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1.  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.
PMCID: PMC3982323  PMID: 24002674
2.  A Nested Case Control Study of Plasma ICAM-1, E-Selectin and TNF Receptor 2 Levels, and Incident Primary Open-Angle Glaucoma 
To evaluate prediagnostic markers of endothelial dysfunction and inflammatory processes in primary open-angle glaucoma (POAG).
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.
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).
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.
PMCID: PMC3626518  PMID: 23412091
3.  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.
PMCID: PMC3728510  PMID: 23956749
4.  The Relationship between Caffeine and Coffee Consumption and Exfoliation Glaucoma or Glaucoma Suspect: A Prospective Study in Two Cohorts 
We examined the association between caffeine and caffeinated beverage consumption in relation to the risk of exfoliation glaucoma or exfoliation glaucoma suspect (EG/EGS).
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.
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).
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
PMCID: PMC3450917  PMID: 22918628
5.  Seafood Types and Age-Related Cognitive Decline in the Women’s Health Study 
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.
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.
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.
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.
PMCID: PMC3779629  PMID: 23554464
Cognition; Epidemiology; Nutrition.
6.  Postmenopausal Hormone Therapy, Timing of Initiation, APOE and Cognitive Decline 
Neurobiology of aging  2010;33(7):1129-1137.
Associations between postmenopausal hormone therapy (HT) and cognitive decline may depend on apolipoprotein E (APOE) status or timing of initiation.
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.
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.
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.
PMCID: PMC3483632  PMID: 21122949
7.  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.
PMCID: PMC3485429  PMID: 22828004
8.  Mediterranean diet and cognitive function in older age: results from the Women’s Health Study 
Epidemiology (Cambridge, Mass.)  2013;24(4):490-499.
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.
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.
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).
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.
PMCID: PMC3674216  PMID: 23676264
9.  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.
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.
Retrospective observational case series.
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.
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).
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.
PMCID: PMC3544983  PMID: 23111177
10.  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.
PMCID: PMC3720123  PMID: 23291589
11.  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.
PMCID: PMC3590037  PMID: 23221724
antioxidants; cognition; cohort studies; diet
12.  Caffeine and cognitive decline in elderly women at high vascular risk 
Journal of Alzheimer's disease : JAD  2013;35(2):10.3233/JAD-122371.
Persons with vascular disorders are at higher risk of cognitive decline.
To determine whether caffeine may be associated with cognitive decline reduction in elderly at high vascular risk.
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.
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).
Caffeine intake was related to moderately better cognitive maintenance over 5 years in older women with vascular disorders.
PMCID: PMC3807252  PMID: 23422357
Cognition; Aging; Caffeine; Cohort studies; Risk factors; Epidemiology
13.  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.
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.
Sedentary lifestyle indicated by prolonged TV watching may accentuate predisposition to elevated adiposity, whereas greater leisure-time physical activity may attenuate the genetic association.
PMCID: PMC3667660  PMID: 22949498
Body mass index; Genetics; Gene-lifestyle interaction; Television watching; Physical activity
14.  Dietary fat types and 4-year cognitive change in community-dwelling older women 
Annals of Neurology  2012;72(1):124-134.
To relate dietary fat types to cognitive change in healthy community-based elders.
Among 6,183 older participants in the Women’s Health Study, we related intake of major fatty acids (FAs) (saturated [SFA], mono-unsaturated [MUFA], total poly-unsaturated [PUFA], trans-unsaturated) to late-life cognitive trajectory. Serial cognitive testing, conducted over 4 years, began 5 years post-dietary assessment. Primary outcomes were global cognition (averaging tests of general cognition, verbal memory and semantic fluency) and verbal memory (averaging tests of recall). We used analyses of response profiles and logistic regression to estimate multivariable-adjusted differences in cognitive trajectory and risk of worst cognitive change (worst 10%) by fat intake.
