Infectious diseases, IL6 -174G>C polymorphism, and human development.

Interleukin-6 (IL6) is a pro-inflammatory cytokine that is required for resistance against many pathogens. However, sustained IL6 activity can cause tissue damage in the periphery and brain. Previous studies have shown that populations in disease-endemic regions adapt by selecting the high-producing G-allele at the -174G>C (rs1800795) polymorphism, while others have linked increased IL6 to cognitive impairments. The present study sought to determine whether up-regulation of IL6 by the G-allele at rs1800795 polymorphism in disease-endemic regions was associated with increased cognitive deficits and corollary reductions in social, economic, and political development. We tested these hypotheses in a global sample of 189 nations with World Health Organization ratings for infectious diseases. We also included the Historical Pathogen Prevalence index, a measure of national average intelligence (IQ), and the United Nation Human Development Index (HDI) including per capita income, life expectancy, child mortality, and fertility rate. IL6 -174G>C allele frequencies were obtained from 171,168 individuals spanning 84 nations. The high-producing G-allele frequency was positively correlated with infectious disease ranking (r=0.745, P<0.001) and negatively with IQ (r=-0.524, P<0.001) and HDI (r=-0.671, P<0.001). These robust findings suggest that in regions with a high pathogen burden the need for a strong IL6 response is accompanied by cognitive deficits and reduced HDI ranking.

The gene-immune-behavioral pathway: Gamma-interferon (IFN-γ) simultaneously coordinates susceptibility to infectious disease and harm avoidance behaviors.

Cytokine gene variants are known to influence both infectious disease susceptibility and harm-avoidant behaviors, suggesting that these risk variants may be pleiotropically linked to instinctual disease-avoidant traits. The gamma-interferon (IFNG) +874 T>A polymorphism (rs2430561) is an ideal candidate gene variant for immune-behavioral studies. It is a functional SNP, regulating IFNG mRNA expression; it is known to modulate serotonergic activity and is therefore capable of modifying behavior; and it has previously been associated with increased susceptibility to malaria, tuberculosis, leprosy and Chagas disease. We hypothesized that the infectious disease-high-risk IFNG +874 A-allele would be associated with four personality traits previously reported as behavioral defenses against infection: Harm Avoidance (HA), Extraversion (E), Exploratory Excitability (Exp E), and Openness to Experience (O). We tested this hypothesis in a sample of 168 healthy university students from Southern California genotyped for IFNG +874 T>A and evaluated by the Temperament and Character Inventory-Revised (TCI-R) and the NEO Five-Factor Inventory (NEO-FFI). We found that the infectious disease-high-risk IFNG +874 A-allele was associated with increased HA (P=0.001) and decreased E (P=0.030) and Exp E (P=0.030). These findings suggest that the IFNG +874 A gene variant is linked both to infectious disease susceptibility and to proactive behavioral defenses that reduce infection risk in healthy subjects.

A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes.

We report that a single-nucleotide polymorphism (SNP) in the gene (PTPN22) encoding the lymphoid protein tyrosine phosphatase (LYP), a suppressor of T-cell activation, is associated with type 1 diabetes mellitus (T1D). The variants encoded by the two alleles, 1858C and 1858T, differ in a crucial amino acid residue involved in association of LYP with the negative regulatory kinase Csk. Unlike the variant encoded by the more common allele 1858C, the variant associated with T1D does not bind Csk.

Risk of late-onset Alzheimer's disease associated with BDNF C270T polymorphism.

We examined the frequency of the T allele of the C270T polymorphism of the brain-derived nerve growth factor (BDNF) gene in a test and replication test design. Our objective was to determine if there is an association between the BDNF gene and Alzheimer's Disease (AD) in a US population. There were 106 autopsy-proven AD cases and 101 controls of similar ages in each test for a total of 212 AD cases and 202 controls. We found that there was a significant increase in the T allele in both the initial set (p=.04) and in the replication set (p=.018). For both groups combined p=.0008. Odds ratio=3.28, 95% CI=1.69-6.34. There were 54 cases of early-onset AD (EOAD) and 159 cases of late-onset AD (LOAD). The results were only significant for LOAD, p=.0002, odds ratio=3.81, 95% CI=1.93-7.52. The r2 or fraction of the variance attributed to the BDNF gene for the LOAD cases was .046. The results were independent of the APOE epsilon4 allele. When the younger controls were removed, providing a close age match to the AD subjects, the frequency of the T allele was even lower and the differences were still significant for both total AD and LOAD cases. In a logistic regression analysis including APOE, age, sex and BDNF, BDNF was significant at p<.0001. We concluded that BDNF gene variants are significant risk factors for late onset AD.

