Deborah M. Herbstman

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.

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

&NA; 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 catastrophizing × COMT 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.

Genetic contributions to pain: a review of findings in humans

Pain represents the major motivating factor for which individuals seek healthcare, and pain responses are characterized by substantial inter-individual differences. Increasing evidence suggests that genetic factors contribute significantly to individual differences in responses to both clinical and experimental pain. The purpose of this review article was to summarize the current literature regarding genetic contributions to pain, highlighting findings relevant to oral pain where available. A brief discussion of methodologic considerations is followed by a review of findings regarding genetic influences on clinical pain. Next, the literature examining genetic contributions to experimental pain responses is presented, emphasizing genetic associations that have been replicated in multiple cohorts. It is hoped that an enhanced understanding of genetic contributions to pain responses will ultimately improve diagnosis and treatment of clinical pain conditions.

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.

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.

Biopsychosocial Influence on Exercise-induced Delayed Onset Muscle Soreness at the Shoulder: Pain Catastrophizing and Catechol-o-methyltransferase ( comt ) Diplotype Predict Pain Ratings

ObjectiveThe 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. MethodsParticipants (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. ResultsThis 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 catastrophizing×COMT 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). DiscussionThese 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.

HPV in head and neck cancers among 5-year survivors.

To the Editor: Human papillomavirus (HPV), in particular the high-risk subtypes such as HPV16 and HPV33 (HR-HPV), has not only a proven role in the pathogenesis of cervical cancer, but is now implicated in some cases of head and neck squamous cell carcinoma (HNSCCA), which can arise in a variety of sites in the upper aerodigestive tract. The overall United State 5-year survival rate for HNSCCA between 1995 and 2001 was 59%. Although the literature shows a wide range in HPV-positivity in unselected HNSCCA (22% metastudy 4 to 74%), differential overall 5-year survival based on HPV status (and/or its putative surrogate marker, p16) has been suggested. In our study, we identified 23-three HNSCCA 5-year survivors whose tumor specimens were positive for presence of p16 (using standard immunohistochemistry, antip16 antibody from Biocare Medical clone JC8 ). Tumor specimen DNA was tested for presence of HPV DNA using our previously published PCRbased method. We obtained results on samples from 17 patients, with the other 6 failing due to insufficient quantity or quality of DNA (Table 1). Of these 17 cases, 12 (70%) were HPV positive (11 for HPV16, 1 for HPV33). The lack of perfect correlation of p16 and HPV-DNA positivity has been seen in previous studies, and suggests that p16 can be overexpressed without HPV infection, or that the HPV-negative samples were actually from HPV-positive tumors but escaped detection due to tissue sampling. Supporting this latter theory, we had one inconsistency among duplicates HANC4–5, in which PCR analysis of the presurgical biopsy (HANC5) was positive while a fragment from the resection was negative (HANC4) (Table 1). Thus, the frequency of HPV positivity may be underestimated. Our data are consistent with other reports suggesting increased survival in patients with HPV-positive tumors. For example, of 80 patients in another study, 74% had disease-free 5-year survival and were also HPV-positive, compared with only 53% of the HPV-negative cases. Ninety-two percent of our positives were HPV16 and 8% were HPV33, consistent with previous reports of HPV16 predominating in cervical cancer and HNSCCA. The 17 tumors occurred in the following anatomic locations: larynx (n 2, 12%) and oropharynx (soft palate, n 1, 6%), base of tongue (n 6, 35%), and tonsil (n 9, 47%). Four of the tongue tumors were HPV-positive (67%), 8 of the tonsil tumors were HPV-positive (89%), and the larynx