Higher SFA intake was associated with worse global cognitive (p-linear-trend=0.008) and verbal memory (p-linear-trend=0.01) trajectories. There was a higher risk of worst cognitive change, comparing highest vs. lowest SFA quintiles: the multivariable-adjusted odds ratio (OR) (95% confidence interval, CI) was 1.64 (1.04,2.58) for global cognition and 1.65 (1.04,2.61) for verbal memory. By contrast, higher MUFA intake was related to better global cognitive (p-linear-trend<0.001) and verbal memory (p-linear-trend=0.009) trajectories, and lower OR (95% CI) of worst cognitive change in global cognition (0.52 [0.31,0.88]) and verbal memory (0.56 [0.34,0.94]). Total fat, PUFA, and trans fat intakes were not associated with cognitive trajectory.
Higher SFA intake was associated with worse global cognitive and verbal memory trajectories, while higher MUFA intake was related to better trajectories. Thus, different consumption levels of the major specific fat types, rather than total fat intake itself, appeared to influence cognitive aging.
PMCID: PMC3405188  PMID: 22605573
15.  Mediterranean diet and cognitive decline in women with cardiovascular disease or risk factors 
Cardiovascular disease and vascular risk factors increase rates of cognitive impairment, but very little is known regarding prevention in this high-risk group. The heart-healthy Mediterranean-type dietary pattern may beneficially influence both vascular and cognitive outcomes.
We examined the association between Mediterranean-style diet and cognitive decline in women with prevalent vascular disease or ≥3 coronary risk factors.
Design / Participants / Setting
Prospective cohort study among 2504 women participants of the Women’s Antioxidant Cardiovascular Study (WACS), a cohort of female health professionals Adherence to the Mediterranean diet was determined at WACS baseline (1995–1996) using a zero-to-nine-point scale with higher scores indicating higher adherence. In 1998–2000, participants aged ≥ 65 years underwent a telephone cognitive battery including five tests of global cognition, verbal memory, and category fluency. Tests were administered three additional times over 5.4 years.
Statistical analyses performed
We used multivariable-adjusted generalized linear models for repeated measures to compare the annual rates of cognitive score changes across tertiles of Mediterranean diet score, as assessed at WACS baseline.
In both basic- and multivariable-adjusted models, Mediterranean diet was not related to cognitive decline. No effect modification was detected by age, education, depression, cardiovascular disease severity at WACS baseline, or level of cognition at initial assessment.
In women at higher risk of cognitive decline due to vascular disease or risk factors, adherence to the Mediterranean diet was not associated with subsequent 5-year cognitive change.
PMCID: PMC3378990  PMID: 22709809
cognitive decline; vascular disease; hypertension; Mediterranean diet; longitudinal study
16.  Sugar-Sweetened Beverages and Genetic Risk of Obesity 
The New England journal of medicine  2012;367(15):1387-1396.
Temporal increases in the consumption of sugar-sweetened beverages have paralleled the rise in obesity prevalence, but whether the intake of such beverages interacts with the genetic predisposition to adiposity is unknown.
We analyzed the interaction between genetic predisposition and the intake of sugar-sweetened beverages in relation to body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) and obesity risk in 6934 women from the Nurses’ Health Study (NHS) and in 4423 men from the Health Professionals Follow-up Study (HPFS) and also in a replication cohort of 21,740 women from the Women’s Genome Health Study (WGHS). The genetic-predisposition score was calculated on the basis of 32 BMI-associated loci. The intake of sugar-sweetened beverages was examined prospectively in relation to BMI.
In the NHS and HPFS cohorts, the genetic association with BMI was stronger among participants with higher intake of sugar-sweetened beverages than among those with lower intake. In the combined cohorts, the increases in BMI per increment of 10 risk alleles were 1.00 for an intake of less than one serving per month, 1.12 for one to four servings per month, 1.38 for two to six servings per week, and 1.78 for one or more servings per day (P<0.001 for interaction). For the same categories of intake, the relative risks of incident obesity per increment of 10 risk alleles were 1.19 (95% confidence interval [CI], 0.90 to 1.59), 1.67 (95% CI, 1.28 to 2.16), 1.58 (95% CI, 1.01 to 2.47), and 5.06 (95% CI, 1.66 to 15.5) (P = 0.02 for interaction). In the WGHS cohort, the increases in BMI per increment of 10 risk alleles were 1.39, 1.64, 1.90, and 2.53 across the four categories of intake (P = 0.001 for interaction); the relative risks for incident obesity were 1.40 (95% CI, 1.19 to 1.64), 1.50 (95% CI, 1.16 to 1.93), 1.54 (95% CI, 1.21 to 1.94), and 3.16 (95% CI, 2.03 to 4.92), respectively (P = 0.007 for interaction).
