Publications by authors named "Jae H Kang"

114 Publications

Effect of vitamin D on cognitive decline: results from two ancillary studies of the VITAL randomized trial.

Sci Rep 2021 Dec 1;11(1):23253. Epub 2021 Dec 1.

Harvard T. H. Chan School of Public Health, Boston, MA, USA.

Low vitamin D levels have been associated with cognitive decline; however, few randomized trials have been conducted. In a trial, we evaluated vitamin D3 supplementation on cognitive decline. We included participants aged 60+ years (mean[SD] = 70.9[5.8] years) free of cardiovascular disease and cancer in two substudies in the VITAL 2 × 2 randomized trial of vitamin D3 (2000 IU/day of cholecalciferol) and fish oil supplements: 3424 had cognitive assessments by phone (eight neuropsychologic tests; 2.8 years follow-up) and 794 had in-person assessments (nine tests; 2.0 years follow-up). The primary, pre-specified outcome was decline over two assessments in global composite score (average z-scores of all tests); substudy-specific results were meta-analyzed. The pooled mean difference in annual rate of decline (MD) for vitamin D3 versus placebo was 0.01 (95% CI - 0.01, 0.02; p = 0.39). We observed no interaction with baseline 25-hydroxyvitamin-D levels (p-interaction = 0.84) and a significant interaction with self-reported race (p-interaction = 0.01). Among Black participants (19%), those assigned vitamin D3 versus placebo had better cognitive maintenance (MD = 0.04, 95% CI 0.01, 0.08, similar to that observed for Black participants 1.2 years apart in age). Thus, vitamin D3 (2000 IU/day cholecalciferol) supplementation was not associated with cognitive decline over 2-3 years among community-dwelling older participants but may provide modest cognitive benefits in older Black adults, although these results need confirmation.Trial registration ClinicalTrials.gov; VITAL (NCT01169259), VITAL-DEP (NCT01696435) and VITAL-Cog (NCT01669915); the date the registration for the parent trial (NCT01169259) was submitted to the registry: 7/26/2010 and the date of first patient enrollment in either of the ancillary studies for cognitive function in a subset of eligible VITAL participants: 9/14/2011.
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http://dx.doi.org/10.1038/s41598-021-02485-8DOI Listing
December 2021

Low-Intensity Exercise and Pregnancy Outcomes: An Examination in the Nurses' Health Study II.

Womens Health Rep (New Rochelle) 2021 15;2(1):389-395. Epub 2021 Sep 15.

Channing Division of Network Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts, USA.

The benefit of low-intensity exercise (LIE) during pregnancy is poorly understood at a time when few women participate in moderate or vigorous exercise. Using data from the Nurses' Health Study II (NHSII), we tested the hypothesis that women who engaged in more LIE before and during pregnancy experience fewer pregnancy complications. Among 116,429 U.S. female registered nurses (25-42 years of age) who were enrolled in NHSII in 1989, we included participants (36-50 years of age) who reported in 2001 or 2005 that they were pregnant and completed questionnaires about pregnancy "low-intensity exercise (yoga, stretching, toning)," and who in 2009, provided a full pregnancy outcome history. Multivariable-adjusted relative risk (RR) and 95% confidence intervals (CIs) were calculated between LIE and adverse pregnancy outcomes using log-binomial regression models. Among 225 eligible pregnant participants, 71 (31.6%) reported engaging in any LIE. LIE was associated with lower preterm birth, but not significantly associated with pregnancy loss or other adverse pregnancy outcomes. The RR for any LIE for preterm birth was 0.31 (95% CI: 0.09-1.07), with a significant dose-response association [RR = 0.65 (95% CI: 0.48-0.89) per every 30-minute session]. Some suggestive inverse associations were also observed for other adverse pregnancy outcomes: the RR for any LIE for low birthweight was 0.35 (95% CI: 0.08-1.48); for preeclampsia/gestational hypertension was 0.51 (95% CI: 0.13-1.96); and for gestational diabetes was 0.64 (95% CI: 0.25-1.64). Pregnant women can include yoga, stretching, and toning exercise for promoting wellbeing.
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http://dx.doi.org/10.1089/whr.2021.0011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8524727PMC
September 2021

Irritable bowel syndrome and risk of glaucoma: An analysis of two independent population-based cohort studies.

United European Gastroenterol J 2021 Nov 25;9(9):1057-1065. Epub 2021 Aug 25.

School of Medicine and Public Health, The Centre for Clinical Epidemiology and Biostatistics, The Australian GastroIntestinal Research Alliance (AGIRA), The University of Newcastle, Callaghan, New South Wales, Australia.

Objective: Irritable bowel syndrome (IBS) is a chronic disorder associated with an abnormal gastrointestinal microbiome. Microbiome-host interactions are known to influence organ function including in the central nervous system; thus, we sought to identify whether IBS may be a risk factor for the development of glaucoma.

Design: Two prospective cohort studies.

Subjects: The 1958 United Kingdom Birth Cohort (UKBC; 9091 individuals) and the Danish National Registry of Patients (DNRP; 62,541 individuals with IBS and 625,410 matched general population cohort members).

Methods: In the UKBC, participants were surveyed throughout life (including at ages 42 and 50). The DNRP contains records of hospital-based contacts and prescription data from the national prescription database.

Main Outcome Measure: The main outcome measure was incidence of glaucoma. In the UKBC, incident glaucoma at age 50 (n = 48) was determined through comparison of survey responses at ages 42 and 50 years. In the DNRP, glaucoma was assessed by hospital diagnosis (n = 1510), glaucoma surgery (n = 582) and initiation of glaucoma medications (n = 1674).

Results: In the UKBC, the odds ratio (OR) of developing glaucoma between ages 42 and 50 in persons with a chronic IBS diagnosis was increased [OR: 5.84, 95% confidence interval (CI): 2.26-15.13]. People with an IBS diagnosis in the DNRP had a hazard ratio (HR) of 1.35 for developing physician-diagnosed glaucoma (95% CI: 1.16-1.56), an HR of 1.35 for undergoing glaucoma surgery (95% CI: 1.06-1.70) and an HR of 1.19 for initiating glaucoma medication (95% CI: 1.03-1.38).

Conclusions: In two large European cohort studies, IBS is a risk factor for glaucoma.
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http://dx.doi.org/10.1002/ueg2.12136DOI Listing
November 2021

Cognitive function in men with non-motor features of Parkinson's disease.

BMJ Neurol Open 2021 21;3(1):e000112. Epub 2021 Jun 21.

Departmet of Epidemiology, Harvard University T H Chan School of Public Health, Boston, Massachusetts, USA.

