Case-control Family Study Research Articles

History and Familial Aggregation of Immune-Mediated Diseases in Sarcoidosis: A Register-Based Case-Control-Family Study

An autoimmune component in the cause of sarcoidosis long has been debated, but population-based data on the clustering of immune-mediated diseases (IMDs) and sarcoidosis in individuals and families suggestive of shared cause is limited. Do patients with a history of IMDs have a higher risk of sarcoidosis and do IMDs cluster in families with sarcoidosis? We conducted a case-control family study (2001-2020). Patients with sarcoidosis (N= 14,146) were identified in the Swedish National Patient Register using a previously validated definition (≥ 2 International Classification of Diseases [ICD]-coded inpatient or outpatient visits). At diagnosis, patients were matched to up to 10 control participants from the general population (N= 118,478) for birth year, sex, and residential location. Patients, control participants, and their first-degree relatives (FDRs; Multi-Generation Register) were ascertained for IMDs by means of ICD codes in the Patient Register (1968-2020). Conditional logistic regression was used to estimate ORs and 95%CIs of sarcoidosis associated with a history of IMDs in patients and control participants and in FDRs. Patients with sarcoidosis exhibited a higher prevalence of IMDs compared with control participants (7.7%vs4.7%), especially connective tissue diseases, cytopenia, and celiac disease. Familial aggregation was observed across IMDs; the strongest association was with celiac disease (OR, 2.09; 95%CI, 1.22-3.58), followed by cytopenia (OR, 1.88; 95%CI, 0.97-3.65), thyroiditis (OR, 1.72; 95%CI, 1.14-2.60), skin psoriasis (OR, 1.70; 95%CI, 1.34-2.15), inflammatory bowel disease (OR, 1.53; 95%CI, 1.14-2.03), immune-mediated arthritis (OR, 1.49; 95%CI, 1.20-1.85), and connective tissue disease (OR, 1.39; 95%CI, 1.00-1.93). IMDs confer a higher risk of sarcoidosis and they aggregate in families with sarcoidosis, signaling a shared cause between IMDs and sarcoidosis. Our findings warrant further evaluation of shared genetic mechanisms.

Familial α-synucleinopathy spectrum features in patients with psychiatric REM sleep behaviour disorder

BackgroundRapid eye movement (REM) sleep behaviour disorder (RBD) is one of the earliest and most specific prodromes of the α-synucleinopathies including Parkinson’s disease (PD). It remains uncertain whether RBD occurring...

Can machine learning identify childhood characteristics that predict future development of bipolar disorder a decade later?

Early identification of bipolar disorder may provide appropriate support and treatment, however there is no current evidence for statistically predicting whether a child will develop bipolar disorder. Machine learning methods offer an opportunity for developing empirically-based predictors of bipolar disorder. This study examined whether bipolar disorder can be predicted using clinical data and machine learning algorithms. 492 children, ages 6–18 at baseline, were recruited from longitudinal case-control family studies. Participants were assessed at baseline, then followed-up after 10 years. In addition to sociodemographic data, children were assessed with psychometric scales, structured diagnostic interviews, and cognitive and social functioning assessments. Using the Balanced Random Forest algorithm, we examined whether the diagnostic outcome of full or subsyndromal bipolar disorder could be predicted from baseline data. 45 children (10%) developed bipolar disorder at follow-up. The model predicted subsequent bipolar disorder with 75% sensitivity, 76% specificity, and an Area Under the Receiver Operating Characteristics of 75%. Predictors best differentiating between children who did or did not develop bipolar disorder were the Child Behavioral Checklist Externalizing and Internalizing behaviors, the Child Behavioral Checklist Total t-score, problematic school functions indexed through the Child Behavioral Checklist School Competence scale, and the Child Behavioral Checklist Anxiety/Depression and Aggression scales. Our study provides the first quantitative model to predict bipolar disorder. Longitudinal prediction may help clinicians assess children with emergent psychopathology for future risk of bipolar disorder, an area of clinical and scientific importance. Machine learning algorithms could be implemented to alert clinicians to risk for bipolar disorder.

Population-based estimates of age-specific cumulative risk of breast cancer for pathogenic variants in ATM

BackgroundMultigene panel tests for breast cancer predisposition routinely include ATM as it is now a well-established breast cancer predisposition gene.MethodsWe included ATM in a multigene panel test applied to the Australian Breast Cancer Family Registry (ABCFR), a population-based case–control–family study of breast cancer, with the purpose of estimating the prevalence and penetrance of heterozygous ATM pathogenic variants from the family data, using segregation analysis.ResultsThe estimated breast cancer hazard ratio for carriers of pathogenic ATM variants in the ABCFR was 1.32 (95% confidence interval 0.45–3.87; P = 0.6). The estimated cumulative risk of breast cancer to age 80 years for heterozygous ATM pathogenic variant carriers was estimated to be 13% (95% CI 4.6–30).ConclusionsAlthough ATM has been definitively identified as a breast cancer predisposition gene, further evidence, such as variant-specific penetrance estimates, are needed to inform risk management strategies for carriers of pathogenic variants to increase the clinical utility of population testing of this gene.

