Low Genetic Susceptibility Research Articles

Effect of air pollution, genetic susceptibility on the risk of all-cause mortality and cardiovascular outcomes among atrial fibrillation patients

Objective: To analyze the association between air pollution, genetic susceptibility, and the risk of all-cause mortality and cardiovascular outcomes in patients with atrial fibrillation (AF). Methods: AF patients aged between 40-69 years old registered in the United Kingdom Biobank from 2006 to 2010 were included. After excluding those lost to follow-up or with incomplete data during follow-up, 5 814 subjects were analyzed. Long-term exposure to air pollution was estimated at the geocoded residential address of each participant. Genetic risk scores for all-cause mortality, cardiovascular disease, heart failure, myocardial infarction, and stroke were constructed separately for each object to assess the corresponding genetic susceptibility. The Cox proportional hazards model was used to analyze the association between air pollution, genetic susceptibility, and the risk of all-cause mortality and cardiovascular outcomes in AF patients. Results: During a median follow-up of 12.4 years, there were 929 of all-cause mortality (15.98%) and 1 772 of cardiovascular events (30.48%). Multivariable-adjusted analyses revealed that higher exposure to PM2.5, PM10, NOx, and NO2 was associated with an increased risk of cardiovascular disease mortality, heart failure, myocardial infarction, and stroke, with hazard ratios (HRs) ranging from 1.26 to 1.48. Specifically, for each interquartile range (IQR) increase in PM2.5 exposure, the HRs for the outcomes mentioned above were 1.33 (95%CI: 1.14-1.54), 1.42 (95%CI: 1.31-1.54), 1.46 (95%CI: 1.30-1.64), and 1.43 (95%CI: 1.27-1.61), respectively. Both NOx and NO2 exposures were associated with a 9% increased risk of all-cause mortality per IQR increment, with corresponding HRs of 1.09 (95%CI: 1.02-1.17) and 1.09 (95%CI: 1.01-1.17), respectively. Individuals with high genetic susceptibility to AF had a higher risk of myocardial infarction and stroke compared to those with low genetic susceptibility, with corresponding HRs of 1.39 (95%CI: 1.04-1.87) and 1.46 (95%CI: 1.09-1.95), respectively. Compared to AF patients with low air pollution exposure, those with high air pollution exposure have adjusted population attributable fractions of up to 33.57% (95%CI: 17.87%-46.26%) for cardiovascular mortality, 28.61% (95%CI: 20.67%-35.75%) for heart failure, 33.35% (95%CI: 20.97%-43.79%) for myocardial infarction, and 42.29% (95%CI: 30.05%-52.71%) for stroke. Furthermore, there was an additive interaction between PM2.5, NOx, and NO2 exposure and high genetic susceptibility on the incidence of myocardial infarction. An additive interaction was also observed between NOx, NO2 exposure, and high genetic susceptibility on the incidence of heart failure (all P<0.05). Conclusions: Both air pollution and genetic susceptibility increase the risk of all-cause mortality and cardiovascular outcomes in AF patients.

8393 Low Polygenic Risk Score For Autoimmune Addison’s Disease Identifies Misdiagnosed Cases of Monogenic Primary Adrenal Insufficiency

Abstract Disclosure: M. Aranda Guillen: None. I. Botusan: None. V. Fernando: None. E. Røyrvik: None. A. Bøe Wolff: None. S. Johansson: None. E.S. Husebye: None. S. Bensing: None. O. Kampe: None. D. Eriksson: None. Background: Primary adrenal insufficiency (PAI) is sometimes misdiagnosed as autoimmune Addison's disease (AAD), affecting clinical management and genetic counselling. We tested a polygenic risk score (PRS) for AAD (PRS14AAD) as a tool to reevaluate disease etiology and identify patients misdiagnosed with AAD. Methods: We calculated the PRS14AAD in a cohort of patients diagnosed with AAD but lacking 21-hydroxylase autoantibodies (n=124). Patients with low genetic susceptibility to AAD were selected for whole-genome sequencing to detect potential monogenic causes (n=35). Results: Among the 35 patients, monogenic PAI was diagnosed in 5 (14%) and suspected in 3 additional cases (9%). Three out of the 5 patients diagnosed with monogenic PAI developed the disease in adulthood, indicating late-onset monogenic disease associated with hypomorphic genetic variants. Conclusion: A PRS for AAD can help identify potential monogenic cases, regardless of the age at diagnosis. Early identification of the underlying cause of PAI enables accurate management and correct genetic counselling. Presentation: 6/2/2024