Objective: Subtle cognitive deficits can occur during the prodromal phase of Parkinson's disease (PD), commonly in conjunction with hyposmia. However, little is known about the association between cognitive function and other features suggestive of prodromal PD. We evaluated the association of non-motor prodromal PD features, including hyposmia, constipation and probable REM sleep behaviour disorder (pRBD), with objective measures of cognitive function and self-reported cognitive decline.

Methods: The study population comprised 804 men who responded to a telephone cognitive interview in 2016-2017. Participants included 680 individuals with hyposmia, of whom 45 had confirmed PD, and 124 men without hyposmia. Among these men, we evaluated objective cognitive function and subjective cognitive decline to determine whether the presence of non-motor features of prodromal PD was associated with cognitive functioning. Analyses were adjusted for age, physical activity, body mass index, smoking status and coffee consumption.

Results: Individuals with non-motor features of prodromal PD had worse objective and subjective cognitive performance relative to men without non-motor features. Cognitive impairment was particularly prevalent among individuals with concurrent hyposmia, pRBD and constipation (multivariate-adjusted OR=3.80; 95% CI 1.52 to 9.47 for objective poor cognitive function; OR=8.71; 95% CI 3.18 to 23.83 for subjective cognitive decline). As expected, both objective (OR=7.91) and subjective (OR=17.42) cognitive impairment were also more common among men with confirmed PD.

Conclusions: Our study suggests that cognition is commonly affected in individuals with non-motor prodromal PD features, particularly when multiple of these features are present.
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http://dx.doi.org/10.1136/bmjno-2020-000112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217956PMC
June 2021

Prospective study of dietary intake of branched-chain amino acids and the risk of primary open-angle glaucoma.

Acta Ophthalmol 2021 Jul 8. Epub 2021 Jul 8.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Purpose: Metabolomic and preclinical studies suggest that branched-chain amino acids (BCAA) may be inversely associated with neurodegenerative diseases including glaucoma. We therefore assessed the long-term association between dietary intake of BCAA and incident primary open-angle glaucoma (POAG) and POAG subtypes.

Methods: We followed biennially participants of the Nurses' Health Study (NHS; 65 531 women: 1984-2016), Health Professionals Follow-up Study (42 254 men: 1986-2016) and NHSII (66 904 women; 1991-2017). Eligible participants were 40+ years old and reported eye examinations. Repeated validated food frequency questionnaires were used to assess dietary intake of BCAA. Incident cases of POAG and POAG subtypes defined by visual field (VF) loss and untreated intraocular pressure (IOP) were confirmed by medical record review. Multivariable-adjusted relative risks (MVRRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models.

Results: We identified 1946 incident POAG cases. The pooled MVRRs of POAG for the highest quintile (Q5 = 17.1 g/day) versus lowest quintile (Q1 = 11.2 g/day) of total BCAA intake was 0.93 (95% CI, 0.73-1.19; p  = 0.45; p  = 0.24). For subtypes of POAG defined by IOP level or POAG with only peripheral VF loss, no associations were observed for men or women (p  ≥ 0.20); however, for the POAG subtype with early paracentral VF loss, there was a suggestion of an inverse association in women (MVRR  = 0.80 [95% CI, 0.57-1.12; p  = 0.12]) but not in men (MVRR  = 1.38 [95% CI, 0.81-2.34; p  = 0.28; p  = 0.06]).

Conclusion: Higher dietary intake of BCAA was not associated with POAG risk.
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http://dx.doi.org/10.1111/aos.14971DOI Listing
July 2021

American Frontline Healthcare Personnel's Access to and Use of Personal Protective Equipment Early in the COVID-19 Pandemic.

J Occup Environ Med 2021 11;63(11):913-920

Division of Women's Health, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (Dr Rich-Edwards); Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts (Dr Rich-Edwards and Dr Chavarro); Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts (Dr Ding and Dr Chavarro); National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Cincinnati, Ohio (Dr Rocheleau, Dr Boiano, and Dr Lawson); Channing Division of Network Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts (Dr Kang and Dr Hart); Tufts University, Somerville, Massachusetts (Ms Becene); Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (Dr Nguyen and Dr Chan); Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, Massachusetts (Dr Hart).

Objectives: To quantify adequacy of personal protective equipment (PPE) for U.S. healthcare personnel (HCP) at the outset of the COVID-19 pandemic and its association with infection risk.

Methods: March-May 2020 survey of the national Nurses' Health Studies and the Growing Up Today study regarding self-reported PPE access, use, and reuse. COVID-19 endpoints included SARS-CoV-2 tests and COVID-19 status predicted from symptoms.

Results: Nearly 22% of 22,232 frontline HCP interacting with COVID-19 patients reported sometimes or always lacking PPE. Fifty percent of HCP reported not needing respirators, including 13% of those working in COVID-19 units. Lack of PPE was cross-sectionally associated with two-fold or greater odds of COVID-19 among those who interacted with infected patients.

Conclusion: These data show the need to improve the U.S. infection prevention culture of safety when confronting a novel pathogen.
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http://dx.doi.org/10.1097/JOM.0000000000002308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8562916PMC
November 2021

Diabetes Risk Reduction Diet and Survival after Breast Cancer Diagnosis.

Cancer Res 2021 Aug 9;81(15):4155-4162. Epub 2021 Jun 9.

Channing Division of Network Medicine, Department of Medicine, Brigham & Women's Hospital, and Harvard Medical School, Boston, Massachusetts.

Type II diabetes is associated with poor breast cancer prognosis. To study the association between a diabetes risk reduction diet (DRRD) and survival following breast cancer, we followed 8,482 women with breast cancer from two large cohort studies. Information on diet and other factors was repeatedly measured in validated questionnaires every two to four years. The DRRD includes 9 components: higher intakes of cereal fiber, coffee, nuts, whole fruits and polyunsaturated/saturated fat ratio; and lower glycemic index, trans fat, sugar-sweetened beverages, and red meat. Cumulative average DRRD score was calculated using repeated measures of postdiagnostic diet. Deaths were assessed by family members or via National Death Index. Multivariable-adjusted HRs and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. During a median of 14 years of follow-up since diagnosis, 2,600 deaths occurred among participants, 1,042 of which were due to breast cancer. Women with higher postdiagnostic DRRD score had a 20% lower risk of breast cancer-specific mortality (top vs. bottom quintile HR = 0.80; 95% CI = 0.65-0.97; = 0.02) and 34% lower risk of all-cause mortality (HR = 0.66; 95% CI = 0.58-0.76; < 0.0001). Compared with women who consistently had lower score (≤median) before and after diagnosis, those whose score improved from low to high had a lower risk of breast cancer-specific mortality (HR = 0.77; 95% CI = 0.62-0.95) and overall mortality (HR = 0.85; 95% CI = 0.74-0.97). These findings demonstrate that greater adherence to DRRD was associated with better survival, suggesting postdiagnosis dietary modification consistent with type II diabetes prevention may be important for breast cancer survivors. SIGNIFICANCE: This study suggests that greater adherence to the diabetes risk reduction diet after diagnosis associates with improved survival outcomes among a large number of breast cancer survivors.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-0256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8338782PMC
August 2021

Photosensitizing Medications and Skin Cancer: A Comprehensive Review.

