X-linked markers in the Duchenne muscular dystrophy gene associated with oral clefts.

As part of an international consortium, case-parent trios were collected for a genome-wide association study of isolated, non-syndromic oral clefts, including cleft lip (CL), cleft palate (CP), and cleft lip and palate (CLP). Non-syndromic oral clefts have a complex and heterogeneous etiology. Risk is influenced by genes and environmental factors, and differs markedly by gender. Family-based association tests (FBAT) were used on 14,486 single nucleotide polymorphisms (SNPs) spanning the X chromosome, stratified by type of cleft and racial group. Significant results, even after multiple-comparisons correction, were obtained for the Duchenne muscular dystrophy (DMD) gene, the largest single gene in the human genome, among CL/P (i.e., both CL and CLP combined) trios. When stratified into groups of European and Asian ancestry, stronger signals were obtained for Asian subjects. Although conventional sliding-window haplotype analysis showed no increase in significance, selected combinations of the 25 most significant SNPs in the DMD gene identified four SNPs together that attained genome-wide significance among Asian CL/P trios, raising the possibility of interaction between distant SNPs within the DMD gene.

Evidence for gene-environment interaction in a genome wide study of nonsyndromic cleft palate.

Nonsyndromic cleft palate (CP) is a common birth defect with a complex and heterogeneous etiology involving both genetic and environmental risk factors. We conducted a genome-wide association study (GWAS) using 550 case-parent trios, ascertained through a CP case collected in an international consortium. Family-based association tests of single nucleotide polymorphisms (SNP) and three common maternal exposures (maternal smoking, alcohol consumption, and multivitamin supplementation) were used in a combined 2 df test for gene (G) and gene-environment (G × E) interaction simultaneously, plus a separate 1 df test for G × E interaction alone. Conditional logistic regression models were used to estimate effects on risk to exposed and unexposed children. While no SNP achieved genome-wide significance when considered alone, markers in several genes attained or approached genome-wide significance when G × E interaction was included. Among these, MLLT3 and SMC2 on chromosome 9 showed multiple SNPs resulting in an increased risk if the mother consumed alcohol during the peri-conceptual period (3 months prior to conception through the first trimester). TBK1 on chr. 12 and ZNF236 on chr. 18 showed multiple SNPs associated with higher risk of CP in the presence of maternal smoking. Additional evidence of reduced risk due to G × E interaction in the presence of multivitamin supplementation was observed for SNPs in BAALC on chr. 8. These results emphasize the need to consider G × E interaction when searching for genes influencing risk to complex and heterogeneous disorders, such as nonsyndromic CP.

Visual outcomes of high-volume compared with low-volume manual small-incision cataract surgery in Nepal.

PURPOSE: To study whether manual small-incision cataract surgery (MSICS) in a high-volume setting gives acceptable postoperative visual outcomes. SETTINGS: Geta Eye Hospital, Kailali, Nepal. DESIGN: Single-center retrospective study. METHODS: One-year records of all MSICS in adult patients without any other ocular comorbidity were analyzed retrospectively. Surgical outcomes of cataract cases when surgeons performed more than 72 surgeries (high volume) in a single operating session (1 day) were compared with when fewer than 30 surgeries (low volume) were performed in a single operating session (1 day). RESULTS: Of 23 717 cases in the study, 20 574 patients (87%) had preoperative visual acuity of less than 3/60; 15 632 patients (66%) achieved good visual outcome (uncorrected distance visual acuity of 6/18 or better) postoperatively. Patients operated during high-volume months achieved good visual outcomes in 9930 cases (66.9%) as compared with 5702 (64.3%) in low-volume months. However, 6235 patients (61.7%) operated on during high-volume days had good visual outcomes as compared with 3053 (71.4%) during low-volume days; 175 patients in the high-volume group and 73 patients in the low-volume group (1.7% each) achieved visual acuity worse than 3/60. There were comparable posterior capsular rupture rates (423 [1.78%]) during high- and low-volume months, and 21 cases (0.09%) of postoperative endophthalmitis were noted. CONCLUSIONS: MSICS can be used to reduce large cataract backlogs in developing countries as good visual outcomes could be achieved in high-volume settings if standard protocols for quality control are followed.