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1.  Polymorphisms in ARMS2/HTRA1 and Complement Genes and Age-Related Macular Degeneration in India: Findings from the INDEYE Study 
Purpose.
Association between genetic variants in complement factor H (CFH), factor B (CFB), component 2 (C2), and in the ARMS2/HTRA1 region with age-related macular degeneration (AMD) comes mainly from studies of European ancestry and case-control studies of late-stage disease. We investigated associations of both early and late AMD with these variants in a population-based study of people aged 60 years and older in India.
Methods.
Fundus images were graded using the Wisconsin Age-Related Maculopathy Grading System and participants assigned to one of four mutually exclusive stages based on the worse affected eye (0 = no AMD, 1–3 = early AMD, 4 = late AMD). Multinomial logistic regression was used to derive risk ratios (RR) accounting for sampling method and adjusting for age, sex, and study center.
Results.
Of 3569 participants, 53.2% had no signs of AMD, 45.6% had features of early AMD, and 1.2% had late AMD. CFH (rs1061170), C2 (rs547154), or CFB (rs438999) was not associated with early or late AMD. In the ARMS2 locus, rs10490924 was associated with both early (adjusted RR 1.22, 95% confidence interval [CI]: 1.13–1.33, P < 0.0001) and late AMD (adjusted RR 1.81, 95% CI: 1.15–2.86; P = 0.01); rs2672598 was associated only with early AMD (adjusted RR 1.12, 95% CI: 1.02–1.23; P = 0.02); rs10490923 was not associated with early or late AMD.
Conclusions.
Two variants in ARMS2/HTRA1 were associated with increased risk of early AMD, and for one of these, the increased risk was also evident for late AMD. The study provides new insights into the role of these variants in early stages of AMD in India.
We report results from a genetic association study of early AMD in an Indian population. Two variants in the ARMS/HTRA1 region were associated with early AMD but variants in C2, CFH, and CFB were not.
doi:10.1167/iovs.12-10073
PMCID: PMC3490538  PMID: 23060141
2.  Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype 
Background Variation in the complement factor H gene (CFH) is associated with risk of late age-related macular degeneration (AMD). Previous studies have been case–control studies in populations of European ancestry with little differentiation in AMD subtype, and insufficient power to confirm or refute effect modification by smoking.
Methods To precisely quantify the association of the single nucleotide polymorphism (SNP rs1061170, ‘Y402H’) with risk of AMD among studies with differing study designs, participant ancestry and AMD grade and to investigate effect modification by smoking, we report two unpublished genetic association studies (n = 2759) combined with data from 24 published studies (26 studies, 26 494 individuals, including 14 174 cases of AMD) of European ancestry, 10 of which provided individual-level data used to test gene–smoking interaction; and 16 published studies from non-European ancestry.
Results In individuals of European ancestry, there was a significant association between Y402H and late-AMD with a per-allele odds ratio (OR) of 2.27 [95% confidence interval (CI) 2.10–2.45; P = 1.1 x 10−161]. There was no evidence of effect modification by smoking (P = 0.75). The frequency of Y402H varied by ancestral origin and the association with AMD in non-Europeans was less clear, limited by paucity of studies.
Conclusion The Y402H variant confers a 2-fold higher risk of late-AMD per copy in individuals of European descent. This was stable to stratification by study design and AMD classification and not modified by smoking. The lack of association in non-Europeans requires further verification. These findings are of direct relevance for disease prediction. New research is needed to ascertain if differences in circulating levels, expression or activity of factor H protein explain the genetic association.
doi:10.1093/ije/dyr204
PMCID: PMC3304526  PMID: 22253316
Age-related macular degeneration (AMD); Complement factor H gene; meta-ananlysis
3.  EPHA2 Polymorphisms and Age-Related Cataract in India 
PLoS ONE  2012;7(3):e33001.
Objective
We investigated whether previously reported single nucleotide polymorphisms (SNPs) of EPHA2 in European studies are associated with cataract in India.
