Family Registry Research Articles

Abstract 819: Consumption of fruits, vegetables and fiber and risk of colorectal cancer: A gene environment interaction analysis

Abstract Introduction: Consumption of fruits, vegetables and fiber has been associated with lower colorectal cancer (CRC) risk however, it is unclear if genetic variants can modify these associations. Methods: Within three genetic CRC consortia including up to 76,157 participants (32,859 cases and 43,298 controls) of European descent: the Colorectal Cancer Family Registry (CCFR), the Colorectal Cancer Transdisciplinary (CORECT) Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), one-step [logistic regression case-control analysis and joint two- and three-degrees of freedom (DF) tests] and two-step methods were implemented to identify novel and biologically plausible gene-environment interactions. Results: Fruits, vegetables and fiber consumption were inversely associated with CRC with odds ratios per quartile increase of 0.89 [95% confidence interval (CI): 0.86, 0.92], 0.91 (95% CI: 0.88, 0.94) and 0.86 (95% CI: 0.84, 0.89) respectively. The logistic regression analysis identified significant interaction effects between rs142981275 adjacent to the ACOT1 gene and fruits consumption (pval:1.91E-8) and the 2DF test, which jointly considers G and GxE effects, also identified this SNP. The 3DF test also considers G and GxE information and further revealed four loci associated with CRC risk, in the genes NEGR1(rs1620977), ZRANB3 (rs1561277), MCM6 (rs4988235), R3HDM1(rs12465802) (all pval:<5E-8) out of which rs1620977 and rs12465802 were the leading independent variants. For vegetables, the 3DF test identified significant interaction effects in the DCBLD1 gene (rs4946259; pval:1.44E-8). Finally, no significant interactions were observed for any genetic variant and fiber consumption. The 2-step approach did not identify additional interactions either. Conclusion: This study identified statistically significant interactions between several genetic variants and the consumption of fruits and vegetables with CRC risk. Further research is needed to elucidate the exact mechanisms through which these interactions might influence CRC risk. Citation Format: Nikos Papadimitriou, Akihisa Hidaka, Andre Kim, Niki Dimou, Neil Murphy, Sonja I. Berndt, David Conti, Peter T. Campbell, Graham Casey, Jane C. Figueiredo, Konstantinos K. Tsilidis, Stephen B. Gruber, Sophia Harlid, Yi Lin, Victor Moreno, Lori C. Sakoda, Virginia D. Obrero, Li Hsu, William J. Gauderman, Marc Gunter, Ulrike Peters. Consumption of fruits, vegetables and fiber and risk of colorectal cancer: A gene environment interaction analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 819.

P0728 - Risk of genitourinary malignancies in Lynch syndrome patients with DNA mismatch repair gene mutations in a large Canadian Familial Registry

P0728 - Risk of genitourinary malignancies in Lynch syndrome patients with DNA mismatch repair gene mutations in a large Canadian Familial Registry

Genetically predicted circulating concentrations of micronutrients and risk of colorectal cancer among individuals of European descent: a Mendelian randomization study

The literature on associations of circulating concentrations of minerals and vitamins with risk of colorectal cancer is limited and inconsistent. Evidence from randomized controlled trials (RCTs) to support the efficacy of dietary modification or nutrient supplementation for colorectal cancer prevention is also limited. To complement observational and RCT findings, we investigated associations of genetically predicted concentrations of 11 micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, and zinc) with colorectal cancer risk using Mendelian randomization (MR). Two-sample MR was conducted using 58,221 individuals with colorectal cancer and 67,694 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions. Nominally significant associations were noted for genetically predicted iron concentration and higher risk of colon cancer [ORs per SD (ORSD): 1.08; 95% CI: 1.00, 1.17; P value = 0.05] and similarly for proximal colon cancer, and for vitamin B-12 concentration and higher risk of colorectal cancer (ORSD: 1.12; 95% CI: 1.03, 1.21; P value = 0.01) and similarly for colon cancer. A nominally significant association was also noted for genetically predicted selenium concentration and lower risk of colon cancer (ORSD: 0.98; 95% CI: 0.96, 1.00; P value = 0.05) and similarly for distal colon cancer. These associations were robust to sensitivity analyses. Nominally significant inverse associations were observed for zinc and risk of colorectal and distal colon cancers, but sensitivity analyses could not be performed. None of these findings survived correction for multiple testing. Genetically predicted concentrations of β-carotene, calcium, copper, folate, magnesium, phosphorus, and vitamin B-6 were not associated with disease risk. These results suggest possible causal associations of circulating iron and vitamin B-12 (positively) and selenium (inversely) with risk of colon cancer.

