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1.  Comparison of Risk Factor Profiles for Primary Open-Angle Glaucoma Subtypes Defined by Pattern of Visual Field Loss: A Prospective Study 
Purpose.
We explored whether risk factor associations differed by primary open-angle glaucoma (POAG) subtypes defined by visual field (VF) loss pattern (i.e., paracentral or peripheral).
Methods.
We included 77,157 women in the Nurses' Health Study (NHS) and 42,773 men in the Health Professionals Follow-up Study (HPFS 1986–2010), and incident medical record confirmed cases of paracentral (n = 440) and peripheral (n = 865) POAG subtypes. We evaluated African heritage, glaucoma family history, body mass index (BMI), mean arterial blood pressure, diabetes mellitus, physical activity, smoking, caffeine intake, and alcohol intake. We used competing risk Cox regression analyses modeling age as the metameter and stratified by age, cohort, and event type. We sequentially identified factors with the least significant differences in associations with POAG subtypes (“stepwise down” approach with P for heterogeneity [P-het] < 0.10 as threshold).
Results.
Body mass index was more inversely associated with the POAG paracentral VF loss subtype than the peripheral VF loss subtype (per 10 kg/m2; hazard ratio [HR] = 0.67 [95% confidence interval (CI): 0.52, 0.86] versus HR = 0.93 [95% CI: 0.78, 1.10]; P-het = 0.03) as was smoking (per 10 pack-years; HR = 0.92 [95% CI: 0.87, 0.98] versus HR = 0.98 [95% CI: 0.94, 1.01]; P-het = 0.09). These findings were robust in sensitivity analyses using a “stepwise up” approach (identify factors that showed the most significant differences). Nonheterogeneous (P-het > 0.10) adverse associations with both POAG subtypes were observed with glaucoma family history, diabetes, African heritage, greater caffeine intake, and higher mean arterial pressure.
Conclusions.
These data indicate that POAG with early paracentral VF loss has distinct as well as common determinants compared with POAG with peripheral VF loss.
We evaluated differences in risk factor associations for primary open-angle glaucoma subtypes defined by visual field (VF) loss pattern and observed that body mass index and cigarette smoking were more strongly inversely associated with POAG with paracentral VF loss versus peripheral VF loss.
doi:10.1167/iovs.14-16088
PMCID: PMC4408886  PMID: 25758813
glaucoma; visual field; epidemiology
2.  Folate, Vitamin B6 and Vitamin B12 Intake and Mild Cognitive Impairment and Probable Dementia in the Women’s Health Initiative Memory Study 
Background
Whether higher B vitamin (B6, B12, and folate) intake is protective against cognitive decline in later life remains uncertain. Several prospective, observational studies find higher B vitamin intake to be associated with lower risk of dementia; other studies, including most trials of B vitamin supplementation, observe no effect on cognition. We examine this question in a large population of older women carefully monitored for development of mild cognitive impairment (MCI) and probable dementia.
Objective
To determine whether baseline folate, vitamin B6 and/or B12 intake, alone or in combination, are associated with incident MCI/probable dementia among older women.
Design
Prospective, longitudinal cohort study. B vitamin intake was self-reported using a food frequency questionnaire administered at baseline between May 1996 and December 1999.
Participants/Setting
Postmenopausal women (n=7,030) free of MCI/probable dementia at baseline in the Women’s Health Initiative Memory Study.
Main outcome measures
Over a mean follow-up of 5.0 years, 238 cases of incident MCI and 69 cases of probable dementia were identified through rigorous screening and expert adjudication.
Statistical analyses
Cox proportional hazard models adjusting for sociodemographic and lifestyle factors examined the association of B vitamin intake above and below the recommended daily allowance and incident MCI/probable dementia.
Results
Folate intake below the RDA at study baseline was associated with increased risk of incident MCI/probable dementia (HR=2.0, 95% CI: 1.3, 2.9), after controlling for multiple confounders. There were no significant associations between vitamins B6 or B12 and MCI/probable dementia, nor any evidence of an interaction between these vitamins and folate intake.
Conclusions
Folate intake below the RDA may increase risk for MCI/probable dementia in later life. Future research should include long-term trials of folic acid supplementation to examine whether folate may impart a protective effect on cognition in later life.
doi:10.1016/j.jand.2014.07.006
PMCID: PMC4312724  PMID: 25201007
Folic acid; vitamin B12; vitamin B6; dementia; cognitive impairment; women’s health; aging
3.  A Nested Case Control Study of Plasma ICAM-1, E-Selectin and TNF Receptor 2 Levels, and Incident Primary Open-Angle Glaucoma 
Purpose.
To evaluate prediagnostic markers of endothelial dysfunction and inflammatory processes in primary open-angle glaucoma (POAG).
Methods.
Blood samples were collected from 1989 to 1990 in the Nurses' Health Study (women) and from 1993 to 1995 in the Health Professionals Follow-up Study (men), and medical-record confirmed incident POAG cases were identified (women: 229 cases and 455 controls; men: 116 cases and 228 controls). Controls were matched on cohort, age, race, ethnicity, cancer status, and date of blood collection. Plasma concentrations of ICAM-1, E-selectin, and soluble TNF receptor 2 (sTNF-R2), a marker related to TNF-α, were measured with ELISA assays. Cohort-specific multivariable conditional logistic regression model results were meta-analyzed.
Results.
We observed no associations with ICAM-1 or E-selectin. For sTNF-R2, the mean (SD) plasma levels (pg/mL) in cases and controls were 2888 (997) and 2993 (913), respectively, in women; and 2622 (664) and 2569 (688), respectively, in men. Pooled multivariable results showed no relation between sTNF-R2 levels and POAG. However, compared with the lowest tertile of sTNF-R2, the highest tertile showed a significant decreased risk of POAG in women (multivariable odds ratio [OR] = 0.58, 95% confidence interval [CI] = 0.36–0.93; Ptrend = 0.03) but not in men (Ptrend = 0.21; P for heterogeneity by sex = 0.03). Also, among women, the inverse association with sTNF-R2 was stronger with normal-tension glaucoma (NTG; maximum intraocular pressure <21 mm Hg at diagnosis): highest versus lowest tertile comparison OR = 0.29 (95% CI = 0.12–0.71; Ptrend = 0.007).
Conclusions.
In women, but not in men, higher sTNF-R2 levels at 6 to 8 years before diagnosis were inversely associated with POAG, but more strongly for NTG.
