High-activity Allele Research Articles

Bright side of the MAOA-uVNTR on trait and situational forgiveness

The stress-and-coping theory of forgiveness posits that forgiveness and aggression are alternative ways of coping with stress of interpersonal offences. Inspired by the link between aggression and MAOA-uVNTR (a genetic variant involving in catabolism of monoamines), we investigated the relationship between this variant and forgiveness with two studies. Study 1 examined the relationship between the MAOA-uVNTR and trait forgiveness in students, and study 2 examined the effect of this variant on third-party forgiveness in response to situational offences in male inmates. The results showed that the MAOA-H (a high activity allele) was associated with higher trait forgiveness in male students and greater third-party forgiveness to accidentally committed harm and attempted but failed harm in male inmates than the MAOA-L. These findings highlight the bright side of MAOA-uVNTR on trait and situational forgiveness.

Maternal Education Potentially Moderates the MAOA uVNTR Effects on Externalizing Behavior in Black South African Children

Interactions between the MAOA uVNTR and rearing environment are suggested to influence the developmental manifestations of childhood internalizing and externalizing behavior. However, few studies in the MAOA literature have included continental African children, or focused on non-clinical samples. We explored the main and interactive effects of the MAOA uVNTR (high and low activity alleles) in Black South African male (n = 478) and female (n = 540) children who were part of the longitudinal Birth to Twenty Plus cohort. Historical data on birth weight, gestational age at delivery, socioeconomic status, and maternal education were combined with genotypic information and analyzed using regression modeling. We found no significant main effects for the MAOA uVNTR on childhood behavior in either sex. A significant interaction (p = .04) was identified between MAOA and maternal education, suggesting that externalizing behavior in boys carrying a low activity MAOA allele varied in direct proportion to the education levels of their mothers. However, the model fit failed to reach significance, possibly due to our inclusion of only non-clinical pre-pubertal males. No significant interactions were detected for female children. Our findings lend tentative credibility to the Environmental Sensitivity metaframework, which suggests that MAOA is an important plasticity factor in childhood development.

IDENTIFICATION OF MONOAMINOXIDASE-A GENE PROMOTER POLYMORPHISM (MAOA-UVNTR) AND THEIR RELATIONSHIP WITH AGGRESSIVE BEHAVIOR IN UKRAINIAN CHILDREN.

to investigate the interactive effect of monoamine oxidase-A gene promoter polymorphism (MAOA-uVNTR) and environmental factors on the development of aggressive behavior. Genotyping of the MAOA-uVNTR polymorphism was performed in 144 boys and girls aged from 10 to 16 years, genotypes were grouped by a high and low transcriptional activity. For the general assessment of the psycho-emotional sphere of children, the projective method «non-existent animal» was used, the indicators and forms of aggression were determined according to the method of A. Bass and A. Darky. It was found the predominant allelic variants of the MAOA gene with 3 (S) and 4 (L) tandem repeats. The presence of close relationships between the dependent variable «aggressive behavior» and the predictor variables: «family disadvantage index» and «MAOA-uVNTR genotype» was established. It has been proven that the presence of the highly active allele (L) in the genotype reduces the chances of developing general aggression, delinquent behavior, physical aggression, open aggression, negativism, and externalization. The MAOA genotype of the high-activity allele (L) moderated the impact of stressful life events, and the low-activity allele S was associated with increased aggression in girls and boys who experienced severe stress.