Population-based estimates of the age-specific cumulative risk of breast cancer for pathogenic variants in CHEK2: Findings from the Australian Breast Cancer Family Registry.

551 Background: Case-control studies of breast cancer have consistently shown that pathogenic variants in CHEK2 are associated with about a 3-fold increased risk of breast cancer. Information about the recurrent protein truncating variant CHEK2c.1100delC dominates this estimate. There have been no formal estimates of age-specific cumulative risk of breast cancer for all CHEK2 pathogenic (including likely pathogenic) variants combined. Methods: We conducted a genetic screen of CHEK2 in an Australian population-based case-control-family study of breast cancer. This study is focused on disease at an early age and participants were unselected for family history. The age-specific cumulative risk (penetrance) of breast cancer was estimated using segregation analysis. Results: The estimated hazard ratio for carriers of pathogenic CHEK2 variants (combined) was 4.9 (95% CI 2.5-9.5; p < 0.0001) relative to non-carriers. The HR for carriers of the CHEK2 c.1100delC variant was estimated to be 3.5 (95% CI 1.02-11.6) and the HR for carriers of all other CHEK2 variants combined was estimated to be 5.7 (95% CI 2.5-12.9). The age-specific cumulative risk of breast cancer was estimated to be 18% (95% CI 11-30%) and 33% (95% CI 21-48%) to age 60 and 80 years, respectively. Conclusions: These findings provide important information for the clinical management of breast cancer risk for women carrying pathogenic variants in CHEK2.

Cumulative risks of colorectal cancer in Han Chinese patients with Lynch syndrome in Taiwan

Patients with Lynch syndrome have a high risk of colorectal cancer (CRC). In this study, we estimated the age- and sex-specific cumulative risks of CRC in Han Chinese patients with Lynch syndrome caused by the pathogenic germline mutations in MLH1 or MSH2 in Taiwan. Based on 321 mutation carriers and 419 non-mutation carriers from 75 pedigrees collected in an Amsterdam criteria family registry in Taiwan, the age- and sex-specific cumulative risks of CRC in male carriers of mutation in MLH1 and MSH2 at the age of 70 years were 60.3% (95% confidence interval (CI) = 31.1%–89.9%) and 76.7% (95% CI = 37.2%–99.0%), respectively. For females, the cumulative risks of CRC at the age of 70 were estimated to be 30.6% (95% CI = 14.3%–57.7%) and 49.3% (95% CI = 21.9%–84.5%) in the carriers of MLH1 and MSH2 germline mutations, respectively. In conclusion, the cumulative risks of CRC at the age of 70 in the Han Chinese patients is higher in mutation carriers than non-mutation carriers and male mutation carriers have a higher cumulative risk of developing CRC than the female mutation carriers.

Two-Sample Mendelian Randomization Analysis of Associations Between Periodontal Disease and Risk of Cancer.

