Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Racial differences in systemic sclerosis disease presentation: a European Scleroderma Trials and Research group study

Objectives. Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations.Methods. SSc characteristics of patients from the EUSTAR cohort were cross-sectionally compared across racial groups using survival and multiple logistic regression analyses.Results. The study included 9162 WP, 341 AP and 181 BP. AP developed the first non-RP feature faster than WP but slower than BP. AP were less frequently anti-centromere (ACA; odds ratio (OR) = 0.4, P &lt; 0.001) and more frequently anti-topoisomerase-I autoantibodies (ATA) positive (OR = 1.2, P = 0.068), while BP were less likely to be ACA and ATA positive than were WP [OR(ACA) = 0.3, P &lt; 0.001; OR(ATA) = 0.5, P = 0.020]. AP had less often (OR = 0.7, P = 0.06) and BP more often (OR = 2.7, P &lt; 0.001) diffuse skin involvement than had WP.AP and BP were more likely to have pulmonary hypertension [OR(AP) = 2.6, P &lt; 0.001; OR(BP) = 2.7, P = 0.03 vs WP] and a reduced forced vital capacity [OR(AP) = 2.5, P &lt; 0.001; OR(BP) = 2.4, P &lt; 0.004] than were WP. AP more often had an impaired diffusing capacity of the lung than had BP and WP [OR(AP vs BP) = 1.9, P = 0.038; OR(AP vs WP) = 2.4, P &lt; 0.001]. After RP onset, AP and BP had a higher hazard to die than had WP [hazard ratio (HR) (AP) = 1.6, P = 0.011; HR(BP) = 2.1, P &lt; 0.001].Conclusion. Compared with WP, and mostly independent of geographical location, AP have a faster and earlier disease onset with high prevalences of ATA, pulmonary hypertension and forced vital capacity impairment and higher mortality. BP had the fastest disease onset, a high prevalence of diffuse skin involvement and nominally the highest mortality

Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits

Peer reviewe

Functional results after surgical treatment for congenital knee dislocation

BACKGROUND: Congenital knee dislocation (CDK) is a rare congenital deformity, which often requires surgery for treatment. Little objective data exist characterizing the outcome of patients who require operative treatment for this condition. The purposes of this study were to objectively evaluate the functional, clinical, and gait outcomes of patients who underwent surgical treatment of CDK; and compare the results of outcome between 2 surgical approaches for this condition: quadricepsplasty and femoral shortening. METHODS: We performed a retrospective review of all patients (7) treated surgically for CDK. Patients were evaluated at an average follow-up of 12+6 years. Each patient underwent a clinical examination, functional evaluation using the Lysholm Knee Questionnaire and Pediatric Outcomes Data Collection Instrument, and a 3-dimensional gait evaluation. The results of the total group were compared with normal controls. Additionally, results of the patients treated with quadricepsplasty were compared with patients treated with femoral shortening. RESULTS: Total knee range of motion for the entire group averaged 112 degrees, with 8 of the 9 knees having flexion\u3e90 degrees. Seven of the 9 knees were found to have some degree of instability on examination, yet none of the patients reported using any form of brace for ambulation. Functional evaluation showed good knee specific and overall function, comparable to normal controls. There were no differences in clinical or functional outcomes between the 2 surgical approaches. Gait analysis revealed a stiff-knee gait pattern to the congenital knee dislocation group, as compared with normal controls, and subtle differences in knee function between the surgical approaches. CONCLUSIONS: The function of patients after surgical treatment for CDK seems to be quite good compared with normal controls. Good knee specific and overall function scores are reported with limitations seen only in higher demand activities. Despite instability of the knee noticed on clinical examination, patients ambulate without braces and have a functional knee range of motion. Little difference in outcome was seen between the 2 surgical approaches used to treat this condition. LEVEL OF EVIDENCE: Therapeutic Study, Level III. Copyright © 2010 by Lippincott Williams & Wilkins

Gait Analysis after Initial Nonoperative Treatment for Clubfeet: Intermediate Term Followup at Age 5

We conducted gait analysis following initial nonoperative clubfoot treatment to compare lower extremity kinematic (eg, ankle motion) and kinetic (eg, ankle power) characteristics between patients treated as infants with Ponseti casting or French physical therapy. This is a followup report of gait characteristics at age 5 years in patients who had previously been tested at age 2 years. One hundred-twenty five clubfeet in 90 patients (34 feet only Ponseti treatment, 40 only French PT, and 51 feet initial nonoperative treatment followed by surgery) were included. The gait characteristics were compared to those of age-matched normal control subjects. Ankle equinus during gait occurred in 5% of feet treated with the French method and none of those treated by the Ponseti method. Increased stance phase ankle dorsiflexion persisted in 24% of feet treated by the Ponseti method. Intoeing was seen in 1/3 of both the French and Ponseti methods. Ankle push-off power was decreased compared to normal in patients treated by both methods, and even more so in operated feet. The presence or absence of Achilles tenotomy did not affect ankle power. Gait characteristics of feet that did not have surgery and maintained correction were superior to those of operated feet

Establishing consensus on the best practice guidelines for the use of bracing in adolescent idiopathic scoliosis

Survey