Hyperglycemia and Hypo-HDL-cholesterolemia Are Primary Risk Factors for Age-related Cataract, and a Korean-style Balanced Diet has a Negative Association, based on the Korean Genome and Epidemiology Study.

BACKGROUND: The prevalence of cataracts is steadily increasing among the middle-aged and elderly worldwide. We hypothesized that adults aged > 50 years with age-related cataracts (ARCs) have an association with metabolic syndrome (MS) and its components, and MS has interactions with different dietary patterns and lifestyles that affect ARC risk. We examined the hypothesis using the Korean Genome and Epidemiology Study (KoGES; a large-scale hospital-based cohort study), which collected data between 2004-2013. METHODS: Participants ≥ 50 years old were classified as cases (1,972 ARC patients) and controls (38,290 healthy controls) based on a diagnosis of cataract by a physician. MS and its components were defined using WHO definitions for Asians. Dietary consumption was evaluated using a validated semi-quantitative food frequency questionnaire (SQFFQ), which contained 106 foods, and dietary patterns were analyzed by principal component analysis. After adjusting for potential covariates, logistic regression was used to investigate associations between MS and its components and between dietary patterns and a positive cataract history. RESULTS: ARC had a positive association with MS after 1.32-fold adjusting for age, sex, residence area, body mass index, and energy intake. Plasma glucose and HbA1c concentrations exhibited an increased ARC risk in the participants with MS by 1.50- and 1.92-fold and without MS by 1.35 and 1.88-fold, respectively. Serum high-density lipoprotein (HDL) concentrations were negatively associated with ARC risk only in the MS patients, but not without MS. However, blood pressure, abdominal obesity, and serum triglyceride concentrations did not associate with ARC risk regardless of MS. High intake of a Korean-balanced diet (KBD) containing fermented food exhibited a negative association with ARC risk (OR = 0.81) only in the MS group. The fat and coffee intake had a negative association with ARC only in the non-MS group. Current- and former-smokers were positively associated with ARC risk. CONCLUSION: Persons who have hyperglycemia and low-HDL-cholesterolemia had increased susceptibility of ARC prevalence. A KBD with a proper amount of fat (≥ 15%) is recommended, and smoking should be prohibited.

Ethnic variation in prevalence, self-reported barriers and outcome of cataract surgery in a rural population in southwestern China: the Yunnan minority eye study.

BACKGROUND: As a part of the Yunnan Minority Eye Studies, the purpose of this study was to determine the prevalence, barriers and visual acuity outcomes of cataract surgery in a multiethnic adult population in rural areas of southwestern China. METHODS: A population-based cross-sectional survey was conducted with participants of Bai, Yi, and Han ethnicity aged ≥50 years in Yunnan. A detailed eye examination was performed. Information on the date, setting, type, and complications of cataract surgery were recorded in the examination of cataract-operated eyes. RESULTS: Of 6546 subjects (2133 Bai ethnicity, 2208 Yi ethnicity and 2205 Han ethnicity), the prevalence of cataract surgery was 6.0%, with 4.6% in Bai, 7.0% in Yi, and 6.4% in Han ethnicity. Cataract Surgical coverage (CSC) among those with presenting visual acuity (PVA) < 20/200 in both eyes because of cataract was 53.3%, with 52.8% in Bai, 64.4% in Yi, and 45.3% in Han ethnicity. CSC was associated with Yi ethnicity, younger age, and higher education level, while unoperated cataract was associated with Han ethnicity, older age, and illiterate. The main barrier to cataract surgery was lack of awareness and knowledge, cost, and fear. Among the 525 cataract-operated eyes, PVA and best-corrected visual acuity (BCVA) of 20/63 or better was 44.5 and 67.2%, respectively, with 48.1 and 65.9% in Bai, 47.8 and 75.4% in Yi, 39.1 and 59.9% in Han ethnicity. Han ethnicity, aphakia, earlier year of surgery, lower-level surgical hospital and illiterate were associated with postoperative visual impairment defined by PVA, while Han ethnicity, aphakia, and illiterate were associated with that defined by BCVA. The principal causes of postoperative visual impairment were retinal disorders (26.8%), posterior capsule opacification (25.1%), refractive error(22.7%), and glaucoma (9.3%). CONCLUSIONS: Han ethnicity had a lower CSC and relatively poor visual outcomes compared with ethnic minorities. Further effective effort to remove barriers and provide sight restoration is warranted.

Psychometric Properties of the Vietnamese Catquest-9 Short Form Questionnaire.