BackgroundObservational studies indicate that periodontal disease may increase the risk of colorectal, lung, and pancreatic cancers. Using a 2-sample Mendelian randomization (MR) analysis, we assessed whether a genetic predisposition index for periodontal disease was associated with colorectal, lung, or pancreatic cancer risks.MethodsOur primary instrument included single nucleotide polymorphisms with strong genome-wide association study evidence for associations with chronic, aggressive, and/or severe periodontal disease (rs729876, rs1537415, rs2738058, rs12461706, rs16870060, rs2521634, rs3826782, and rs7762544). We used summary-level genetic data for colorectal cancer (n = 58 131 cases; Genetics and Epidemiology of Colorectal Cancer Consortium, Colon Cancer Family Registry, and Colorectal Transdisciplinary Study), lung cancer (n = 18 082 cases; International Lung Cancer Consortium), and pancreatic cancer (n = 9254 cases; Pancreatic Cancer Consortia). Four MR approaches were employed for this analysis: random-effects inverse‐variance weighted (primary analyses), Mendelian Randomization-Pleiotropy RESidual Sum and Outlier, simple median, and weighted median. We conducted secondary analyses to determine if associations varied by cancer subtype (colorectal cancer location, lung cancer histology), sex (colorectal and pancreatic cancers), or smoking history (lung and pancreatic cancer). All statistical tests were 2-sided.ResultsThe genetic predisposition index for chronic or aggressive periodontitis was statistically significantly associated with a 3% increased risk of colorectal cancer (per unit increase in genetic index of periodontal disease; P = .03), 3% increased risk of colon cancer (P = .02), 4% increased risk of proximal colon cancer (P = .01), and 3% increased risk of colorectal cancer among females (P = .04); however, it was not statistically significantly associated with the risk of lung cancer or pancreatic cancer, overall or within most subgroups.ConclusionsGenetic predisposition to periodontitis may be associated with colorectal cancer risk. Further research should determine whether increased periodontitis prevention and increased cancer surveillance of patients with periodontitis is warranted.

How to Help Your Patients Enroll in the New-Onset Refractory Status Epilepticus (NORSE) and Febrile Infection-Related Epilepsy Syndrome (FIRES) Family Registry, and Other Rare Epilepsy Registries.

How to Help Your Patients Enroll in the New-Onset Refractory Status Epilepticus (NORSE) and Febrile Infection-Related Epilepsy Syndrome (FIRES) Family Registry, and Other Rare Epilepsy Registries.

Population-Based Estimates of the Age-Specific Cumulative Risk of Breast Cancer for Pathogenic Variants in CHEK2: Findings from the Australian Breast Cancer Family Registry.

Simple SummaryIt is well established that women who carry pathogenic CHEK2 variants have about a 3-fold increased risk of developing breast cancer. CHEK2 is now commonly included in genetic tests for breast cancer predisposition and increasingly used to inform the clinical management of women who are identified to carry pathogenic variants. Important information for counselling these women includes knowing how breast cancer risk, due to having a pathogenic variant in CHEK2, changes over a woman’s lifetime. This information is currently not well established. By conducting a population-based case-control-family study of pathogenic CHEK2 variants we aimed to provide this information and estimated the penetrance (age-specific cumulative risk) of breast cancer to be 18% (95% CI 11–30%) to age 60 years and 33% (95% CI 21–48%) to age 80 years. These findings provide new and important information for the clinical management of breast cancer risk for women carrying pathogenic variants in CHEK2.Case-control studies of breast cancer have consistently shown that pathogenic variants in CHEK2 are associated with about a 3-fold increased risk of breast cancer. Information about the recurrent protein-truncating variant CHEK2 c.1100delC dominates this estimate. There have been no formal estimates of age-specific cumulative risk of breast cancer for all CHEK2 pathogenic (including likely pathogenic) variants combined. We conducted a population-based case-control-family study of pathogenic CHEK2 variants (26 families, 1071 relatives) and estimated the age-specific cumulative risk of breast cancer using segregation analysis. The estimated hazard ratio for carriers of pathogenic CHEK2 variants (combined) was 4.9 (95% CI 2.5–9.5) relative to non-carriers. The HR for carriers of the CHEK2 c.1100delC variant was estimated to be 3.5 (95% CI 1.02–11.6) and the HR for carriers of all other CHEK2 variants combined was estimated to be 5.7 (95% CI 2.5–12.9). The age-specific cumulative risk of breast cancer was estimated to be 18% (95% CI 11–30%) and 33% (95% CI 21–48%) to age 60 and 80 years, respectively. These findings provide important information for the clinical management of breast cancer risk for women carrying pathogenic variants in CHEK2.

A Combined Proteomics and Mendelian Randomization Approach to Investigate the Effects of Aspirin-Targeted Proteins on Colorectal Cancer.