The genetic association with adiposity appeared to be more pronounced with greater intake of sugar-sweetened beverages.
PMCID: PMC3518794  PMID: 22998338
17.  Soluble Guanylate Cyclase α1–Deficient Mice: A Novel Murine Model for Primary Open Angle Glaucoma 
PLoS ONE  2013;8(3):e60156.
Primary open angle glaucoma (POAG) is a leading cause of blindness worldwide. The molecular signaling involved in the pathogenesis of POAG remains unknown. Here, we report that mice lacking the α1 subunit of the nitric oxide receptor soluble guanylate cyclase represent a novel and translatable animal model of POAG, characterized by thinning of the retinal nerve fiber layer and loss of optic nerve axons in the context of an open iridocorneal angle. The optic neuropathy associated with soluble guanylate cyclase α1–deficiency was accompanied by modestly increased intraocular pressure and retinal vascular dysfunction. Moreover, data from a candidate gene association study suggests that a variant in the locus containing the genes encoding for the α1 and β1 subunits of soluble guanylate cyclase is associated with POAG in patients presenting with initial paracentral vision loss, a disease subtype thought to be associated with vascular dysregulation. These findings provide new insights into the pathogenesis and genetics of POAG and suggest new therapeutic strategies for POAG.
PMCID: PMC3603933  PMID: 23527308
18.  Exploring genome-wide – dietary heme iron intake interactions and the risk of type 2 diabetes 
Aims/hypothesis: Genome-wide association studies have identified over 50 new genetic loci for type 2 diabetes (T2D). Several studies conclude that higher dietary heme iron intake increases the risk of T2D. Therefore we assessed whether the relation between genetic loci and T2D is modified by dietary heme iron intake.
Methods: We used Affymetrix Genome-Wide Human 6.0 array data [681,770 single nucleotide polymorphisms (SNPs)] and dietary information collected in the Health Professionals Follow-up Study (n = 725 cases; n = 1,273 controls) and the Nurses’ Health Study (n = 1,081 cases; n = 1,692 controls). We assessed whether genome-wide SNPs or iron metabolism SNPs interacted with dietary heme iron intake in relation to T2D, testing for associations in each cohort separately and then meta-analyzing to pool the results. Finally, we created 1,000 synthetic pathways matched to an iron metabolism pathway on number of genes, and number of SNPs in each gene. We compared the iron metabolic pathway SNPs with these synthetic SNP assemblies in their relation to T2D to assess if the pathway as a whole interacts with dietary heme iron intake.
Results: Using a genomic approach, we found no significant gene–environment interactions with dietary heme iron intake in relation to T2D at a Bonferroni corrected genome-wide significance level of 7.33 ×10-8 (top SNP in pooled analysis: intergenic rs10980508; p = 1.03 × 10-6). Furthermore, no SNP in the iron metabolic pathway significantly interacted with dietary heme iron intake at a Bonferroni corrected significance level of 2.10 × 10-4 (top SNP in pooled analysis: rs1805313; p = 1.14 × 10-3). Finally, neither the main genetic effects (pooled empirical p by SNP = 0.41), nor gene – dietary heme–iron interactions (pooled empirical p-value for the interactions = 0.72) were significant for the iron metabolic pathway as a whole.
Conclusions: We found no significant interactions between dietary heme iron intake and common SNPs in relation to T2D.
PMCID: PMC3558725  PMID: 23386860
type 2 diabetes; gene environment interactions; dietary heme iron; pathway analysis
19.  Female reproductive factors and risk of Seizure or Epilepsy: Data from the Nurses’ Health Study II 
Epilepsia  2011;53(1):e1-e4.