SIGNIFICANCE: The Catquest-9 Short Form (SF) has good psychometric properties but was not available in Vietnamese. This study provides the Vietnamese Catquest-9SF and evidence supporting for its use in hospital settings along with clinical assessment to evaluate visual function. PURPOSE: The purpose of this study was to evaluate the psychometric properties of the Vietnamese Catquest-9SF. METHODS: Literate patients with unilateral/bilateral cataract, without severe systemic and ocular comorbidities, aged 50+ years, and scheduled for first-eye surgery were screened and recruited at the University of Medicine and Pharmacy at Ho Chi Minh City and Trung Vuong Hospital. Age, sex, and education were self-reported. The Catquest-9SF and the 25-item National Eye Institute Visual Function Questionnaire were used to assess vision-related quality of life (VRQOL). Best-corrected unilateral and bilateral log of the minimum angle of resolution (logMAR) visual acuity was measured, as was best-corrected Pelli-Robson contrast sensitivity. Rasch analysis was performed on the Vietnamese version of the Catquest-9SF. Criterion validity and convergent validity were also evaluated. RESULTS: Andrich thresholds and response categories on each Catquest-9SF item were ordered, indicating that patients were able to discriminate VRQOL levels. Person separation index and reliability were 2.51 and 0.86, respectively, indicating that the Catquest-9SF was able to distinguish between patients with low- and high-vision difficulties. The tool was unidimensional, with all items fitting well within the construct. There was no evidence of differential item functioning by sex, age group, or cataract status. The tool also showed criterion validity, correlating significantly with visual acuity in the better eye (r = -0.46), the worse eye (r = -0.39), and both eyes (r = -0.44), and with contrast sensitivity for the better eye (r = 0.41), the worse eye (r = 0.32), and both eyes (r = 0.39). A strong correlation between the Catquest-9SF and the 25-item National Eye Institute Visual Function Questionnaire (r = 0.87) indicated convergent validity. CONCLUSIONS: The Vietnamese Catquest-9SF is valid and psychometrically robust for assessing VRQOL among cataract patients.

[PREVALENCE OF ASTIGMATISM BEFORE ROUTINE CATARACT SURGERY: COMPARISON BETWEEN BEDOUIN AND JEWISH POPULATION IN SOUTHERN ISRAEL].

OBJECTIVES: To assess the prevalence of corneal astigmatism among patients before routine cataract surgery and overall ocular difference between Jewish and Bedouin population in the south of Israel. METHODS: Retrospective research collecting biometric information from IOLMaster (Carl Zeiss Meditec AG, Germany) in patients attending cataract surgery at Soroka University Medical Center, Beer-Sheva, Israel between the years 2015 -2016. RESULTS: Mean corneal astigmatism among all cohorts was 1.20D ± 0.83, with 1.26D ± 0.84 in Bedouins patients vs 1.17D ± 0.82 in Jews patients (p-value=0.08). Corneal astigmatism lower than 0.5D was seen in 20% of the population, 28% of the population had corneal astigmatism above 1.5D and 9% showed corneal astigmatism higher than 2.5D. When comparing axial length and keratometric characteristics between the two populations, Bedouins had shorter axial length (23.41mm± 1.62 vs. 23.67mm ± 1.55, p=0.01), and flatter corneas on both axes (flat - 43.18D ± 1.76 vs. 43.62D ± 1.79, p<0.01); (steep - 44.44D ± 1.84 vs. 44.77D± 1.89, p<0.01). Higher astigmatism was found in men than in women (1.24D vs.1.15D p- value=0.04) of study group. CONCLUSIONS: In our study we found more than 25% of patients had astigmatism more than 1.5D. Patients attending cataract surgery may therefore benefit the use of advanced IOL types and surgical techniques. In addition, a statistically significant difference between the Bedouin and Jewish populations biometric measurements in patients attending cataract surgery found.

Cataract Surgery Incidence Trends in a Tertiary Public Hospital in Malaysia.