Evidence for aspirin's chemopreventative properties on colorectal cancer (CRC) is substantial, but its mechanism of action is not well-understood. We combined a proteomic approach with Mendelian randomization (MR) to identify possible new aspirin targets that decrease CRC risk. Human colorectal adenoma cells (RG/C2) were treated with aspirin (24 hours) and a stable isotope labeling with amino acids in cell culture (SILAC) based proteomics approach identified altered protein expression. Protein quantitative trait loci (pQTLs) from INTERVAL (N = 3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium (N = 31,684) were used as genetic proxies for protein and mRNA expression levels. Two-sample MR of mRNA/protein expression on CRC risk was performed using eQTL/pQTL data combined with CRC genetic summary data from the Colon Cancer Family Registry (CCFR), Colorectal Transdisciplinary (CORECT), Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia and UK Biobank (55,168 cases and 65,160 controls). Altered expression was detected for 125/5886 proteins. Of these, aspirin decreased MCM6, RRM2, and ARFIP2 expression, and MR analysis showed that a standard deviation increase in mRNA/protein expression was associated with increased CRC risk (OR: 1.08, 95% CI, 1.03-1.13; OR: 3.33, 95% CI, 2.46-4.50; and OR: 1.15, 95% CI, 1.02-1.29, respectively). MCM6 and RRM2 are involved in DNA repair whereby reduced expression may lead to increased DNA aberrations and ultimately cancer cell death, whereas ARFIP2 is involved in actin cytoskeletal regulation, indicating a possible role in aspirin's reduction of metastasis. Our approach has shown how laboratory experiments and population-based approaches can combine to identify aspirin-targeted proteins possibly affecting CRC risk.

Association of Risk-Reducing Salpingo-Oophorectomy With Breast Cancer Risk in Women With BRCA1 and BRCA2 Pathogenic Variants

Women with pathogenic variants in BRCA1 and BRCA2 are at high risk of developing breast and ovarian cancers. They usually undergo intensive cancer surveillance and may also consider surgical interventions, such as risk-reducing mastectomy or risk-reducing salpingo-oophorectomy (RRSO). Risk-reducing salpingo-oophorectomy has been shown to reduce ovarian cancer risk, but its association with breast cancer risk is less clear. To assess the association of RRSO with the risk of breast cancer in women with BRCA1 and BRCA2 pathogenic variants. This case series included families enrolled in the Breast Cancer Family Registry between 1996 and 2000 that carried an inherited pathogenic variant in BRCA1 (498 families) or BRCA2 (378 families). A survival analysis approach was used that was designed specifically to assess the time-varying association of RRSO with breast cancer risk and accounting for other potential biases. Data were analyzed from August 2019 to November 2020. Risk-reducing salpingo-oophorectomy. In all analyses, the primary end point was the time to a first primary breast cancer. A total of 876 families were evaluated, including 498 with BRCA1 (2650 individuals; mean [SD] event age, 55.8 [19.1] years; 437 White probands [87.8%]) and 378 with BRCA2 (1925 individuals; mean [SD] event age, 57.0 [18.6] years; 299 White probands [79.1%]). Risk-reducing salpingo-oophorectomy was associated with a reduced risk of breast cancer for BRCA1 and BRCA2 pathogenic variant carriers within 5 years after surgery (hazard ratios [HRs], 0.28 [95% CI, 0.10-0.63] and 0.19 [95% CI, 0.06-0.71], respectively), whereas the corresponding HRs were weaker after 5 years postsurgery (HRs, 0.64 [95% CI, 0.38-0.97] and 0.99 [95% CI; 0.84-1.00], respectively). For BRCA1 and BRCA2 pathogenic variant carriers who underwent RRSO at age 40 years, the cause-specific cumulative risk of breast cancer was 49.7% (95% CI, 40.0-60.3) and 52.7% (95% CI, 47.9-58.7) by age 70 years, respectively, compared with 61.0% (95% CI, 56.7-66.0) and 54.0% (95% CI, 49.3-60.1), respectively, for women without RRSO. Although the primary indication for RRSO is the prevention of ovarian cancer, it is also critical to assess its association with breast cancer risk in order to guide clinical decision-making about RRSO use and timing. The results of this case series suggest a reduced risk of breast cancer associated with RRSO in the immediate 5 years after surgery in women carrying BRCA1 and BRCA2 pathogenic variants, and a longer-term association with cumulative breast cancer risk in women carrying BRCA1 pathogenic variants.