Alcohol and tobacco use and risk of multiple myeloma: A case-control study.

Multiple myeloma (MM) is the second most common hematological cancer and causes significant mortality and morbidity. Knowledge regarding modifiable risk factors for MM remains limited. This analysis of an Australian population‐based case–control family study investigates whether smoking or alcohol consumption is associated with risk of MM and related diseases. Incident cases (n = 789) of MM were recruited via cancer registries in Victoria and New South Wales. Controls (n = 1,113) were either family members of cases (n = 696) or controls recruited for a similarly designed study of renal cancers (n = 417). Adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional multivariable logistic regression. Heavy intake (>20 g ethanol/day) of alcohol had a lower risk of MM compared with nondrinkers (OR = 0.68, 95% CI: 0.50–0.93), and there was an inverse dose–response relationship for average daily alcohol intake (OR per 10 g ethanol per day = 0.92, 95% CI: 0.86–0.99); there was no evidence of an interaction with sex. There was no evidence of an association with MM risk for smoking‐related exposures (p > 0.18). The associations between smoking and alcohol with MM are similar to those with non‐Hodgkin lymphoma. Further research into potential underlying mechanisms is warranted.

1411Alcohol and tobacco use and risk of multiple myeloma: a case-control study

Abstract Background Although responsible for significant mortality and morbidity, our knowledge of modifiable causes of multiple myeloma (MM) remains limited. This analysis of an Australian population-based case-control family study investigated associations between smoking and alcohol consumption and MM risk. Methods Incident cases (n = 789) of MM were recruited mainly via cancer registries in Victoria and NSW. The controls included in the analysis (n = 1,113) were either family members of cases (n = 696) or recruited as part of a similarly designed case-control family study of renal cancer (n = 417). Unconditional multivariable logistic regression was used to estimate ORs, 95% CIs and p-values for associations between alcohol- and tobacco-related exposures and risk of MM. Results Heavy drinkers of alcohol had lower MM risk compared with non-drinkers (OR = 0.68, 95% CI = 0.50 – 0.93), and there was an inverse dose-response relationship for alcohol intake (OR per 10g ethanol per day = 0.92, 95% CI: 0.86 – 0.99); there was no evidence of interaction with sex (p = 0.27). There was no evidence of association between smoking-related exposures and MM risk. Conclusions These findings extend the knowledge of MM risk factor epidemiology. Further research into the causality of the association of alcohol with MM risk and potential underlying mechanisms is recommended. Key messages We found alcohol consumption to be inversely associated with risk of multiple myeloma.

Family history of REM sleep behavior disorder and neurodegeneration in REM sleep behavior disorder comorbid with psychiatric disorders: preliminary findings from a case-control family study

Family history of REM sleep behavior disorder and neurodegeneration in REM sleep behavior disorder comorbid with psychiatric disorders: preliminary findings from a case-control family study

Predictive utility of autistic traits in youth with ADHD: a controlled 10-year longitudinal follow-up study

The objective of this study was to investigate the stability and predictive utility of autistic traits (ATs) in youth with attention-deficit/hyperactivity disorder (ADHD). Participants were referred youth with and without ADHD, without a diagnosis of autism spectrum disorder, and their siblings, derived from identically designed longitudinal case-control family studies of boys and girls with ADHD. Subjects were assessed with structured diagnostic interviews and measures of social, cognitive, and educational functioning. The presence of ATs at baseline was operationalized using a unique profile of the Child Behavior Checklist (CBCL) consisting of an aggregate T score of ≥ 195 on the Withdrawn, Social, and Thought Problems subscales (CBCL-AT profile). At the follow-up, 83% of the ADHD youth with a positive AT profile at baseline continued to have a positive CBCL-AT profile. The presence of a positive CBCL-AT profile at baseline in youth with ADHD heralded a more compromised course characterized by a greater burden of psychopathology that emerged at an earlier age, along with poorer interpersonal, educational, and neurocognitive outcomes. Findings indicate a high level of persisting ATs in ADHD youth over time, as indexed through the CBCL-AT profile, and the presence of this profile prognosticates a compromised course in adult life in multiple domains of functioning.

A case-control-family study of idiopathic rapid eye movement sleep behavior disorder.

