Mutations in genes encoding subunits of the phagocyte NADPH oxidase complex are recognized to cause chronic granulomatous disease (CGD), a severe primary immunodeficiency. Here we describe how deficiency of CYBC1, a previously uncharacterized protein in humans (C17orf62), leads to reduced expression of NADPH oxidase’s main subunit (gp91phox) and results in CGD. Analyzing two brothers diagnosed with CGD we identify a homozygous loss-of-function mutation, p.Tyr2Ter, in CYBC1. Imputation of p.Tyr2Ter into 155K chip-genotyped Icelanders reveals six additional homozygotes, all with signs of CGD, manifesting as colitis, rare infections, or a severely impaired PMA-induced neutrophil oxidative burst. Homozygosity for p.Tyr2Ter consequently associates with inflammatory bowel disease (IBD) in Iceland (P = 8.3 × 10−8; OR = 67.6), as well as reduced height (P = 3.3 × 10−4; −8.5 cm). Overall, we find that CYBC1 deficiency results in CGD characterized by colitis and a distinct profile of infections indicative of macrophage dysfunction.
Objective. Patients with ankylosing spondylitis (AS) and ϳ50% of their first-degree relatives may have a genetic abnormality that results in subclinical intestinal inflammation. This study was undertaken to examine the familial occurrence and cosegregation of AS and inflammatory bowel disease (IBD) in order to determine whether there is a shared genetic risk factor in families.Methods. The Icelandic genealogy database and population-wide data on all living Icelanders diagnosed as having AS (n ؍ 205) and/or IBD (n ؍ 1,352) were used to estimate the risk ratios of AS for relatives of patients with AS, the risk ratios of IBD for relatives of patients with IBD, and the cross-risk ratios of AS for relatives of patients with IBD or of IBD for relatives of patients with AS. The mean kinship coefficients for each disease were calculated. The control population for disease risk calculations comprised 10,000-100,000 sets of matched Icelandic subjects.Results. First-, second-, and third-degree relatives of patients with AS had risk ratios of 94, 25, and 3.5, respectively, indicating an increased risk of developing AS (each P < 0.0005), while first-, second-, and thirddegree relatives of patients with IBD had risk ratios for IBD of 4.4, 2.2, and 1.4, respectively (each P < 0.0001). The cross-risk ratios of IBD were 3.0 and 2.1 in firstand second-degree relatives of patients with AS, respectively, and were the same for AS in first-and seconddegree relatives of patients with IBD. With the exception of Crohn's disease, the risk of having AS, ulcerative colitis, or IBD in spouses of patients with these diseases did not differ significantly from that in controls. Calculation of the kinship coefficients confirmed these patterns of familial risk.Conclusion. Patients with AS or IBD in Iceland are significantly more related to each other than are randomly sampled control subjects, in terms of an increased risk of either or both conditions developing in third-degree relatives. These findings suggest that one or more undiscovered genetic variants may underlie the risk of both diseases.
Under a national program established in 1980, the eyes of approximately 90% of the insulin dependent diabetic patients in Iceland have undergone annual eye examination and fundus photography. Laser treatment was given for proliferative retinopathy or diabetic macular edema according to Diabetic Retinopathy Study and Early Treatment Diabetic Retinopathy Study criteria. We report on 205 insulin-taking patients whose age at diagnosis was less than 30 years of age. Retinopathy was present in 106 (52%) patients and proliferative retinopathy in 26 (13%). 196 patients (96%) had visual acuity equal or better than 6/12 in their better eye, 6 patients (3%) with 6/18-6/48 in their better eye, and 2 patients (1%) equal or worse than 6/60 in their better eye.
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