Genome-wide analysis identifies a quantitative trait locus in the MHC class II region associated with generalized vitiligo age of onset.

Generalized vitiligo is a common autoimmune disease in which acquired patchy depigmentation of skin, hair, and mucous membranes results from loss of melanocytes from involved areas. Previous genetic analyses have focused on vitiligo susceptibility, and have identified a number of genes involved in disease risk. Age of onset of generalized vitiligo also involves a substantial genetic component, but has not previously been studied systematically. In this study, we report a genome-wide association study of vitiligo age of onset in 1,339 generalized vitiligo patients, with replication in an independent cohort of 677 cases. We identified a quantitative trait locus for vitiligo age of onset in the major histocompatibility complex (MHC) class II region, located near c6orf10-BTNL2 (rs7758128; P=8.14 × 10(-11)), a region that is also associated with generalized vitiligo susceptibility. In contrast, there was no association of vitiligo age of onset with any other MHC or non-MHC loci that are associated with vitiligo susceptibility. These findings highlight the differing roles played by genes involved in vitiligo susceptibility versus vitiligo age of onset, and illustrate that genome-wide analyses can be used to identify genes involved in quantitative aspects of disease natural history, as well as disease susceptibility per se.

Comprehensive association analysis of candidate genes for generalized vitiligo supports XBP1, FOXP3, and TSLP.

We previously carried out a genome-wide association study of generalized vitiligo (GV) in non-Hispanic whites, identifying 13 confirmed susceptibility loci. In this study, we re-analyzed the genome-wide data set (comprising 1,392 cases and 2,629 controls) to specifically test association of all 33 GV candidate genes that have previously been suggested for GV, followed by meta-analysis incorporating both current and previously published data. We detected association of three of the candidate genes tested: TSLP (rs764916, P=3.0E-04, odds ratio (OR)=1.60; meta-P for rs3806933=3.1E-03), XBP1 (rs6005863, P=3.6E-04, OR=1.17; meta-P for rs2269577=9.5E-09), and FOXP3 (rs11798415, P=5.8E-04, OR=1.19). Association of GV with CTLA4 (rs12992492, P=5.9E-05, OR=1.20; meta-P for rs231775=1.0E-04) seems to be secondary to epidemiological association with other concomitant autoimmune diseases. Within the major histocompatibility complex (MHC), at 6p21.33, association with TAP1-PSMB8 (rs3819721, P=5.2E-06) seems to derive from linkage disequilibrium with major primary signals in the MHC class I and class II regions.

Allelic variation in TAS2R bitter receptor genes associates with variation in sensations from and ingestive behaviors toward common bitter beverages in adults.

The 25 human bitter receptors and their respective genes (TAS2Rs) contain unusually high levels of allelic variation, which may influence response to bitter compounds in the food supply. Phenotypes based on the perceived bitterness of single bitter compounds were first linked to food preference over 50 years ago. The most studied phenotype is propylthiouracil bitterness, which is mediated primarily by the TAS2R38 gene and possibly others. In a laboratory-based study, we tested for associations between TAS2R variants and sensations, liking, or intake of bitter beverages among healthy adults who were primarily of European ancestry. A haploblock across TAS2R3, TAS2R4, and TAS2R5 explained some variability in the bitterness of espresso coffee. For grapefruit juice, variation at a TAS2R19 single nucleotide polymorphism (SNP) was associated with increased bitterness and decreased liking. An association between a TAS2R16 SNP and alcohol intake was identified, and the putative TAS2R38-alcohol relationship was confirmed, although these polymorphisms did not explain sensory or hedonic responses to sampled scotch whisky. In summary, TAS2R polymorphisms appear to influence the sensations, liking, or intake of common and nutritionally significant beverages. Studying perceptual and behavioral differences in vivo using real foods and beverages may potentially identify polymorphisms related to dietary behavior even in the absence of known ligands.

Biopsychosocial influence on exercise-induced delayed onset muscle soreness at the shoulder: pain catastrophizing and catechol-o-methyltransferase (COMT) diplotype predict pain ratings.

OBJECTIVE: The experience of pain is believed to be influenced by psychologic and genetic factors. A previous study suggested pain catastrophizing and catechol-O-methyltransferase (COMT) genotype influenced clinical pain ratings for patients seeking operative treatment of shoulder pain. This study investigated whether these same psychologic and genetic factors predicted responses to induced shoulder pain. METHODS: Participants (n=63) completed self-report questionnaires and had COMT genotype determined before performing a standardized fatigue protocol to induce delayed onset muscle soreness. Then, shoulder pain ratings, self-report of upper-extremity disability ratings, and muscle torque production were reassessed 24, 48, and 72 hours later. RESULTS: This cohort consisted of 35 women and 28 men, with a mean age of 20.9 years (SD=1.7). The frequency of COMT diplotypes was 42 with "high COMT enzyme activity" (low pain sensitivity group) and 21 with "low COMT enzyme activity" (average pain sensitivity/high pain sensitivity group). A hierarchical regression model indicated that an interaction between pain catastrophizing and COMT diplotype was the strongest unique predictor of 72-hour pain ratings. The same interaction was not predictive of self-report of disability or muscle torque production at 72 hours. The pain catastrophizingxCOMT diplotype interaction indicated that participants with high pain catastrophizing and low COMT enzyme activity (average pain sensitivity/high pain sensitivity group) were more likely (relative risk=3.5, P=0.025) to have elevated pain intensity ratings (40/100 or higher). DISCUSSION: These findings from an experimental model converge with those from a surgical cohort and provide additional evidence that the presence of elevated pain catastrophizing and COMT diplotype indicative of low COMT enzyme activity have the potential to increase the risk of developing chronic pain syndromes.

Evidence for a biopsychosocial influence on shoulder pain: pain catastrophizing and catechol-O-methyltransferase (COMT) diplotype predict clinical pain ratings.

The experience of pain is believed to be influenced by social, cultural, environmental, psychological, and genetic factors. Despite this assertion, few studies have included clinically relevant pain phenotypes when investigating interactions among these variables. This study investigated whether psychological variables specific to fear-avoidance models and catechol-O-methyltransferase (COMT) genotype influenced pain ratings for a cohort of patients receiving operative treatment of shoulder pain. Patients (n=58) completed questionnaires and had COMT genotype determined pre-operatively. Then, shoulder pain ratings were collected 3-5 months post-operatively. This cohort consisted of 24 females and 34 males, with mean age of 50.3 (SD=15.0) and pre-operative pain rating of 4.5/10 (SD=1.8). The frequency of COMT diplotypes was 34 with "high COMT activity" (LPS group) and 24 with "low COMT activity" (APS/HPS group). Preliminary analysis indicated that of all the fear-avoidance variables considered (fear of pain, kinesiophobia, pain catastrophizing, and anxiety), only pain catastrophizing was a unique contributor to clinical pain ratings. A hierarchical regression model indicated that an interaction between pain catastrophizing and COMT diplotype contributed additional variance in pre-operative pain ratings. The pain catastrophizingxCOMT diplotype interaction demonstrated predictive validity as patients with high pain catastrophizing and low COMT activity (APS/HPS group) were more likely (RR=6.8, 95% CI=2.8-16.7) to have post-operative pain ratings of 4.0/10 or higher. Our findings suggest that an interaction between pain catastrophizing and COMT diplotype has the potential to influence pain ratings in patients seeking operative treatment of their shoulder pain.