Air pollutants, genetic susceptibility, and incident schizophrenia in later life: A prospective study in the UK Biobank

ObjectiveAir pollution has been linked to multiple psychiatric disorders, but little is known on its long-term association with schizophrenia. The interaction between air pollution and genetic susceptibility on incident schizophrenia has never been reported. We aimed to explore the associations between long-term air pollution exposure and late-onset schizophrenia and evaluate whether genetic susceptibility could modify the association. MethodsThis population-based prospective cohort study included 437,802 middle-aged and elderly individuals free of schizophrenia at baseline in the UK Biobank. Land use regression models were applied in the estimation of the annual average concentrations of nitrogen dioxide (NO2), nitrogen oxides (NOx), fine particulate matter (PM2.5), and inhalable particulate matter (PM10) at residence. The associations between air pollutants and schizophrenia were evaluated by using Cox proportional hazard models. A polygenic risk score of schizophrenia was constructed for exploring potential interaction of air pollutants with genetic susceptibility. ResultsAn interquartile range increase in PM2.5, PM10, NO2, and NOx was associated with the hazard ratios (HR) for incident schizophrenia at 1.19, 1.16, 1.22, and 1.09, respectively. The exposure-response curves for the association of air pollution with incident schizophrenia were approximately linear. There are additive interactions of air pollution score (APS), PM10, NO2, and NOx with genetic risk. Specifically, compared with participants with low genetic susceptibility and low APS, the HR was 3.23 for individuals with high genetic risk and high APS, among which 0.49 excess risk could be attributed to the additive interaction, accounting for 15 % of the schizophrenia risk. ConclusionThis large-scale, prospective cohort study conveys the first-hand evidence that long-term air pollution exposure could elevate schizophrenia incidence in later life, especially for individuals with higher genetic risks. The findings highlight the importance of improving air quality for preventing the late-onset schizophrenia in an aging era, especially among those with high genetic risks.

Joint Exposure to Multiple Air Pollutants, Genetic Susceptibility, and Incident Dementia: A Prospective Analysis in the UK Biobank Cohort.

Objectives: This study aimed to evaluate the joint effects of multiple air pollutants including PM2.5, PM10, NO2, and NOx with dementia and examined the modifying effects of genetic susceptibility. Methods: This study included 220,963 UK Biobank participants without dementia at baseline. Weighted air pollution score reflecting the joint exposure to multiple air pollutants were constructed by cross-validation analyses, and inverse-variance weighted meta-analyses were performed to create a pooled effect. The modifying effect of genetic susceptibility on air pollution score was assessed by genetic risk score and APOE ε4 genotype. Results: The HR (95% CI) of dementia for per interquartile range increase of air pollution score was 1.13 (1.07∼1.18). Compared with the lowest quartile (Q1) of air pollution score, the HR (95% CI) of Q4 was 1.26 (1.13∼1.40) (P trend = 2.17 × 10-5). Participants with high air pollution score and high genetic susceptibility had higher risk of dementia compared to those with low air pollution score and low genetic susceptibility. Conclusion: Our study provides evidence that joint exposure to multiple air pollutants substantially increases the risk of dementia, especially among individuals with high genetic susceptibility.

The association between blue light exposure and incidence of type 2 diabetes: A prospective study of UK biobank

BackgroundType 2 diabetes (T2D) is the most common type of diabetes. However, research on the relationship between blue light exposure and diabetes development is limited. ObjectiveThe present study aimed to investigate the relationship between blue light exposure and T2D incidence and whether it is affected by sleep duration, physical activity, outdoor activity time, and genetic susceptibility. MethodsA total of 471,686 participants without diabetes were recruited from the UK Biobank cohort. T2D incidence was assessed using hospital inpatient records. Blue light exposure was calculated based on the time spent watching TV, using a computer, and playing computer games, which was determined using an online questionnaire. Cox proportional hazards regression models were used to assess the survival relationship between blue light exposure and T2D, as well as the potential modification effects. ResultA total of 18,738 cases of T2D were documented during the median follow-up of 13.04 years. After adjusting for potential confounders, the participants with heavy blue light exposure had a greater risk of T2D compared to those with mild blue light exposure (hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.12–1.23). A significant association between blue light exposure and T2D risk was observed among the participants with heavy physical activity (HR = 1.39, 95%CI: 1.25–1.55), healthy sleep habits (HR = 1.23, 95%CI: 1.10–1.36), higher outdoor activity time (HR = 1.14, 95%CI: 1.07–1.22), or high genetic susceptibility (HR = 1.24, 95%CI: 1.14–1.35). However, this association became non-significant among the participants with low genetic susceptibility (HR = 1.05, 95%CI: 0.97–1.15). ConclusionThe present study showed that blue light exposure is associated with a greater risk of T2D independent of classical T2D risk factors.