Cancers (Basel) 2021 May 12;13(10). Epub 2021 May 12.

Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

(1) The incidence of skin cancer is increasing in the United States (US) despite scientific advances in our understanding of skin cancer risk factors and treatments. In vitro and in vivo studies have provided evidence that suggests that certain photosensitizing medications (PSMs) increase skin cancer risk. This review summarizes current epidemiological evidence on the association between common PSMs and skin cancer. (2) A comprehensive literature search was conducted to identify meta-analyses, observational studies and clinical trials that report on skin cancer events in PSM users. The associated risks of keratinocyte carcinoma (squamous cell carcinoma and basal cell carcinoma) and melanoma are summarized, for each PSM. (3) There are extensive reports on antihypertensives and statins relative to other PSMs, with positive and null findings, respectively. Fewer studies have explored amiodarone, metformin, antimicrobials and vemurafenib. No studies report on the individual skin cancer risks in glyburide, naproxen, piroxicam, chlorpromazine, thioridazine and nalidixic acid users. (4) The research gaps in understanding the relationship between PSMs and skin cancer outlined in this review should be prioritized because the US population is aging. Thus the number of patients prescribed PSMs is likely to continue to rise.
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http://dx.doi.org/10.3390/cancers13102344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152064PMC
May 2021

Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries.

Nat Commun 2021 02 24;12(1):1258. Epub 2021 Feb 24.

Faculty of Medicine, University of Southampton, Southampton, UK.

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.
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http://dx.doi.org/10.1038/s41467-020-20851-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904932PMC
February 2021

Association of Rare CYP39A1 Variants With Exfoliation Syndrome Involving the Anterior Chamber of the Eye.

JAMA 2021 02;325(8):753-764

Department of Ophthalmology, Asahikawa Medical University, Asahikawa, Japan.

Importance: Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness.

Objective: To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function.

Design, Setting, And Participants: A 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome.

Exposures: Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function.

Main Outcomes And Measures: The primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 × 10-6. The secondary outcomes included biochemical enzymatic assays and gene expression analyses.

Results: The discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 × 10-7). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4% [interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome.

Conclusions And Relevance: In this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings.
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http://dx.doi.org/10.1001/jama.2021.0507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903258PMC
February 2021

Intraocular Pressure, Glaucoma, and Dietary Caffeine Consumption: A Gene-Diet Interaction Study from the UK Biobank.

Ophthalmology 2021 06 14;128(6):866-876. Epub 2020 Dec 14.

Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, New York.

Purpose: We examined the association of habitual caffeine intake with intraocular pressure (IOP) and glaucoma and whether genetic predisposition to higher IOP modified these associations. We also assessed whether genetic predisposition to higher coffee consumption was related to IOP.

Design: Cross-sectional study in the UK Biobank.

Participants: We included 121 374 participants (baseline ages, 39-73 years) with data on coffee and tea intake (collected 2006-2010) and corneal-compensated IOP measurements in 2009. In a subset of 77 906 participants with up to 5 web-based 24-hour-recall food frequency questionnaires (2009-2012), we evaluated total caffeine intake. We also assessed the same relationships with glaucoma (9286 cases and 189 763 controls).

Methods: We evaluated multivariable-adjusted associations with IOP using linear regression and with glaucoma using logistic regression. For both outcomes, we examined gene-diet interactions using a polygenic risk score (PRS) that combined the effects of 111 genetic variants associated with IOP. We also performed Mendelian randomization using 8 genetic variants associated with coffee intake to assess potential causal effects of coffee consumption on IOP.

Main Outcome Measures: Intraocular pressure and glaucoma.

Results: Mendelian randomization analysis did not support a causal effect of coffee drinking on IOP (P > 0.1). Greater caffeine intake was associated weakly with lower IOP: the highest (≥232 mg/day) versus lowest (<87 mg/day) caffeine consumption was associated with a 0.10-mmHg lower IOP (P = 0.01). However, the IOP PRS modified this association: among those in the highest IOP PRS quartile, consuming > 480 mg/day versus < 80 mg/day was associated with a 0.35-mmHg higher IOP (P = 0.01). The relationship between caffeine intake and glaucoma was null (P ≥ 0.1). However, the IOP PRS also modified this relationship: compared with those in the lowest IOP PRS quartile consuming no caffeine, those in the highest IOP PRS quartile consuming ≥ 321 mg/day showed a 3.90-fold higher glaucoma prevalence (P = 0.0003).

Conclusions: Habitual caffeine consumption was associated weakly with lower IOP, and the association between caffeine consumption and glaucoma was null. However, among participants with the strongest genetic predisposition to elevated IOP, greater caffeine consumption was associated with higher IOP and higher glaucoma prevalence.
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http://dx.doi.org/10.1016/j.ophtha.2020.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154631PMC
June 2021

Prospective study of a diabetes risk reduction diet and the risk of breast cancer.

Am J Clin Nutr 2020 12;112(6):1492-1503

Channing Division of Network Medicine, Department of Medicine, Brigham & Women's Hospital, Boston, MA, USA.

Background: Hyperinsulinemia and higher insulin-like growth factors may increase breast cancer risk. We evaluated a diabetes risk reduction diet (DRRD) and breast cancer risk.

Objectives: We prospectively evaluated the association between adherence to a DRRD and the incidence of breast cancer.

Methods: We followed 88,739 women from the Nurses' Health Study (NHS; 1980-2016) and 93,915 women from the NHSII (1991-2017). Incident breast cancer cases (n = 11,943) were confirmed with medical records, and subtypes were determined by tissue microarray data and pathology reports. Information on diet and breast cancer risk factors was repeatedly ascertained in follow-up questionnaires. A DRRD score was derived with 9 factors: lower glycemic index of diet; lower intakes of trans fat, sugar-sweetened beverages/fruit juices, and red/processed meat; higher intakes of cereal fiber, coffee, nuts, and whole fruits; and a higher ratio of polyunsaturated to saturated fat (score range: 9-45). Multivariable-adjusted hazard ratios (MVHRs) and 95% CIs were calculated with Cox proportional hazards models.