Background Since cataract is the leading cause of blindness and no study has been done on the surgical incidence trends, we conducted this research in Melaka. Objective To describe incidences of cataract surgery according to basic demographic variables and types of surgery performed. Method Using the National Eye Database (NED), we performed descriptive statistics calculating incidence rates per 1,000 population by demographic features and types of cataract operations to look at the trends of surgeries in the population. Statistics for population were obtained from the department of statistics. Result From 2007-2010, 6270 patients mostly 60-69 years underwent cataract surgery. Phacoemulsification (78.2%) was the commonest surgery performed. The annual incidence rate of cataract surgery reduced from 2.05 per 1000 population in 2007 to 2.02 per 1000 population in 2010 (p<0.05). Incidence rates for those aged 60 and above rose while for those aged below nine years it declined. Indians had the highest incidence rates followed by Chinese and Malays per 1000 population. Females had a higher incidence rate although there was a declining trend over the years. Conclusion Cataract surgery rates showed a decline. Public health education and awareness on detection and operating upon cataracts should be increased and especially targeted towards vulnerable groups such as women, individuals of Indian ethnicity and those aged 50 years and above.

A novel mutation in the CRYAA gene associated with congenital cataract and microphthalmia in a Chinese family.

BACKGROUND: Congenital cataract is the leading cause of blindness in children worldwide. Approximately half of all congenital cataracts have a genetic basis. Protein aggregation is the single most important factor in cataract formation. METHODS: A four-generation Chinese family diagnosed with autosomal dominant congenital cataracts and microphthalmia was recruited at the Shengjing Hospital of China Medical University. Genomic DNA was extracted from the peripheral blood of the participants. All coding exons and flanking regions of seven candidate genes (CRYAA, CRYBA4, CRYBB2, CRYGC, GJA8, MAF, and PITX3) were amplified and sequenced. Restriction fragment length polymorphism (RFLP) assays were performed to confirm the candidate causative variant, c.35G > T in the CRYAA gene. We constructed pcDNA3.1(+)-CRYAA expression plasmids containing either the wild-type or the R12L mutant alleles and respectively transfected them into HEK293T cells and into HeLa cells. Western blotting was performed to determine protein expression levels and protein solubility. Immunofluorescence was performed to determine protein sub-cellular localization. RESULTS: A heterozygous variant c.35G > T was identified in exon 1 of CRYAA, which resulted in a substitution of arginine to leucine at codon 12 (p.R12L). The nucleotide substitution c.35G > T was co-segregated with the disease phenotype in the family. The mutant R12L-CRYAA in HEK293T cells showed a significant increase in the expression level of the CRYAA protein compared with the wild-type cells. Moreover, a large amount of the mutant protein aggregated in the precipitate where the wild-type protein was not detected. Immunofluorescence studies showed that the overexpressed mutant CRYAA in HeLa cells formed large cytoplasmic aggregates and aggresomes. CONCLUSIONS: In summary, we described a case of human congenital cataract and microphthalmia caused by a novel mutation in the CRYAA gene, which substituted an arginine at position 12 in the N-terminal region of αA-crystallin. The molecular mechanisms that underlie the pathogenesis of human congenital cataract may be characterized by the prominent effects of the p.R12L mutation on αA-crystallin aggregation and solubility. Our study also expands the spectrum of known CRYAA mutations.

Mutation profiles of congenital cataract genes in 21 northern Chinese families.

Purpose: To identify disease-causing gene mutations in 21 northern Chinese families with congenital cataracts. Methods: Medical record collection and ophthalmologic examinations were conducted for 21 families with congenital cataracts. A volume of 5 ml of peripheral blood was drawn from each participant for genomic DNA isolation. Thirty-four known candidate genes for congenital cataracts were analyzed in the probands of 21 families with targeted next-generation sequencing (NGS). Bioinformatics analysis of the sequence variants was performed through computational predictive programs. Sanger sequencing was used to perform the cosegregation analysis. Genotyping and haplotype analyses were performed in two patients with a p.V44M mutation in the GJA8 gene. Results: Twelve disease-causing mutations were detected in 13 of the 21 patients, and the mutation detection rate was 61.9%. The 12 gene mutations included one nonsense, one splice site, seven missense, and three insert and deletion (INDELs) mutations. Four mutations were novel. Of the 13 patients with pathogenic gene mutations, five (38.5%) were affected by mutations in lens crystallin genes, three (23%) were affected by mutations in connexin genes, three (23%) were affected by mutations in transcription factor genes, one (7.7%) was affected by a mutation in a transmembrane transporter gene, and one (7.7%) was affected by a mutation in a chromatin-modifying protein gene. Two families carried the p.V44M mutation in the GJA8 gene. Haplotype analysis revealed a chromosome region of 475 kb containing the mutation in the GJA8 gene was harbored by two families. Conclusions: Compared with traditional Sanger sequencing, targeted NGS for genetic testing of congenital cataracts markedly increases the mutation detection rate and is cost-effective. The p.V44M mutation in the GJA8 gene was the most common mutation and was due to a founder effect within the Chinese cohort studied. The results of this study expand the gene mutation spectrum of congenital cataracts.

