Insights into the multifactorial causation of obesity by integrated genetic and epigenetic analysis

Obesity is a highly heritable multifactorial disease that places an enormous burden on human health. Its increasing prevalence and the concomitant‐reduced life expectancy has intensified the search for new analytical methods that can reduce the knowledge gap between genetic susceptibility and functional consequences of the disease pathology. Although the influence of genetics and epigenetics has been studied independently in the past, there is increasing evidence that genetic variants interact with environmental factors through epigenetic regulation. This suggests that a combined analysis of genetic and epigenetic variation may be more effective in characterizing the obesity phenotype. To date, limited genome‐wide integrative analyses have been performed. In this review, we provide an overview of the latest findings, advantages, and challenges and discuss future perspectives.     

ZmCCT and the genetic basis of day-length adaptation underlying the postdomestication spread of maize

Teosinte, the progenitor of maize, is restricted to tropical environments in Mexico and Central America. The pre-Columbian spread of maize from its center of origin in tropical Southern Mexico to the higher latitudes of the Americas required postdomestication selection for adaptation to longer day lengths. Flowering time of teosinte and tropical maize is delayed under long day lengths, whereas temperate maize evolved a reduced sensitivity to photoperiod. We measured flowering time of the maize nested association and diverse association mapping panels in the field under both short and long day lengths, and of a maize-teosinte mapping population under long day lengths. Flowering time in maize is a complex trait affected by many genes and the environment. Photoperiod response is one component of flowering time involving a subset of flowering time genes whose effects are strongly influenced by day length. Genome-wide association and targeted high-resolution linkage mapping identified ZmCCT, a homologue of the rice photoperiod response regulator Ghd7, as the most important gene affecting photoperiod response in maize. Under long day lengths ZmCCT alleles from diverse teosintes are consistently expressed at higher levels and confer later flowering than temperate maize alleles. Many maize inbred lines, including some adapted to tropical regions, carry ZmCCT alleles with no sensitivity to day length. Indigenous farmers of the Americas were remarkably successful at selecting on genetic variation at key genes affecting the photoperiod response to create maize varieties adapted to vastly diverse environments despite the hindrance of the geographic axis of the Americas and the complex genetic control of flowering time.     

Hazardous alcohol consumption and alcohol-related problems are associated with unknown and HIV-positive status in fishing communities in Uganda

In Uganda, alcohol consumption is associated with higher HIV prevalence. However, research is needed to better understand how different patterns of alcohol consumption and alcohol-related problems may drive this association. In this cross-sectional study, we examined how hazardous alcohol use and alcohol-related problems such as psychological, physical, and social harms are associated with HIV status in fishing communities in Uganda. 300 (132 male, 168 female) residents of fishing communities in Uganda (75 participants from each of the following occupational groups: fishmongers, alcohol sellers, commercial sex workers (CSW), and fishermen) completed an interviewer-assisted computerized interview. We captured information on sociodemographics and HIV testing history. Prior 12-month hazardous alcohol consumption patterns and alcohol-related problems were assessed with the AUDIT and AUDADIS. 19.7%, 58.0%, and 23.3% of the sample reported being HIV positive, being HIV negative from a test within the prior 12 months, and not knowing their HIV status respectively. 18.7% reported the co-occurrence of hazardous alcohol consumption patterns and alcohol-related problems. 7.7% reported either hazardous alcohol consumption patterns or alcohol-related problems. Compared to non-drinkers, those with co-occurring hazardous consumption and alcohol-related problems had greater odds of being HIV positive (adjOR 2.75, 95% CI 1.17–6.43) and of unknown HIV status (adjOR 3.35, 95% CI 1.52–7.42). Reporting only hazardous consumption levels, only alcohol-related problems, or low-risk drinking, did not increase the odds of being HIV positive or of unknown status. Among those not HIV positive, those with co-occurring hazardous consumption and alcohol-related problems had greater odds of never having had an HIV test (adjOR 3.78, 95% CI 1.63–8.68). The co-occurrence of hazardous alcohol use and alcohol related problems appears to be a prominent risk factor for HIV infection, not knowing one's HIV status, and never testing for HIV in this setting.     

Not all non-drinkers with HIV are equal: demographic and clinical comparisons among current non-drinkers with and without a history of prior alcohol use disorders*