Methods
We carried out a population-based genetic association study. We enumerated randomly sampled villages in two areas of north and south India to identify people aged 40 and over. Participants attended a clinical examination including lens photography and provided a blood sample for genotyping. Lens images were graded by the Lens Opacification Classification System (LOCS III). Cataract was defined as a LOCS III grade of nuclear ≥4, cortical ≥3, posterior sub-capsular (PSC) ≥2, or dense opacities or aphakia/pseudophakia in either eye. We genotyped SNPs rs3754334, rs7543472 and rs11260867 on genomic DNA extracted from peripheral blood leukocytes using TaqMan assays in an ABI 7900 real-time PCR. We used logistic regression with robust standard errors to examine the association between cataract and the EPHA2 SNPs, adjusting for age, sex and location.
Results
7418 participants had data on at least one of the SNPs investigated. Genotype frequencies of controls were in Hardy-Weinberg Equilibrium (p>0.05). There was no association of rs3754334 with cataract or type of cataract. Minor allele homozygous genotypes of rs7543472 and rs11260867 compared to the major homozygote genotype were associated with cortical cataract, Odds ratio (OR) = 1.8, 95% Confidence Interval (CI) (1.1, 3.1) p = 0.03 and 2.9 (1.2, 7.1) p = 0.01 respectively, and with PSC cataract, OR = 1.5 (1.1, 2.2) p = 0.02 and 1.8 (0.9, 3.6) p = 0.07 respectively. There was no consistent association of SNPs with nuclear cataract or a combined variable of any type of cataract including operated cataract.
Conclusions
Our results in the Indian population agree with previous studies of the association of EPHA2 variants with cortical cataracts. We report new findings for the association with PSC which is particularly prevalent in Indians.
doi:10.1371/journal.pone.0033001
PMCID: PMC3297613  PMID: 22412971
4.  CKD and Hospitalization in the Elderly: A Community-Based Cohort Study in the United Kingdom 
Background
We previously have shown that chronic kidney disease (CKD) is associated with cardiovascular and all-cause mortality in community-dwelling people 75 years and older. The present study addresses the hypothesis that CKD is associated with a higher rate of hospital admission at an older age.
Study Design
Cohort study.
Setting & Participants
15,336 participants from 53 UK general practices underwent comprehensive health assessment between 1994 and 1999.
Predictor
Data for estimated glomerular filtration rate (eGFR, derived from creatinine levels using the CKD Epidemiology Collaboration [CKD-EPI] study equation) and dipstick proteinuria were available for 12,371 participants.
Outcomes
Hospital admissions collected from hospital discharge letters for 2 years after assessment.
Measurements
Age, sex, cardiovascular risk factors, possible biochemical and health consequences of kidney disease (hemoglobin, phosphate, and albumin levels; physical and mental health problems).
Results
2,310 (17%) participants had 1 hospital admission, and 981 (7%) had 2 or more. After adjusting for age, sex, and cardiovascular risk factors, HRs were 1.66 (95% CI, 1.21-2.27), 1.17 (95% CI, 0.95-1.43), 1.08 (95% CI, 0.90-1.30), and 1.11 (95% CI, 0.91-1.35) for eGFRs <30, 30-44, 45-59, and ≥75 mL/min/1.73 m2, respectively, compared with eGFRs of 60-74 mL/min/1.73 m2 for hospitalizations during <6 months of follow-up. HRs were weaker for follow-up of 6-18 months. Dipstick-positive proteinuria was associated with an increased HR throughout follow-up (HR, 1.29 [95% CI, 1.11-1.49], adjusting for cardiovascular risk factors). Dipstick-positive proteinuria and eGFR <30 mL/min/1.73 m2 were independently associated with 2 or more hospital admissions during the 2-year follow-up. Adjustment for other health factors and laboratory measurements attenuated the effect of eGFR, but not the effect of proteinuria.
Limitations
Follow-up limited to 2 years, selection bias due to nonparticipation in study, missing data for potential covariates, and single noncalibrated measurements from multiple laboratories.
Conclusions
The study indicates that community-dwelling older people who have dipstick-positive proteinuria and/or eGFR <30 mL/min/1.73 m2 are at increased risk of hospitalization.
doi:10.1053/j.ajkd.2010.09.026
PMCID: PMC3392651  PMID: 21146270
Chronic kidney disease; cohort study; dipstick proteinuria testing; general population; hospitalization; older people
5.  An Ecological Correlation Study of Late Age-Related Macular Degeneration and the Complement Factor H Y402H Polymorphism 
Based on published data, this ecological correlation study showed evidence to support the hypothesis that variation in the risk allele frequency of the Y402H polymorphism across ethnicities explains variation in prevalence of late AMD when data on people of African ancestry are excluded.