Six-Year Incidence of and Risk Factors for Cataract Surgery in a Multi-ethnic Asian Population: The Singapore Epidemiology of Eye Diseases Study.

PURPOSE: To report the 6-year incidence of cataract surgery in an Asian population-based cohort of Malay, Indian, and Chinese persons living in Singapore and factors associated with undergoing cataract surgery over the follow-up period. DESIGN: Population-based prospective cohort study. PARTICIPANTS: From 2004 through 2011, 10 033 participants (3280 Malays, 3400 Indians, and 3353 Chinese) 40 years of age or older participated in the Singapore Epidemiology of Eye Diseases Study. Six years later, 6762 participants (78.7% of those eligible, including 1901 Malays [72.1% of eligible], 2200 Indians [75.5% of eligible], and 2661 Chinese [87.7% of eligible]) were re-examined. METHODS: Detailed eye examinations including slit-lamp biomicroscopy were conducted at both visits. Logistic regression models were used to assess factors associated with cataract surgery after adjusting for age, gender, socioeconomic status, and other risk factors. MAIN OUTCOME MEASURE: Incident cataract surgery. RESULTS: The age-adjusted 6-year incidence of cataract surgery was 11.0% (9.5%, 12.6%, and 11.1% for Malays, Indians, and Chinese, respectively) and was strongly age related (P < 0.001 for trend). After adjustment, baseline factors associated with incident cataract surgery included older age (odds ratio [OR], 1.13 per 1-year increase; 95% confidence interval [CI], 1.11-1.14), diabetes (OR, 1.90; 95% CI, 1.54-2.33), myopia (OR, 1.78; 95% CI, 1.44-2.20), and baseline presence of any cataract, including nuclear cataract (OR, 3.78; 95% CI, 2.91-4.89), cortical cataract (OR, 3.01; 95% CI, 2.45-3.71), and posterior subcapsular cataract (OR, 5.00; 95% CI, 3.91-6.41). The population attributable risks of cataract surgery related to diabetes and myopia were 17.6% and 19.1%, respectively. CONCLUSIONS: One in 10 Malay, Indian, and Chinese Singaporeans 40 years of age or older underwent cataract surgery in at least 1 eye over 6 years. In Asian populations, diabetes and myopia, 2 well-known factors associated with cataract prevalence, are significant and potentially modifiable factors associated with the need for cataract surgery.

Prevalence and causes of blindness, visual impairment among different ethnical minority groups in Xinjiang Uygur autonomous region, China.

BACKGROUND: The aim of this cross-sectional study is to ascertain the prevalence and causes of blindness, visual impairment, uptake of cataract surgery among different ethnic groups in Xinjiang Uygur Autonomous Region, China. METHODS: Four thousand one hundred fifty people at 50 years and above from different minority ethnic groups were randomly selected for an eye examination. The four trained eye teams collected data using tumbling E visual chart, torch, portable slit lamp and direct ophthalmoscope in 2015. The World Health Organization's definition of blindness and visual impairment (VI) was used to classify patients in each ethnic group. Data were analyzed by different minority groups and were compared with Han Chinese. RESULTS: 3977 (95.8%) out of 4150 people were examined. The prevalence of blindness from the study population was 1.7% (95% confidence interval: 1.3-2.2%).There was no significant difference in prevalence of blindness between Han Chinese and people of Khazak and other minority ethnic groups, nor, between male and female. Cataract was the leading course (65.5%) of blindness and uncorrected refractive error was the most common cause of VI (36.3%) followed by myopic retinopathy. The most common barrier to cataract surgery was lack of awareness of service availability. CONCLUSIONS: This study documented a low blindness prevalence among people aged 50 years and over comparing to prevalence identified through studies of other regions in China. It still indicates blindness and un-operated cataract as the significant public health issue, with no evidence of eye health inequalities, but some inequities in accessing to cataract surgery amongst ethnic minority groups in Xinjiang.

Association of alpha A-crystallin polymorphisms with susceptibility to nuclear age-related cataract in a Han Chinese population.