Results: Being in the highest compared with the lowest DRRD adherence quintile was associated with a modestly lower breast cancer risk (MVHRQ5vsQ1: 0.89; 95% CI: 0.84, 0.95; P-trend = 0.0002); this was attenuated after adjusting for weight change since age 18 y (MVHRQ5vsQ1: 0.92; 95% CI: 0.87, 0.98; P-trend = 0.01). The inverse association was strongest among women with current BMI < 25 kg/m2 (MVHRQ5vsQ1: 0.89; 95% CI: 0.81, 0.98; P-trend = 0.004; P-interaction = 0.04). Among tumor molecular subtypes, the strongest inverse association was observed with basal-type tumors (MVHRQ5vsQ1: 0.67; 95% CI: 0.45, 1.01; P-trend = 0.04).

Conclusions: Greater DRRD-adherence was associated with lower breast cancer risk, likely mediated by less weight gain with a DRRD; however, independently of weight change, DRRD-adherence was modestly associated with lower breast cancer risk, particularly among lean women.
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http://dx.doi.org/10.1093/ajcn/nqaa268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727476PMC
December 2020

Cohort Study of Nonmelanoma Skin Cancer and the Risk of Exfoliation Glaucoma.

J Glaucoma 2020 06;29(6):448-455

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital.

Precis: In a cohort study of 120,307 participants with 25+ years of follow-up, a history of nonmelanoma skin cancer (NMSC) was associated with a 40% higher exfoliation glaucoma (XFG) risk.

Purpose: The purpose of this study was to evaluate the relationship between NMSC (a marker of ultraviolet radiation exposure) and XFG.

Methods: We performed a cohort study of US women (n=79,102; 1980-2014) and men (n=41,205; 1986-2014), aged 40+ years and at risk for glaucoma who reported eye examinations. From 1984 (women)/1988 (men), we asked about basal cell carcinoma or squamous cell carcinoma history separately; in prior years, we asked about any NMSC history in a single question. Squamous cell carcinoma was confirmed with histopathology reports while basal cell carcinoma and any early (<1984/<1988) NMSC history was self-reported. Incident XFG cases (362 women and 83 men) were confirmed with medical records. Using pooled data, we estimated multivariable-adjusted relative risks [MVRRs; 95% confidence intervals (CIs)] with Cox proportional hazards models that were stratified by age (in mo), 2-year time period at risk and average lifetime residential latitude.

Results: In multivariable-adjusted analyses, we observed a 40% higher XFG risk with any NMSC history (MVRR=1.40; 95% CI=1.08-1.82); the association was observed even with 4 and 8-year lags in NMSC history. Also, the NMSC association was stronger in younger (below 65 y; MVRR=2.56; 95% CI=1.62-4.05) versus older participants (65 y and above; MVRR=1.25; 95% CI=0.94-1.66; P for interaction=0.01) and those living in the northern latitudes (≥42°N; MVRR=1.92; 95% CI=1.28-2.88) versus more southern latitudes (<42°N; MVRR=1.19; 95% CI=0.86-1.66; P for interaction=0.04).

Conclusion: NMSC was associated with higher XFG risk, particularly among younger participants and those living in the Northern US.
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http://dx.doi.org/10.1097/IJG.0000000000001496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317065PMC
June 2020

Low-carbohydrate-diet scores and the risk of primary open-angle glaucoma: data from three US cohorts.

Eye (Lond) 2020 08 2;34(8):1465-1475. Epub 2020 Mar 2.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Background/objectives: To assess the long-term association between low-carbohydrate dietary patterns and incident primary open-angle glaucoma (POAG), and POAG subtypes defined by highest untreated intraocular pressure (IOP) and by pattern of visual field (VF) loss at diagnosis.

Subjects/methods: We followed 185,638 participants of three large US prospective cohorts biennially (1976-2016, 1986-2016 and 1991-2017). Deciles of three low-carbohydrate-diet scores were calculated to represent adherence to diets lower in carbohydrate and higher in protein and fat from any source, animal sources or plant sources. We confirmed POAG cases (n = 2112) by medical record review and used Cox proportional hazards models to estimate multivariable-adjusted relative risks (MVRRs) and 95% confidence intervals (CIs).

Results: There was no association between the three types of low-carbohydrate-diet scores and POAG: the MVRR for POAG in the highest vs. lowest deciles was 1.13 (95% CI, 0.91-1.39; P = 0.40) for the overall score; 1.10 (95% CI, 0.89-1.35; P = 0.38) for the animal score and 0.96 (95% CI, 0.79-1.18; P = 0.88) for the vegetable score. No differential associations by IOP level was found (P ≥ 0.06). However, the vegetable score showed a suggestive inverse association with early paracentral VF loss (highest vs. lowest decile MVRR = 0.78 [95% CI, 0.55-1.10]; P = 0.12) but not with peripheral VF loss only (MVRR = 1.09 [95% CI, 0.83-1.44]; P = 0.14; P = 0.03).

Conclusions: Low-carbohydrate diets were not associated with risk of POAG. Our data suggested that higher consumption of fat and protein from vegetable sources substituting for carbohydrates was associated with lower risk of the POAG subtype with initial paracentral VF loss.
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http://dx.doi.org/10.1038/s41433-020-0820-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470850PMC
August 2020

Interaction between apolipoprotein E genotype and hypertension on cognitive function in older women in the Nurses' Health Study.

PLoS One 2019 7;14(11):e0224975. Epub 2019 Nov 7.

Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, United States of America.

Objective: To examine the interaction between APOE genotypes and both treated and untreated hypertension on cognitive function in an updated analysis of Nurses' Health Study (NHS) data.

Design: At baseline (1995-2001) and 3 biennial follow-up assessments over ~6 years, cognitive function was assessed.

Setting And Participants: 8300 NHS participants aged 70+ years underwent a cognitive battery, which comprised 6 tests including the Telephone Interview for Cognitive Status (TICS) and tests of verbal memory, category fluency, and working memory.

Measures: We estimated the mean differences in average cognitive scores across up to 4 assessments using multiple linear regression. We also tested for interaction between APOE e4 allele carrier status and hypertension overall, as well as for apparently untreated and treated hypertension.

