We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH ( P < 10 ⁻⁷⁵ ), ARMS2 ( P < 10 ⁻⁵⁹ ), C2/CFB ( P < 10 ⁻²⁰ ), C3 ( P < 10 ⁻⁹ ), and CFI ( P < 10 ⁻⁶ ). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 × 10 ⁻¹¹ ), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci ( LIPC , P = 1.3 × 10 ⁻⁷ ; CETP , P = 7.4 × 10 ⁻⁷ ) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c—associated alleles near LPL ( P = 3.0 × 10 ⁻³ ) and ABCA1 ( P = 5.6 × 10 ⁻⁴ ). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies.

The transcription factor PAX6 is essential in ocular development in vertebrates, being considered the master regulator of the eye. During eye development, it is essential for the correct patterning and formation of the multi-layered optic cup and it is involved in the developing lens and corneal epithelium. In adulthood, it is mostly expressed in cornea, iris, and lens. PAX6 is a dosage-sensitive gene and it is highly regulated by several elements located upstream, downstream, and within the gene. There are more than 500 different mutations described to affect PAX6 and its regulatory regions, the majority of which lead to PAX6 haploinsufficiency, causing several ocular and systemic abnormalities. Aniridia is an autosomal dominant disorder that is marked by the complete or partial absence of the iris, foveal hypoplasia, and nystagmus, and is caused by heterozygous PAX6 mutations. Other ocular abnormalities have also been associated with PAX6 changes, and genotype-phenotype correlations are emerging. This review will cover recent advancements in PAX6 regulation, particularly the role of several enhancers that are known to regulate PAX6 during eye development and disease. We will also present an updated overview of the mutation spectrum, where an increasing number of mutations in the non-coding regions have been reported. Novel genotype-phenotype correlations will also be discussed.

Worldwide deaths from diabetes mellitus (DM) and colorectal cancer increased by 90% and 57%, respectively, over the past 20 years. The risk of colorectal cancer was estimated to be 27% higher in patients with type 2 DM than in non-diabetic controls. However, there are potential confounders, information from lower income countries is scarce, across the globe there is no correlation between DM prevalence and colorectal cancer incidence and the association has evolved over time, suggesting the impact of additional environmental factors. The clinical relevance of these associations depends on understanding the mechanism involved. Although evidence is limited, insulin use has been associated with increased and metformin with decreased incidence of colorectal cancer. In addition, colorectal cancer shares some cellular and molecular pathways with diabetes target organ damage, exemplified by diabetic kidney disease. These include epithelial cell injury, activation of inflammation and Wnt/β-catenin pathways and iron homeostasis defects, among others. Indeed, some drugs have undergone clinical trials for both cancer and diabetic kidney disease. Genome-wide association studies have identified diabetes-associated genes (e.g. TCF7L2) that may also contribute to colorectal cancer. We review the epidemiological evidence, potential pathophysiological mechanisms and therapeutic implications of the association between DM and colorectal cancer. Further studies should clarify the worldwide association between DM and colorectal cancer, strengthen the biological plausibility of a cause-and-effect relationship through characterization of the molecular pathways involved, search for specific molecular signatures of colorectal cancer under diabetic conditions, and eventually explore DM-specific strategies to prevent or treat colorectal cancer.

Context: The polycystic ovary syndrome (PCOS) is frequently associated with visceral obesity, suggesting that omental adipose tissue might play an important role in the pathogenesis of the syndrome. Objective: The objective was to study the expression profiles of omental fat biopsy samples obtained from morbidly obese women with or without PCOS at the time of bariatric surgery. Design: This was a case-control study. Settings: We conducted the study in an academic hospital. Patients: Eight PCOS patients and seven nonhyperandrogenic women submitted to bariatric surgery because of morbid obesity. Interventions: Biopsy samples of omental fat were obtained during bariatric surgery. Main Outcome Measure: The main outcome measure was high-density oligonucleotide arrays. Results: After statistical analysis, we identified changes in the expression patterns of 63 genes between PCOS and control samples. Gene classification was assessed through data mining of Gene Ontology annotations and cluster analysis of dysregulated genes between both groups. These methods highlighted abnormal expression of genes encoding certain components of several biological pathways related to insulin signaling and Wnt signaling, oxidative stress, inflammation, immune function, and lipid metabolism, as well as other genes previously related to PCOS or to the metabolic syndrome. Conclusion: The differences in the gene expression profiles in visceral adipose tissue of PCOS patients compared with nonhyperandrogenic women involve multiple genes related to several biological pathways, suggesting that the involvement of abdominal obesity in the pathogenesis of PCOS is more ample than previously thought and is not restricted to the induction of insulin resistance.

Inherited retinal diseases (IRDs), defined by dysfunction or progressive loss of photoreceptors, are disorders characterized by elevated heterogeneity, both at the clinical and genetic levels. Our main goal was to address the genetic landscape of IRD in the largest cohort of Spanish patients reported to date. A retrospective hospital-based cross-sectional study was carried out on 6089 IRD affected individuals (from 4403 unrelated families), referred for genetic testing from all the Spanish autonomous communities. Clinical, demographic and familiar data were collected from each patient, including family pedigree, age of appearance of visual symptoms, presence of any systemic findings and geographical origin. Genetic studies were performed to the 3951 families with available DNA using different molecular techniques. Overall, 53.2% (2100/3951) of the studied families were genetically characterized, and 1549 different likely causative variants in 142 genes were identified. The most common phenotype encountered is retinitis pigmentosa (RP) (55.6% of families, 2447/4403). The most recurrently mutated genes were PRPH2, ABCA4 and RS1 in autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) NON-RP cases, respectively; RHO, USH2A and RPGR in AD, AR and XL for non-syndromic RP; and USH2A and MYO7A in syndromic IRD. Pathogenic variants c.3386G > T (p.Arg1129Leu) in ABCA4 and c.2276G > T (p.Cys759Phe) in USH2A were the most frequent variants identified. Our study provides the general landscape for IRD in Spain, reporting the largest cohort ever presented. Our results have important implications for genetic diagnosis, counselling and new therapeutic strategies to both the Spanish population and other related populations.

We have evaluated the possible association of polycystic ovary syndrome (PCOS) with 15 genomic variants previously described to influence insulin resistance, obesity, and/or type 2 diabetes mellitus. Seventy-two PCOS patients and 42 healthy controls were genotyped for 15 variants in the genes encoding for paraoxonase (three variants), plasma cell differentiation antigen glycoprotein, human sorbin and SH3 domain containing 1, plasminogen activator inhibitor-1, peroxisome proliferator-activated receptor-gamma2, protein tyrosine phosphatase 1B (two variants), adiponectin (two variants), IGF1, IGF2, IGF1 receptor, and IGF2 receptor. Compared with controls, PCOS patients were more frequently homozygous for the -108T variant in paraoxonase (36.6% vs. 9.5%; P = 0.002) and homozygous for G alleles of the ApaI variant in IGF2 (62.9% vs. 38.1%; P = 0.018). Paraoxonase is a serum antioxidant enzyme and, because -108T alleles result in decreased paraoxonase expression, this increase in oxidative stress might result in insulin resistance. G alleles of the ApaI variant in IGF2 may increase IGF2 expression, and IGF2 stimulates adrenal and ovarian androgen secretion. In conclusion, the paraoxonase -108 C-->T variant and the ApaI polymorphism in the IGF2 gene are associated with PCOS and might contribute to increased oxidative stress, insulin resistance, and hyperandrogenism in this prevalent disorder.