Reproductive factors are associated with seizures in women with epilepsy. We prospectively examined the association between reproductive factors and the risk of adult-onset isolated seizure, epilepsy, or any unprovoked seizure (defined as single unprovoked seizure or epilepsy) among 114,847 Nurses’ Health Study II participants followed from 1989–2005. Validated seizure questionnaires and medical records were used to confirm incident cases of isolated seizure (n=95) or epilepsy (n=151). Overall, there were no significant associations between any reproductive factor and risk of any unprovoked seizure (n=196). However, menstrual irregularity at ages 18–22 years was specifically associated with an increased risk of epilepsy (Relative Risk (RR) = 1.67, 95% Confidence Interval (CI), 1.12, 2.51). Menstrual irregularity during follow-up (RR = 2.21, 95% CI, 1.16, 4.20) and early age at menarche (<12 years vs. 12–13 years; RR=1.76, 95% CI, 1.10, 2.81) increased the risk of isolated seizure. Oral contraceptive use and parity were not associated with isolated seizure or epilepsy. Thus, menstrual factors were associated with risk of seizure/epilepsy.
PMCID: PMC3253207  PMID: 22050476
epidemiology; oral contraceptives; menstrual irregularities; hormones; women
20.  Genome-Wide Analysis of Central Corneal Thickness in Primary Open-Angle Glaucoma Cases in the NEIGHBOR and GLAUGEN Consortia 
To investigate the effects of central corneal thickness (CCT)-associated variants on primary open-angle glaucoma (POAG) risk using single nucleotide polymorphisms (SNP) data from the Glaucoma Genes and Environment (GLAUGEN) and National Eye Institute (NEI) Glaucoma Human Genetics Collaboration (NEIGHBOR) consortia.
A replication analysis of previously reported CCT SNPs was performed in a CCT dataset (n = 1117) and these SNPs were then tested for association with POAG using a larger POAG dataset (n = 6470). Then a CCT genome-wide association study (GWAS) was performed. Top SNPs from this analysis were selected and tested for association with POAG. cDNA libraries from fetal and adult brain and ocular tissue samples were generated and used for candidate gene expression analysis.
Association with one of 20 previously published CCT SNPs was replicated: rs12447690, near the ZNF469 gene (P = 0.001; β = −5.08 μm/allele). None of these SNPs were significantly associated with POAG. In the CCT GWAS, no SNPs reached genome-wide significance. After testing 50 candidate SNPs for association with POAG, one SNP was identified, rs7481514 within the neurotrimin (NTM) gene, that was significantly associated with POAG in a low-tension subset (P = 0.00099; Odds Ratio [OR] = 1.28). Additionally, SNPs in the CNTNAP4 gene showed suggestive association with POAG (top SNP = rs1428758; P = 0.018; OR = 0.84). NTM and CNTNAP4 were shown to be expressed in ocular tissues.
The results suggest previously reported CCT loci are not significantly associated with POAG susceptibility. By performing a quantitative analysis of CCT and a subsequent analysis of POAG, SNPs in two cell adhesion molecules, NTM and CNTNAP4, were identified and may increase POAG susceptibility in a subset of cases.
Reduced central corneal thickness (CCT) is associated with primary open-angle glaucoma (POAG) risk. We investigated the effects of known CCT-associated variants, performed a genome-wide analysis of CCT, and tested the effects of these SNPs on POAG.
PMCID: PMC3394688  PMID: 22661486
21.  Estrogen pathway polymorphisms in relation to primary open angle glaucoma: An analysis accounting for gender from the United States 
Molecular Vision  2013;19:1471-1481.
Circulating estrogen levels are relevant in glaucoma phenotypic traits. We assessed the association between an estrogen metabolism single nucleotide polymorphism (SNP) panel in relation to primary open angle glaucoma (POAG), accounting for gender.
We included 3,108 POAG cases and 3,430 controls of both genders from the Glaucoma Genes and Environment (GLAUGEN) study and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium genotyped on the Illumina 660W-Quad platform. We assessed the relation between the SNP panels representative of estrogen metabolism and POAG using pathway- and gene-based approaches with the Pathway Analysis by Randomization Incorporating Structure (PARIS) software. PARIS executes a permutation algorithm to assess statistical significance relative to the pathways and genes of comparable genetic architecture. These analyses were performed using the meta-analyzed results from the GLAUGEN and NEIGHBOR data sets. We evaluated POAG overall as well as two subtypes of POAG defined as intraocular pressure (IOP) ≥22 mmHg (high-pressure glaucoma [HPG]) or IOP <22 mmHg (normal pressure glaucoma [NPG]) at diagnosis. We conducted these analyses for each gender separately and then jointly in men and women.