Results: We confirmed that, compared with those with APOE e3/3 genotype, APOE e4 allele carriers scored lower by 0.55 units on the average TICS score (95%CI:-0.67,-0.43). We also observed a significantly worse average TICS score among women with untreated hypertension compared with women without hypertension (difference = -0.23, 95%CI:-0.37,-0.09), while no significant difference was observed for women with treated hypertension. Significant interaction was detected between the APOE e4 allele and untreated hypertension (p-int = 0.02 for the TICS; p-int = 0.045 for global score), but not with treated hypertension. Specifically, compared with normotensive women with the APOE e3/3 genotype, APOE e4 allele carriers with treated hypertension scored lower by 0.50 units (95%CI:-0.69,-0.31); however, the APOE e4 allele carriers with untreated hypertension scored lower by 1.02 units on the TICS score (95%CI:-1.29, -0.76). This interaction of APOE e4 and untreated hypertension was also consistently observed for the global score.

Conclusions: Women with hypertension and at least one APOE e4 allele had worse average cognitive function compared with women without hypertension with the e3/3 genotype; this difference was amplified among APOE e4 allele carriers with untreated hypertension.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224975PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6837309PMC
March 2020

Association of a Primary Open-Angle Glaucoma Genetic Risk Score With Earlier Age at Diagnosis.

JAMA Ophthalmol 2019 Oct;137(10):1190-1194

Wilmer Eye Institute, Johns Hopkins University Hospital, Baltimore, Maryland.

Importance: Genetic variants associated with primary open-angle glaucoma (POAG) are known to influence disease risk. However, the clinical effect of associated variants individually or in aggregate is not known. Genetic risk scores (GRS) examine the cumulative genetic load by combining individual genetic variants into a single measure, which is assumed to have a larger effect and increased power to detect relevant disease-related associations.

Objective: To investigate if a GRS that comprised 12 POAG genetic risk variants is associated with age at disease diagnosis.

Design, Setting, And Participants: A cross-sectional study included individuals with POAG and controls from the Glaucoma Genes and Environment (GLAUGEN) study and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) study. A GRS was formulated using 12 variants known to be associated with POAG, and the alleles associated with increasing risk of POAG were aligned in the case-control sets. In case-only analyses, the association of the GRS with age at diagnosis was analyzed as an estimate of disease onset. Results from cohort-specific analyses were combined with meta-analysis. Data collection started in August 2012 for the NEIGHBOR cohort and in July 2008 for the GLAUGEN cohort and were analyzed starting in March 2018.

Main Outcomes And Measures: Association of a 12 single-nucleotide polymorphism POAG GRS with age at diagnosis in individuals with POAG using linear regression.

Results: The GLAUGEN study included 976 individuals with POAG and 1140 controls. The NEIGHBOR study included 2132 individuals with POAG and 2290 controls. For individuals with POAG, the mean (SD) age at diagnosis was 63.6 (9.8) years in the GLAUGEN cohort and 66.0 (13.7) years in the NEIGHBOR cohort. For controls, the mean (SD) age at enrollment was 65.5 (9.2) years in the GLAUGEN cohort and 68.9 (11.4) years in the NEIGHBOR cohort. All study participants were European white. The GRS was strongly associated with POAG risk in case-control analysis (odds ratio per 1-point increase in score = 1.24; 95% CI, 1.21-1.27; P = 3.4 × 10-66). In case-only analyses, each higher GRS unit was associated with a 0.36-year earlier age at diagnosis (β = -0.36; 95% CI, -0.56 to -0.16; P = 4.0 × 10-4). Individuals in the top 5% of the GRS had a mean (SD) age at diagnosis of 5.2 (12.8) years earlier than those in the bottom 5% GRS (61.4 [12.7] vs 66.6 [12.9] years; P = 5.0 × 10-4).

Conclusions And Relevance: A higher dose of POAG risk alleles was associated with an earlier age at glaucoma diagnosis. On average, individuals with POAG with the highest GRS had 5.2-year earlier age at diagnosis of disease. These results suggest that a GRS that comprised genetic variants associated with POAG could help identify patients with risk of earlier disease onset impacting screening and therapeutic strategies.
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http://dx.doi.org/10.1001/jamaophthalmol.2019.3109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707005PMC
October 2019

Genetic Correlations Between Diabetes and Glaucoma: An Analysis of Continuous and Dichotomous Phenotypes.

Am J Ophthalmol 2019 10 20;206:245-255. Epub 2019 May 20.

Channing Division of Network Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address:

Purpose: A genetic correlation is the proportion of phenotypic variance between traits that is shared on a genetic basis. Here we explore genetic correlations between diabetes- and glaucoma-related traits.

Design: Cross-sectional study.

Methods: We assembled genome-wide association study summary statistics from European-derived participants regarding diabetes-related traits like fasting blood sugar (FBS) and type 2 diabetes (T2D) and glaucoma-related traits (intraocular pressure [IOP], central corneal thickness [CCT], corneal hysteresis [CH], corneal resistance factor [CRF], cup-to-disc ratio [CDR], and primary open-angle glaucoma [POAG]). We included data from the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database, the UK Biobank, and the International Glaucoma Genetics Consortium. We calculated genetic correlation (r) between traits using linkage disequilibrium score regression. We also calculated genetic correlations between IOP, CCT, and select diabetes-related traits based on individual level phenotype data in 2 Northern European population-based samples using pedigree information and Sequential Oligogenic Linkage Analysis Routines.

Results: Overall, there was little r between diabetes- and glaucoma-related traits. Specifically, we found a nonsignificant negative correlation between T2D and POAG (r = -0.14; P = .16). Using Sequential Oligogenic Linkage Analysis Routines, the genetic correlations between measured IOP, CCT, FBS, fasting insulin, and hemoglobin A1c were null. In contrast, genetic correlations between IOP and POAG (r ≥ 0.45; P ≤ 3.0 × 10) and between CDR and POAG were high (r = 0.57; P = 2.8 × 10). However, genetic correlations between corneal properties (CCT, CRF, and CH) and POAG were low (r range -0.18 to 0.11) and nonsignificant (P ≥ .07).

Conclusion: These analyses suggest that there is limited genetic correlation between diabetes- and glaucoma-related traits.
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http://dx.doi.org/10.1016/j.ajo.2019.05.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864262PMC
October 2019

Association of Statin Use and High Serum Cholesterol Levels With Risk of Primary Open-Angle Glaucoma.

JAMA Ophthalmol 2019 07;137(7):756-765

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Importance: The use of statins (hydroxymethylglutaryl coenzyme A inhibitors) has been associated with a lower risk of primary open-angle glaucoma (POAG); however, results have been conflicting, and little is known about the association between high cholesterol levels and POAG.

Objective: To assess the association of elevated cholesterol levels and statin use with incident POAG.

Design, Setting, And Participants: This study used data collected biennially from participants aged 40 years or older who were free of glaucoma and reported eye examinations, within 3 population-based cohorts: the Nurses' Health Study (N = 50 710; followed up from 2000 to 2014), the Nurses' Health Study 2 (N = 62 992; 1999-2015), and the Health Professionals Follow-up Study (N = 23 080; 2000-2014). Incident cases of POAG were confirmed by medical record review. The analyses were performed in January 2019.