We evaluated prediagnostic plasma ICAM-1, E-selectin and soluble TNF receptor 2 (sTNF-R2) levels and risk of incident primary open-angle glaucoma (POAG). In women, but not in men, higher sTNF-R2 levels were inversely associated with POAG, particularly normal-tension glaucoma.
doi:10.1167/iovs.12-11191
PMCID: PMC3626518  PMID: 23412091
4.  FTO genetic variants, dietary intake and body mass index: insights from 177 330 individuals 
Qi, Qibin | Kilpeläinen, Tuomas O. | Downer, Mary K. | Tanaka, Toshiko | Smith, Caren E. | Sluijs, Ivonne | Sonestedt, Emily | Chu, Audrey Y. | Renström, Frida | Lin, Xiaochen | Ängquist, Lars H. | Huang, Jinyan | Liu, Zhonghua | Li, Yanping | Asif Ali, Muhammad | Xu, Min | Ahluwalia, Tarunveer Singh | Boer, Jolanda M.A. | Chen, Peng | Daimon, Makoto | Eriksson, Johan | Perola, Markus | Friedlander, Yechiel | Gao, Yu-Tang | Heppe, Denise H.M. | Holloway, John W. | Houston, Denise K. | Kanoni, Stavroula | Kim, Yu-Mi | Laaksonen, Maarit A. | Jääskeläinen, Tiina | Lee, Nanette R. | Lehtimäki, Terho | Lemaitre, Rozenn N. | Lu, Wei | Luben, Robert N. | Manichaikul, Ani | Männistö, Satu | Marques-Vidal, Pedro | Monda, Keri L. | Ngwa, Julius S. | Perusse, Louis | van Rooij, Frank J.A. | Xiang, Yong-Bing | Wen, Wanqing | Wojczynski, Mary K | Zhu, Jingwen | Borecki, Ingrid B. | Bouchard, Claude | Cai, Qiuyin | Cooper, Cyrus | Dedoussis, George V. | Deloukas, Panos | Ferrucci, Luigi | Forouhi, Nita G. | Hansen, Torben | Christiansen, Lene | Hofman, Albert | Johansson, Ingegerd | Jørgensen, Torben | Karasawa, Shigeru | Khaw, Kay-Tee | Kim, Mi-Kyung | Kristiansson, Kati | Li, Huaixing | Lin, Xu | Liu, Yongmei | Lohman, Kurt K. | Long, Jirong | Mikkilä, Vera | Mozaffarian, Dariush | North, Kari | Pedersen, Oluf | Raitakari, Olli | Rissanen, Harri | Tuomilehto, Jaakko | van der Schouw, Yvonne T. | Uitterlinden, André G. | Zillikens, M. Carola | Franco, Oscar H. | Shyong Tai, E. | Ou Shu, Xiao | Siscovick, David S. | Toft, Ulla | Verschuren, W.M. Monique | Vollenweider, Peter | Wareham, Nicholas J. | Witteman, Jacqueline C.M. | Zheng, Wei | Ridker, Paul M. | Kang, Jae H. | Liang, Liming | Jensen, Majken K. | Curhan, Gary C. | Pasquale, Louis R. | Hunter, David J. | Mohlke, Karen L. | Uusitupa, Matti | Cupples, L. Adrienne | Rankinen, Tuomo | Orho-Melander, Marju | Wang, Tao | Chasman, Daniel I. | Franks, Paul W. | Sørensen, Thorkild I.A. | Hu, Frank B. | Loos, Ruth J. F. | Nettleton, Jennifer A. | Qi, Lu
Human Molecular Genetics  2014;23(25):6961-6972.
FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177 330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m2, P = 1.9 × 10−105), and all participants (0.30 [0.30, 0.35] kg/m2, P = 3.6 × 10−107). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10−16), and relative weak associations with lower total energy intake (−6.4 [−10.1, −2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (−0.07 [−0.11, −0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10−9) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.
doi:10.1093/hmg/ddu411
PMCID: PMC4271061  PMID: 25104851
5.  A Large Cohort Study of Hypothyroidism and Hyperthyroidism in Relation to Gynecologic Cancers 
Background. Thyroid status may influence tumorigenesis of gynecologic cancers, yet epidemiologic studies of this relationship are limited and inconsistent. Methods. We evaluated the association of self-reported history of physician-diagnosed hypothyroidism and hyperthyroidism with medical-record confirmed endometrial (EC; all invasive adenocarcinomas) and ovarian cancer (OC; epithelial ovarian or peritoneal cancers) in Nurses' Health Study (NHS) from 1976 to 2010 and NHSII from 1989 to 2011. Cox proportional hazard models were used to estimate multivariable rate ratios (RRs) and 95% confidence intervals based on pooled cohort data. Results. We confirmed 1314 incident cases of EC and 1150 cases of OC. Neither a history of hypothyroidism nor hyperthyroidism was significantly associated with risk of EC or OC. However, having a history of hypothyroidism for 8+ years (median) was nonsignificantly inversely associated with EC (RR = 0.81; 95% CI = 0.63–1.04; P-trend with history duration = 0.11) and OC (RR = 0.87, 95% CI = 0.66–1.15; P-trend = 0.13). Having a history of hyperthyroidism for 6+ years (median) was non-significantly positively associated with EC (RR = 1.69; 95% CI = 0.86–3.30; P-trend = 0.12) but not OC (RR = 1.12; 95% CI = 0.46–2.72; P-trend = 0.95). Conclusions. A history of hypothyroidism or hyperthyroidism was not significantly associated with risk of EC or OC.
doi:10.1155/2013/743721
PMCID: PMC3728510  PMID: 23956749
6.  Solar Exposure and Residential Geographic History in Relation to Exfoliation Syndrome in the United States and Israel 
JAMA ophthalmology  2014;132(12):1439-1445.
Importance
Residential (geographic) history and extent of solar exposure may be important risk factors for exfoliation syndrome, but detailed lifetime solar exposure has not been previously evaluated in exfoliation syndrome.
Objective
To assess the relation between residential history, solar exposure and exfoliation syndrome.
Design
Clinic-based, case control studies.
Setting
A clinical center in the United States and in Israel.
Participants
Exfoliation syndrome cases and controls (all 60+ years old Caucasians) enrolled from 2010 to 2012 (United States: 118 cases and 106 controls; Israel: 67 cases and 72 controls).
Main Outcomes and Measures
Weighted lifetime average latitude of residence and average number of hours per week spent outdoors as determined by validated questionnaires.
Results
In multivariable analyses, each degree of weighted lifetime average residential latitude away from the equator was associated with an 11% increased odds of exfoliation syndrome (pooled odds ratio = 1.11; 95% CI: 1.05-1.17; p < .001). Furthermore, every hour per week spent outdoors during the summer, averaged over a lifetime, was associated with a 4% increased odds of exfoliation syndrome (pooled odds ratio = 1.04; 95% CI: 1.00-1.07; p = .03). For every 1% of average lifetime summer time between 10 a.m. and 4 p.m. that sunglasses were worn, the odds of exfoliation syndrome decreased by 2% (odds ratio = 0.98; 95% CI: 0.97-0.99; p < .001) in the United States, but not in Israel (odds ratio = 1.00; 95% CI: 0.99-1.01; p = .92; p for heterogeneity = .005). In the United States, after controlling for important environmental covariates, history of work over water or snow was associated with increased odds of exfoliation syndrome (odds ratio = 3.86; 95% CI: 1.36-10.9); in Israel, there were too few people with such history for analysis. We did not identify an association between brimmed hat wear and exfoliation syndrome (p>.57).