Abstract PS7-04: Population-based estimates of breast cancer risk for germline pathogenic variants identified by gene-panel testing: An Australian perspective

Abstract BRA-STRAP is an Australia-wide study of breast cancer predisposition that brings together gene-panel data from 30,000 adult Australian women of all ages, across the breast cancer risk spectrum, with and without a diagnosis of breast cancer. The “BRA-STRAP panel” includes 24 genes* that are involved in, or putatively associated with, predisposition to breast and/or ovarian cancer. Despite insufficient evidence for clinical translation for some of these genes, all 24 are commonly included on panel tests for breast cancer predisposition. We present findings from the population-based case-control sub-study of BRA-STRAP, which involved 1451 women diagnosed with breast cancer and 857 age-matched controls participating in the Australian Breast Cancer Family Registry (ABCFR), and 6101 healthy, elderly Australian women enrolled in the ASPREE study. These analyses focus on rare genetic variants predicted to lead to loss of function and/or classified as pathogenic/likely pathogenic (P/LP) in ClinVar. Odds ratios (ORs) for their associations with breast cancer were estimated by aggregating genetic variants for each gene. For the women diagnosed with breast cancer, the median age at diagnosis (inter-quartile range, IQR) was 40.0 (14.0) years and the overall frequency of P/LP variant carriers across all genes was 156/1451 (10.8%). The median age (IQR) of the ABCFR and ASPREE controls were 39.4 (14.9) and 73.9 (5.8) years, respectively. The frequencies of P/LP variant carriers were 33/857 (3.9%) and 268/6101 (4.4%) in the ABCFR and ASPREE controls, respectively. We combined both control datasets and, after adjusting for age and other potential confounders, the ORs associated with P/LP variants in BRCA1 and BRCA2 were 4.1 [95% confidence interval (CI): 1.8-10.2] and 2.9 [95% CI: 1.5-6], respectively. We also found that the OR for P/LP variants in ATM was 4.0 [95% CI: 1.5-10.4] and the OR for P/LP variants in PALB2 was 2.2 [95% CI: 0.75-5.7] although this did not reach statistical significance. These results contribute to international efforts to refine the breast cancer risk estimates for genetic variants identified from population-based screening of unselected women using genes that are included on panel tests and thought to be potentially breast cancer predisposition genes.The case-control-family design of the ABCFR will also allow us to estimate the age specific cumulative risk (penetrance) of these genetic variants, which is important for genetic counselling and the clinical management of carrier families. *ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, FANCM, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, NF1, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, RECQL, STK11 and TP53 Citation Format: Tu Nguyen-Dumont, James Dowty, Katherine Tucker, Judy Kirk, Paul James, Alison Trainer, Ingrid Winship, Nicholas Pachter, Nicola Poplawski, Scott Grist, Daniel J Park, Anne-Laure Renault, Fleur Hammet, Maryam Mahmoodi, Helen Tsimiklis, Jason A Steen, Derrick Theys, Amanda Rewse, Amanda Willis, April Morrow, Catherine Speechly, Rebecca Harris, Moeen Riaz, Robert Sebra, Eric Schadt, Paul Lacaze, John McNeil, John L Hopper, Melissa C Southey. Population-based estimates of breast cancer risk for germline pathogenic variants identified by gene-panel testing: An Australian perspective [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-04.

Addressing Gaps in Racial/Ethnic Representation in Familial Hypercholesterolemia Registries: Implications and Recommendations for Equitable Access to Research and Care.

Addressing Gaps in Racial/Ethnic Representation in Familial Hypercholesterolemia Registries: Implications and Recommendations for Equitable Access to Research and Care.