Association between the phenylethanolamine N-methyltransferase gene and multiple sclerosis.

Phenylethanolamine N-methyltransferase (PNMT), the terminal enzyme of the catecholamine biosynthesis pathway, catalyzes the conversion of norepinephrine (NE) to epinephrine (EPI). PNMT is a candidate gene for multiple sclerosis (MS) for two reasons. PNMT is known to map to a region identified in two genome screens for MS and it directly regulates the amounts of NE and EPI, both of which play a significant role in the modulation of the innate immune response. The frequencies of two promoter polymorphisms of the PNMT gene showed genetic association in a case-control study of 108 patients with MS and 774 ethnically and age-matched control subjects. In subjects with MS, significant differences in the frequency of the GG genotype at the G-387A marker and the AA genotype at the G-182A marker were observed. Additionally, when both markers were combined and evaluated, highly significant differences between the polymorphism distributions in patients with MS and control subjects were detected. The data suggest that these promoter polymorphisms of the PNMT gene, both independently and cumulatively, show association with MS.

Association of the muscarinic cholinergic 2 receptor (CHRM2) gene with major depression in women.

Cholinergic neurons have been implicated in depression and in the disorders of REM sleep in depression. We examined a common A-> T 1890 polymorphism in the 3' UTR of the cholinergic muscarinic receptor 2 (CHRM2) gene. There was a significant increase in the frequency of 11 homozygotes in 126 women with major depression (43.7%) compared to 304 women without major depression (25.7%), P =.001. There was no increase in the frequency of 11 homozygotes in 52 men with depression (26.9%) compared to 278 men without depression (27.7%). Regression analysis, scoring subjects with the 11 genotype as 1, and those with other genotypes as 0, showed that in women r(2) =.030, F = 13.37, P =.0003. By contrast, in men r(2) =.00001, F = 0.002, P =.96. These results are consistent with a gender-specific role of the CHRM2 gene in depression in women.

Association between the low molecular weight cytosolic acid phosphatase gene ACP1*A and comorbid features of Tourette syndrome.

Protein tyrosine phosphatases have been implicated in the regulation of serotonergic and dopaminergic activity in the central nervous system. In a recent study we found that nonA/nonA homozygosity at the locus codifying for the low molecular weight protein tyrosine phosphatase (ACP1) was associated with increased rates of major depression in males (P<0.00003), suggesting that the ACP1*A single nucleotide polymorphism (SNP) may be an important marker for psychopathology. In the present study we examined the ACP1*A SNP in 539 screened controls and 184 male Tourette syndrome (TS) cases, all Caucasians of European descent. The frequency of the nonA allele was markedly increased in TS cases relative to controls (P<0.0005), but this difference was restricted to cases with comorbid attention-deficit hyperactivity disorder (P<0.0001) and conduct disorder (P<0.0002), while having little relevance to TS itself.

Interaction between infectious diseases and personality traits: ACP1*C as a potential mediator.

In geographical regions characterized by high pathogen prevalence, it has been shown that human populations tend to be characterized by lower levels of extraversion (E) and openness to experience (OtE). According to the "behavioral immune system" hypothesis, the reduction of extraversion and openness levels represents a behavioral defense against infections. Like the 'classical' immune system, the "behavioral immune system" could also be shaped by its underlying genetic background. Previous studies have shown that the *C allele of the ACP1 gene confers increased susceptibility to infectious/parasitic diseases. We hypothesized that carriers of the ACP1*C allele should likewise be associated with reduced E and OtE. We tested this hypothesis using two samples comprised of 153 students from Southern California (Group 1), and 162 female subjects recruited from an executive health program (Group 2), genotyped for ACP1 polymorphism and evaluated by the NEO Five-Factor Inventory (NEO-FFI). ACP1 was significantly associated with E: we found that carriers of ACP1*C showed reduced scores for E (Group 1: ß=-4.263, P=0.027; Group 2: ß=-8.315, P=0.003; Group 1+Group 2: ß=-5.366, P=0.001). Across groups, ACP1 was only marginally associated with OtE. In conclusion, the present study found that the ACP1*C allele, previously associated with an increased vulnerability to infectious/parasitic diseases may also be able to shape behavioral immune defenses by interaction with the level of E.

Modulation of a number of genes on personality traits in a sample of healthy subjects.