Conclusion and Relevance
Lifetime outdoor activities may contribute to exfoliation syndrome. The association with work over snow or water and the lack of association with brimmed hat wear suggests that ocular exposure to light from reflective surfaces may be an important type of exposure in exfoliation syndrome etiology.
doi:10.1001/jamaophthalmol.2014.3326
PMCID: PMC4268013  PMID: 25188364
7.  The Relationship between Caffeine and Coffee Consumption and Exfoliation Glaucoma or Glaucoma Suspect: A Prospective Study in Two Cohorts 
Purpose.
We examined the association between caffeine and caffeinated beverage consumption in relation to the risk of exfoliation glaucoma or exfoliation glaucoma suspect (EG/EGS).
Methods.
We followed 78,977 women from the Nurses' Health Study (NHS) and 41,202 men from the Health Professionals Follow-up Study (HPFS) who were at least 40 years of age, did not have glaucoma, and reported undergoing eye examinations from 1980 (NHS) or 1986 (HPFS) to 2008. Information on consumption of caffeine-containing beverages and potential confounders were repeatedly ascertained in validated follow-up questionnaires. Confirmation with medical record review revealed 360 incident EG/EGS cases. Multivariate rate ratios (RRs) for EG/EGS were calculated in each cohort and then pooled using meta-analytic techniques.
Results.
Compared with participants whose cumulatively updated total caffeine consumption was <125 mg/day, participants who consumed ≥500 mg/day had a trend toward increased risk of EG/EGS that was not statistically significant (RR = 1.43; 95% confidence interval [CI], 0.98–2.08); P trend = 0.06). Compared to abstainers, those who drank ≥3 cups of caffeinated coffee daily were at increased risk of EG/EGS (RR = 1.66; 95% CI, 1.09–2.54; P trend = 0.02). These results were not materially altered after adjustment for total fluid intake. Associations were stronger among women with a family history of glaucoma (P interaction = 0.06 for coffee; P interaction = 0.03 for caffeine). We did not find associations with consumption of other caffeinated products (caffeinated soda, caffeinated tea, decaffeinated coffee or chocolate) and risk of EG/EGS (P trend ≥0.31).
Conclusions.
We observed a positive association between heavier coffee consumption with risk of EG/EGS in this large prospective study.
In a large 28-year-old prospective study including 360 incident cases, caffeinated coffee consumption was significantly associated with an increased risk of exfoliation glaucoma or exfoliation glaucoma suspect. The association between caffeine consumption was particularly strong among those with a positive family history of glaucoma
doi:10.1167/iovs.12-10085
PMCID: PMC3450917  PMID: 22918628
8.  Postmenopausal Hormone Therapy, Timing of Initiation, APOE and Cognitive Decline 
Neurobiology of aging  2010;33(7):1129-1137.
Background
Associations between postmenopausal hormone therapy (HT) and cognitive decline may depend on apolipoprotein E (APOE) status or timing of initiation.
Methods
We included 16,514 Nurses’ Health Study participants aged 70–81 years who were followed since 1976 and completed up to three telephone cognitive assessments (2 years apart), between 1995 and 2006. The tests assessed general cognition (Telephone Interview of Cognitive Status (TICS)), verbal memory, and category fluency. We used longitudinal analyses to estimate differences in cognitive decline across hormone groups. APOE genotype was available in 3697 participants.
Results
Compared with never users, past or current HT users showed modest but statistically significant worse rates of decline in the TICS: the multivariable-adjusted difference in annual rate of decline in the TICS among current estrogen only users versus never users was −0.04 (95% CI = −0.07, −0.004); for current estrogen+progestin users, the mean difference was −0.05 (95% CI = −0.10, −0.002). These differences were equivalent to those observed in women who are 1–2 years apart in age. We observed no protective associations with early timing of hormone initiation. We found suggestive interactions with APOE e4 status (e.g., on TICS, p-interaction = 0.10), where the fastest rate of decline was observed among APOE e4 carriers who were current HT users.
Conclusion
Regardless of timing of initiation, HT may be associated with worse rates of decline in general cognition, especially among those with an APOE e4 allele.
doi:10.1016/j.neurobiolaging.2010.10.007
PMCID: PMC3483632  PMID: 21122949
9.  Hypothesis-independent pathway analysis implicates GABA and Acetyl-CoA metabolism in primary open-angle glaucoma and normal-pressure glaucoma 
Human genetics  2014;133(10):1319-1330.
Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. Using genome-wide association single-nucleotide polymorphism data from the Glaucoma Genes and Environment study and National Eye Institute Glaucoma Human Genetics Collaboration comprising 3,108 cases and 3,430 controls, we assessed biologic pathways as annotated in the KEGG database for association with risk of POAG. After correction for genic overlap among pathways, we found 4 pathways, butanoate metabolism (hsa00650), hematopoietic cell lineage (hsa04640), lysine degradation (hsa00310) and basal transcription factors (hsa03022) related to POAG with permuted p < 0.001. In addition, the human leukocyte antigen (HLA) gene family was significantly associated with POAG (p < 0.001). In the POAG subset with normal-pressure glaucoma (NPG), the butanoate metabolism pathway was also significantly associated (p < 0.001) as well as the MAPK and Hedgehog signaling pathways (hsa04010 and hsa04340), glycosaminoglycan biosynthesis-heparan sulfate pathway (hsa00534) and the phenylalanine, tyrosine and tryptophan biosynthesis pathway (hsa0400). The butanoate metabolism pathway overall, and specifically the aspects of the pathway that contribute to GABA and acetyl-CoA metabolism, was the only pathway significantly associated with both POAG and NPG. Collectively these results implicate GABA and acetyl-CoA metabolism in glaucoma pathogenesis, and suggest new potential therapeutic targets.
doi:10.1007/s00439-014-1468-7
PMCID: PMC4273559  PMID: 25037249
10.  DNA Copy Number Variants of Known Glaucoma Genes in Relation to Primary Open-Angle Glaucoma 
Purpose.
We examined the role of DNA copy number variants (CNVs) of known glaucoma genes in relation to primary open angle glaucoma (POAG).
Methods.
Our study included DNA samples from two studies (NEIGHBOR and GLAUGEN). All the samples were genotyped with the Illumina Human660W_Quad_v1 BeadChip. After removing non–blood-derived and amplified DNA samples, we applied quality control steps based on the mean Log R Ratio and the mean B allele frequency. Subsequently, data from 3057 DNA samples (1599 cases and 1458 controls) were analyzed with PennCNV software. We defined CNVs as those ≥5 kilobases (kb) in size and interrogated by ≥5 consecutive probes. We further limited our investigation to CNVs in known POAG-related genes, including CDKN2B-AS1, TMCO1, SIX1/SIX6, CAV1/CAV2, the LRP12-ZFPM2 region, GAS7, ATOH7, FNDC3B, CYP1B1, MYOC, OPTN, WDR36, SRBD1, TBK1, and GALC.