Exposures: Biennially updated self-reported information on elevated cholesterol level status, serum cholesterol levels, and duration of statin use.

Main Outcomes And Measures: Multivariable-adjusted relative risks (RRs) and 95% CIs were estimated using Cox proportional hazards regression models on pooled data, with stratification by cohort.

Results: Among the 136 782 participants in the 3 cohorts (113 702 women and 23 080 men), 886 incident cases of POAG were identified. Every 20-mg/dL increase in total serum cholesterol was associated with a 7% increase in risk of POAG (RR, 1.07 [95% CI, 1.02-1.11]; P = .004). Any self-reported history of elevated cholesterol was also associated with a higher risk of POAG (RR, 1.17 [95% CI, 1.00-1.37]). A history of any statin use was associated with a 15% lower risk of POAG (RR, 0.85 [95% CI, 0.73-0.99]). Use of statins for 5 or more years vs never use of statins was associated with a 21% lower risk of POAG (RR, 0.79 [95% CI, 0.65-0.97]; P = .02 for linear trend). The association between use of statins for 5 or more years vs never use of statins and risk of POAG was more inverse in those who were older (≥65 years: RR, 0.70 [95% CI, 0.56-0.87] vs <65 years: RR, 1.05 [95% CI, 0.68-1.63]; P = .01 for interaction).

Conclusions And Relevance: Among adults aged 40 years or older, higher serum cholesterol levels were associated with higher risk of POAG, while 5 or more years of statin use compared with never use of statins was associated with a lower risk of POAG.
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http://dx.doi.org/10.1001/jamaophthalmol.2019.0900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499123PMC
July 2019

Habitual consumption of long-chain n-3 PUFAs and fish attenuates genetically associated long-term weight gain.

Am J Clin Nutr 2019 03;109(3):665-673

Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA.

Background: A growing amount of data suggests that n-3 (ω-3) polyunsaturated fatty acid (PUFA) intake may modify the genetic association with weight change.

Objectives: We aimed to prospectively test interactions of habitual consumption of n-3 PUFAs or fish, the major food source, with overall genetic susceptibility on long-term weight change.

Design: Gene-diet interactions were examined in 11,330 women from the Nurses' Health Study (NHS), 6773 men from the Health Professionals Follow-Up Study (HPFS), and 6254 women from the Women's Health Initiative (WHI).

Results: In the NHS and HPFS cohorts, food-sourced long-chain n-3 PUFA intake showed directionally consistent interactions with genetic risk score on long-term changes in BMI (P-interaction = 0.01 in the HPFS, 0.15 in the NHS, and 0.01 in both cohorts combined). Such interactions were successfully replicated in the WHI, an independent cohort (P-interaction = 0.02 in the WHI and 0.01 in the combined 3 cohorts). The genetic associations with changes in BMI (in kg/m2) consistently decreased (0.15, 0.10, 0.07, and -0.14 per 10 BMI-increasing alleles) across the quartiles of long-chain n-3 PUFAs in the combined cohorts. In addition, high fish intake also attenuated the genetic associations with long-term changes in BMI in the HPFS (P-interaction = 0.01), NHS (P-interaction = 0.03), WHI (P-interaction = 0.10), and the combined cohorts (P-interaction = 0.01); and the differences in BMI changes per 10 BMI-increasing alleles were 0.16, 0.06, -0.08, and -0.18, respectively, across the categories (≤1, 1∼4, 4∼6, and ≥7 servings/wk) of total fish intake. Similar interactions on body weight were observed for fish intake (P-interaction = 0.003) and long-chain n-3 PUFA intake (P-interaction = 0.12).

Conclusion: Our study provides replicable evidence to show that high intakes of fish and long-chain n-3 PUFAs are associated with an attenuation of the genetic association with long-term weight gain based on results from 3 prospective cohorts of Caucasians.
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http://dx.doi.org/10.1093/ajcn/nqy238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6408206PMC
March 2019

Predictors of Advance Care Planning in Older Women: The Nurses' Health Study.

J Am Geriatr Soc 2019 02 10;67(2):292-301. Epub 2018 Dec 10.

Department of Health Policy, Vanderbilt University School of Medicine, Nashville, Tennessee.

Background/objectives: Relatively little is known regarding predictors of advance care planning (ACP) in former nurses. We aimed to evaluate potential predictors of ACP documentation and discussion.

Design: Cross-sectional study, 2012-2014.

Setting: Nurses' Health Study.

Participants: A total of 60,917 community-dwelling female nurses aged 66 to 93 years living across the United States.

Measurements: Based on self-reports, participants were categorized as having (1) only ACP documentation, (2) ACP documentation and a recent ACP discussion with a healthcare provider, or (3) neither. Multivariable log-binomial models were used to estimate prevalence ratios (PRs) and 95% confidence intervals (CIs) of the two separate ACP categories vs those with neither. We evaluated various demographic, health, and social factors.

Results: The large majority (84%) reported ACP documentation; 35% reported a recent ACP discussion. Demographic factors such as age and race were associated with both ACP categories. In multivariable analyses, race was most strongly associated: compared with whites, African Americans were 27% less likely (PR = 0.73; 95% CI = 0.69-0.78) to report ACP documentation alone and 41% (PR = 0.59; 95% CI = 0.54-0.66) less likely to report documentation with discussion. Additionally, health/healthcare-related characteristics were more strongly associated with ACP documentation plus discussion. Women with functional limitations (PR = 1.15; 95% CI = 1.10-1.20), women who were recently hospitalized (PR: 1.10; 95% CI = 1.08-1.12) or women who had seen a physician for health symptoms (PR = 1.43; 95% CI = 1.35-1.52) or screening (PR = 1.40; 95% CI = 1.32-1.49) were more likely to report having both ACP documentation and discussion. Social factors showed limited relationships with ACP documentation only; for documentation plus discussion, being widowed and living alone was associated with higher prevalence (PR = 1.21; 95% CI = 1.19-1.24) and having little emotional support was associated with lower prevalence (PR = 0.84; 95% CI = 0.81-0.86).

Conclusions: Among older nurses, most of whom reported having documented ACP, 35% reported recent patient-clinician ACP discussions, indicating a major participatory gap in an element critical to ACP effectiveness. Even in nurses, African Americans reported less ACP documentation or discussion. J Am Geriatr Soc 67:292-301, 2019.
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http://dx.doi.org/10.1111/jgs.15656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698382PMC
February 2019

Posttraumatic stress disorder and incidence of thyroid dysfunction in women.