Studies of persons living with HIV (PLWH) have compared current non-drinkers to at-risk drinkers without differentiating whether current non-drinkers had a prior alcohol use disorder (AUD). The purpose of this study was to compare current non-drinkers with and without a prior AUD on demographic and clinical characteristics to understand the impact of combining them. We included data from six sites across the US from 1/2013 to 3/2015. Patients completed tablet-based clinical assessments at routine clinic appointments using the most recent assessment. Current non-drinkers were identified by AUDIT-C scores of 0. We identified a prior probable AUD by a prior AUD diagnosis in the electronic medical record (EMR) or a report of attendance at alcohol treatment in the clinical assessment. We used multivariate logistic regression to examine factors associated with prior AUD. Among 2235 PLWH who were current non-drinkers, 36% had a prior AUD with more patients with an AUD identified by the clinical assessment than the EMR. Higher proportions with a prior AUD were male, depressed, and reported current drug use compared to non-drinkers without a prior AUD. Former cocaine/crack (70% vs. 25%), methamphetamine/crystal (49% vs. 16%), and opioid/heroin use (35% vs. 7%) were more commonly reported by those with a prior AUD. In adjusted analyses, male sex, past methamphetamine/crystal use, past marijuana use, past opioid/heroin use, past and current cocaine/crack use, and cigarette use were associated with a prior AUD. In conclusion, this study found that among non-drinking PLWH in routine clinical care, 36% had a prior AUD. We found key differences between those with and without prior AUD in demographic and clinical characteristics, including drug use and depression. These results suggest that non-drinkers are heterogeneous and need further differentiation in studies and that prior alcohol misuse (including alcohol treatment) should be included in behavioural health assessments as part of clinical care.     

Lifetime alcohol intake and pattern of alcohol consumption in patients with alcohol-induced pancreatitis in comparison with patients with alcohol use disorder

Objective: To examine lifetime drinking patterns in men and women with alcohol-induced pancreatitis (AIP) in comparison with patients with alcoholic use disorder (AUD) without pancreatic disease.

Methods: Alcohol consumption patterns were assessed using a validated questionnaire, the Lifetime Drinking History (LDH), during an outpatient visit. Patients diagnosed with AIP were matched for gender and age (+/? 5 years) with patients with AUD in addiction treatment.

Results: A total of 45 patients with AIP (35 males, 10 females) and 45 AUD patients were included. Alcohol consumption patterns were not significantly different between males and females with AIP and those with history of acute AIP and chronic pancreatitis (CP). Alcohol consumption patterns of AIP and AUD patients were similar in terms of onset age and duration of alcohol consumption, lifetime alcohol intake and drinks per drinking day. A higher proportion of binge drinking was found among patients with AUD than those with AIP (median 1.00 vs. 0.94, p?=?.01). Males with AUD had lower onset age (15 vs. 16 years, p?=?.03), higher total amount of spirits (35520 vs. 10450 drinks, p?=?.04) and higher proportion of binge drinking (1.00 vs. 0.97, p?=?.01) than males with AIP, whereas females with AIP and AUD had similar drinking patterns.

Conclusions: Alcohol drinking patterns and lifetime drinking history was similar in patients with AIP and patients with AUD. Males with AIP had lower total amount of spirits and lower proportion of binge drinking than those with AUD, suggesting the idiosyncratic etiology of AIP.     

Physician awareness of alcohol use disorders among older patients

OBJECTIVES: To determine primary care physicians’ awareness of, and screening practices for, alcohol use disorders (AUDs) among older patients. DESIGN: Cross-sectional telephone survey of a national sample of primary care physicians. PARTICIPANTS: Physicians randomly sampled from the Masterfile database of the American Medical Association and stratified by specialty as family practice physicians, internal medicine physicians, and either family practice or internal medicine physicians with geriatric certification. MAIN RESULTS: A total of 171 physicians were contacted: 155 (91%) agreed to participate, and responses were analyzed from 150 (50 family practice, 50 internal medicine, 50 with geriatric certification). The median prevalence estimate of AUDs among older patients was 5% for each group of physicians. In contrast to published prevalence rates of AUDs ranging from 5% to 23%, 38% of physicians reported prevalence estimates of less than 5%, and 5% cited estimates of at least 25%. Compared with the other groups, the physicians with geriatric certification were more likely to report no regular screening (42% vs 20% for family practice vs 18% for internal medicine, p=.01), while younger (<40 years) and middle-aged physicians (40–55 years) reported higher annual screening rates relative to older physicians (>55 years) (77% vs 60% vs 44% respectively, p=.03). Among physicians who regularly screened (n=110), 100% asked quantity-frequency questions, 39% also used the CAGE questions, and 15% also cited use of biochemical markers. CONCLUSIONS: Primary care physicians may “underdetect” AUDs among older patients. The development of age-specific screening methods and physician education may facilitate detection of older patients with (or at risk for) these disorders.     

Timing of first alcohol use and alcohol dependence: evidence of common genetic influences

Aims   To estimate the magnitude of genetic and environmental influences on timing of first alcohol use and alcohol dependence (AD) and to quantify the overlap in these influences across the two alcohol-related outcomes.
Participants    The sample consisted of 5382 twins (2691 complete pairs), aged 24–36 years, from the Australian Twin Registry.
Measurements   History of alcohol use and DSM-IV alcohol dependence were assessed by structured telephone interview.
Findings   In both sexes, the relationship between age at first alcohol use and risk for AD followed a linear trend, such that the highest rates of AD were observed in individuals who began drinking at an earlier than average age (14 years or younger). Heritability estimates for timing of first alcohol use and AD were 36% and 53%, respectively. Shared environmental factors accounted for 15% of variance in initiation. There was no evidence of shared environmental influences on AD. The genetic correlation between timing of first alcohol use and AD was 0.59.
Conclusions   Findings highlight the substantial role of genetics in the development of AD and the early manifestation of that genetic risk in the timing of alcohol use initiation which, unlike AD, is also influenced to a modest degree by shared environmental factors. The considerable overlap in heritable influences—and the virtual absence of overlap in individual-specific environmental influences—on initiation of alcohol use and AD indicates that the association between age at first drink and AD is attributable in large part to common genetic sources of variance.     