Among women, the estrogen SNP pathway was associated with POAG overall (permuted p=0.006) and HPG (permuted p<0.001) but not NPG (permuted p=0.09). Interestingly, there was no relation between the estrogen SNP pathway and POAG when men were considered alone (permuted p>0.99). Among women, gene-based analyses revealed that the catechol-O-methyltransferase gene showed strong associations with HTG (permuted gene p≤0.001) and NPG (permuted gene p=0.01).
The estrogen SNP pathway was associated with POAG among women.
PMCID: PMC3712669  PMID: 23869166
22.  Detectable clonal mosaicism from birth to old age and its relationship to cancer 
Laurie, Cathy C. | Laurie, Cecelia A. | Rice, Kenneth | Doheny, Kimberly F. | Zelnick, Leila R. | McHugh, Caitlin P. | Ling, Hua | Hetrick, Kurt N. | Pugh, Elizabeth W. | Amos, Chris | Wei, Qingyi | Wang, Li-e | Lee, Jeffrey E. | Barnes, Kathleen C. | Hansel, Nadia N. | Mathias, Rasika | Daley, Denise | Beaty, Terri H. | Scott, Alan F. | Ruczinski, Ingo | Scharpf, Rob B. | Bierut, Laura J. | Hartz, Sarah M. | Landi, Maria Teresa | Freedman, Neal D. | Goldin, Lynn R. | Ginsburg, David | Li, Jun | Desch, Karl C. | Strom, Sara S. | Blot, William J. | Signorello, Lisa B. | Ingles, Sue A. | Chanock, Stephen J. | Berndt, Sonja I. | Le Marchand, Loic | Henderson, Brian E. | Monroe, Kristine R | Heit, John A. | de Andrade, Mariza | Armasu, Sebastian M. | Regnier, Cynthia | Lowe, William L. | Hayes, M. Geoffrey | Marazita, Mary L. | Feingold, Eleanor | Murray, Jeffrey C. | Melbye, Mads | Feenstra, Bjarke | Kang, Jae H. | Wiggs, Janey L. | Jarvik, Gail P. | McDavid, Andrew N. | Seshan, Venkatraman E. | Mirel, Daniel B. | Crenshaw, Andrew | Sharopova, Nataliya | Wise, Anastasia | Shen, Jess | Crosslin, David R. | Levine, David M. | Zheng, Xiuwen | Udren, Jenna I | Bennett, Siiri | Nelson, Sarah C. | Gogarten, Stephanie M. | Conomos, Matthew P. | Heagerty, Patrick | Manolio, Teri | Pasquale, Louis R. | Haiman, Christopher A. | Caporaso, Neil | Weir, Bruce S.
Nature genetics  2012;44(6):642-650.
Clonal mosaicism for large chromosomal anomalies (duplications, deletions and uniparental disomy) was detected using SNP microarray data from over 50,000 subjects recruited for genome-wide association studies. This detection method requires a relatively high frequency of cells (>5–10%) with the same abnormal karyotype (presumably of clonal origin) in the presence of normal cells. The frequency of detectable clonal mosaicism in peripheral blood is low (<0.5%) from birth until 50 years of age, after which it rises rapidly to 2–3% in the elderly. Many of the mosaic anomalies are characteristic of those found in hematological cancers and identify common deleted regions that pinpoint the locations of genes previously associated with hematological cancers. Although only 3% of subjects with detectable clonal mosaicism had any record of hematological cancer prior to DNA sampling, those without a prior diagnosis have an estimated 10-fold higher risk of a subsequent hematological cancer (95% confidence interval = 6–18).
PMCID: PMC3366033  PMID: 22561516
23.  Common Variants at 9p21 and 8q22 Are Associated with Increased Susceptibility to Optic Nerve Degeneration in Glaucoma 
PLoS Genetics  2012;8(4):e1002654.
Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63–0.75], p = 1.86×10−18), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21–1.43], p = 3.87×10−11). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50–0.67], p = 1.17×10−12) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53–0.72], p = 8.88×10−10). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41–0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54–1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma.