#6737 ESTIMATED GLOMERULAR FILTRATION RATE BY FIVE DIFFERING MEASURES, RACE, GENETIC RISK AND PREDICTION OF CARDIOVASCULAR DISEASE AND MORTALITY

Abstract Background and Aims Estimated glomerular filtration rate (eGFR), a significant measurement of chronic kidney disease (CKD), is associated with adverse health outcomes in the general population but whether its utility differs by race and genetic risk remains unclear. The current study aims to investigate the performance of CKD staging and risk prediction in cardiovascular disease and mortality based on five eGFR measures among people of different ethnic groups and genetic background. Method In this prospective cohort study, we included 431,126 participants from the UK Biobank, deriving hazard ratios and 95% confidence intervals from multivariable adjusted Cox proportional hazards models. C statistic and net reclassification improvement (NRI) were utilized for comparing the predictive benefit of eGFR measures when added to the traditional cardiovascular risk factors. Results Over a median of 13.4 (IQR 12.7-14.9) years of follow-up, 27,757 (6.4%) participants died from any cause, of which 3272 (0.8%) died primarily from CVD. 39,522 (9.2%) incident composite CVD hospitalization and 911 (0.2%) ESRD occurred. Two new eGFR equations refitted without race provided lower estimates in Black population but higher in other ethnic backgrounds than the corresponding old ones. The relative risk of adverse outcomes was generally greater in Blacks and participants with low genetic susceptibility to impaired kidney function. The superiority of cystatin C-based eGFR measures in risk prediction did not differ by race and genetic risk. Conclusion Eliminating the use of racial categories in eGFR calculation help enhance the access to specialist care and intervention at the early stage of CKD for Black population. Cystatin C-based eGFR measures can be extensively used in risk assessment in clinical practice.

Secondhand smoke, genetic susceptibility, and incident chronic kidney disease in never smokers: A prospective study of a selected population from the UK Biobank.

A large number of people around the world are exposed to the risks of passive smoking. This prospective study aimed to examine the association between secondhand smoke exposure, exposure time, and the incidence of chronic kidney disease (CKD) and determine whether this association was influenced by genetic susceptibility. The study included 214244 participants of the UK Biobank who were initially free of CKD. Cox proportional hazards model was used to estimate the associations between secondhand smoke exposure time and the risks of CKD in people who have never smoked. The genetic risk score for CKD was calculated by a weighted method. The likelihood ratio test comparing models was used to examine the cross-product term between secondhand smoke exposure and genetic susceptibility to CKD outcomes. During a median of 11.9 years of follow-up, 6583 incidents of CKD were documented. Secondhand smoke exposure increased the risk of CKD (HR=1.09; 95% CI: 1.03-1.16, p<0.01), and a dose-response relationship between CKD prevalence and secondhand smoke exposure time was found (p for trend<0.01). Secondhand smoke exposure increases the risk of CKD even in people who never smoke and have a low genetic risk (HR=1.13; 95% CI: 1.02-1.26, p=0.02). There was no statistically significant interaction between secondhand smoke exposure and genetic susceptibility to CKD (p for interaction=0.80). Secondhand smoke exposure is associated with higher risk of CKD, even in people with low genetic risk, and the relationship is dose dependent. These findings change the belief that people with low genetic susceptibility and without direct participation in smoking activities are not prone to CKD, emphasizing the need to avoid the harm of secondhand smoke in public places.