Results.
Genomic duplications of CDKN2B-AS1 and TMCO1 were each found in a single case. Two cases carried duplications in the GAS7 region. Genomic deletions of SIX6 and ATOH7 were each identified in one case. One case carried a TBK1 deletion and another case carried a TBK1 duplication. No controls had duplications or deletions in these six genes. A single control had a duplication in the MYOC region. Deletions of GALC were observed in five cases and two controls.
Conclusions.
The CNV analysis of a large set of cases and controls revealed the presence of rare CNVs in known POAG susceptibility genes. Our data suggest that these rare CNVs may contribute to POAG pathogenesis and merit functional evaluation.
Our study examined DNA copy number variants of known glaucoma genes in two large cohorts - NEIGHBOR and GLAUGEN. We identified rare deletions and/or duplications in a few glaucoma genes only in POAG cases. Our data suggest potential role of these rare CNVs in POAG pathogenesis.
doi:10.1167/iovs.14-15712
PMCID: PMC4271633  PMID: 25414181
DNA copy number variants; POAG; genetics; SIX6; GAS7
11.  A prospective study of folate, vitamin B6 and vitamin B12 in relation to exfoliation glaucoma or exfoliation glaucoma suspect 
JAMA ophthalmology  2014;132(5):549-559.
IMPORTANCE
Effective strategies for primary prevention are lacking for exfoliation glaucoma, which is the most common type of secondary glaucoma.
OBJECTIVE
We examined the association of B vitamin intake and exfoliation glaucoma or exfoliation glaucoma suspect (EG/EGS) risk.
DESIGN
Prospective cohort study using 20+ years follow-up data from Nurses’ Health Study (NHS; all female registered nurses) and the Health Professionals Follow-up Study (HPFS; all male health professionals) from 1980 (NHS) / 1986 (HPFS) to 2010.
SETTING
United States.
PARTICIPANTS
We included a subset of 78,980 NHS women and 41,221 HPFS men who were 40+ years of age, free of glaucoma, had completed diet questionnaires and reported eye exams (follow-up rate >85%).
EXPOSURE
Cumulatively updated intake of B vitamins (folate, vitamin B6 and vitamin B12) as ascertained by repeated administration of validated questionnaires.
MAIN OUTCOME MEASURE
Incident cases of EG/EGS, totaling 399 cases (329 women and 70 men), were first identified with the questionnaires and were subsequently confirmed with medical records. Multivariate rate ratios (MVRRs) for EG/EGS were calculated in each cohort and then pooled with meta-analysis.
RESULTS
Vitamin B6 and vitamin B12 intake were not associated with EG/EGS risk in pooled analyses (p for linear trend was 0.52 and 0.99, respectively). However, a suggestive trend of a reduced risk was observed with higher intake of folate: compared with the lowest quintile (Q1) of cumulatively averaged updated total folate intake, the MVRR of EG/EGS for the highest quintile (Q5; ≥ 654 μg/day) was 0.75 (95% Confidence Interval[CI]: 0.54 - 1.04; p for linear trend=0.02). These results were not materially altered after adjustment for vitamin B6 and vitamin B12. An association was observed for supplemental folate intake but not for folate from diet only (p for linear trend was 0.03 and 0.64, respectively). Greater frequency of multivitamin use showed a modest suggestive inverse association (current multivitamin use of 6+times / week versus non-use MVRR= 0.84, 95% CI, 0.64-1.11; p for linear trend=0.06).
CONCLUSIONS AND RELEVANCE
Higher total folate intake was associated with a suggestive lower risk of EG/EGS, supporting a possible etiologic role of homocysteine in EG/EGS.
doi:10.1001/jamaophthalmol.2014.100
PMCID: PMC4170522  PMID: 24699833
12.  Bupropion Use and Risk of Open-Angle Glaucoma among Enrollees in a Large U.S. Managed Care Network 
PLoS ONE  2015;10(4):e0123682.
Objective
Tumor Necrosis Factor (TNF) mediates retinal ganglion cell death in glaucoma. Anti-TNF drugs are neuroprotective in an animal model of glaucoma. It is unclear whether medications with anti-TNF properties such as bupropion have an impact on the risk of developing open-angle glaucoma (OAG) in humans. The purpose of this study is to determine whether bupropion use alters the risk of developing OAG.
Methods
Claims data for beneficiaries age ≥35 years with no pre-existing OAG enrolled in a large nationwide U.S. managed care network continuously for ≥4 years between 2001-2011 was analyzed to identify patients who had been newly-diagnosed with OAG. The amount of bupropion use as captured from outpatient pharmacy claims over a four-year period was also quantified for each beneficiary. Multivariable Cox regression modeling assessed the impact of bupropion and other antidepressant medications on the risk of developing OAG with adjustment for sociodemographic characteristics of the enrollees along with medical and ocular comorbidities.
Results
Of 638,481 eligible enrollees, 15,292 (2.4%) developed OAG. After adjustment for confounding factors including use of other antidepressant medication classes, each additional month of bupropion use was associated with a 0.6% reduced risk of OAG (HR = 0.994, (95% CI: 0.989-0.998), p = 0.007). Compared to nonusers, those with 24-48 months of bupropion use had a 21% reduced hazard (HR=0.79, (CI: 0.65-0.94), p = 0.0099) of OAG. This association did not differ among persons taking bupropion for depression or for other reasons (p-interaction = 0.82). There was no significant association between use of tricyclic antidepressants (HR = 1.000, (CI: 0.997-1.004), p = 0.95) or selective serotonin reuptake inhibitors (HR = 0.999, (CI: 0.997-1.001), p = 0.39) and development of OAG.
