPs) in the complex without nominal signals have significant contribution to the overall genetic effect within the complex (P = 0.015). Our results show that the multi-locus GRS association model can improve the genetic risk assessment on IBD by taking into account both confirmed and as yet unconfirmed disease susceptibility variants.
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Project description:BACKGROUND/OBJECTIVES:Individually, genetic variants only moderately influence cardiometabolic (CM) traits, such as lipid and inflammatory markers. In this study we generated genetic risk scores from a combination of previously reported variants influencing CM traits, and used these scores to explore how adiposity levels could mediate genetic contributions to CM traits. SUBJECTS/METHODS:Participants included 1649 women from the 2005 Cebu Longitudinal Health and Nutrition Survey. Three genetic risk scores were constructed for C-reactive protein (CRP), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TGs). We used linear regression models to assess the association between each genetic risk score and its related trait. We also tested for interactions between each score and measures of adiposity. RESULTS:Each genetic risk score explained a greater proportion of variance in trait levels than any individual genetic variant. We found an interaction between the TG genetic risk score (2.29-14.34 risk alleles) and waist circumference (WC) (Pinteraction=1.66 × 10(-2)). Based on model predictions, for individuals with a higher TG genetic risk score (75th percentile=12), having an elevated WC (?80?cm) increased TG levels from 1.32 to 1.71?mmol?l(-1). However, for individuals with a lower score (25th percentile=7), having an elevated WC did not significantly change TG levels. CONCLUSIONS:The TG genetic risk score interacted with adiposity to synergistically influence TG levels. For individuals with a genetic predisposition to elevated TG levels, our results suggest that reducing adiposity could possibly prevent further increases in TG levels and thereby lessen the likelihood of adverse health outcomes such as cardiovascular disease.
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Project description:Importance:Myopia is a leading cause of untreatable visual impairment and is increasing in prevalence worldwide. Interventions for slowing childhood myopia progression have shown success in randomized clinical trials; hence, there is a need to identify which children would benefit most from treatment intervention. Objectives:To examine whether genetic information alone can identify children at risk of myopia development and whether including a child's genetic predisposition to educational attainment is associated with improved genetic prediction of the risk of myopia. Design, Setting, and Participants:Meta-analysis of 3 genome-wide association studies (GWAS) including a total of 711 984 individuals. These were a published GWAS for educational attainment and 2 GWAS for refractive error in the UK Biobank, which is a multisite cohort study that recruited participants between January 2006 and October 2010. A polygenic risk score was applied in a population-based validation sample examined between September 1998 and September 2000 (Avon Longitudinal Study of Parents and Children [ALSPAC] mothers). Data analysis was performed from February 2018 to May 2019. Main Outcomes and Measures:The primary outcome was the area under the receiver operating characteristic curve (AUROC) in analyses for predicting myopia, using noncycloplegic autorefraction measurements for myopia severity levels of less than or equal to -0.75 diopter (D) (any), less than or equal to -3.00 D (moderate), or less than or equal to -5.00 D (high). The predictor variable was a polygenic risk score (PRS) derived from genome-wide association study data for refractive error (n?=?95?619), age of onset of spectacle wear (n?=?287?448), and educational attainment (n?=?328?917). Results:A total of 383 067 adults aged 40 to 69 years from the UK Biobank were included in the new GWAS analyses. The PRS was evaluated in 1516 adults aged 24 to 51 years from the ALSPAC mothers cohort. The PRS had an AUROC of 0.67 (95% CI, 0.65-0.70) for myopia, 0.75 (95% CI, 0.70-0.79) for moderate myopia, and 0.73 (95% CI, 0.66-0.80) for high myopia. Inclusion in the PRS of information associated with genetic predisposition to educational attainment marginally improved the AUROC for myopia (AUROC, 0.674 vs 0.668; P?=?.02), but not those for moderate and high myopia. Individuals with a PRS in the top 10% were at 6.1-fold higher risk (95% CI, 3.4-10.9) of high myopia. Conclusions and Relevance:A personalized medicine approach may be feasible for detecting very young children at risk of myopia. However, accuracy must improve further to merit uptake in clinical practice; currently, cycloplegic autorefraction remains a better indicator of myopia risk (AUROC, 0.87).
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Project description:The association between body fatness before adulthood and later risk of colorectal cancer remains unclear. We hypothesized that, independent of adult body fatness, early life body fatness would be associated with a higher risk of developing colorectal cancer.We assessed body fatness during childhood and adolescence using a validated 9-level somatotype and inquired body weight in young adulthood in the Nurses' Health Study and Health Professionals Follow-up Study. We used the Cox proportional hazard regression modeling to estimate relative risks [RR, 95% confidence intervals (CI)] adjusting for adult body mass index (BMI) and other known colorectal cancer risk factors.We identified 2,100 incident colorectal cancer cases (1,292 in women and 808 in men) during 22 years of follow-up. Among women, the RR (95% CI) for childhood body fatness of level 5 or higher versus level 1 was 1.28 (1.04-1.58; Ptrend = 0.08) and for adolescent body fatness, it was 1.27 (1.01-1.60; Ptrend = 0.23). The corresponding RRs for men were 1.04 (0.82-1.31; Ptrend = 0.48) and 0.98 (0.75-1.27; Ptrend = 0.20), respectively. Results were generally similar across anatomic subsites within the colorectum. In addition, the RRs comparing BMI categories ?27.5 to <19 kg/m(2) were 1.44 (1.06-1.95, at age 18; Ptrend = 0.009) for women and 1.18 (0.84-1.65, at age 21; Ptrend = 0.57) for men.Increased body fatness in early life, independent of adult obesity, might be a risk factor for colorectal cancer in women, but we observed a weaker association in men.Our findings support the growing evidence that early life body fatness affects the risk of colorectal cancer many decades later.
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