Monoamine oxidase A (MAOA) interaction with parenting practices on callous-unemotional traits in preschoolers

Background and ObjectivesFrom a gene-by-environment perspective, parenting in interaction with the polymorphism in the Monoamine oxidase A (MAOA) gene (MAOA-uVNTR) might also be associated with increased callous-unemotional traits (CU) in preschoolers. MAOA-uVNTR results in differential enzyme activity, so that high-activity alleles (MAOA-H) are linked to reduced dopamine, serotonin, and norepinephrine availability in comparison to low-activity allele (MAOA-L). As MAOA-uVNTR has been previously described to moderate the relationship between childhood parental maltreatment and aggressive and antisocial behavior, it may also play a role in CU traits etiology. MethodsData was collected through questionnaires answered by parents and teachers. MAOA-uVNTR was genotyped in 368 Caucasian children from a community sample (51.9% male). Multiple linear regression analyses were conducted to analyze the interaction effect of MAOA genotypes and both positive parenting and punitive parenting practices on CU traits at two different periods (3 and 5 years old) and separately by sex. ResultsNo significant interactions were found for boys. Among girls, a significant interaction effect was found for MAOA-LL carriers, who showed higher CU traits at age 5 when exposed to higher punitive or positive parenting at age 3. ConclusionsOur study provides the first evidence for significant MAOA × early parenting effects on CU traits in preschoolers, specifically among female MAOA-LL carriers. This suggests that the MAOA-LL genotype for girls is associated with higher sensitivity to both positive and punitive parenting in girls, so that MAOA-LL emerges as a genotype that confers higher vulnerability to parental influences.

Genetic and epigenetic serotonergic markers predict the ability to recognize mental states

The serotonergic (5-HT) system is related to affective and cognitive processes and explains behavioral variability in the normal and psychopathological range. For this reason, the hypothesis was put forward that genetic and epigenetic markers related to 5-HT metabolism predict individual differences in social cognitive functioning. Social cognitions are complex mental processes necessary for perceiving, interpreting and reacting to the behaviors of others. In order to test this hypothesis one of the most prominent theory of mind tasks, the reading the mind in the eye test (RMET), was administered to N = 435 participants and measures of performance were related to the functional MAO-A VNTR polymorphism (relevant for 5-HT catabolism) and to epigenetic markers in the promoter of the TPH-2 gene (relevant for 5-HT synthesis). It was postulated that genetic and epigenetic markers of high 5-HT activity are positively related to RMET performance.Results show that the MAO-A high activity allele, together with the degree of methylation at a promoter CpG site on the TPH-2 gene explain significant proportions of variance in the RMET performance even after controlling for age and sex effects.Present findings yield evidence for the importance of 5-HT for social cognition. Based on additional findings, the role of a TRP-rich diet for theory of mind functions is discussed.

Association of low activity of UGT1A7 with Lung Cancer in Taiwan: A preliminary case control study

This study was aimed to evaluate the correlation between the polymorphisms of the UDP-glucuronosyltransferases1A7 (UGT1A7) gene and the risk of lung carcinogenesis in the Taiwanese population. A total of 230 lung cancer patients and 230 age- and gender-matched healthy individuals were enrolled in this case control study. UGT1A7*1 was defined as a high activity allele, while UGT1A7*2, UGT1A7*3 and UGT1A7*4 were categorized as low activity alleles. The relationship between EGFR mutations and UGT1A7 polymorphisms was investigated in this study. The frequency of UGT1A7*2 and UGT1A7*3 was significantly higher in the lung cancer group than in the control group (p = 0.03, odds ratio (OR) = 1.44, 95% confidence interval (CI) = 1.04-1.99 for UGT1A7*2; and p = 0.01, OR = 1.56, 95% CI = 1.11-2.18 for UGT1A7*3). The frequency of lower activity alleles was significantly higher in the lung cancer group than in the control group (p = 0.03, OR = 1.58, 95% CI = 1.04-2.40 for the high-activity allele/low-activity allele (H/L) group; and p < 0.01, OR = 2.23, 95% CI = 1.29-3.84 for the low-activity allele/low-activity allele (L/L) group). This difference was only significant in the male subgroup, with odds ratio of 1.87 (95% CI = 1.05-3.36, p = 0.03) for the H/L group and 2.638 (95% CI = 1.28-5.42, p < 0.01) for the L/L allele group. Yet, pathologic type and epidermal growth factor receptor (EGFR) mutations did not affect the distribution of UGT1A7 in the patient group. The results suggested that the polymorphisms of the metabolic gene, UGT1A7, may contribute to reduced enzyme activity and subsequently affect the detoxification of carcinogens. It is therefore concluded that UGT1A7 polymorphism is associated with lung carcinogenesis for the Taiwanese population.