Conclusion
These findings suggest bupropion use may be beneficial in reducing the risk of OAG. If prospective studies confirm the findings of this analysis, this may identify a novel therapeutic target for OAG.
doi:10.1371/journal.pone.0123682
PMCID: PMC4395241  PMID: 25875446
13.  A common variant near TGFBR3 is associated with primary open angle glaucoma 
Li, Zheng | Allingham, R. Rand | Nakano, Masakazu | Jia, Liyun | Chen, Yuhong | Ikeda, Yoko | Mani, Baskaran | Chen, Li-Jia | Kee, Changwon | Garway-Heath, David F. | Sripriya, Sarangapani | Fuse, Nobuo | Abu-Amero, Khaled K. | Huang, Chukai | Namburi, Prasanthi | Burdon, Kathryn | Perera, Shamira A. | Gharahkhani, Puya | Lin, Ying | Ueno, Morio | Ozaki, Mineo | Mizoguchi, Takanori | Krishnadas, Subbiah Ramasamy | Osman, Essam A. | Lee, Mei Chin | Chan, Anita S.Y. | Tajudin, Liza-Sharmini A. | Do, Tan | Goncalves, Aurelien | Reynier, Pascal | Zhang, Hong | Bourne, Rupert | Goh, David | Broadway, David | Husain, Rahat | Negi, Anil K. | Su, Daniel H | Ho, Ching-Lin | Blanco, Augusto Azuara | Leung, Christopher K.S. | Wong, Tina T. | Yakub, Azhany | Liu, Yutao | Nongpiur, Monisha E. | Han, Jong Chul | Hon, Do Nhu | Shantha, Balekudaru | Zhao, Bowen | Sang, Jinghong | Zhang, NiHong | Sato, Ryuichi | Yoshii, Kengo | Panda-Jonas, Songhomita | Ashley Koch, Allison E. | Herndon, Leon W. | Moroi, Sayoko E. | Challa, Pratap | Foo, Jia Nee | Bei, Jin-Xin | Zeng, Yi-Xin | Simmons, Cameron P. | Bich Chau, Tran Nguyen | Sharmila, Philomenadin Ferdinamarie | Chew, Merwyn | Lim, Blanche | Tam, Pansy O.S. | Chua, Elaine | Ng, Xiao Yu | Yong, Victor H.K. | Chong, Yaan Fun | Meah, Wee Yang | Vijayan, Saravanan | Seongsoo, Sohn | Xu, Wang | Teo, Yik Ying | Cooke Bailey, Jessica N. | Kang, Jae H. | Haines, Jonathan L. | Cheng, Ching Yu | Saw, Seang-Mei | Tai, E-Shyong | Richards, Julia E. | Ritch, Robert | Gaasterland, Douglas E. | Pasquale, Louis R. | Liu, Jianjun | Jonas, Jost B. | Milea, Dan | George, Ronnie | Al-Obeidan, Saleh A. | Mori, Kazuhiko | Macgregor, Stuart | Hewitt, Alex W. | Girkin, Christopher A. | Zhang, Mingzhi | Sundaresan, Periasamy | Vijaya, Lingam | Mackey, David A. | Wong, Tien Yin | Craig, Jamie E. | Sun, Xinghuai | Kinoshita, Shigeru | Wiggs, Janey L. | Khor, Chiea-Chuen | Yang, Zhenglin | Pang, Chi Pui | Wang, Ningli | Hauser, Michael A. | Tashiro, Kei | Aung, Tin | Vithana, Eranga N.
Human Molecular Genetics  2015;24(13):3880-3892.
Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution. We performed Exome Array (Illumina) analysis on 3504 POAG cases and 9746 controls with replication of the most significant findings in 9173 POAG cases and 26 780 controls across 18 collections of Asian, African and European descent. Apart from confirming strong evidence of association at CDKN2B-AS1 (rs2157719 [G], odds ratio [OR] = 0.71, P = 2.81 × 10−33), we observed one SNP showing significant association to POAG (CDC7–TGFBR3 rs1192415, ORG-allele = 1.13, Pmeta = 1.60 × 10−8). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis.
doi:10.1093/hmg/ddv128
PMCID: PMC4459396  PMID: 25861811
14.  Genome-wide analysis of multiethnic cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma 
Hysi, Pirro G | Cheng, Ching-Yu | Springelkamp, Henriët | Macgregor, Stuart | Bailey, Jessica N Cooke | Wojciechowski, Robert | Vitart, Veronique | Nag, Abhishek | Hewitt, Alex W | Höhn, René | Venturini, Cristina | Mirshahi, Alireza | Ramdas, Wishal D. | Thorleifsson, Gudmar | Vithana, Eranga | Khor, Chiea-Chuen | Stefansson, Arni B | Liao, Jiemin | Haines, Jonathan L | Amin, Najaf | Wang, Ya Xing | Wild, Philipp S | Ozel, Ayse B | Li, Jun Z | Fleck, Brian W | Zeller, Tanja | Staffieri, Sandra E | Teo, Yik-Ying | Cuellar-Partida, Gabriel | Luo, Xiaoyan | Allingham, R Rand | Richards, Julia E | Senft, Andrea | Karssen, Lennart C | Zheng, Yingfeng | Bellenguez, Céline | Xu, Liang | Iglesias, Adriana I | Wilson, James F | Kang, Jae H | van Leeuwen, Elisabeth M | Jonsson, Vesteinn | Thorsteinsdottir, Unnur | Despriet, Dominiek D.G. | Ennis, Sarah | Moroi, Sayoko E | Martin, Nicholas G | Jansonius, Nomdo M | Yazar, Seyhan | Tai, E-Shyong | Amouyel, Philippe | Kirwan, James | van Koolwijk, Leonieke M.E. | Hauser, Michael A | Jonasson, Fridbert | Leo, Paul | Loomis, Stephanie J | Fogarty, Rhys | Rivadeneira, Fernando | Kearns, Lisa | Lackner, Karl J | de Jong, Paulus T.V.M. | Simpson, Claire L | Pennell, Craig E | Oostra, Ben A | Uitterlinden, André G | Saw, Seang-Mei | Lotery, Andrew J | Bailey-Wilson, Joan E | Hofman, Albert | Vingerling, Johannes R | Maubaret, Cécilia | Pfeiffer, Norbert | Wolfs, Roger C.W. | Lemij, Hans G | Young, Terri L | Pasquale, Louis R | Delcourt, Cécile | Spector, Timothy D | Klaver, Caroline C.W. | Small, Kerrin S | Burdon, Kathryn P | Stefansson, Kari | Wong, Tien-Yin | Viswanathan, Ananth | Mackey, David A | Craig, Jamie E | Wiggs, Janey L | van Duijn, Cornelia M | Hammond, Christopher J | Aung, Tin
Nature genetics  2014;46(10):1126-1130.
Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma and IOP variability may herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multiethnic participants for IOP. We confirm genetic association of known loci for IOP and primary open angle glaucoma (POAG) and identify four new IOP loci located on chromosome 3q25.31 within the FNDC3B gene (p=4.19×10−08 for rs6445055), two on chromosome 9 (p=2.80×10−11 for rs2472493 near ABCA1 and p=6.39×10−11 for rs8176693 within ABO) and one on chromosome 11p11.2 (best p=1.04×10−11 for rs747782). Separate meta-analyses of four independent POAG cohorts, totaling 4,284 cases and 95,560 controls, show that three of these IOP loci are also associated with POAG.
doi:10.1038/ng.3087
PMCID: PMC4177225  PMID: 25173106
15.  Plasma vitamin D levels and cognitive function in aging women: the Nurses’ Health Study 
Background
Vitamin D may play a role in preserving cognitive function. However, there is a paucity of prospective studies on the relationship between vitamin D and cognition with aging. The aim of this study was to examine the association between plasma levels of vitamin D and subsequent cognitive function.
