Katherine Jernigan

The Dopamine Receptor D4 Gene (DRD4) Moderates Family Environmental Effects on ADHD

Attention-Deficit/Hyperactivity Disorder (ADHD) is a prime candidate for exploration of gene-by-environment interaction (i.e., G x E), particularly in relation to dopamine system genes, due to strong evidence that dopamine systems are dysregulated in the disorder. Using a G x E design, we examined whether the DRD4 promoter 120-bp tandem repeat polymorphism, previously associated with ADHD, moderated the effects of inconsistent parenting and marital conflict on ADHD or Oppositional-Defiant Disorder (ODD). Participants were 548 children with ADHD and non-ADHD comparison children and their parents. Homozygosity for the DRD4 promoter 120-bp tandem repeat insertion allele increased vulnerability for ADHD and ODD only in the presence of inconsistent parenting and appeared to increase susceptibility to the influence of increased child self-blame for marital conflict on ADHD inattention. DRD4 genotypes may interact with these proximal family environmental risk factors by increasing the individual’s responsivity to environmental contingencies.

Interplay of cytokine polymorphisms and bacterial vaginosis in the etiology of preterm delivery.

Recent findings suggest that the association between inflammation-related genes and preterm delivery may be stronger in the presence of bacterial vaginosis (BV). Tumor necrosis factor-alpha (TNFα) and interleukin 1-beta (IL-1β) are pro-inflammatory cytokines capable of inducing preterm labor in non-human primates. In this study the authors tested associations among two TNFα promoter polymorphisms (-G308A and -G238A), a single IL-1β polymorphism (+C3954T), vaginal microbial findings, and risk of preterm delivery. Data were from the Pregnancy Outcomes and Community Health (POUCH) Study (n=777 term and n=230 preterm deliveries). Vaginal smears collected at mid-pregnancy (15-27 weeks gestation) were scored according to Nugents criteria. A Nugent score of ≥ 4 was modeled as the cut-point for intermediate and positive BV. Logistic regression was used to estimate odds ratios for associations among independent covariates (vaginal flora, genotype) and preterm delivery. Results showed that women with a Nugent score of≥ 4 and the TNFα -238 A/G or A/A were at increased risk of delivering preterm (race/ethnicity adjusted OR 2.6, 95% CI 1.2, 5.8). The p-value for the genotype and Nugent score interaction=0.02. This study points to one more example of a potential gene-environment interaction in a preterm delivery pathway. Future tests of this finding will determine the robustness of these results.

Intestinal microbial communities associated with acute enteric infections and disease recovery.

BackgroundThe intestinal microbiome represents a complex network of microbes that are important for human health and preventing pathogen invasion. Studies that examine differences in intestinal microbial communities across individuals with and without enteric infections are useful for identifying microbes that support or impede intestinal health.Results16S rRNA gene sequencing was conducted on stool DNA from patients with enteric infections (n = 200) and 75 healthy family members to identify differences in intestinal community composition. Stools from 13 patients were also examined post-infection to better understand how intestinal communities recover. Patient communities had lower species richness, evenness, and diversity versus uninfected communities, while principle coordinate analysis demonstrated close clustering of uninfected communities, but not the patient communities, irrespective of age, gender, and race. Differences in community composition between patients and family members were mostly due to variation in the abundance of phyla Proteobacteria, Bacteroidetes, and Firmicutes. Patient communities had significantly more Proteobacteria representing genus Escherichia relative to uninfected communities, which were dominated by Bacteroides. Intestinal communities from patients with bloody diarrhea clustered together in the neighbor-joining phylogeny, while communities from 13 patients’ post-infection had a significant increase in Bacteroidetes and Firmicutes and clustered together with uninfected communities.ConclusionsThese data demonstrate that the intestinal communities in patients with enteric bacterial infections get altered in similar ways. Furthermore, preventing an increase in Escherichia abundance may be an important consideration for future prevention strategies.