The clinical course of alcohol dependence associated with a low level of response to alcohol

Aims . To evaluate the clinical course of specific alcohol-related life problems and the risk for dependence on illicit drugs in individuals with relatively low and high levels of response (LR) to alcohol earlier in life. Subjects . From among 439 men who were part of the 15-year follow-up of sons of alcoholics and controls, 108 were identified as having fulfilled criteria for DSM-III-R alcohol dependence. Measures . The LR to alcohol was originally evaluated following the consumption of 0.61 g/kg of ethanol at age 20 by determining the levels of change in subjective feelings of intoxication, body sway and several hormones such as cortisol. From the 453 original subjects, 450 completed a face-to-face 10-year follow-up evaluation, and 439 completed the 15-year protocol. Findings . A comparison of the clinical course of 50 alcohol-dependent men with clearly low LR values at age 20 with that for 42 individuals whose LR scores were above the median revealed few differences. Those with a low LR had a slightly earlier age of onset of alcohol dependence (24.8 ± 3.41 vs. 26.6 ± 4.48 years), and this finding was unrelated to the presence of an alcohol-dependent father. Otherwise the members of the two groups demonstrated a similar course of alcohol dependence. There was no relationship between a low LR at age 20 and either the pattern of substances used or the rate of dependence on illicit drugs. Conclusions . The results indicate that for this sample a low LR to alcohol, while associated with a high risk for alcohol dependence, was not related to most aspects of the course of alcohol problems once dependence developed.     

Genes regulating levels of ω-3 long-chain polyunsaturated fatty acids are associated with alcohol use disorder and consumption,and broader externalizing behavior in humans

Background

Individual variation in the physiological response to alcohol is predictive of an individual's likelihood to develop alcohol use disorder (AUD). Evidence from diverse model organisms indicates that the levels of long-chain polyunsaturated omega-3 fatty acids (ω-3 LC-PUFAs) can modulate the behavioral response to ethanol and therefore may impact the propensity to develop AUD. While most ω-3 LC-PUFAs come from diet, humans can produce these fatty acids from shorter chain precursors through a series of enzymatic steps. Natural variation in the genes encoding these enzymes has been shown to affect ω-3 LC-PUFA levels. We hypothesized that variation in these genes could contribute to the susceptibility to develop AUD.

Methods

We identified nine genes (FADS1, FADS2, FADS3, ELOVL2, GCKR, ELOVL1, ACOX1, APOE, and PPARA) that are required to generate ω-3 LC-PUFAs and/or have been shown or predicted to affect ω-3 LC-PUFA levels. Using both set-based and gene-based analyses we examined their association with AUD and two AUD-related phenotypes, alcohol consumption, and an externalizing phenotype.

Results

We found that the set of nine genes is associated with all three phenotypes. When examined individually, GCKR, FADS2, and ACOX1 showed significant association signals with alcohol consumption. GCKR was significantly associated with AUD. ELOVL1 and APOE were associated with externalizing.

Conclusions

Taken together with observations that dietary ω-3 LC-PUFAs can affect ethanol-related phenotypes, this work suggests that these fatty acids provide a link between the environmental and genetic influences on the risk of developing AUD.

     

Prevalence of alcohol use disorders and associated factors: a population-based study using AUDIT in southern Brazil

Aims   To assess the prevalence of potential alcohol use disorders and associated factors using the Alcohol Use Disorders Identification Test (AUDIT).
Design   Cross-sectional study.
Setting   A town in southern Brazil.
Participants   A representative sample of 1260 people aged 15 and over.
Measurements   Demographic, socioeconomic, smoking habit and mental health data were collected. Logistic regression was used in the multivariate analysis, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated.
Findings   Overall prevalence of alcohol use disorder was 7.9%, with 14.5% prevalence among men and 2.4% among women. The risk of alcohol misuse increased across social class ( P linear trend = 0.03) and compared with the highest classes (A and B), groups C through E had ORs of 1.48, 1.51 and 2.36, respectively. Males had an OR of 6.89 (CI 3.61–13.16) compared with women. A linear trend was found ( P  = 0.001) between smoking categories, and smokers (OR 3.27; CI 1.91–5.58) and ex-smokers (OR 1.30; CI 0.56–2.98) were at higher risk than non-smokers. Those with minor psychiatric disorders had a 2.48 OR (CI 1.35–4.56) of presenting a positive test.
Conclusions   The AUDIT detected a high prevalence of potential alcohol use disorders in the population sampled. Those identified are potential targets for preventive measures implemented through health policies.