Methods
This is a prospective study including 1,185 women aged 60–70 years from the Nurses’ Health Study, who had plasma 25-hydroxy-vitamin D levels measured in 1989–1990 and completed an initial Telephone Interview of Cognitive Status approximately 9 years later. Subsequently, three follow-up cognitive assessments were conducted at 1.5–2.0 years intervals. We used multivariable-adjusted linear regression to model initial cognitive function, and mixed linear regression to model change in cognitive function over time.
Results
Lower vitamin D levels were associated with significantly worse cognitive function 9 years later. For example, the mean global composite score averaging all the cognitive tests was 0.20 lower (95% Confidence Interval (CI):−0.33,−0.08; p-trend=0.009) in women in the lowest quintile (median=14.1 ng/mL) compared with women in the highest quintile of vitamin D (median=38.4 ng/mL). The observed differences were equivalent to the effect estimates we found for women who were approximately 4–6 years apart in age. However, vitamin D levels were not significantly associated with subsequent cognitive decline during 6 years of follow-up.
Conclusions
Higher levels of plasma vitamin D in women aged 60–70 years were associated with better cognitive function about a decade later but were not associated with cognitive decline during 6 years of follow-up.
doi:10.1007/s12603-013-0409-9
PMCID: PMC4198067  PMID: 24676321
Vitamin D; Cognitive Function; Women’s Health
16.  Genome-wide association study and meta-analysis of intraocular pressure 
Human genetics  2013;133(1):41-57.
Elevated intraocular pressure (IOP) is a major risk factor for glaucoma and is influenced by genetic and environmental factors. Recent genome-wide association studies (GWAS) reported associations with IOP at TMCO1 and GAS7, and with primary open-angle glaucoma (POAG) at CDKN2B-AS1, CAV1/CAV2, and SIX1/SIX6. To identify novel genetic variants and replicate the published findings, we performed GWAS and meta-analysis of IOP in >6,000 subjects of European ancestry collected in three datasets: the NEI Glaucoma Human genetics collaBORation, GLAUcoma Genes and ENvironment study, and a subset of the Age-related Macular Degeneration-Michigan, Mayo, AREDS and Pennsylvania study. While no signal achieved genome-wide significance in individual datasets, a meta-analysis identified significant associations with IOP at TMCO1 (rs7518099-G, p = 8.0 × 10−8). Focused analyses of five loci previously reported for IOP and/or POAG, i.e., TMCO1, CDKN2B-AS1, GAS7, CAV1/CAV2, and SIX1/SIX6, revealed associations with IOP that were largely consistent across our three datasets, and replicated the previously reported associations in both effect size and direction. These results confirm the involvement of common variants in multiple genomic regions in regulating IOP and/or glaucoma risk.
doi:10.1007/s00439-013-1349-5
PMCID: PMC3982323  PMID: 24002674
17.  Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process 
Springelkamp, Henriët. | Höhn, René | Mishra, Aniket | Hysi, Pirro G. | Khor, Chiea-Chuen | Loomis, Stephanie J. | Bailey, Jessica N. Cooke | Gibson, Jane | Thorleifsson, Gudmar | Janssen, Sarah F. | Luo, Xiaoyan | Ramdas, Wishal D. | Vithana, Eranga | Nongpiur, Monisha E. | Montgomery, Grant W. | Xu, Liang | Mountain, Jenny E. | Gharahkhani, Puya | Lu, Yi | Amin, Najaf | Karssen, Lennart C. | Sim, Kar-Seng | van Leeuwen, Elisabeth M. | Iglesias, Adriana I. | Verhoeven, Virginie J. M. | Hauser, Michael A. | Loon, Seng-Chee | Despriet, Dominiek D. G. | Nag, Abhishek | Venturini, Cristina | Sanfilippo, Paul G. | Schillert, Arne | Kang, Jae H. | Landers, John | Jonasson, Fridbert | Cree, Angela J. | van Koolwijk, Leonieke M. E. | Rivadeneira, Fernando | Souzeau, Emmanuelle | Jonsson, Vesteinn | Menon, Geeta | Weinreb, Robert N. | de Jong, Paulus T. V. M. | Oostra, Ben A. | Uitterlinden, André G. | Hofman, Albert | Ennis, Sarah | Thorsteinsdottir, Unnur | Burdon, Kathryn P. | Spector, Timothy D. | Mirshahi, Alireza | Saw, Seang-Mei | Vingerling, Johannes R. | Teo, Yik-Ying | Haines, Jonathan L. | Wolfs, Roger C. W. | Lemij, Hans G. | Tai, E-Shyong | Jansonius, Nomdo M. | Jonas, Jost B. | Cheng, Ching-Yu | Aung, Tin | Viswanathan, Ananth C. | Klaver, Caroline C. W. | Craig, Jamie E. | Macgregor, Stuart | Mackey, David A. | Lotery, Andrew J. | Stefansson, Kari | Bergen, Arthur A. B. | Young, Terri L. | Wiggs, Janey L. | Pfeiffer, Norbert | Wong, Tien-Yin | Pasquale, Louis R. | Hewitt, Alex W. | van Duijn, Cornelia M. | Hammond, Christopher J.
Nature Communications  2014;5:4883.
Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 individuals of European ancestry and 6,784 individuals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition.
Glaucoma is the most common cause of irreversible blindness worldwide. Here, the authors carry out a large meta-analysis of genetic data from individuals of European and Asian ancestry and identify 10 new loci associated with vertical cup-disc ratio, a key factor in the clinical assessment of patients with glaucoma.
doi:10.1038/ncomms5883
PMCID: PMC4199103  PMID: 25241763
18.  Seafood Types and Age-Related Cognitive Decline in the Women’s Health Study 
Background.
Seafood consumption may prevent age-related cognitive decline. However, benefits may vary by nutrient contents in different seafood types. We examined associations between total seafood consumption and cognitive decline and whether these associations differ by seafood types.
Methods.
We conducted a prospective cohort study of 5,988 women (mean age, 72 years) from the Women’s Health Study who self-reported seafood intake at Women’s Health Study baseline and also participated in telephone assessments of general cognition, verbal memory, and category fluency administered 5.6 years after Women’s Health Study baseline and 2 and 4 years thereafter. Primary outcomes were standardized composite scores of global cognition and verbal memory.
Results.
After adjusting for potential confounders, different amounts of total seafood consumption were not associated with changes in global cognition (p = .56) or verbal memory (p = .29). Considering seafood types, however, compared with women consuming less than once-weekly tuna or dark-meat finfish, those with once-weekly or higher consumption had significantly better verbal memory (0.079 standard units; p < .01) after 4 years—a difference comparable to that for women 2.1 years apart in age. There was also a statistically nonsignificant suggestion of better global cognition (p = .13) with once-weekly or higher tuna or dark-meat fish consumption. No significant associations were observed for light-meat finfish or shellfish.