Purpose.
To investigate whether variation in the distribution of the risk allele frequency of the Y402H single-nucleotide polymorphism (SNP) across various ethnicities and geographic regions reflects differences in the prevalence of late age-related macular degeneration (AMD) in those ethnicities.
Methods.
Published data were obtained via a systematic search. Study samples were grouped into clusters by ethnicity and geographic location and the Spearman correlation coefficient of the prevalence of late AMD and risk allele frequencies was calculated across clusters.
Results.
Across all ethnicities, AMD prevalence was seen to increase with age. Populations of European descent had both higher risk allele frequencies and prevalence of late AMD than did Japanese, Chinese, and Hispanic descendants. Results for African descendants were anomalous: although allele frequency was similar to that in European populations, the age-specific prevalence of late AMD was considerably lower. The correlation coefficient for the association between allele frequency and AMD prevalence was 0.40 (95% confidence interval [CI] = −0.36 to 0.84, P = 0.28) in all populations combined and 0.71 (95% CI = 0.02–0.94, P = 0.04) when people of African descent were excluded.
Conclusions.
Evidence was found at the population level to support a positive association between the Y204H risk allele and the prevalence of AMD after exclusion of studies undertaken on persons of African ancestry. Data in African, Middle Eastern, and South American populations are needed to provide a better understanding of the association of late AMD genetic risk across ethnicities.
doi:10.1167/iovs.09-4228
PMCID: PMC2868481  PMID: 20042653
6.  Hospital admissions in older people with visual impairment in Britain 
BMC Ophthalmology  2008;8:16.
Background
We aimed to assess the risk of hospital admission associated with visual impairment in a representative sample of older people living in the community in Britain.
Methods
Design: Prospective study of hospital admission in a population-based sample of community dwelling people aged 75 years and above in Britain. Setting: 53 general practices. Participants: 14,394 participants in the MRC Trial of Assessment and Management of Older people in the Community. Main outcome measure: Hospital admission.
Results
Visually impaired older people had 238.7 admissions/1000 person-years compared to 169.7 admissions/1000 person-years in people with good vision: age and sex adjusted rate ratio (RR) 1.32 (95% CI 1.19 to 1.47). Adjusting for a wide range of potential explanatory factors largely eliminated this association: RR 1.06 (95% CI 0.94 to 1.20). However, adjusting for a more limited range of confounding factors, excluding those factors possibly a consequence of reduced vision, left a modest increased risk: RR 1.19 (95% CI 1.06 to 1.34).
Conclusion
The association between visual impairment and rate of hospital admission can be attributed to higher levels of co-morbidity and reduced functional ability among people with reduced vision. Visual impairment is likely to be an important contributor to reduced functional ability, but other factors may also be involved.
doi:10.1186/1471-2415-8-16
PMCID: PMC2564910  PMID: 18786264
7.  Is the NEI-VFQ-25 a useful tool in identifying visual impairment in an elderly population? 
BMC Ophthalmology  2006;6:24.
Background
The use of self-report questionnaires to substitute for visual acuity measurement has been limited. We examined the association between visual impairment and self reported visual function in a population sample of older people in the UK.
Methods
Cross sectional study of people aged more than 75 years who initially participated in a trial of health screening. The association between 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ) scores and visual impairment (defined as an acuity of less than 6/18 in the better eye) was examined using logistic regression.
Results
Visual acuity and NEI-VFQ scores were obtained from 1807 participants (aged 77 to 101 years, 36% male), from 20 general practices throughout the UK. After adjustment for age, gender, practice and NEI-VFQ sub-scale scores, those complaining of poor vision in general were 4.77 times (95% CI 3.03 to 7.53) more likely to be visually impaired compared to those who did not report difficulty. Self-reported limitations with social functioning and dependency on others due to poor vision were also associated with visual impairment (odds ratios, 2.52, 95% CI 1.55 to 4.11; 1.73, 95% CI 1.05 to 2.86 respectively). Those reporting difficulties with near vision and colour vision were more likely to be visually impaired (odds ratios, 2.32, 95% CI 1.30 to 4.15; 2.25, 95% CI 1.35 to 3.73 respectively). Other NEI-VFQ sub-scale scores were unrelated to measures of acuity. Similar but weaker odds ratios were found with reduced visual acuity (defined as less than 6/12 in the better eye). Although differences in NEI-VFQ scores were small, scores were strongly associated with visual acuity, binocular status, and difference in acuity between eyes.