The Steroid Metabolome and Breast Cancer Risk in Women with a Family History of Breast Cancer: The Novel Role of Adrenal Androgens and Glucocorticoids.

No study has comprehensively examined how the steroid metabolome is associated with breast cancer risk in women with familial risk. We examined 36 steroid metabolites across the spectrum of familial risk (5-year risk ranged from 0.14% to 23.8%) in pre- and postmenopausal women participating in the New York site of the Breast Cancer Family Registry (BCFR). We conducted a nested case-control study with 62 cases/124 controls individually matched on menopausal status, age, and race. We measured metabolites using GC-MS in urine samples collected at baseline before the onset of prospectively ascertained cases. We used conditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) per doubling in hormone levels. The average proportion of total steroid metabolites in the study sample were glucocorticoids (61%), androgens (26%), progestogens (11%), and estrogens (2%). A doubling in glucocorticoids (aOR = 2.7; 95% CI = 1.3-5.3) and androgens (aOR = 1.6; 95% CI = 1.0-2.7) was associated with increased breast cancer risk. Specific glucocorticoids (THE, THF αTHF, 6β-OH-F, THA, and α-THB) were associated with 49% to 161% increased risk. Two androgen metabolites (AN and 11-OH-AN) were associated with 70% (aOR = 1.7; 95% CI = 1.1-2.7) and 90% (aOR = 1.9; 95% CI = 1.2-3.1) increased risk, respectively. One intermediate metabolite of a cortisol precursor (THS) was associated with 65% (OR = 1.65; 95% CI = 1.0-2.7) increased risk. E1 and E2 estrogens were associated with 20% and 27% decreased risk, respectively. Results suggest that glucocorticoids and 11-oxygenated androgens are positively associated with breast cancer risk across the familial risk spectrum. If replicated, our findings suggest great potential of including steroids into existing breast cancer risk assessment tools.

The Character and Function of Shoen’iku, An Adoption and Support Practices: A Study of a Family Registry in Mizubaura District, Sonemura Village, Kumage County, Suoh Province

The Character and Function of <i>Shoen’iku</i>, An Adoption and Support Practices: A Study of a Family Registry in Mizubaura District, Sonemura Village, Kumage County, Suoh Province

Lifetime risk of suicide among survivors of the atomic bombings of Japan.

The long-term physical health effects of the atomic bombings of Hiroshima and Nagasaki are well characterised, but the psychological effects remain unclear. Therefore, we sought to determine whether measures of exposure severity, as indirect measures of psychological trauma arising from exposure to the atomic bombings, are associated with suicide mortality among atomic bomb survivors. The Life Span Study is a prospective cohort study of 93 741 Japanese atomic bomb survivors who were located within 10 km of the hypocentre in Hiroshima or Nagasaki at the time of the bombings in 1945, and 26 579 residents of Hiroshima and Nagasaki who were not in either city at the time of the bombings, matched to survivors on city, sex and age. Measures of exposure severity included: proximity to the hypocentre, type of shielding between the survivor and the blast and self-reported occurrence of acute radiation and thermal injuries. Date of death was obtained from the Japanese National Family Registry system. Cause of death was obtained from death certificates. Adjusted hazard ratios (HRs) were estimated from Cox regression models overall and stratified by sex and age. During the 60-year follow-up period (1950-2009), 1150 suicide deaths were recorded among 120 231 participants (23.6 per 100 000 person-years): 510 among 70 092 women (17.2 per 100 000 person-years) and 640 among 50 139 men (33.6 per 100 000 person-years). Overall, there was no association of proximity, type of shielding or the occurrence of acute injuries with suicide mortality. Among those <25 years of age at the time of the bombings, increased suicide risk was observed for survivors outside v. shielded inside any structure (HR: 1.24; 95% confidence interval (CI): 1.03, 1.48; interaction p = 0.054) and for those who reported flash burns (HR: 1.32; 95% CI: 1.00, 1.73; interaction p = 0.025). Sex-stratified analyses indicated that these associations were limited to men. Among women, closer proximity to the hypocentre was associated with a non-significant increase in suicide risk, with a positive association between proximity and suicide risk observed among women <15 years of age (HR: 1.09 per km; 95% CI: 1.00, 1.18; interaction p = 0.067). Proximity to the hypocentre, shielding and acute injury presence do not generally appear to influence suicide mortality among atomic bomb survivors. However, heterogeneity may exist by age and sex, with younger survivors potentially more sensitive to psychological trauma. Coupled with other studies, our results suggest the importance of long-term monitoring of mental health among young populations exposed to catastrophic events or mass trauma.