Conclusions.
The relation of seafood to cognition may depend on the types consumed. Total consumption levels of seafood were unrelated to cognitive change. However, consumption of tuna and dark-meat fish once weekly or higher was associated with lower decline in verbal memory for a period of 4 years.
doi:10.1093/gerona/glt037
PMCID: PMC3779629  PMID: 23554464
Cognition; Epidemiology; Nutrition.
19.  The NEIGHBOR Consortium Primary Open Angle Glaucoma Genome-wide Association Study: Rationale, Study design and Clinical variables 
Journal of glaucoma  2013;22(7):517-525.
Primary open-angle glaucoma (POAG) is a common disease with complex inheritance. The identification of genes predisposing to POAG is an important step toward the development of novel gene-based methods of diagnosis and treatment. Genome-wide association studies (GWAS) have successfully identified genes contributing to complex traits such as POAG however, such studies frequently require very large sample sizes, and thus, collaborations and consortia have been of critical importance for the GWAS approach. In this report we describe the formation of the NEIGHBOR consortium, the harmonized case control definitions used for a POAG GWAS, the clinical features of the cases and controls and the rationale for the GWAS study design.
doi:10.1097/IJG.0b013e31824d4fd8
PMCID: PMC3485429  PMID: 22828004
20.  Mediterranean diet and cognitive function in older age: results from the Women’s Health Study 
Epidemiology (Cambridge, Mass.)  2013;24(4):490-499.
Background
Adherence to a Mediterranean diet may help prevent cognitive decline in older age, but studies are limited. We examined the association of adherence to the Mediterranean diet with cognitive function and decline.
Methods
We included 6,174 participants, aged 65+ years, from the cognitive sub-study of the Women’s Health Study. Women provided dietary information in 1998 and completed a cognitive battery 5 years later, followed by two assessments at 2-year intervals. The primary outcomes were composite scores of global cognition and verbal memory. The alternate Mediterranean diet adherence 9-point-score was constructed based on intakes of: vegetables, fruits, legumes, whole grains, nuts, fish, red and processed meats, moderate alcohol, and the ratio of monounsaturated-to-saturated fats.
Results
After multivariable adjustment, the alternate Mediterranean diet score was not associated with trajectories of repeated cognitive scores (P-trend across quintiles=0.26 and 0.40 for global cognition and verbal memory, respectively), nor with overall global cognition and verbal memory at older ages, assessed by averaging the three cognitive measures (P-trend=0.63 and 0.44, respectively). Among alternate Mediterranean diet components, higher monounsaturated-to-saturated fats ratio was associated with more favorable cognitive trajectories (P-trend=0.03 and 0.05 for global cognition and verbal memory, respectively). Greater whole grain intake was not associated with cognitive trajectories, but was related to better average global cognition (P-trend=0.02).
Conclusions
In this large study of older women, we observed no association of the Mediterranean diet with cognitive decline. Relations between individual Mediterranean diet components, particularly whole grains, and cognitive function merit further study.
doi:10.1097/EDE.0b013e318294a065
PMCID: PMC3674216  PMID: 23676264
21.  CDKN2B-AS1 Genotype – Glaucoma Feature Correlations in Primary Open-Angle Glaucoma Patients from the United States 
American journal of ophthalmology  2012;155(2):342-353.e5.
PURPOSE
To assess the association between single nucleotide polymorphisms (SNPs) of the gene region containing cyclin dependent kinase inhibitor 2B antisense noncoding RNA (CDKN2B-AS1) and glaucoma features among primary open-angle glaucoma (POAG) patients.
DESIGN
Retrospective observational case series.
METHODS
We studied associations between ten CDKN2B-AS1 SNPs and glaucoma features among 976 POAG cases from the Glaucoma Genes and Environment (GLAUGEN) study and 1971 cases from the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium. For each patient, we chose the feature from the eye with the higher value. We created cohort-specific multivariable models for glaucoma features and then meta-analyzed the results.
RESULTS
For nine of the ten protective CDKN2B-AS1 SNPs with minor alleles associated with reduced disease risk (e.g., the G allele at rs2157719), POAG patients carrying these minor alleles had smaller cup-disc ratio (0.05 units smaller per G allele at diagnosis; 95% CI: −0.08, −0.03; p=6.23E-05) despite having higher intraocular pressure (IOP) (0.70 mm Hg higher per G allele at DNA collection; 95% CI: 0.40, 1.00; P=5.45E-06). For the one adverse rs3217992 SNP with minor allele A associated with increased disease risk, POAG patients with A alleles had larger cup-disc ratio (0.05 units larger per A allele at diagnosis; 95% CI: 0.02, 0.07; P=4.74E-04) despite having lower IOP (−0.57 mm Hg per A allele at DNA collection; 95% CI: −0.84, −0.29; P=6.55E-05).
CONCLUSION
Alleles of CDKN2B-AS1 SNPs, which influence risk of developing POAG, also modulate optic nerve degeneration among POAG patients, underscoring the role of CDKN2B-AS1 in POAG.
doi:10.1016/j.ajo.2012.07.023
PMCID: PMC3544983  PMID: 23111177
22.  Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus 
Lu, Yi | Vitart, Veronique | Burdon, Kathryn P | Khor, Chiea Chuen | Bykhovskaya, Yelena | Mirshahi, Alireza | Hewitt, Alex W | Koehn, Demelza | Hysi, Pirro G | Ramdas, Wishal D | Zeller, Tanja | Vithana, Eranga N | Cornes, Belinda K | Tay, Wan-Ting | Tai, E Shyong | Cheng, Ching-Yu | Liu, Jianjun | Foo, Jia-Nee | Saw, Seang Mei | Thorleifsson, Gudmar | Stefansson, Kari | Dimasi, David P | Mills, Richard A | Mountain, Jenny | Ang, Wei | Hoehn, René | Verhoeven, Virginie J M | Grus, Franz | Wolfs, Roger | Castagne, Raphaële | Lackner, Karl J | Springelkamp, Henriët | Yang, Jian | Jonasson, Fridbert | Leung, Dexter Y L | Chen, Li J | Tham, Clement C Y | Rudan, Igor | Vatavuk, Zoran | Hayward, Caroline | Gibson, Jane | Cree, Angela J | MacLeod, Alex | Ennis, Sarah | Polasek, Ozren | Campbell, Harry | Wilson, James F | Viswanathan, Ananth C | Fleck, Brian | Li, Xiaohui | Siscovick, David | Taylor, Kent D | Rotter, Jerome I | Yazar, Seyhan | Ulmer, Megan | Li, Jun | Yaspan, Brian L | Ozel, Ayse B | Richards, Julia E | Moroi, Sayoko E | Haines, Jonathan L | Kang, Jae H | Pasquale, Louis R | Allingham, R Rand | Ashley-Koch, Allison | Mitchell, Paul | Wang, Jie Jin | Wright, Alan F | Pennell, Craig | Spector, Timothy D | Young, Terri L | Klaver, Caroline C W | Martin, Nicholas G | Montgomery, Grant W | Anderson, Michael G | Aung, Tin | Willoughby, Colin E | Wiggs, Janey L | Pang, Chi P | Thorsteinsdottir, Unnur | Lotery, Andrew J | Hammond, Christopher J | van Duijn, Cornelia M | Hauser, Michael A | Rabinowitz, Yaron S | Pfeiffer, Norbert | Mackey, David A | Craig, Jamie E | Macgregor, Stuart | Wong, Tien Y
Nature genetics  2013;45(2):155-163.