Author Summary
Loss of vision from glaucoma, a common cause of blindness worldwide, is due to irreversible damage to the optic nerve. Current therapies cannot prevent glaucoma-related optic nerve disease and very little is known about the underlying responsible molecular events. Glaucoma patients affected by the “normal-pressure” subtype of glaucoma (NPG) have increased susceptibility to optic nerve degeneration. Although NPG has a high heritability, common predisposing genetic variants have not been identified. Therefore, we performed a meta-analysis of two independent genome-wide association studies for a common form of glaucoma, primary open angle glaucoma (POAG), followed by NPG subgroup analysis. We found that SNPs in the CDKN2BAS gene region on 9p21 and a highly conserved region with a probable regulatory function on 8q22 were associated with NPG and with optic nerve disease in a second type of glaucoma, exfoliation glaucoma. Both genomic regions are predicted to influence TGF-beta activity, and using whole-genome data we showed that the TGF-beta signaling pathway overall is associated with NPG. These results reveal new insights into the molecular pathogenesis of optic nerve disease in glaucoma and are an important step toward the development of preventative and protective therapies.
PMCID: PMC3343074  PMID: 22570617
24.  Caffeine Consumption and the Risk of Primary Open - Angle Glaucoma: A Prospective Cohort Study 
We investigated whether caffeine, which transiently increases intraocular pressure (IOP) is associated with risk of primary open-angle glaucoma (POAG).
We followed 79,120 women from 1980 and 42,052 men from 1986 to 2004 who were 40+ years old, did not have POAG, and reported receiving eye examinations. Information on caffeine consumption, potential confounders and POAG diagnoses were repeatedly updated in validated follow-up questionnaires. We confirmed 1,011 incident POAG cases with medical record review. Cohort-specific and pooled analyses across cohorts were conducted to calculate multivariable rate ratios (RR).
Compared with daily intake of < 150 mg, the pooled multivariable RRs were 1.05 [95% Confidence Interval (CI), 0.89–1.25] for consuming 150–299 mg, 1.19 [95% CI, 0.99–1.43] for 300 – 449 mg/day, 1.13 [95% CI, 0.89–1.43] for 450–559 mg and 1.17 [95% CI, 0.90, 1.53] for 600+ mg+ [p for trend = 0.11]. However, for consuming 5+ cups of caffeinated coffee daily, RR was 1.61 [95% CI, 1.00, 2.59; p for trend=0.02]; tea or caffeinated cola intake were not associated with risk. Greater caffeine intake was more adversely associated with POAG among those reporting family history of glaucoma, particularly in relation to POAG with elevated IOP (p for trend =0.0009; p-interaction=0.04).
Overall caffeine intake was not associated with increased risk of POAG. However, in secondary analyses, caffeine appeared to elevate risk of high-tension POAG among those with a family history of glaucoma; this may be due to chance, but warrants further study.
PMCID: PMC3100584  PMID: 18263806
25.  A prospective study of smoking, caffeine, and alcohol as risk factors for seizures or epilepsy in young adult women: Data from the Nurses’ Health Study II 
Epilepsia  2009;51(2):198-205.
Seizures and epilepsy are associated with significant disability and substantial treatment costs, yet little is known about primary prevention. We prospectively examined the association of cigarette smoking, caffeine use, and alcohol intake with risk of seizure or epilepsy among women, aged 25-42 years, in the Nurses’ Health Study II.
Participants provided dietary and cigarette smoking information on multiple questionnaires beginning in 1989. Among 116,363 women at-risk for incident seizure or epilepsy, we confirmed 95 cases of seizure and 151 cases of epilepsy occurring from 1989 to 2005 using information from a detailed supplementary questionnaire and medical records. Multivariable-adjusted relative risks (RR) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression.
Compared with never smoking, current cigarette smoking was associated with an increased risk of seizure (RR 2.60, 95% CI 1.53-4.42), after adjustment for stroke and other potential confounding factors. Past smoking was not associated with risk of seizure, but was associated with modestly increased risk of epilepsy (RR 1.46, 95% CI 1.01-2.12). Long-term caffeine and moderate alcohol intake were not associated with seizure or epilepsy.
Cigarette smoking may be associated with increased risk of seizure. More prospective studies are needed to investigate potential factors to ultimately prevent the development of seizures or epilepsy.
PMCID: PMC3090289  PMID: 19694796
risk factors; epilepsy; seizures; epidemiology; smoking; alcohol; caffeine

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