Polymorphisms in thrombophilia and renin–angiotensin system pathways, preterm delivery, and evidence of placental hemorrhage

OBJECTIVE The purpose of this study was to analyze functional polymorphisms in candidate genes (methylenetetrahydrofolate reductase [MTHFR]677C>T, MTHFR1298A>C, factor 5 1691G>A [FVL], and angiotensinogen (AGT)-6G>A) in relation to a hypothesized placental hemorrhage pathway to preterm delivery (PTD). STUDY DESIGN We assessed maternal genotypes, pregnancy outcomes, and placental pathologic evidence among 560 white and 399 black women who were recruited at mid trimester into a prospective cohort study (1998-2004). Odds of dominant genotypes were calculated for PTDs with (n = 56) or without (n = 177) evidence of placental hemorrhage (referent = term) with the use of race-stratified polytomous logistic regression models. RESULTS Among white women, FVL GA/AA and AGT(-6) GA/AA were both associated with hemorrhage-related PTDs (odds ratio [OR], 4.8; 95% confidence interval [CI], 1.6-14.2 and OR, 3.8; 95% CI, 1.3-10.5, respectively), but not other PTDs (ORs, 1.2 and 0.9, respectively). FVL GA/AA was associated with placental abruption (OR, 5.8; 95% CI, 1.1-30) among white women. All results were null for MTHFR genotypes. CONCLUSION FVL and AGT variant genotypes were associated specifically with hemorrhage-related PTDs.

Angiotensinogen gene G-6A polymorphism influences idiopathic pulmonary fibrosis disease progression

Angiotensin II is a growth factor that plays a key role in the physiopathology of idiopathic pulmonary fibrosis (IPF). A nucleotide substitution of an adenine instead of a guanine (G-6A) in the proximal promoter region of angiotensinogen (AGT), the precursor of angiotensin II, has been associated with an increased gene transcription rate. In order to investigate whether the G-6A polymorphism of the AGT gene is associated with IPF development, severity and progression, the present study utilised a case–control study design and genotyped G-6A in 219 patients with IPF and 224 control subjects. The distribution of G-6A genotypes and alleles did not significantly differ between cases and controls. The G-6A polymorphism of the AGT gene was not associated with disease severity at diagnosis. The presence of the A allele was strongly associated with increased alveolar arterial oxygen tension difference during follow-up, after controlling for the confounding factors. Higher alveolar arterial oxygen tension changes over time were observed in patients with the AA genotype (0.37±0.7 mmHg (0.049±0.093 kPa) per month) compared to GA genotype (0.12±1 mmHg (0.016±0.133 kPa) per month) and GG genotype (0.2±0.6 mmHg (0.027±0.080 kPa) per month). G-6A polymorphism of the angiotensinogen gene is associated with idiopathic pulmonary fibrosis progression but not with disease predisposition. This polymorphism could have a predictive significance in idiopathic pulmonary fibrosis patients.

Personality Mediation of Genetic Effects on Attention-Deficit/Hyperactivity Disorder.

Personality traits may be viable candidates for mediators of the relationship between genetic risk and ADHD. Participants were 578 children (331 boys; 320 children with ADHD) between the ages of six and 18. Parents and teachers completed a comprehensive, multi-stage diagnostic procedure to assess ADHD and comorbid disorders. Mother completed the California Q-Sort to assess child Big Five personality traits. Children provided buccal samples of DNA which were assayed for selected markers on DRD4, DAT1, and ADRA2A. An additive genetic risk composite was associated with ADHD symptoms and maladaptive personality traits; maladaptive personality traits were associated with ADHD symptoms. Low conscientiousness and high neuroticism partially mediated the relationship between genetic risk and ADHD symptoms. Mediation effects for conscientiousness were specific to inattentive symptoms; effects for neuroticism generalized to all disruptive behaviors. High neuroticism and low conscientiousness may be useful as early markers for children at risk for ADHD.

Innate immune system gene polymorphisms in maternal and child genotype and risk of preterm delivery