Development and characterization of &lt;i&gt;wheat yellow mosaic virus&lt;/i&gt;-resistant lines carrying &lt;i&gt;Q.Ymym&lt;/i&gt;, breaking off the tightly-linked high-activity allele of the polyphenol oxidase gene in the Japanese wheat variety ‘Yumechikara’

Development and characterization of &lt;i&gt;wheat yellow mosaic virus&lt;/i&gt;-resistant lines carrying &lt;i&gt;Q.Ymym&lt;/i&gt;, breaking off the tightly-linked high-activity allele of the polyphenol oxidase gene in the Japanese wheat variety ‘Yumechikara’

Evaluation of the relationship between MAOA-uVNTR gene polymorphism and impulsivity, anger, temperament and personality traits in healthy male subjects

Aim: Serotonergic activity in the central nervous system negatively correlates with personality traits associated with aggression, impulsivity and anger. MAOA is involved in the catabolism of serotonin and norepinephrine, so the gene encoding MAOA is a candidate gene for aggression-related behavior. It is thought that MAOA genetic variants affect the MAOA activity at different degrees, leading to behavioral changes as a result of a decrease in enzyme activity. The aim of this study is investigating the possible relationship between the MAOA-uVNTR polymorphism genotypes and aggression, anger, impulsivity, temperament-character traits in healthy male subjects. Materials and Methods: 101 Turkish healthy male subjects were included in the study. The participants were given scales to evaluate impulsivity, temperament and character traits, anger and aggression levels. MAOA-uVNTR polymorphism was examined with a sample taken from peripheral blood.Results: A total of 101 people, 33.6% had low-activity allele and 66.4% had high-activity allele of MAOA gene. There was no significant relationship between the temperament-character traits of the participants and MAOA-uVNTR polymorphism. Impulsivity scales were higher in the low-activity allele group, which was statistically significant in terms of motor impulsivity (p = 0.007), non-planning impulsivity (p = 0.031) and total scores (p = 0.029). Conclusion: The low-activity allele of MAOA gene may be a marker for impulsivity. This requires both repetitive studies with healthy controls in the Turkish population and studies in different cultures.

Main and interaction effects of childhood trauma and the MAOA uVNTR polymorphism on psychopathy

Psychopathy is characterized by callous affect, interpersonal manipulation, a deviant lifestyle, and antisocial behavior. Previous research has linked psychopathic traits to childhood trauma, but also to the upstream variable number tandem repeat (uVNTR) polymorphism of the monoamine oxidase A (MAOA) gene. An interaction between childhood trauma and MAOA genotype has been associated with antisocial behavior, but so far little is known about interaction effects of childhood trauma and the MAOA uVNTR on psychopathy. In order to bridge this gap, we used data of 1531 male and 1265 female twins and their siblings from a Finnish community sample to estimate structural equation models. The psychopathy and childhood trauma constructs were conceptualized as bifactor models with one general and two orthogonal group factors. Data comprised self-reports on childhood trauma and psychopathic traits as well as MAOA uVNTR genotype. In both genders, childhood trauma was associated with the general factor that represents the overarching psychopathy construct, and with the group factor that captures social deviance, but not with the group factor capturing psychopathic core personality traits. Women with a low activity variant of the MAOA uVNTR reported slightly higher levels of psychopathy than those with a high activity allele, but only with respect to the general psychopathy factor. There was no evidence for an interaction effect between MAOA uVNTR genotype and childhood trauma on psychopathy in either gender. Our results suggest that psychopathy in general and social deviance in particular are associated with childhood trauma in men and women, and that psychopathic traits are subject to variation in the MAOA uVNTR genotype in women.

Catechol-O-Methyltransferase moderates effect of stress mindset on affect and cognition.