Psychol Med 2019 11 29;49(15):2551-2560. Epub 2018 Nov 29.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background: Abnormal thyroid function is prevalent among women and has been linked to increased risk of chronic disease. Posttraumatic stress disorder (PTSD) has been linked to thyroid dysfunction in some studies; however, the results have been inconsistent. Thus, we evaluated trauma exposure and PTSD symptoms in relation to incident thyroid dysfunction in a large longitudinal cohort of civilian women.

Methods: We used data from 45 992 women from the ongoing Nurses' Health Study II, a longitudinal US cohort study that began in 1989. In 2008, history of trauma and PTSD were assessed with the Short Screening Scale for Diagnostic and Statistical Manual of Mental Disorders, fourth edition, PTSD, and incident thyroid dysfunction was determined by participants' self-report in biennial questionnaires of physician-diagnosed hypothyroidism and Graves' hyperthyroidism. The study period was from 1989 to 2013. Proportional hazard models were used to estimate multivariable-adjusted hazard ratios and 95% confidence intervals (CIs) for incident hypothyroidism and Graves' hyperthyroidism.

Results: In multivariable-adjusted models, we found significant associations for PTSD only with hypothyroidism [p-trend <0.001; trauma with no PTSD symptoms, 1.08 (95% CI 1.02-1.15); 1-3 PTSD symptoms, 1.12 (95% CI 1.04-1.21); 4-5 PTSD symptoms, 1.23 (95% CI 1.13-1.34); and 6-7 PTSD symptoms, 1.26 (95% CI 1.14-1.40)]. PTSD was not associated with risk of Graves' hyperthyroidism (p-trend = 0.34). Associations were similar in sensitivity analyses restricted to outcomes with onset after 2008, when PTSD was assessed.

Conclusions: PTSD was associated with higher risk of hypothyroidism in a dose-dependent fashion. Highlighted awareness for thyroid dysfunction may be especially important in women with PTSD.
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http://dx.doi.org/10.1017/S0033291718003495DOI Listing
November 2019

A Network Analysis of Biomarkers for Type 2 Diabetes.

Diabetes 2019 02 8;68(2):281-290. Epub 2018 Nov 8.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.

Numerous studies have investigated individual biomarkers in relation to risk of type 2 diabetes. However, few have considered the interconnectivity of these biomarkers in the etiology of diabetes as well as the potential changes in the biomarker correlation network during diabetes development. We conducted a secondary analysis of 27 plasma biomarkers representing glucose metabolism, inflammation, adipokines, endothelial dysfunction, IGF axis, and iron store plus age and BMI at blood collection from an existing case-control study nested in the Nurses' Health Study (NHS), including 1,303 incident diabetes case subjects and 1,627 healthy women. A correlation network was constructed based on pairwise Spearman correlations of the above factors that were statistically different between case and noncase subjects using permutation tests ( < 0.0005). We further evaluated the network structure separately among diabetes case subjects diagnosed <5, 5-10, and >10 years after blood collection versus noncase subjects. Although pairwise biomarker correlations tended to have similar directions comparing diabetes case subjects to noncase subjects, most correlations were stronger in noncase than in case subjects, with the largest differences observed for the insulin/HbA and leptin/adiponectin correlations. Leptin and soluble leptin receptor were two hubs of the network, with large numbers of different correlations with other biomarkers in case versus noncase subjects. When examining the correlation network by timing of diabetes onset, there were more perturbations in the network for case subjects diagnosed >10 years versus <5 years after blood collection, with consistent differential correlations of insulin and HbA C-peptide was the most highly connected node in the early-stage network, whereas leptin was the hub for mid- or late-stage networks. Our results suggest that perturbations of the diabetes-related biomarker network may occur decades prior to clinical recognition. In addition to the persistent dysregulation between insulin and HbA, our results highlight the central role of the leptin system in diabetes development.
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http://dx.doi.org/10.2337/db18-0892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341308PMC
February 2019

Diet quality and genetic association with body mass index: results from 3 observational studies.

Am J Clin Nutr 2018 12;108(6):1291-1300

Department of Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, NY.

Background: It is unknown whether dietary quality modifies genetic association with body mass index (BMI).

Objective: This study examined whether dietary quality modifies genetic association with BMI.

Design: We calculated 3 diet quality scores including the Alternative Healthy Eating Index 2010 (AHEI-2010), the Alternative Mediterranean Diet score (AMED), and the Dietary Approach to Stop Hypertension (DASH) diet score. We examined the interactions of a genetic risk score (GRS) based on 97 BMI-associated variants with the 3 diet quality scores on BMI in 30,904 participants from 3 large cohorts.

Results: We found significant interactions between total GRS and all 3 diet scores on BMI assessed after 2-3 y, with an attenuated genetic effect observed in individuals with healthier diets (AHEI: P-interaction = 0.003; AMED: P = 0.001; DASH: P = 0.004). For example, the difference in BMI (kg/m2) per 10-unit increment of the GRS was smaller among participants in the highest tertile of AHEI score compared with those in the lowest tertile (0.84; 95% CI: 0.72, 0.96 compared with 1.14; 95% CI: 0.99, 1.29). Results were consistent across the 3 cohorts with no significant heterogeneity. The interactions with diet scores on BMI appeared more significant for central nervous system GRSs (P < 0.01 for 3 diet scores) than for non-central nervous system GRSs (P > 0.05 for 3 diet scores).

Conclusions: A higher diet quality attenuated genetic predisposition to obesity. These findings underscore the importance of maintaining a healthful diet for the prevention of obesity, particularly for those individuals with a strong genetic predisposition to obesity. This trial was registered with the Clinical Trial Registry as NCT03577639.
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http://dx.doi.org/10.1093/ajcn/nqy203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290366PMC
December 2018

Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases.

Nat Commun 2018 05 14;9(1):1864. Epub 2018 May 14.

Department of Ophthalmology, Flinders University, SA 5042, Adelaide, Australia.

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P = 5.30 × 10) but not between CCT and primary open-angle glaucoma (r = -0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.
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http://dx.doi.org/10.1038/s41467-018-03646-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951816PMC
May 2018

Studies of advanced glycation end products and oxidation biomarkers for type 2 diabetes.

Biofactors 2018 May 2;44(3):281-288. Epub 2018 May 2.

Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA.