Central corneal thickness (CCT) is associated with eye conditions including keratoconus and glaucoma. We performed a meta-analysis on >20,000 individuals in European and Asian populations that identified 16 new loci associated with CCT at genome-wide significance (P < 5 × 10−8). We further showed that 2 CCT-associated loci, FOXO1 and FNDC3B, conferred relatively large risks for keratoconus in 2 cohorts with 874 cases and 6,085 controls (rs2721051 near FOXO1 had odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.4–1.88, P = 2.7 × 10−10, and rs4894535 in FNDC3B had OR = 1.47, 95% CI = 1.29–1.68, P = 4.9 × 10−9). FNDC3B was also associated with primary open-angle glaucoma (P = 5.6 × 10−4; tested in 3 cohorts with 2,979 cases and 7,399 controls). Further analyses implicate the collagen and extracellular matrix pathways in the regulation of CCT.
doi:10.1038/ng.2506
PMCID: PMC3720123  PMID: 23291589
23.  The Association of Antioxidants and Cognition in the Nurses’ Health Study 
American Journal of Epidemiology  2012;177(1):33-41.
The authors examined long-term antioxidant intake in relation to cognitive decline among older women. Beginning in 1980, Nurses’ Health Study (NHS) participants completed dietary assessments every 4 years; in 1995–2001, 16,010 participants aged ≥70 years completed initial cognitive assessments, which were repeated 3 times at 2-year intervals. Long-term antioxidant intake was averaged from 1980 through the time of initial cognitive interviews. Multivariable-adjusted linear regression was used to estimate mean differences in rates of cognitive decline across categories of vitamin E, vitamin C, and carotenoid intake; statistical tests were 2-sided. No associations were evident for vitamin E or total carotenoid intake and cognitive decline (e.g., after multivariable adjustment, P-trend = 0.44 and P-trend = 0.51, respectively, for a global composite score averaging all 6 cognitive tests), although higher lycopene intake and lower vitamin C intake were related to slower cognitive decline. In alternative analyses of overall cognitive status at older ages (averaging all 4 cognitive assessments), results for vitamins E and C were generally null, but higher carotenoid intake was related to better cognition. Overall, long-term vitamin E and C intakes were not consistently related to cognition, although greater consumption of carotenoids may have cognitive benefits in older adults.
doi:10.1093/aje/kws202
PMCID: PMC3590037  PMID: 23221724
antioxidants; cognition; cohort studies; diet
24.  Caffeine and cognitive decline in elderly women at high vascular risk 
Journal of Alzheimer's disease : JAD  2013;35(2):10.3233/JAD-122371.
Background
Persons with vascular disorders are at higher risk of cognitive decline.
Objective
To determine whether caffeine may be associated with cognitive decline reduction in elderly at high vascular risk.
Methods
We included 2475 women aged 65+ years in the Women’s Antioxidant Cardiovascular Study, a randomized trial of antioxidants and B vitamins for cardiovascular disease secondary prevention. We ascertained regular caffeine intake at baseline (1995–1996) using a validated 116 item-food frequency questionnaire. From 1998–2000 to 2005–2006, we administered four telephone cognitive assessments at two-year intervals evaluating global cognition, verbal memory and category fluency. The primary outcome was the change in global cognitive score, which was the average of the z-scores of all tests. We used generalized linear models for repeated measures that were adjusted for various sociodemographic, health and lifestyle factors to evaluate the difference in cognitive decline rates across quintiles of caffeine intake.
Results
We observed significantly slower rates of cognitive decline with increasing caffeine intake (p-trend=0.02). The rate difference between the highest and lowest quintiles of usual caffeine intake (> 371 versus < 30 mg/day) was equivalent to that observed between those who were 7 years apart in age (p=0.006). Consumption of caffeinated coffee was significantly related to slower cognitive decline (p-trend=0.05), but not other caffeinated products (e.g., decaf, tea, cola, chocolate). We conducted interaction analyses and observed stronger associations in women assigned to vitamin B supplementation (p-interaction = 0.02).
Conclusions
Caffeine intake was related to moderately better cognitive maintenance over 5 years in older women with vascular disorders.
doi:10.3233/JAD-122371
PMCID: PMC3807252  PMID: 23422357
Cognition; Aging; Caffeine; Cohort studies; Risk factors; Epidemiology
25.  Television Watching, Leisure-Time Physical Activity and the Genetic Predisposition in Relation to Body Mass Index in Women and Men 
Circulation  2012;126(15):1821-1827.
Background
Previous studies on gene-lifestyle interaction and obesity have mostly focused on the FTO gene and physical activity, while little attention has been paid to sedentary behavior as indicated by television (TV) watching.
Methods and Results
We analyzed interactions between TV watching, leisure-time physical activity and genetic predisposition in relation to body mass index (BMI) in 7740 women and 4564 men from 2 prospective cohorts: the Nurses’ Health Study and Health Professionals Follow-up Study. Data on physical activity and TV watching were collected 2 years prior to assessment of BMI. A weighted genetic risk score (GRS) was calculated on the basis of 32 established BMI-associated variants. In both women and men, the genetic associations with BMI strengthened with increased hours of TV watching. An increment of 10 points in the weighted GRS was associated with 0.8 [SE 0.4], 0.8 [0.2], 1.4 [0.2], 1.5 [0.2] and 3.4 [1.0] kg/m2 higher BMI across the 5 categories of TV watching (0-1, 2-5, 6-20, 21-40, and >40h/wk) (P for interaction=0.001). In contrast, the genetic association with BMI weakened with increased levels of physical activity. An increment of 10 points in the weighted GRS was associated with 1.5 [0.2], 1.3 [0.2], 1.2 [0.2], 1.2 [0.2] and 0.8 [0.2] kg/m2 higher BMI across the quintiles of physical activity. The interactions of TV watching and physical activity with genetic predisposition in relation to BMI were independent of each other.
Conclusions
Sedentary lifestyle indicated by prolonged TV watching may accentuate predisposition to elevated adiposity, whereas greater leisure-time physical activity may attenuate the genetic association.
doi:10.1161/CIRCULATIONAHA.112.098061
PMCID: PMC3667660  PMID: 22949498
Body mass index; Genetics; Gene-lifestyle interaction; Television watching; Physical activity

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