There is evidence that altering stress mindset—the belief that stress is enhancing vs. debilitating—can change cognitive, affective and physiological responses to stress. However individual differences in responsiveness to stress mindset manipulations have not been explored. Given the previously established role of catecholamines in both placebo effects and stress, we hypothesized that genetic variation in catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, would moderate responses to an intervention intended to alter participants’ mindsets about stress. Participants (N = 107) were exposed to a stress mindset manipulation (videos highlighting either the enhancing or debilitating effects of stress) prior to engaging in a Trier Social Stress task and subsequent cognitive tasks. The associations of the COMT rs4680 polymorphism with the effect of stress mindset video manipulations on cognitive and affective responses were examined. Genetic variation at rs4680 modified the effects of stress mindset on affective and cognitive responses to stress. Individuals homozygous for rs4680 low-activity allele (met/met) were responsive to the stress-is-enhancing mindset manipulation as indicated by greater increases in positive affect, improved cognitive functioning, and happiness bias in response to stress. Conversely, individuals homozygous for the high-activity allele (val/val) were not as responsive to the stress mindset manipulation. These results suggest that responses to stress mindset intervention may vary with COMT genotype. These findings contribute to the understanding of gene by environment interactions for mindset interventions and stress reactivity and therefore warrant further investigations.

Catechol-O-methyltransferase gene polymorphism and vulvar pain in women with vulvodynia

The underlying causes of vulvar pain in women with vulvodynia remain poorly understood. Catechol-O-methyltransferase, an enzyme that metabolizes catecholamines, is a neuromodulator that isinvolved with perception and sensitivity to pain. The catechol-O-methyltransferasegene is polymorphic, and a single nucleotide polymorphism is associated with low activity and heightened pain sensitivity. The variant allele that encodes this polymorphism commonly is called the "L allele" because of its low enzyme activity as opposed to the normal H (high activity) allele. The methionine-containing catechol-O-methyltransferase protein coded by the L allele results in elevated catecholamine levels, reduced inactivation of the dopaminergic and adrenergic systems, and increased sensitivity to pain. This polymorphism not only may decrease the pain threshold in response to acute pain but also may facilitate the development of chronic pain. Therefore, the objective of our study was to assess whether a variation in the catechol-O-methyltransferase genotype is involved in increased pain sensitivity in women with vulvodynia. We conducted a prospective cohort study. Buccal swabs were collected from 167 white women with vulvodynia and 107 control subjects; the DNA was tested for a single nucleotide polymorphism at position 158 (rs4680) in the catechol-O-methyltransferase gene. Women with vulvodynia had a marginally increased, yet not significant, prevalence of the catechol-O-methyltransferase genotype that is associated with high activity of the coded protein: 32.9% in the women with vulvodynia, as opposed to 21.5% in the control subjects (odds ratio, 1.80; 95% confidence interval, 1.02-3.15). Subgrouping the cases based on pain frequency revealed that the elevated occurrence of this catechol-O-methyltransferase genotype was present in 40.6% of the subset of women who experienced pain only with sexual intercourse vs only 21.5% of control subjects (odds ratio, 2.50; 95% confidence interval, 1.27-4.93). Also, women with primary vulvodynia had a significantly higher prevalence of the H allele than did the control subjects (62.9% vs 48.1%; odds ratio, 1.82; 95% confidence interval, 1.05-3.17). Increased pain sensitivity in women with vulvodynia is not due to a genetically determined low catechol-O-methyltransferaseenzyme activity. Other mechanisms may account for alterations in catechol-O-methyltransferase activity in women with pain that is limited to intercourse or primary vulvodynia that contributes to pain sensitivity.

Genetic variation in catechol-O-methyltransferase modifies effects of clonidine treatment in chronic fatigue syndrome.