BACKGROUND: Alpha A-crystallin (CRYAA) is considered critical for the maintenance of lens transparency and is related to the pathogenesis of age-related cataracts (ARCs), especially the nuclear subtype. As the 5' untranslated region (5' UTR) modulates gene expression, the purpose of current study was to investigate whether single nucleotide polymorphisms (SNPs) in the 5' UTR of CRYAA were associated with susceptibility to ARC in a Han Chinese population and to clarify the mechanism of this association. METHODS: SNPs in the 5' UTR (-1 to -1000) of CRYAA were identified in 243 nuclear ARC patients and 263 controls using polymerase chain reaction and DNA sequencing. Allele and genotype frequencies were calculated and compared between two groups. Haploview 4.2 was used to calculate the linkage disequilibrium index, and the SHEsis analysis platform was used to infer haplotype construction. A dual-luciferase reporter gene assay was used for transcription of CRYAA in the presence of a protective haplotype with individual SNP alteration, Chromatin immunoprecipitation (ChIP) was employed to determine whether SNPs regulated CRYAA expression by altering the binding affinity of transcription factors. RESULTS: Three polymorphisms were identified in the 5' UTR of CRYAA: rs3761381 (P = 0.000357, odds ratio [OR] = 1.837), rs13053109 (P = 0.788, OR = 1.086), and rs7278468 (P = 0.00136, OR = 0.652). The haplotype C-G-T (P = 0.0014, OR = 1.536) increased the risk of nuclear ARC, whereas the haplotype T-G-G (P = 0.00029, OR = 0.535) decreased the risk. The haplotype C-G-T decreased CRYAA transcription through rs7278468, which is located in the binding site of specificity protein 1 (Sp1). Furthermore, the G allele of rs7278468 increased CRYAA transcription by enhancing the binding affinity of Sp1. CONCLUSIONS: These data indicate that the CRYAA polymorphism is a genetic marker of inter-individual differences in the risk of nuclear ARC.

Meta-analysis of genome-wide association studies in multiethnic Asians identifies two loci for age-related nuclear cataract.

Age-related cataract is a leading cause of blindness worldwide, especially in developing countries where access to cataract surgery remains limited. Previous linkage and candidate gene studies suggested genetic influences on age-related nuclear cataract but few genetic markers have been identified thus far. We conducted genome-wide association studies on 4569 Asians (including 2369 Malays and 2200 Indians), and replicated our analysis in 2481 Chinese from two independent cohorts (1768 Chinese in Singapore and 803 Chinese in Beijing). We confirmed two genome-wide significant loci for nuclear cataract in the combined meta-analysis of four cohorts (n = 7140). The first locus was at chromosome 3q25.31 in KCNAB1 (rs7615568, fixed-effect Pmeta = 2.30 × 10(-8); random-effect Pmeta = 1.08 × 10(-8)). The second locus was at chromosome 21 in the proximity of CRYAA (rs11911275, fixed-effect Pmeta = 2.77 × 10(-8); random-effect Pmeta = 1.98 × 10(-9)), a major protein component of eye lens. The findings were further supported by up-regulation and down-regulation of KCNAB1 and CRYAA in human lens capsule, respectively, as the severity of nuclear cataract increases. The results offer additional insights into the pathogenesis of nuclear cataract in Asians.

Demographics and ocular biometric characteristics of patients undergoing cataract surgery in Auckland, New Zealand.

BACKGROUND: The aim is to investigate ethnic variation, in presentation and biometric parameters, within the population undergoing cataract surgery in Auckland. DESIGN: The design is a retrospective study. PARTICIPANTS: Four thousand nine hundred thirty-one eyes of 3524 consecutive patients undergoing cataract surgery in Auckland Public Hospital over 18 months were included in the study. METHODS: Analysis of preoperative medical records was performed. MAIN OUTCOME MEASURES: Age, gender, self-reported ethnicity, keratometry, anterior chamber depth, axial length and intraocular lens (IOL) power data were collected. RESULTS: Maori (4.7%) were under-represented compared with the proportion of Maori attending the eye clinic (5.5%) and in the major patient catchment area (8.2%). People of Maori, Pacific and Indian ethnicities presented at a significantly younger age (66.4, 65.9 and 67.9 years, respectively) than those of Caucasian and Asian ethnicities (76.4 and 71.3 years, respectively, P < 0.001). Advanced cataract was more likely in Pacific peoples and Maori than Caucasians. The mean axial length was longest in Asian eyes (23.83 ± 1.52 mm). The mean anterior chamber depth in the eyes of Pacific peoples (3.20 ± 0.39 mm) was significantly greater than that of Caucasians (3.09 ± 0.42 mm, P = 0.001) and Asians (3.05 ± 0.49 mm, P < 0.001). The mean IOL power in Asian eyes was 19.45D. This was significantly lower than the IOL power required by Caucasian (20.72D, P < 0.001) and Pacific ethnicities (20.61D, P = 0.001). With-the-rule astigmatism was highly prevalent in Maori and Pacific peoples, whereas in all other ethnicities, against-the-rule astigmatism was more common. CONCLUSIONS: This study identified significant ethnic variation in presentation for cataract surgery and ocular biometric parameters. These data may help identify potential biometric refinements and those at risk of developing ocular morbidities known to be associated with these parameters.