Cardiorespiratory fitness, genetic susceptibility, inflammation and risk of incident type 2 diabetes: A population-based longitudinal study

ObjectiveTo examine whether the association between cardiorespiratory fitness (CRF) and type 2 diabetes (T2D) is modified by genetic susceptibility and inflammation. ParticipantsThe prospective study included 57,185 participants (40–70 years) who were free from T2D and received the CRF assessment at enrollment (2006–2010) in the UK biobank. CRF was examined through a submaximal cycle ergometer test and expressed in metabolic equivalent of tasks (METs), genetic susceptibility was quantified using a genetic risk score, and inflammation was assessed according to the concentration of C-reactive protein. All these three factors were categorized into tertiles. ResultsDuring a median follow-up of 10.4 years, 5477 (7.0%) cases of T2D were ascertained. CRF was inversely associated with the risk of T2D in a dose-response manner. The hazard ratio (HR) was 0.85 (95% confidence interval [CI]: 0.79–0.92) per 1 MET increment of CRF. There was a significant interaction between CRF and genetic susceptibility to T2D in relation to the risk of T2D (P for interaction = 0.03). Compared with participants with high CRF and low genetic susceptibility, the HR was 4.98 (95% CI: 3.17–7.82) for those with low CRF and high genetic susceptibility. A similar pattern was observed in participants with low CRF and high inflammation compared with those who had high CRF and low inflammation (HR = 2.53; 95% CI: 1.83–3.48), though the interaction between CRF and inflammation did not reach statistical significance. T2D risk declined progressively with increased CRF among different inflammation categories. ConclusionOur study reveals that genetic susceptibility may modify the association between CRF and T2D, highlighting that risk of T2D associated with genetics could benefit most from interventions on improving CRF.

A study looking at UV exposure and genetic risks in relation to melanoma

British Journal of DermatologyVolume 183, Issue 2 p. e39-e39 Plain Language Summary Free Access A study looking at UV exposure and genetic risks in relation to melanoma First published: 02 August 2020 https://doi.org/10.1111/bjd.19273 AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat Abstract Melanomas are common cancers among people of European ancestry, accounting for 1·6% of all new cancer cases and 0·6% of all cancer deaths worldwide in 2018. The only environmental factor consistently implicated as a cause of melanoma is ultraviolet (UV) radiation, but the relationship is complex, and little is known about how genetic factors influence the association between UV and melanoma. The effects of UV exposure are affected by ‘host factors’ (meaning factors that are specific to the individual, such as their genes), and by ‘host behaviours’ (such as their patterns of sun exposure and history of sunburns). The aim of this study was to examine whether melanoma risk varies according to reported levels of sun exposure, even within populations exposed to year-round high levels of sunlight (i.e. Queensland, Australia). More particularly, the authors sought to determine whether the associations with sunlight differ according to a person's inherent genetic risk. In a large Australian study, country of birth, age at migration and sunburns during all periods of life were all strongly associated with melanoma risk. People who had a past history of other types of skin cancer (specifically, BCC or SCC) and of other skin lesions caused by sun exposure had a higher risk of developing melanoma than people without sun-related skin lesions. The authors found evidence for gene-environment interactions that are consistent with the ‘divergent pathway’ hypothesis for melanoma development, which almost 20 years ago proposed that people with a high genetic susceptibility (i.e. at higher risk of melanoma, genetically) may only need modest levels of sun exposure to trigger melanoma development, whereas those with low genetic susceptibility require continued high levels of sun exposure to trigger melanoma development. In line with this hypothesis, the authors found that people who were at low genetic risk for melanoma, but who did eventually develop melanoma, were more likely to have been treated for sun-related skin lesions than people at high genetic risk. In other words, the people at low genetic risk who developed melanoma appeared to need a much larger dose of sun exposure than those at high genetic risk. In contrast, among people at high genetic risk, markers of high-level early life ambient exposure were relatively more important. These findings may help to identify and inform people at high risk of melanoma who stand to benefit most from adopting sun protective behaviours. Linked Article: Olsen et al. Br J Dermatol 2020; 183:303–310. Volume183, Issue2August 2020Pages e39-e39 RelatedInformation

Role of polygenic risk in susceptibility to accelerated pubertal onset following chronic stress exposure.

