Haplotype frequencies in a sub-region of chromosome 19q13.3, related to risk and prognosis of cancer, differ dramatically between ethnic groups

<p>Abstract</p> <p>Background</p> <p>A small region of about 70 kb on human chromosome 19q13.3 encompasses 4 genes of which 3, <it>ERCC1</it>, <it>ERCC2</it>, and <it>PPP1R13L </it>(aka <it>RAI</it>) are related to DNA repair and cell survival, and one, <it>CD3EAP</it>, aka <it>ASE1</it>, may be related to cell proliferation. The whole region seems related to the cellular response to external damaging agents and markers in it are associated with risk of several cancers.</p> <p>Methods</p> <p>We downloaded the genotypes of all markers typed in the 19q13.3 region in the HapMap populations of European, Asian and African descent and inferred haplotypes. We combined the European HapMap individuals with a Danish breast cancer case-control data set and inferred the association between HapMap haplotypes and disease risk.</p> <p>Results</p> <p>We found that the susceptibility haplotype in our European sample had increased from 2 to 50 percent very recently in the European population, and to almost the same extent in the Asian population. The cause of this increase is unknown. The maximal proportion of overall genetic variation due to differences between groups for Europeans versus Africans and Europeans versus Asians (the F_stvalue) closely matched the putative location of the susceptibility variant as judged from haplotype-based association mapping.</p> <p>Conclusion</p> <p>The combined observation that a common haplotype causing an increased risk of cancer in Europeans and a high differentiation between human populations is highly unusual and suggests a causal relationship with a recent increase in Europeans caused either by genetic drift overruling selection against the susceptibility variant or a positive selection for the same haplotype. The data does not allow us to distinguish between these two scenarios. The analysis suggests that the region is not involved in cancer risk in Africans and that the susceptibility variants may be more finely mapped in Asian populations.</p

Association of melanocortin 1 receptor gene (MC1R) polymorphisms with skin reflectance and freckles in Japanese.

Most studies on the genetic basis of human skin pigmentation have focused on people of European ancestry and only a few studies have focused on Asian populations. We investigated the association of skin reflectance and freckling with genetic variants of melanocortin 1 receptor (MC1R) gene in Japanese. DNA samples were obtained from a total of 653 Japanese individuals (ages 19-40 years) residing in Okinawa; skin reflectance was measured using a spectrophotometer and freckling status was determined for each individual. Lightness index (L*) and freckling status were not correlated with age, body mass index or ancestry (Ryukyuan or Main Islanders of Japan). Among the 10 nonsynonymous variants that were identified by direct sequencing of the coding region of MC1R, two variants--R163Q and V92M--with the derived allele frequencies of 78.6 and 5.5%, respectively, were most common. Multiple regression analysis showed that the 163Q allele and the presence of nonsynonymous rare variants (allele frequencies <5%) were significantly associated with an increase in sex-standardized skin lightness (L* of CIELAB (CIE 1976 (L*a*b*) color space)) of the inner upper arm. Relative to the 92V allele, the 92M allele was significantly associated with increased odds of freckling. This is the first study to show an association between the 163Q allele and skin reflectance values; this association indicated that light-toned skin may have been subjected to positive selection in East Asian people

A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis

Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF = up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P = 6.89 x 10(-7), odds ratio = 0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain.Peer reviewe

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. </p

Fluid simulations of plasma turbulence at ion scales: comparison with Vlasov-Maxwell simulations

Comparisons are presented between a hybrid Vlasov-Maxwell (HVM ) simulation of turbulence in a collisionless plasma and fluid reductions. These includ e Hall- magnetohydrodynamics (HMHD) and Landau fluid (LF) or FLR-Land au fluid (FLR- LF) models that retain pressure anisotropy and low-frequency kin etic effects such as Landau damping and, for the last model, finite Larmor radius (FLR) c orrections. The problem is considered in two space dimensions, when initial conditio ns involve moderate-amplitude perturbations of a homogeneous equilibrium pla sma subject to an out-of-plane magnetic field. LF turns out to provide an accurat e description of the velocity field up to the ion Larmor radius scale, and even to smaller scales for the magnetic field. Compressibility nevertheless appears significant ly larger at the sub-ion scales in the fluid models than in the HVM simulation. High freque ncy ki- netic effects, such as cyclotron resonances, not retained by fluid descriptions, could be at the origin of this discrepancy. A significant temperature anisotr opy is generated, with a bias towards the perpendicular component, the more intense fluctuations being rather spread out and located in a broad vicinity of current sheets . Non-gyrotropic pressure tensor components are measured and their fluctuation s are shown to reach a significant fraction of the total pressure fluctuation, with inten se regions closely correlated with current sheets