Q192R paraoxonase1 polymorphism is a risk factor for cataract in Pakistani population.

Cataract, the lens opacity, is among major causes of blindness in Pakistani population. In recent past, oxidative stress is suggested to play crucial role in loss of transparency. Along with other antioxidants, Paraoxonase 1 (PON1) has also shown decreased activity in patients suffering from cataract. The aim of current study was to examine the possible association of PON polymorphism with predisposition of cataract formation in local population. The study was conducted on 51 cataract patients and 50 control subjects considering all ethical issues. DNA was extracted from whole blood and PON1 polymorphism was identified using tetra primer ARMS-PCR method for both positions L55M and Q192R. Tetra primer ARMS-PCR results revealed that association between L55M polymorphism and cataract was insignificant while 192R genotype PON1 frequency was higher among the people suffering from cataract (78.4%) as compared to control subjects (56%), (odds ratio=2.857, confidence interval=1.197-6.820). Hence, R allele is likely to be a risk factor for cataract with allele frequency (82.3%) and (odds ratio=4.552, confidence interval=1.716-12.073, p-value=0.002). PON1 Q192R polymorphism is likely to be a risk factor for cataract development in Pakistani population while PON1 L55M was not found to be associated with cataract.

The link between apolipoprotein E, presenilin 1, and kinesin light chain 1 gene polymorphisms and age-related cortical cataracts in the Chinese population.

PURPOSE: To study whether presenilin 1 (PSEN1), apolipoprotein E (APOE), and kinesin light chain 1 (KLC1) genotypes are associated with the risk of developing age-related cortical cataracts in the Han Chinese population. METHODS: We collected and analyzed the blood samples of 227 cortical cataract patients and 263 controls. Genotyping was performed by direct sequencing after PCR amplification, and allele frequencies were tested for the Hardy-Weinberg equilibrium. RESULTS: The G allele and GG genotype of KLC1 rs8702 were significantly over-represented among cataract patients, as compared to healthy controls (allele P[χ2]=0.001 and genotype P[χ2]=0.008, respectively) and are associated with an odds ratio for cataract development of 1.54 (95% confidence interval of 1.19-2.01). More specifically, carrying the rs8702 C allele was associated with a decreased cortical cataract risk among individuals devoid of the APOE4 allele (OR=0.55; P[χ2]=0.003), whereas it has no significant effect among APOE4 carriers (OR=0.57; P[χ2]=0.36). CONCLUSIONS: The KLC1 and APOE genes may be novel susceptibility genes for age-related cataracts.

Ancestry, Socioeconomic Status, and Age-Related Cataract in Asians: The Singapore Epidemiology of Eye Diseases Study.

PURPOSE: To determine the prevalence of age-related cataract and its ancestral and socioeconomic risk factors in a multi-ethnic Asian population. DESIGN: Population-based, cross-sectional study. PARTICIPANTS: A total of 10 033 adults (3353 Chinese, 3280 Malays, and 3400 Indians) aged >40 years in the Singapore Epidemiology of Eye Diseases Study. METHODS: Study participants were invited for a structured interview and received a standardized comprehensive eye examination. Digital lens photographs were taken from eyes of each participant and graded for nuclear, cortical, and posterior subcapsular (PSC) cataract, following the Wisconsin Cataract Grading System. Prevalence data were compared with the Blue Mountains Eye Study (BMES) in Australia. Information on medical and lifestyle factors was collected using questionnaires and blood samples. To increase the precision of racial definition, genetic ancestry was derived from genome-wide single nucleotide polymorphism markers using principal component analysis. Regression models were used to investigate the association of cataract with socioeconomic factors (education and income) and genetic ancestry. MAIN OUTCOME MEASURES: Age-related cataract. RESULTS: A total of 8750 participants (94.0%) had gradable lens photographs. The age-standardized prevalence of cataract surgery in Chinese (16.0%), Malays (10.6%), and Indians (20.2%) was higher than in white subjects (4.1%). We found the age-standardized cataract prevalence in Chinese (30.4%), Malays (37.8%), and Indians (33.1%) was higher than in whites (18.5%). Cataract was 1.5 to 2 times more common in Asians and began 10 years earlier than in white subjects. Malays had significantly higher age-standardized prevalence of nuclear, cortical, and PSC cataract than Chinese (P<0.001). The severity of nuclear, cortical, and PSC cataract was significantly correlated with genetic ancestry in our South East Asian population. Less education and lower income were associated with cataract for Chinese and Indians but not Malays. The presence of visual impairment associated with cataract was higher in people aged ≥60 years and Malays. CONCLUSIONS: We showed that people of different Asian ethnicities had a higher prevalence and earlier age of onset of cataract than Europeans. People of Malay ancestry have a greater severity for all cataract subtypes than people of Chinese ancestry. Education and income were associated with cataract for certain Asian subgroups.