Previous finding suggests that children growing up under chronic stress tend to experience earlier sexual maturity. The present study aims to examine polygenic risk by experience interaction in predicting pubertal timing, as well as provide insight regarding the relevance of two G × E paradigms. Data were analyzed from a 3-year prospective puberty cohort in Anhui Province, China. Breast Tanner stage and testicular volume (TV) of 997 children were annually assessed. The polygenic risk score (PRS) was computed based on 17 SNPs for early pubertal timing. Hair cortisol concentrations (HCC) were assessed in the first 3 cm hair segment as a biological marker of chronic stress. Comparing with participants under moderate levels of stress as measured by HCC, the puberty-accelerating effects of chronic stress were only observed among girls with moderate (1.7 months earlier, P = 0.007) and low genetic susceptibility (2.2 months earlier, P < 0.001) and among boys with high genetic susceptibility (2.0 months earlier, P = 0.005). Polygenic differences (PRSs) in age at thelarche was most prominent in those with low levels of stress by HCC (9.06, 9.36 and 9.53 years for high, moderate and low PRS, respectively; F = 105.06, P < 0.0001), while polygenic differences in age at TV ≥4 mL was strongest in those under chronic stress (10.91, 11.06 and 11.17 years for high, moderate and low PRS, respectively; F = 100.48, P < 0.0001). Chronic stress predicts earlier age at pubertal onset in a sex-specific and genetic background-dependent manner. The bioecological G × E model for girls and diathesis stress model for boys in pubertal timing warrants further investigation.

Frequency and phenotype of type 1 diabetes in the first six decades of life: a cross-sectional, genetically stratified survival analysis from UK Biobank

SummaryBackgroundType 1 diabetes is typically considered a disease of children and young adults. Genetic susceptibility to young-onset type 1 diabetes is well defined and does not predispose to type 2 diabetes. It is not known how frequently genetic susceptibility to type 1 diabetes leads to a diagnosis of diabetes after age 30 years. We aimed to investigate the frequency and phenotype of type 1 diabetes resulting from high genetic susceptibility in the first six decades of life.MethodsIn this cross-sectional analysis, we used a type 1 diabetes genetic risk score based on 29 common variants to identify individuals of white European descent in UK Biobank in the half of the population with high or low genetic susceptibility to type 1 diabetes. We used Kaplan-Meier analysis to evaluate the number of cases of diabetes in both groups in the first six decades of life. We genetically defined type 1 diabetes as the additional cases of diabetes that occurred in the high genetic susceptibility group compared with the low genetic susceptibility group. All remaining cases were defined as type 2 diabetes. We assessed the clinical characteristics of the groups with genetically defined type 1 or type 2 diabetes.Findings13 250 (3·5%) of 379 511 white European individuals in UK Biobank had developed diabetes in the first six decades of life. 1286 more cases of diabetes were in the half of the population with high genetic susceptibility to type 1 diabetes than in the half of the population with low genetic susceptibility. These genetically defined cases of type 1 diabetes were distributed across all ages of diagnosis; 537 (42%) were in individuals diagnosed when aged 31–60 years, representing 4% (537/12 233) of all diabetes cases diagnosed after age 30 years. The clinical characteristics of the group diagnosed with type 1 diabetes when aged 31–60 years were similar to the clinical characteristics of the group diagnosed with type 1 diabetes when aged 30 years or younger. For individuals diagnosed with diabetes when aged 31–60 years, the clinical characteristics of type 1 diabetes differed from those of type 2 diabetes: they had a lower BMI (27·4 kg/m2 [95% CI 26·7–28·0] vs 32·4 kg/m2 [32·2–32·5]; p<0·0001), were more likely to use insulin in the first year after diagnosis (89% [476/537] vs 6% [648/11 696]; p<0·0001), and were more likely to have diabetic ketoacidosis (11% [61/537] vs 0·3% [30/11 696]; p<0·0001).InterpretationGenetic susceptibility to type 1 diabetes results in non-obesity-related, insulin-dependent diabetes, which presents throughout the first six decades of life. Our results highlight the difficulty of identifying type 1 diabetes after age 30 years because of the increasing background prevalence of type 2 diabetes. Failure to diagnose late-onset type 1 diabetes can have serious consequences because these patients rapidly develop insulin dependency.FundingWellcome Trust and Diabetes UK.

Caffeine intake and genetic susceptibility to Parkinson's disease

Objectives: The interaction between caffeine intake and genetic susceptibility to Parkinson's disease (PD) has seldom been studied We examined if caffeine intake has a differential effect in subjects with high and low genetic susceptibility to Parkinson’s disease (PD), a common neurodegenerative disorder.

Differential effect of caffeine intake in subjects with genetic susceptibility to Parkinson's Disease.

