| 1. |
- Justice, Anne E., et al.
(författare)
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Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:3, s. 452-469
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Tidskriftsartikel (refereegranskat)abstract
- Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF >= 5%) and nine low-frequency or rare (MAF < 5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
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| 2. |
- Shu, Xiang, et al.
(författare)
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Associations of obesity and circulating insulin and glucose with breast cancer risk : a Mendelian randomization analysis
- 2019
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Ingår i: International Journal of Epidemiology. - : OXFORD UNIV PRESS. - 0300-5771 .- 1464-3685. ; 48:3, s. 795-806
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Tidskriftsartikel (refereegranskat)abstract
- Background: In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear. Methods: We conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium. Results: All sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p = 5.09 x 10(-4)], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p = 4.02 x 10(-4)), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p = 5.05 x 10(-19)) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p = 9.22 x 10(-6)). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer. Conclusions: We confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer.
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| 3. |
- Li, Jingmei, et al.
(författare)
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Prevalence of BRCA1 and BRCA2 pathogenic variants in a large, unselected breast cancer cohort
- 2019
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 144:5, s. 1195-1204
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer patients with BRCA1/2-driven tumors may benefit from targeted therapy. It is not clear whether current BRCA screening guidelines are effective at identifying these patients. The purpose of our study was to evaluate the prevalence of inherited BRCA1/2 pathogenic variants in a large, clinically representative breast cancer cohort and to estimate the proportion of BRCA1/2 carriers not detected by selectively screening individuals with the highest probability of being carriers according to current clinical guidelines. The study included 5,122 unselected Swedish breast cancer patients diagnosed from 2001 to 2008. Target sequence enrichment (48.48 Fluidigm Access Arrays) and sequencing were performed (Illumina Hi-Seq 2,500 instrument, v4 chemistry). Differences in patient and tumor characteristics of BRCA1/2 carriers who were already identified as part of clinical BRCA1/2 testing routines and additional BRCA1/2 carriers found by sequencing the entire study population were compared using logistic regression models. Ninety-two of 5,099 patients with valid variant calls were identified as BRCA1/2 carriers by screening all study participants (1.8%). Only 416 study participants (8.2%) were screened as part of clinical practice, but this identified 35 out of 92 carriers (38.0%). Clinically identified carriers were younger, less likely postmenopausal and more likely to be associated with familiar ovarian cancer compared to the additional carriers identified by screening all patients. More BRCA2 (34/42, 81.0%) than BRCA1 carriers (23/50, 46%) were missed by clinical screening. In conclusion, BRCA1/2 mutation prevalence in unselected breast cancer patients was 1.8%. Six in ten BRCA carriers were not detected by selective clinical screening of individuals.
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