Conclusion
NEI-VFQ questions regarding the quality of general vision, social functioning, visual dependency, near vision and colour vision are strongly and independently associated with an objective measure of visual impairment in an elderly population.
doi:10.1186/1471-2415-6-24
PMCID: PMC1523367  PMID: 16764714
8.  Screening older people for impaired vision in primary care: cluster randomised trial 
BMJ : British Medical Journal  2003;327(7422):1027.
Objective To determine the effectiveness of screening for visual impairment in people aged 75 or over as part of a multidimensional screening programme.
Design Cluster randomised trial.
Setting General practices in the United Kingdom participating in the MRC trial of assessment and management of older people in the community.
Participants 4340 people aged 75 years or over randomly sampled from 20 general practices, excluding people resident in hospitals or nursing homes.
Intervention Visual acuity testing and referral to eye services for people with visual impairment. Universal screening (assessment and visual acuity testing) was compared with targeted screening, in which only participants with a range of health related problems were offered an assessment that included acuity screening.
Main outcome measures Proportion of people with visual acuity less than 6/18 in either eye; mean composite score of 25 item version of the National Eye Institute visual function questionnaire.
Results Three to five years after screening, the relative risk of having visual acuity < 6/18 in either eye, comparing universal with targeted screening, was 1.07 (95% confidence interval 0.84 to 1.36; P = 0.58). The mean composite score of the visual function questionnaire was 85.6 in the targeted screening group and 86.0 in the universal group (difference 0.4, 95% confidence interval -1.7 to 2.5, P = 0.69).
Conclusions Including a vision screening component by a practice nurse in a pragmatic trial of multidimensional screening for older people did not lead to improved visual outcomes.
PMCID: PMC261660  PMID: 14593039
10.  Randomised comparison of three methods of administering a screening questionnaire to elderly people: findings from the MRC trial of the assessment and management of older people in the community 
BMJ : British Medical Journal  2001;323(7326):1403.
Objective
To compare three different methods of administering a brief screening questionnaire to elderly people: post, interview by lay interviewer, and interview by nurse.
Design
Randomised comparison of methods within a cluster randomised trial.
Setting
106 general practices in the United Kingdom.
Participants
32 990 people aged 75 years or over registered with participating practices.
Main outcome measures
Response rates, proportion of missing values, prevalence of self reported morbidity, and sensitivity and specificity of self reported measures by method of administration of questionnaire for four domains.
Results
The response rate was higher for the postal questionnaire than for the two interview methods combined (83.5% v 74.9%; difference 8.5%, 95% confidence interval 4.4% to 12.7%, P<0.001). The proportion of missing or invalid responses was low overall (mean 2.1%) but was greater for the postal method than for the interview methods combined (4.1% v 0.9%; difference 3.2%, 2.7% to 3.6%, P<0.001). With a few exceptions, levels of self reported morbidity were lower in the interview groups, particularly for interviews by nurses. The sensitivity of the self reported measures was lower in the nurse interview group for three out of four domains, but 95% confidence intervals for the estimates overlapped. Specificity of the self reported measures varied little by method of administration.
Conclusions
Postal questionnaires were associated with higher response rates but also higher proportions of missing values than were interview methods. Lower estimates of self reported morbidity were obtained with the nurse interview method and to a lesser extent with the lay interview method than with postal questionnaires.
What is already known on this topicThe optimum method of administering a brief multidimensional screening assessment to elderly people is not knownWhat this study addsPostal questionnaires produce a higher response rate than interviews by nurses or lay interviewers but also higher proportions of missing dataInterview by nurses and to a lesser degree by lay interviewers is associated with lower levels of self reported morbidity than are postal questionnaires
PMCID: PMC60986  PMID: 11744565

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