Ovarian antibodies among SLE women with premature menopause after cyclophosphamide.

Women with systemic lupus erythematosus (SLE) are at risk of premature ovarian failure when treated with cyclophosphamide. This risk is increased when autoimmune thyroid disease is present. We undertook this study to determine whether the presence of ovarian autoimmunity also increased the risk of early ovarian failure among women receiving cyclophosphamide. We examined the records of women enrolled in the Lupus Family Registry and Repository, a cross-sectional study of ~3300 SLE subjects, for treatment with cyclophosphamide as well as menopausal status. We defined premature menopause as permanent, spontaneous cessation of menstruation before age 45. We measured anti-ovarian antibodies by enzyme-linked immunosorbent assay using stored sera. There were 258 women treated with cyclophosphamide in whom presence of absence or premature menopause could by defined. A total of 169 (65.6%) had premature ovarian failure, while 89 (34.6%) did not. While anti-ovarian antibodies were present in a small percentage of patients, there was no association of premature menopause to either level of these antibodies (16.2±20.3 units vs 17.4±21.7 units, P=NS by Fisher's exact test), or positivity on this testing (11 of 169 [6.5%] positive vs 8 of 89 [8.9%], χ2 =0.53, P=.46, 95% CI 0.95-1.1). Neither renal disease nor hypothyroidism increased the risk of premature ovarian failure in these women receiving cyclophosphamide. Anti-ovarian antibodies among women with SLE are not associated with premature ovarian failure after treatment with cyclophosphamide.

Integrated Guidance for Enhancing the Care of Familial Hypercholesterolaemia in Australia

Familial hypercholesterolaemia (FH) is a dominant and highly penetrant monogenic disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL)-cholesterol concentration and, if untreated, leads to premature atherosclerosis and coronary artery disease (CAD). There are approximately 100,000 people with FH in Australia. However, an overwhelming majority of those affected remain undetected and inadequately treated, consistent with FH being a leading challenge for public health genomics. To further address the unmet need, we provide an updated guidance, presented as a series of systematically collated recommendations, on the care of patients and families with FH. These recommendations have been informed by an exponential growth in published works and new evidence over the last 5 years and are compatible with a contemporary global call to action on FH. Recommendations are given on the detection, diagnosis, assessment and management of FH in adults and children. Recommendations are also made on genetic testing and risk notification of biological relatives who should undergo cascade testing for FH. Guidance on management is based on the concepts of risk re-stratification, adherence to heart healthy lifestyles, treatment of non-cholesterol risk factors, and safe and appropriate use of LDL-cholesterol lowering therapies, including statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors and lipoprotein apheresis. Broad recommendations are also provided for the organisation and development of health care services. Recommendations on best practice need to be underpinned by good clinical judgment and shared decision making with patients and families. Models of care for FH need to be adapted to local and regional health care needs and available resources. A comprehensive and realistic implementation strategy, informed by further research, including assessments of cost-benefit, will be required to ensure that this new guidance benefits all Australian families with or at risk of FH.

Predictors of cardiovascular outcomes in patients with heterozygous familial hypercholesterolemia according the russian familial hypercholesterolemia registry

Predictors of cardiovascular outcomes in patients with heterozygous familial hypercholesterolemia according the russian familial hypercholesterolemia registry

Gender specificities of the Ukrainian familial hypercholesterolemia registry

Background and Aims: To estimate gender-specific differences of patients with possible familial hypercholesterolemia (FH) (LDL-C ≥ 5 mmol/l) based on the data of the Ukrainian FH Registry.

Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study

BackgroundHigher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood.MethodsWe examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models.ResultsIn sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles.ConclusionsOur results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.