To determine the familial aggregation of idiopathic rapid eye movement sleep behavior disorder (iRBD), neurodegenerative diseases, and related biomarkers. A total of 404 and 387 first-degree relatives of 102 patients with iRBD and of 89 controls were recruited, respectively. Among them, 204 and 208 relatives of patients and controls underwent face-to-face clinical assessment, whereas 97 and 75 relatives underwent further video-polysomnographic assessment, respectively. Compared with relatives of controls, relatives of patients demonstrated higher levels of RBD features, including chin tonic electromyography activity (mean = 1.5 ± 7.5 vs 0.3 ± 1.0, p = 0.04) and behavioral events (n [weighted %] = 12 [11.3] vs 2 [1.9], adjusted hazard ratio [aHR] = 7.69, 95% confidence interval [CI] = 1.54-33.33, p = 0.009) during rapid eye movement sleep, probable diagnosis (n [%] = 57 [14.9] vs 20 [4.9], aHR = 3.45, 95% CI = 1.96-6.25, p < 0.001), and definite diagnosis (n [weighted %] = 10 [8.4] vs 2 [1.4], aHR = 5.56, 95% CI = 1.16-25.00, p = 0.03). They also had higher risks of Parkinson disease (3.1% vs 0.5%, aHR = 5.88, 95% CI = 1.37-25.00, p = 0.02), dementia (6.9% vs 2.6%, aHR = 2.44, 95% CI = 1.15-5.26, p = 0.02), constipation (8.3% vs 2.4%, adjusted odds ratio = 4.21, 95% CI = 1.34-13.17, p = 0.01), and motor dysfunction (Movement Disorders Society Unified Parkinson's Disease Rating Scale part III motor score, mean = 1.9 ± 3.2 vs 0.9 ± 2.3, p = 0.002). The unaffected relatives of patients demonstrated a higher likelihood ratio of prodromal Parkinson disease (median [interquartile range] = 0.27 [1.19] vs 0.22 [0.51], p = 0.03). iRBD is familially aggregated from isolated features to full-blown sleep disorder. Relatives of patients carry a higher risk of alpha-synucleinopathy in terms of neurodegenerative diseases and prodromal markers, suggesting a familial aggregation and staging pathology of alpha-synucleinopathy. Ann Neurol 2019;85:582-592.

Sunscreen Use and Melanoma Risk Among Young Australian Adults

There are limited data among young adults on sunscreen use during childhood and adulthood and on the association of sunscreen use with melanoma risk. To assess correlates of early-life sunscreen use and the association between sunscreen use and risk of cutaneous melanoma before age 40 years. This population-based, case-control family study analyzed Australian Melanoma Family Study data for persons with questionnaire data on sunscreen use collected by interview from 2001 to 2005 across 3 states in Australia, representing two-thirds of the country's population. Case participants (aged 18-39 years) had confirmed first primary melanoma. Siblings of case participants were included, and case participants without a sibling control were excluded. Unrelated controls (aged 18-44 years) were recruited from the electoral roll or were a spouse, partner, or friend nominated by case participants. Data analyses were conducted from October 2017 to February 2018. Self- and parent-reported sunscreen use, sun exposure, and other candidate risk factors during childhood and adulthood. Logistic regression analyses adjusted for potential confounders were used to estimate odds ratios (ORs) for melanoma and for correlates of sunscreen use. Participation was 629 of 830 contactable cases (76%) (629 of 1197 overall [53%]), 240 of 570 contactable controls (42%) from the electoral roll (240 of 1068 overall [23%]), and 295 of 371 nominated spouse or friend controls (80%); analysis incuded 603 cases and 1088 controls. The median (interquartile range) age was 32 (28-36) years for 603 cases, 35 (30-38) years for 478 unrelated controls, and 34 (29-38) years for 610 sibling controls. There were more women than men (range, 57%-62%) in all groups, approximately 40% (range, 39%-43%) of participants had a university education, and most participants (range, 58%-73%) had British/northern European ethnicity. Risk of melanoma was less with higher use of sunscreen in childhood (OR for highest vs lowest tertiles, 0.60; 95% CI, 0.42-0.87; P = .02 for trend) and across the lifetime (OR, 0.65; 95% CI, 0.45-0.93; P = .07 for trend). Subgroup analyses suggested that the protective association of sunscreen with melanoma was stronger for people reporting blistering sunburn, receiving a diagnosis of melanoma at a younger age, or having some or many nevi. Total lifetime sun exposure was unrelated to melanoma risk (OR for highest vs lowest tertile, 0.97; 95% CI, 0.66-1.43; P = .94 for trend). By contrast, total sun exposure inversely weighted by sunscreen use (as a measure of sun exposure unprotected by sunscreen) was significantly associated with melanoma risk (OR, 1.80; 95% CI, 1.22-2.65; P = .007 for trend) and appeared stronger for people having lighter pigmentation or some or many nevi or using sunscreen to stay longer in the sun. Regular users of sunscreen were more likely to be female, younger, and of British or northern European ancestry and to have higher educational levels, lighter skin pigmentation, and a stronger history of blistering sunburn. Our findings provided evidence that regular sunscreen use is significantly associated with reduced risk of cutaneous melanoma among young adults and identified several characteristics associated with less sunscreen use.