Clonidine, an α2-adrenergic receptor agonist, decreases circulating norepinephrine and epinephrine, attenuating sympathetic activity. Although catechol-O-methyltransferase (COMT) metabolizes catecholamines, main effectors of sympathetic function, COMT genetic variation effects on clonidine treatment are unknown. Chronic fatigue syndrome (CFS) is hypothesized to result in part from dysregulated sympathetic function. A candidate gene analysis of COMT rs4680 effects on clinical outcomes in the Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL), a randomized double-blinded clonidine versus placebo trial, was conducted (N=104). Patients homozygous for rs4680 high-activity allele randomized to clonidine took 2,500 fewer steps compared to placebo (pinteraction=0.04). There were no differences between clonidine and placebo amongst patients with COMT low-activity alleles. Similar gene-drug interactions were observed for sleep (pint=0.003) and quality of life (pint=0.018). Detrimental effects of clonidine in the subset of CFS patients homozygous for COMT high-activity allele warrant investigation of potential clonidine-COMT interaction effects in other conditions.

The interactive effect of the MAOA-VNTR genotype and childhood abuse on aggressive behaviors in Chinese male adolescents.

Gene-environment interactions that moderate aggressive behavior have been identified in association with the MAOA (monoamine oxidase A) gene. The present study examined the moderating effect of MAOA-VNTR (variable number of tandem repeats) on aggression behavior relating to child abuse among Chinese adolescents. A sample of 507 healthy Chinese male adolescents completed the Child Trauma Questionnaire-Short Form (CTQ-SF) and Youth Self-report of the Child Behavior Checklist. The participants' buccal cells were sampled and subjected to DNA analysis. The effects of childhood abuse (CTQ-SF scores), MAOA-VNTR [high-activity allele (H) versus low-activity allele (L)], and their interaction in aggressive behaviors were analyzed by linear regression. Child maltreatment was found to be a significant independent factor in the manifestation of aggressive behavior, whereas MAOA activity was not. There was a significant interaction between MAOA-VNTR and childhood maltreatment in the exhibition of aggressive behaviors. In the context of physical or emotional abuse, boys in the MAOA-L group showed a greater tendency toward aggression than those in the MAOA-H group. Aggressive behavior arising from childhood maltreatment is moderated by MAOA-VNTR, which may be differentially sensitive to the subtype of childhood maltreatment experienced, among Chinese adolescents.

Longitudinal study of premorbid adjustment in 22q11.2 deletion (velocardiofacial) syndrome and association with psychosis.

Velocardiofacial syndrome, also known as 22q11.2 deletion syndrome (22q11DS), is associated with an increased risk of major psychiatric disorders, including schizophrenia. The emergence of psychotic symptoms in individuals with schizophrenia in the general population is often preceded by a premorbid period of poor or worsening social and/or academic functioning. Our current study evaluated premorbid adjustment (via the Cannon-Spoor Premorbid Adjustment Scale [PAS]) and psychotic symptoms (via the Structured Interview for Prodromal Symptoms and the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version) in youth with 22q11DS (N = 96), unaffected siblings (N = 40), and community controls (N = 50). The PAS scores indicated greater maladjustment during all developmental periods in individuals with 22q11DS compared to the controls. Many participants with 22q11DS had chronically poor (n = 33) or deteriorating (n = 6) PAS scores. In 22q11DS, chronically poor PAS trajectories and poor childhood and early adolescence academic domain and total PAS scores significantly increased the risk of prodromal symptoms or overt psychosis. Taking into account the catechol-O-methyltransferase (COMT) genotype, the best predictor of (prodromal) psychosis was the early adolescence academic domain score, which yielded higher sensitivity and specificity in the subgroup of youth with 22q11DS and the high-activity (valine) allele. PAS scores may help identify individuals at higher risk for psychosis.