A large number of studies investigated the genetic modulation of personality with mixed results. As a confirmatory analysis of previous findings, we firstly examined the association between several previously examined single nucleotide polymorphisms (SNPs) and personality traits in a sample of 158 healthy subjects. As a secondary aim, we tested the potential modulation of additional never previously investigated genes on personality. A blood sample was collected and the Temperament and Character Inventory (TCI) has been administered to all participants. Multivariate analysis of covariance, controlling for sex and age, was used to test SNP influence on TCI scores. Examination of previously studied gene variants showed an effect of adrenergic alpha 2B receptor (ADRA2B) on Cooperativeness and of serotonin receptor HTR2A on Self Directedness. Examination of new variants revealed that sex hormone binding protein (SHBG) was associated with reward dependence. Moreover, several additional variants showed a tendency towards association with some TCI traits, confirming previous results. This study suggests that ADRA2B, HTR2A and SHBG genes may be involved in the modulation of personality in healthy subjects. The major limitation of this study was the small sample size.

GSK3ß genetic variability in patients with Multiple Sclerosis.

Glycogen synthase kinase-3 beta (GSK3ß) is a ubiquitous kinase that is part of multiple signaling pathways. It has neurotrophic/neuroprotective effects by mediating the actions of neurotrophic molecules in the brain, thus providing neuroprotection through modulation of energy metabolism. Notably, it has been demonstrated that GSK3ß is involved in Wnt-beta-catenin signaling, which contributes to the inhibition of myelination and remyelination processes in mammals. Three-hundred nineteen patients with MS and 294 age-matched controls were genotyped by allelic discrimination for four common GSK3ß variants (rs2199503, rs9826659, rs334558 and rs6438552) tagging about 100% of GSK-3ß variability. A statistically significant increased frequency of the rs334558 GG genotype was observed in patients as compared with controls (25.4% versus 17.7%, P=0.02; OR:1.58, 95%CI: 1.07-2.34). Stratifying MS patients according to the disease subtype, a statistically significant difference of rs334558 GG frequency was found between Relapsing Remitting (RR), but not Primary Progressive or Secondary MS, and controls (27.0% versus 17.7%, P=0.01; OR: 1.72, 95%CI: 1.13-2.61). GSK3ß rs334558 is a susceptibility factor for MS. As it is located in the promoter region, a possible explanatory mechanism could be an influence of the variant on the gene transcription rate.

Maternal age at the birth of the first child as an epistatic factor in polygenic disorders.

The identification of the genes for complex, polygenic disorders has proven difficult. This is due to the small effect size of each gene and genetic heterogeneity. An additional important factor could be the presence of unidentified epistatic factors. In the broad definition of epistasis, the effect of one unit is not predicable unless the value of another unit is known and one of the units may not be a gene. We have previously identified maternal age as an epistatic factor for the effect of the LEP gene on the age of onset of menarche. We report here the effect of maternal age and the age of the mother at the birth of her first child (maternal age 1st) as epistatic factors for the interaction of the dopamine D1 gene (DRD1) with obsessive-compulsive behaviors and with stuttering. The epistatic effects of maternal age 1st were stronger than maternal age. This type of epistatic factor may be generalizable to many other gene-trait interactions.

A multigene test for the risk of sporadic breast carcinoma.

BACKGROUND: Although the identification of the BRCA1 and BRCA2 genes have been of great interest, these genes account for less than 5% of all breast carcinoma cases. The remaining cases are sporadic. Reanalysis of a large twin study suggested that genetic factors may play a significant role in sporadic breast and other carcinomas. Sporadic breast carcinoma is polygenically inherited. Multiple genes are likely to have an additive effect, each gene accounting for a fraction of the variance. One factor that may have an impact on the development of hormonally responsive breast tumors is the duration of exposure of the breast to estrogen. Therefore, one of the demographic risk factors for breast carcinoma is an early age of onset of menarche. The current study was based on the hypothesis that genes that play a role in demographic risk factors may be breast carcinoma risk genes in their own right. The authors hypothesized that six genes relevant to the timing of the onset of menarche and related risk factors might be candidate genes for breast carcinoma. These were the leptin gene (LEP), the leptin receptor gene (LEPR), the catechol-0-methyltransferase gene (COMT), the dopamine D(2) receptor gene (DRD2), the estrogen 1 receptor gene (ESR1), and the androgen receptor gene (AR). METHODS: The authors examined 67 women with postmenopausal sporadic breast carcinoma and 145 gender and race-matched controls. RESULTS: Five of these genes accounted for a significant percent of the variance (r(2)) of breast carcinoma. The following r(2) and P values were calculated: LEP: 0.073, P < or = 0.0001; LEPR: 0.064, P < or = 0.0002; COMT: 0.073, P < or = 0.0001; AR: 0.040, P < or = 0.0035; and DRD2: 0.018, P < or = 0.05. When evaluated in a multivariate regression analysis, they accounted collectively for 24% of the variance of breast carcinoma (P < or = 0.0001). These genes accounted for 40% of the variance (P < or = 0.00001) in a subset of age-matched cases. Individual gene scores were added to form a breast carcinoma risk score (BCRS) that ranged from 0 to 17. When the BCRS was evaluated in a receiver operator characteristic plot, the area under the curve was 0.80 for the full set and 0.869 for the age-matched set. The relative breast carcinoma risk for the different BCRS scores ranged from 0.10 to 11.9. CONCLUSIONS: These results demonstrate a potentially powerful method of evaluating the additive effect of multiple breast carcinoma risk genes to form a potentially clinically useful assessment of women's risk for sporadic breast carcinoma.