Advanced glycation end products (AGEs) are formed upon nonenzymatic reactions of sugars or their metabolites with proteins and other cellular constituents. Many AGEs are long lived. Recent findings suggest that AGEs may predict diabetes and its complications and thus may warrant further study. The objective of this study was to assess the validity of our experimental procedures for measuring AGEs in stored blood sample and to conduct a pilot study for developing AGE biomarkers for diabetes and/or age-related changes of glucose metabolism. We conducted a reliability study of the samples and methods using liquid chromatography-tandem mass spectrometry (LC-MS)/MS assays for 10 AGEs (including methylglyoxal-derived hydroimidazolone (MG-H1), glucosepane (GSP) and two oxidation measures, in stored repository blood samples from the Nurses' Health Study and the Health Professionals Follow-up Study. We also analyzed data relating blood GSP levels to type 2 diabetes status in a case-control study (25 cases and 15 controls). Among the AGEs, GSP, and MG-H1 showed the highest reliability across the various measures: reliability in duplicate samples and stability with delayed processing and storage over 1-2 year period. Furthermore, plasma GSP was associated with older age (P = 0.04) and type 2 diabetes status (age-adjusted P = 0.0475). Our findings suggest that analysis of these AGEs may be developed as biomarkers for diabetes and/or age-related changes of glucose metabolism. © 2018 BioFactors, 44(3):281-288, 2018.
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http://dx.doi.org/10.1002/biof.1423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8527553PMC
May 2018

Prospective study of flavonoid intake and risk of primary open-angle glaucoma.

Acta Ophthalmol 2018 Sep 14;96(6):e692-e700. Epub 2018 Mar 14.

Channing Division of Network Medicine, Department of Medicine, Brigham & Women's Hospital/Harvard Medical School, Boston, MA, USA.

Purpose: To evaluate the association between flavonoid intake and incident primary open-angle glaucoma (POAG).

Methods: We followed 65 516 women from the Nurses' Health Study (from 1984) and 42 156 men from the Health Professionals Follow-up Study (from 1986) biennially to 2012, who were 40+ years old, free of POAG, and reported eye examinations. Dietary flavonoid intake was assessed with validated repeated semi-quantitative food frequency questionnaires. Incident POAG cases (n = 1575) were confirmed with medical record review. Cohort-specific multivariable-adjusted relative risks (RRs) and 95% confidence intervals (CIs) were calculated and meta-analysed.

Results: Total flavonoid intake was not associated with risk of POAG development [RR for highest (Q5: median ~645 mg/day) versus lowest quintile (Q1: ~130 mg/day) = 0.91 (95% CI = 0.77, 1.08); p for trend (p-trend) = 0.19]; the flavonoid subclasses of flavones, flavanones, polymeric flavanols or anthocyanidins were also not associated (Q5 versus Q1 comparison p-values ≥0.05 and p-trend ≥0.09). Higher intakes of flavonols and monomeric flavanols were nominally associated with lower POAG risk, based on the Q5 versus Q1 comparisons or p-trends. The Q5 versus Q1 comparison RRs were: for flavonols, 0.82 (95% CI = 0.69, 0.97; p-trend = 0.05; ~28 versus ~8 mg/day), and for monomeric flavanols, 0.86 (95% CI = 0.72, 1.02; p-trend=0.04; ~110 versus 10 mg/day). The food/beverage that contributed most to both the variation of flavonols and monomeric flavanols was tea; consuming ~2 cups/day was associated with 18% lower POAG risk (RR=0.82; 95% CI = 0.68, 0.99; p-trend = 0.02).

Conclusion: Total flavonoid intake was not associated with POAG risk. Greater intakes of flavonols and monomeric flavanols and of tea showed suggestive modest associations with lower risk; these results need confirmation.
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http://dx.doi.org/10.1111/aos.13705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6138582PMC
September 2018

Genome-wide association study identifies seven novel susceptibility loci for primary open-angle glaucoma.

Hum Mol Genet 2018 04;27(8):1486-1496

Department of Ophthalmology and Visual Sciences, Hiroshima University, Hiroshima, Japan.

Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide for which 15 disease-associated loci had been discovered. Among them, only 5 loci have been associated with POAG in Asians. We carried out a genome-wide association study and a replication study that included a total of 7378 POAG cases and 36 385 controls from a Japanese population. After combining the genome-wide association study and the two replication sets, we identified 11 POAG-associated loci, including 4 known (CDKN2B-AS1, ABCA1, SIX6 and AFAP1) and 7 novel loci (FNDC3B, ANKRD55-MAP3K1, LMX1B, LHPP, HMGA2, MEIS2 and LOXL1) at a genome-wide significance level (P < 5.0×10-8), bringing the total number of POAG-susceptibility loci to 22. The 7 novel variants were subsequently evaluated in a multiethnic population comprising non-Japanese East Asians (1008 cases, 591 controls), Europeans (5008 cases, 35 472 controls) and Africans (2341 cases, 2037 controls). The candidate genes located within the new loci were related to ocular development (LMX1B, HMGA2 and MAP3K1) and glaucoma-related phenotypes (FNDC3B, LMX1B and LOXL1). Pathway analysis suggested epidermal growth factor receptor signaling might be involved in POAG pathogenesis. Genetic correlation analysis revealed the relationships between POAG and systemic diseases, including type 2 diabetes and cardiovascular diseases. These results improve our understanding of the genetic factors that affect the risk of developing POAG and provide new insight into the genetic architecture of POAG in Asians.
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http://dx.doi.org/10.1093/hmg/ddy053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251544PMC
April 2018

Analysis combining correlated glaucoma traits identifies five new risk loci for open-angle glaucoma.

Sci Rep 2018 02 15;8(1):3124. Epub 2018 Feb 15.

Department of Ophthalmology, University of Auckland, Auckland, New Zealand.

Open-angle glaucoma (OAG) is a major cause of blindness worldwide. To identify new risk loci for OAG, we performed a genome-wide association study in 3,071 OAG cases and 6,750 unscreened controls, and meta-analysed the results with GWAS data for intraocular pressure (IOP) and optic disc parameters (the overall meta-analysis sample size varying between 32,000 to 48,000 participants), which are glaucoma-related traits. We identified and independently validated four novel genome-wide significant associations within or near MYOF and CYP26A1, LINC02052 and CRYGS, LMX1B, and LMO7 using single variant tests, one additional locus (C9) using gene-based tests, and two genetic pathways - "response to fluid shear stress" and "abnormal retina morphology" - in pathway-based tests. Interestingly, some of the new risk loci contribute to risk of other genetically-correlated eye diseases including myopia and age-related macular degeneration. To our knowledge, this study is the first integrative study to combine genetic data from OAG and its correlated traits to identify new risk variants and genetic pathways, highlighting the future potential of combining genetic data from genetically-correlated eye traits for the purpose of gene discovery and mapping.
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http://dx.doi.org/10.1038/s41598-018-20435-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814451PMC
February 2018
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