Congenital cataracts: de novo gene conversion event in CRYBB2.

PURPOSE: To identify the cause of congenital cataracts in a consanguineous family of Ashkenazi Jewish ancestry. METHODS: We performed genome-wide linkage analysis and whole-exome sequencing for the initial discovery of variants, and we confirmed the variants using gene-specific primers and Sanger sequencing. RESULTS: We found significant evidence of linkage to chromosome 22, under an autosomal dominant inheritance model, with a maximum logarithm of the odds (LOD) score of 3.91 (16.918 to 25.641 Mb). Exome sequencing identified three nonsynonymous changes in the CRYBB2 exon 5 coding sequence that are consistent with the sequence of the corresponding region of the pseudogene CRYBB2P1. The identification of these changes was complicated by possible mismapping of some mutated CRYBB2 sequences to CRYBB2P1. Sequencing with gene-specific primers confirmed that the changes--rs2330991, c.433 C>T (p.R145W); rs2330992, c.440A>G (p.Q147R); and rs4049504, c.449C>T (p.T150M)--present in all ten affected family members are located in CRYBB2 and are not artifacts of cross-reaction with CRYBB2P1. We did not find these changes in six unaffected family members, including the unaffected grandfather who contributed the affected haplotype, nor did we find them in the 100 Ashkenazi Jewish controls. CONCLUSIONS: Our data are consistent with a de novo gene conversion event, transferring 270 base pairs at most from CRYBB2P1 to exon 5 of CRYBB2. This study highlights how linkage mapping can be complicated by de novo mutation events, as well as how sequence-analysis pipeline mapping of short reads from next-generation sequencing can be complicated by the existence of pseudogenes or other highly homologous sequences.

Association Between Endothelial Cell Density and Corneal Thickness in Medium, Short, and Long Eyes of Han Chinese Cataract Patients.

PURPOSE: To evaluate the association between the endothelial cell density (ECD) and central corneal thickness (CCT) in medium, short, and long eyes of preoperative Han Chinese cataract patients. DESIGN: Retrospective cross-sectional study. METHODS: We consecutively enrolled 410 eyes, namely, 50 short eyes (axial length [AL]<22.0 mm), 150 medium eyes (22.0≤AL<24.0 mm), 120 medium-long eyes (24.0≤AL<26.0 mm), and 90 long eyes (AL≥26.0 mm), of 410 adult patients scheduled for cataract surgery. The ECD and CCT were determined preoperatively with a noncontact specular microscope. The association between the CCT and ECD was identified by using a multivariable regression analysis. A thin cornea was defined as having a CCT less than 500 µm. RESULTS: After adjusting for age, the presence of arterial hypertension, the presence of diabetes mellitus, intraocular pressure, and AL, a positive association between the CCT and ECD was identified in short eyes (linear regression coefficient [B]=3.40; standardized B [ß]=0.52; P = .03), medium eyes (B = 2.33; ß=0.28; P = .002), medium-long eyes (B = 1.84; ß=0.25; P = .02), and long eyes (B = 2.69; ß=0.41; P = .04). In the total group, the multivariable logistic analysis showed a significant link between the presence of a thin cornea and a lower ECD (odds ratio [OR]=0.80 per 100 cells/mm2 increase; P = .001). CONCLUSIONS: For cataract patients of Han ethnicity, a significant association between a thin CCT and a lower ECD was shown across the AL spectrum and was most prominent in short eyes. Eyes with a thin cornea are more likely to have a lower ECD.

A novel donor splice-site mutation of major intrinsic protein gene associated with congenital cataract in a Chinese family.