Susceptibility to methamphetamine dependence associated with high transcriptional activity alleles of VNTR polymorphism in the promoter region of monoamine oxidase A (MAOA)

Background and purposeMonoamine oxidase A (MAOA, Xp11.3; OMIM: 309850) can modulate the level of neurotransmitters in the central nervous system. A 30bp variable number of tandem repeat (VNTR) genetic polymorphism on the promoter region of the MAOA can modulate the transcriptional activity of the gene. Association between this polymorphism and dependency to methamphetamine was investigated. Subjects and methodsA total of 65 methamphetamine abusers (52 males and 13 females) and 635 healthy controls (525 males and 110 females) were included in the present case–control study. Genotypic analysis for the MAOA VNTR polymorphism was determined by conventional PCR. Based on transcriptional activity of the VNTR alleles, the alleles were categorized into two classes: L allele (2R and 3R alleles) and H allele (3.5R, 4R and 5R alleles), which have low and high transcriptional activities, respectively. ResultsOur data show that the H allele significantly increases the risk of methamphetamine dependence in males (OR=2.03, 95% CI: 1.04–3.67, P=0.037). The H allele seems positively associated with the risk of dependency to methamphetamine among females, but the observed OR did not reach the significance level, probability due to small sample size of the patients. ConclusionThe present study supports the role of the VNTR polymorphism on the promoter region of the MAOA on methamphetamine dependence.

A proposal for an individualized pharmacogenetic-guided isoniazid dosage regimen for patients with tuberculosis

Background/aimIsoniazid (INH) is an essential component of first-line anti-tuberculosis (TB) treatment. However, treatment with INH is complicated by polymorphisms in the expression of the enzyme system primarily responsible for its elimination, N-acetyltransferase 2 (NAT2), and its associated hepatotoxicity. The objective of this study was to develop an individualized INH dosing regimen using a pharmacogenetic-driven model and to apply this regimen in a pilot study.MethodsA total of 206 patients with TB who received anti-TB treatment were included in this prospective study. The 2-hour post-dose concentrations of INH were obtained, and their NAT2 genotype was determined using polymerase chain reaction and sequencing. A multivariate regression analysis that included the variables of age, sex, body weight, and NAT2 genotype was performed to determine the best model for estimating the INH dose that achieves a concentration of 3.0–6.0 mg/L. This dosing algorithm was then used for newly enrolled 53 patients.ResultsSerum concentrations of INH were significantly lower in the rapid-acetylators than in the slow-acetylators (2.55 mg/L vs 6.78 mg/L, median, P<0.001). A multivariate stepwise linear regression analysis revealed that NAT2 and body weight independently affected INH concentrations: INH concentration (mg/L) =13.821–0.1× (body weight, kg) −2.273× (number of high activity alleles of NAT2; 0, 1, 2). In 53 newly enrolled patients, the frequency at which they were within the therapeutic range of 3.0–6.0 mg/L was higher in the model-based treatment group compared to the standard treatment group (80.8% vs 59.3%).ConclusionThe use of individualized pharmacogenetic-guided INH dosage regimens that incorporate NAT2 genotype and body weight may help to ensure achievement of therapeutic concentrations of INH in the TB patients.

DRD4 and SLC6A3 gene polymorphisms are associated with food intake and nutritional status in children in early stages of development

Variants of dopamine system genes such as the DRD4 and the SLC6A3 genes may be involved in food intake regulation because the dopaminergic system influences food reward. We investigated an association of polymorphisms in the DRD4 (exon 3 VNTR) and SLC6A3 (3′UTR VNTR, rs2550948, rs2652511 and rs1048953) genes with food intake and nutritional status in children. This prospective cohort study recruited 359 children at birth. Dietary data and nutritional status were collected at 1 year, 3–4 years, and 7–8 years of age. The polymorphisms were analyzed using polymerase chain reaction based techniques. Food intake and nutritional status were compared among the different SNP genotypes. In the first year of life, DRD4.7R− children showed higher BMI Z-scores (P=.019) than the DRD4.7R+ cohort. At 3–4 years old, DRD4.7R− and SLC6A3.10R/10R children showed a higher intake of palatable foods (P=.024) and a higher waist circumference (P=.017). The rs1048953 SLC6A3 polymorphism was associated with average daily energy intake (P=.003) at 3–4 years and with a waist-to-height ratio of children at 7–8 years (P=.041). Carriers of high dopamine activity alleles of the VNTRs studied in DRD4 and SLC6A3 genes and carriers of T/T genotype of the variant rs1048953 SLC6A3 can present an increased risk for obesity related to overeating because high dopamine activity can increase the perceived incentive value of food reward.