Association of the acid phosphatase (ACP1) gene with triglyceride levels in obese women.

The acid phosphatase (ACP1) locus codes for a low molecular weight protein tyrosine phosphatase (LMPTP) that is found ubiquitously in human tissues. The *A allele of the ACP1 gene is associated with lower total enzymatic activity than the *B and *C alleles. An association between the *A allele and extreme values of body-mass-index (BMI) and dyslipidemia has previously been described in several samples of obese subjects from the Italian population. In the present study, we investigated the relationship between ACP1 *A allele genotypes (*A/*A, *A/*B, and *A/*C) and non-*A allele genotypes (*B/*B, *B/*C, and *C/*C) and metabolic variables in 277 Caucasian post-menopausal subjects consisting of 82 non-obese subjects (BMI/=35) subjects. ACP1 genotypes were found to be significantly associated with total cholesterol (p

Parent-daughter transmission of the androgen receptor gene as an explanation of the effect of father absence on age of menarche.

Based on an evolutionary theory of socialization, Belsky and colleagues proposed that girls exposed to a stressful environment, especially when due to father absence in the first 7 years of life, showed an early onset of puberty, precocious sexuality, and unstable relationships as adults. The authors of this article examined an alternative explanation that a variant X-linked androgen receptor (AR) gene, predisposing the father to behaviors that include family abandonment, may be passed to their daughters causing early puberty, precocious sexuality, and behavior problems. The results of a study of 121 White males and 164 White females showed a significant association of the short alleles of the GGC repeat polymorphism of the AR gene with a range of measures of aggression and impulsivity, increased number of sexual partners, sexual compulsivity, and lifetime number of sex partners in males; and paternal divorce, father absence, and early age of menarche in females. These findings support a genetic explanation of the Belsky psychosocial evolutionary hypothesis regarding the association of fathers' absence and parental stress with early age of onset of menarche and early sexual activity in their daughters. A genetic explanation of the father absence effect is proposed in which fathers carrying the AR alleles are more likely to abandon a marriage (father absence) and pass those alleles to their daughters in whom they produce an earlier age of menarche and behavioral problems.

Association of CCR5 delta32 deletion with early death in multiple sclerosis.

PURPOSE: The interaction between chemokines and their receptors is extremely important in controlling T cell migration into sites of CNS inflammation. Because trafficking of inflammatory T cells into the central nervous system (CNS) is a key player in the pathogenesis of multiple sclerosis (MS), we investigated the possible association of CCR5 delta32 deletion in this disorder. METHODS: DNA isolated from postmortem brain tissue samples of 132 patients with MS and from blood tissue samples of 163 gender and ethnicity-matched healthy controls was used to screen for the CCR5 delta32 deletion allele. RESULTS: An increased frequency of 32-bp deletion allele was found to be associated with early death (P = 0.00005) and with a progressive reduction in the years of survival (onset to death). The death hazard ratio of CCR5 with deletion versus no deletion was 2.12, suggesting that MS patients with the 32-bp deletion have twice the mortality rate of patients with the normal genotype. This effect was more significant in females (hazard ratio 3.58). CONCLUSION: A strong association of the CCR5delta32 deletion with early death could serve as a prognostic marker for MS.

RANTES: a genetic risk marker for multiple sclerosis.

UNLABELLED: Regulated upon activation, normal T-cell expressed and secreted (RANTES) is a beta-chemokine and has been detected in brain lesions of multiple sclerosis (MS) patients. Considering its potential role in MS, we screened two functional polymorphisms in the proximal promoter region of the RANTES in MS patients versus controls. METHODS: We examined 140 postmortem brain samples from subjects with a primary diagnosis of MS, and peripheral blood samples from 216 control subjects. The RANTES-28C/G and -403G/A promoter polymorphisms were examined. All subjects were non-Hispanic Caucasians. RESULTS: MS cases differed from controls showing a significant association with the 403G/A polymorphism (odds ratio, 2.359, [1.465-3.799]; P=0.0001), but not the -28C/G (P=NS) polymorphism. There was a significant association of the -28G allele with both early onset (P=0.031) and longer survival (P=0.006). CONCLUSION: There is a significant but complex association of the RANTES gene with MS.