Abstract Objective. There is little information about the combination of genetic variability in pregnant women and their children in relation to the risk of preterm delivery (PTD). In a sub-cohort of 487 non-Hispanic white and 288 African-American mother/child pairs, the Pregnancy Outcomes and Community Health Study assessed 10 functional polymorphisms in 9 genes involved in innate immune function. Methods. Race-stratified weighted logistic regression models were used to calculate odds ratios for genotype and PTD/PTD subtypes. Polymorphisms significantly associated with PTD/PTD subtypes were tested for mother/child genotype interactions. Results. Three maternal polymorphisms (IL-1 receptor antagonist intron two repeat (IL-1RN), matrix metalloproteinase- −C1562T, and TNF receptor two M196R (TNFR2)) and three child polymorphisms (IL1-RN, tumor necrosis factor-alpha −G308A, and TNFR2) were associated with PTD, but associations varied by PTD subtype and race. Two interactions were detected for maternal and child genotype. Among non-Hispanic white women, the odds of PTD was higher when both mother and child carried the IL-1RN allele two (additive interaction p < 0.05). Among African-American women, the odds of PTD were higher when both mother and child carried the TNFR2 R allele (multiplicative interaction p < 0.05). Conclusion. These results highlight the importance of assessing both maternal and child genotype in relation to PTD risk.

Life stressors and 5-HTTLPR interaction in relation to midpregnancy depressive symptoms among African-American women

Objective In earlier analyses of nonHispanic White women we found a stronger relation between abuse history and midpregnancy elevated depressive symptoms in women with the serotonin transporter (5-HTTLPR) S/S genotype. Here, we focus on African–American women (N=698). Our inquiry is motivated by racial differences in depression diagnosis/treatment, stressors, and frequency of major 5-HTTLPR alleles (S, LA, LG). Materials and methods Stressful life events (lifetime) and depressive symptoms (current) were ascertained at 15–27 weeks gestation. A Center for Epidemiological Studies Depression Score of more than or equal to 18 was considered ‘elevated’. Life events were scored together and separated into six subconstructs. 5-HTTLPR genotypes were grouped as follows: (i) L and S alleles, (ii) S-LG equivalence (‘triallelic to biallelic’), and (iii) LA/LA, all others, S/S (‘high/intermediate/low’). Odds ratios (OR) for ‘elevated’ depressive symptoms-life events (total and subconstructs) relations were calculated for each genotype grouping. Results The prevalence of ‘elevated’ depressive symptoms did not vary by genotype. The relation between stressful life events and ‘elevated’ depressive symptoms was stronger in S/S compared with LA/LA genotype (interaction P=0.11). Of the six subconstructs, only abuse showed a statistically significant gene–environment interaction. The OR for the abuse-‘elevated’ depressive symptoms association was greater for S/S vs. LA/LA genotype (interaction P=0.03) and in the ‘triallelic to biallelic’ grouping (interaction P=0.04). In the ‘high/intermediate/low’ grouping, ‘low’ (S/S) had a higher OR (5.5) than both ‘intermediate’ and ‘high’ (ORs⩽2.3) (interaction P=0.10). Conclusions These results show the importance of examining racial groups, specific stressful events, and different 5-HTTLPR genotype groupings when exploring gene–environment interactions in depression.

Does 5HTTLPR Genotype Moderate the Association of Family Environment With Child Attention-Deficit Hyperactivity Disorder Symptomatology?

Problematic family dynamics are common among youth with attention-deficit hyperactivity disorder (ADHD). Multiple mechanisms, including diathesis-stress (vulnerability) and differential susceptibility Gene × Environment interaction effects (G × E), have been proposed to account for this association. G × E effects for ADHD were examined via interactions between a genetic marker hypothesized to influence sensitivity to the environment (the promoter polymorphism of the serotonin transporter gene −5HTTLPR) and family conflict and cohesion in predicting ADHD symptoms. There were 498 youth ages 6–17 years (251 ADHD, 213 non-ADHD) and their parents who completed a multistage, multi-informant assessment (including parent and youth reports on the Family Environment Scale), and saliva sample collection for genotyping. Linear regression analyses examined interactions between 5HTTLPR genotype and the Family Environment Scale scales of conflict and cohesion reported by parent and child. Criteria laid out by Roisman et al. (2012) were applied to evaluate diathesis stress versus differential susceptibility G × E mechanisms. Results demonstrated interactions between 5HTTLPR genotype and both conflict and cohesion in predicting inattention but not hyperactivity-impulsivity. Both interactions were highly consistent with differential susceptibility models of G × E effects. 5HTTLPR genotype appeared to moderate the relationship between family conflict/cohesion and inattentive symptoms. Interactions highlight the role of 5HTTLPR genotype as a potential marker of environmental sensitivity and provide support for differential susceptibility models of G × E effects for ADHD.