PURPOSE: To identify the disease-causing gene in a Chinese family with autosomal dominant congenital cataract. METHODS: Clinical and ophthalmologic examinations were performed on all members of a Chinese family with congenital cataract. Nine genes associated with congenital cataract were screened using direct DNA sequencing. Mutations were confirmed using restriction fragment length polymorphism (RFLP) analysis. The mutated multi-intronic plasmid (MIP) minigene, which carries the disease-causing splice-site mutation, and the wild-type (WT) MIP minigene were constructed using the pcDNA3.1 expression vector. Wild-type and mutant MIP minigene constructs were transiently transfected into HeLa cells. After 48 h of incubation at 37 °C, total RNA isolation and reverse transcription (RT)-PCR analysis were performed, and PCR products were separated and confirmed with sequencing. RESULTS: Direct DNA sequence analysis identified a novel splice-site mutation in intron 3 (c.606+1 G>A) of the MIP gene. To investigate the manner in which the splice donor mutation could affect mRNA splicing, WT and mutant MIP minigenes were inserted in the pcDNA3.1 (+) vector. Constructs were transfected into HeLa cells. RT-PCR analysis showed that the donor splice site mutation led to deletion of exon 3 in the mRNA encoded by the MIP gene. CONCLUSIONS: The present study identified a novel donor splice-site mutation (c.606+1G>A) in the MIP gene in a Chinese family with congenital cataract. In vitro RT-PCR analysis showed that this splice-site mutation resulted in the deletion of exon 3 from mRNA encoded by the MIP gene. This is the first report to show that donor splice-site mutation in MIP genes can cause autosomal dominant congenital cataract.

Molecular and structural analysis of genetic variations in congenital cataract.

OBJECTIVE: To determine the relative contributions of mutations in congenital cataract cases in an Indian population by systematic screening of genes associated with cataract. METHODS: We enrolled 100 congenital cataract cases presenting at the Dr. R. P. Centre for Ophthalmic Sciences, a tertiary research and referral hospital (AIIMS, New Delhi, India). Crystallin, alpha A (CRYAA), CRYAB, CRYGs, CRYBA1, CRYBA4, CRYBB1, CRYBB2, CRYBB3, beaded filament structural protein 1 (BFSP1), gap function protein, alpha 3 (GJA3), GJA8, and heat shock transcription factor 4 gene genes were amplified. Protein structure differences analysis was performed using Discovery Studio (DS) 2.0. RESULTS: The mean age of the patients was 17.45±16.51 months, and the age of onset was 1.618±0.7181 months. Sequencing analysis of 14 genes identified 18 nucleotide variations. Fourteen variations were found in the crystallin genes, one in Cx-46 (GJA3), and three in BFSP1. CONCLUSIONS: Congenital cataract shows marked clinical and genetic heterogeneity. Five nucleotide variations (CRYBA4:p.Y67N, CRYBB1:p.D85N, CRYBB1:p.E75K, CRYBB1:p.E155K, and GJA3:p.M1V) were predicted to be pathogenic. Variants in other genes might also be involved in maintaining lens development, growth, and transparency. The study confirms that the crystallin beta cluster on chromosome 22, Cx-46, and BFSP1 plays a major role in maintaining lens transparency. This study also expands the mutation spectrum of the genes associated with congenital cataract.

A novel beaded filament structural protein 1 (BFSP1) gene mutation associated with autosomal dominant congenital cataract in a Chinese family.

PURPOSE: To identify the disease-causing mutation in a five-generation Chinese family affected with bilateral congenital nuclear cataract. METHODS: Linkage analysis was performed for the known candidate genes and whole-exome sequencing was used in two affected family members to screen for potential genetic mutations; Sanger sequencing was used to verify the mutations throughout family. RESULTS: A novel beaded filament structural protein 1 (BFSP1) gene missense mutation was identified. Direct sequencing revealed a heterozygous G>A transversion at c.1042 of the coding sequence in exon 7 of BFSP1 (c.1042G>A) in all affected members, which resulted in the substitution of a wild-type aspartate to an asparagine (D348N). This mutation was neither seen in unaffected family members nor in 200 unrelated people as controls. CONCLUSIONS: A novel mutation (c.1042G>A) at exon 7 of BFSP1, which creates a substitution of an aspartate to an asparagine (p.D348N) was identified to be associated with autosomal dominant congenital cataract in a Chinese family. This is the first report of autosomal dominant congenital cataract being associated with a mutation in BFSP1, highlighting the important role of BFSP1 for physiological lens function and optical properties.