Association study of monoamine oxidase-A gene promoter polymorphism (MAOA-uVNTR) with self-reported anxiety and other psychopathological symptoms in a community sample of early adolescents

The polymorphism upstream of the gene for monoamine oxidase A (MAOA-uVNTR) is reported to be an important enzyme involved in human physiology and behavior. With a sample of 228 early-adolescents from a community sample (143 girls) and adjusting for environmental variables, we examined the influence of MAOA-uVNTR alleles on the scores obtained in the Screen for Childhood Anxiety and Related Emotional Disorders and in the Child Symptom Inventory-4. Our results showed that girls with the high-activity MAOA allele had higher scores for generalized and total anxiety than their low-activity peers, whereas boys with the low-activity allele had higher social phobia scores than boys with the high-activity allele. Results for conduct disorder symptoms did not show a significant relationship between the MAOA alleles and the presence of these symptoms. Our findings support a possible association, depending on gender, between the MAOA-uVNTR polymorphism and psychopathological disorders such as anxiety, which affects high rates of children and adolescents.

0143: Serum thiolactonase activity and paraoxonase gene polymorphism in coronary artery Tunisian patients with or without diabetes

Serum homocysteine thiolactonase activity is closely related to homocysteine and ox-LDL levels in coronary artery disease patients. Homocysteine thiolactonase activities are the result of environmental factors and genetic polymorphisms of paroxosonase. The relevance of gene polymorphism in coronary patients with or without diabetes was investigated in a case-control study. The population included 140 control subjects, 47 coronary artery disease patient without diabetes and 44 patients with type 2 diabetes. Serum thiolactonase activity decreased significantly in coronary artery disease patients: 318.9±156 U/l those without diabetes and 388.8±180 in the diabetic ones compared with the controls: 568.8±250U/l (p<0.001). These activities were associated with increased plasma homocysteine and ox-LDL levels (p<0.001). The paroxonase allele frequency is significantly higher in controls than coronary artery patients (p<0.001). The frequency of R high activity allele was also higher in diabetic coronary patients (11.3%), than in those without diabetes (4.2%). No significant association was found between paroxonase LN gene polymorphisms and diabetes in coronary patients. The difference in allele frequency for the paroxonase R gene polymorphism may be the cause of the high thiolactonase activity observed in coronary patients with type 2 diabetes mellitus. Further studies are needed to be conducted to elucidate the role of the enzyme in the development of vascular complications in these patients.

Natural allelic variations of xenobiotic-metabolizing enzymes affect sexual dimorphism in Oryzias latipes.

Sexual dimorphisms, which are phenotypic differences between males and females, are driven by sexual selection. Interestingly, sexually selected traits show geographical variations within species despite strong directional selective pressures. This paradox has eluded many evolutionary biologists for some time, and several models have been proposed (e.g. 'indicator model' and 'trade-off model'). However, disentangling which of these theories explains empirical patterns remains difficult, because genetic polymorphisms that cause variation in sexual differences are still unknown. In this study, we show that polymorphisms in cytochrome P450 (CYP) 1B1, which encodes a xenobiotic-metabolizing enzyme, are associated with geographical differences in sexual dimorphism in the anal fin morphology of medaka fish (Oryzias latipes). Biochemical assays and genetic cross experiments show that high- and low-activity CYP1B1 alleles enhanced and declined sex differences in anal fin shapes, respectively. Behavioural and phylogenetic analyses suggest maintenance of the high-activity allele by sexual selection, whereas the low-activity allele possibly has experienced positive selection due to by-product effects of CYP1B1 in inferred ancestral populations. The present data can elucidate evolutionary mechanisms behind genetic variations in sexual dimorphism and indicate trade-off interactions between two distinct mechanisms acting on the two alleles with pleiotropic effects of xenobiotic-metabolizing enzymes.