We examined if caffeine intake has a differential effect in subjects with high and low genetic susceptibility to Parkinson’s disease (PD), a common neurodegenerative disorder. A case control study involving 812 subjects consisting of PD and healthy controls were conducted. Caffeine intake assessed by a validated questionnaire and genotyping of PD gene risk variant (LRRK2 R1628P) was carried out. Compared to caffeine takers with the wild-type genotype (low genetic susceptibility), non-caffeine takers with R1628P variant (high genetic susceptibility) had a 15 times increased risk of developing PD (OR = 15.4, 95% CI = (1.94, 122), P = 0.01), whereas caffeine takers with R1628P (intermediate susceptibility) had a 3 times risk (OR = 3.07, 95% CI = (2.02, 4.66), P < 0.001). Caffeine intake would significantly reduce the risk of PD much more in those with high genetic susceptibility compared to those with low genetic susceptibility.

The Role of Prenatal, Obstetric and Neonatal Factors in the Development of Autism

We conducted a linked database cohort study of infants born between 1990 and 2002 in Nova Scotia, Canada. Diagnoses of autism were identified from administrative databases with relevant diagnostic information to 2005. A factor representing genetic susceptibility was defined as having an affected sibling or a mother with a history of a psychiatric or neurologic condition. Among 129,733 children, there were 924 children with an autism diagnosis. The results suggest that among those with low genetic susceptibility, some maternal and obstetric factors may have an independent role in autism etiology whereas among genetically susceptible children, these factors appear to play a lesser role. The role of pre-pregnancy obesity and excessive weight gain during pregnancy on autism risk require further investigation.

Pathogenicity of a human thyroglobulin peptide (2340–2359) in mice with high or low genetic susceptibility to thyroiditis

We have previously identified a 20-mer peptide of human thyroglobulin (hTg), p2340 (aa2340-2359), which induced experimental autoimmune thyroiditis (EAT) in AKR/J (H-2(k)) and HLA-DR3 transgenic mice. In this study, we investigated the thyroiditogenic potential of p2340 in 'high responder' CBA/J (H-2(k)) and SJL/J (H-2(s)) or 'low responder' C57BL/6 (H-2(b)) and BALB/c (H-2(d)) mice. Mice were immunized subcutaneously with 100 nmol of p2340 in complete Freund's adjuvant (CFA) and both the proliferative capacity of their lymph node cells in the presence of p2340 or intact Tg and the production of peptide-specific antibodies were investigated. The p2340 peptide was found to contain B-cell and non-dominant T-cell epitope(s) in all strains tested. Moreover, it elicited EAT in CBA/J (2/6, infiltration index (I.I.) 1) and SJL/J (5/5, I.I. 1-3) mice after direct challenge and in BALB/c (4/7, I.I. 1) and C57BL/6 (1/5, I.I. 1) after adoptive transfer of p2340-primed lymph node cells. P2340 is the first Tg peptide found to be pathogenic in low as well as high responder mouse strains and thus will allow us to investigate mechanisms of EAT induction in a genetically resistant host.

Molecular Mechanisms of Toxic Chemicals

Most human cancers are caused by toxic organic or inorganic chemicals. Environmental exposure allows these chemicals to enter the body and almost every body cell. Within the body cells, five multi-enzyme systems process these chemicals. The chemicals can be activated to their ultimate carcinogenic molecular structures (usually to free radicals) or they can generate free radicals from water molecules. As electrophilic radicals, they can attack and co-valently bind to guanine in G-C or other DNA base pair units within the chromosomes resulting in genomic alterations, possibly in mutations. As protection against this, the radicals can be inactivated and any altered/mutated genes may be repaired. The five carcinogen-processing systems contain more than 300 enzymes. Each enzyme is coded from inherited genes. Therefore, one inherits high versus low genetic susceptibility to the processing of toxic chemicals and the repair of damaged genes through these intracellular carcinogen-processing enzyme systems. Hence, carcinogenesis is a multifactorial process based on both environmental and genetic factors.

Mouse models for genetic dissection of polygenic gastrointestinal diseases

Many diseases with a major public health impact are the result of complex interactions between environmental factors and multiple genes. In the past decade, methods for genome analysis, in particular quantitative trait locus (QTL) analysis in animal models, were developed to identify and localize the genes responsible for multifactorial (polygenic) diseases; QTL analysis is based on experimental crosses between inbred strains with high and low genetic susceptibility. Recently the genes underlying several QTLs could be cloned successfully. Here we describe the impact of these genomic approaches in mice on our understanding of the multifactorial genetics of three gastrointestinal diseases related to metabolism (cholesterol cholelithiasis), development (gastroschisis), and colorectal cancer. The examples demonstrate how mouse models continue to be an invaluable tool in unravelling complex pathomechanisms and unlocking our understanding of human diseases.