Familial aggregation and heritability of sarcoidosis: a Swedish nested case-control study.

Sarcoidosis is believed to be caused by both genetic and environmental risk factors, but the proportion of the susceptibility to sarcoidosis that is mediated by genetics remains unknown. We aimed to estimate the familial aggregation and heritability of sarcoidosis using a case-control-family study design and population-based Swedish registers.We identified 23 880 individuals with visits for sarcoidosis in the Swedish National Patient Register using International Classification of Diseases codes (1964‒2013). Information on Löfgren's syndrome was available for a subset diagnosed at Karolinska University Hospital (Stockholm, Sweden). General population controls were matched to cases (10:1). Relatives of cases and controls were identified from the Swedish Multi-Generation Register and ascertained for sarcoidosis in the National Patient Register. We estimated familial relative risks for sarcoidosis using conditional logistic regression and heritability using biometric models.Having at least one first-degree relative with sarcoidosis was associated with a 3.7-fold increase in the risk of sarcoidosis (95% CI 3.4-4.1). The relative risk increased in those with two or more relatives (relative risk 4.7) and in Löfgren's syndrome (relative risk 4.1). The heritability was 39% (95% CI 12-65%).This large investigation showed that having a relative with sarcoidosis is a very strong risk factor for the disease. Genetic variation is an important, albeit partial, contributing factor to the risk for sarcoidosis.

Familial aggregation of REM sleep behavior disorder and neurodegenerative biomarkers: a case-control family study

Familial aggregation of REM sleep behavior disorder and neurodegenerative biomarkers: a case-control family study

Can subsyndromal manifestations of major depression be identified in children at risk?

Children of parents with major depression are at significantly increased risk for developing major depression themselves; however, not all children at genetic risk will develop major depressive disorder (MDD). We investigated the utility of subsyndromal scores on the Child Behavior Checklist (CBCL) Anxiety/Depression scale in identifying children at the highest risk for pediatric MDD from among the pool of children of parents with MDD or bipolar disorder. The sample was derived from two previously conducted longitudinal case-control family studies of psychiatrically and pediatrically referred youth and their families. For this study, probands were stratified based on the presence or absence of a parental mood disorder. Subsyndromal scores on the CBCL Anxiety/Depression scale significantly separated the children at high risk for pediatric MDD from those at low risk in a variety of functional areas, including social and academic functioning. Additionally, children at genetic risk without elevated CBCL Anxiety/Depression scale scores were largely indistinguishable from controls. These results suggest that the CBCL Anxiety/Depression scale can help identify children at highest risk for pediatric MDD. If implemented clinically, this scale would cost-effectively screen children and identify those most in need of early intervention resources to impede the progression of depression.

Examining the association between attention deficit hyperactivity disorder and substance use disorders: A familial risk analysis

ObjectiveThe main aim of this study was to use familial risk analysis to examine the association between attention deficit hyperactivity disorder (ADHD) and substance use disorders (SUDs) attending to sex effects and the specificity of alcohol and drug use disorder risks. MethodsSubjects were derived from two longitudinal case-control family studies of probands aged 6–17 years with and without DSM-III-R ADHD of both sexes and their first degree relatives followed from childhood onto young adult years. Cox proportional hazard models were used to estimate rates of ADHD and SUDs (any SUD, alcohol dependence, and drug dependence). Logistic regression was used to test both co-segregation and assortative mating. ResultsOur sample included 404 probands (ADHD: 112 boys and 96 girls; Control: 105 boys and 91 girls) and their 1336 relatives. SUDs in probands increased the risk for SUDs in relatives irrespective of ADHD status. The risk for dependence to drug or alcohol in relatives was non-specific. There was evidence that even in the absence of a SUD in the proband, ADHD by itself increased the risk of SUDs in relatives. Proband sex did not moderate the familial relationship between ADHD and SUDs. There was evidence of co-segregation between ADHD and SUD. ConclusionsFindings indicate that various independent pathways are involved in the transmission of SUD in ADHD and that these risks were not moderated by proband sex. ADHD children and siblings should benefit from preventive and early intervention strategies to decrease their elevated risk for developing a SUD.

A fully nonparametric estimator of the marginal survival function based on case-control clustered age-at-onset data.

Consider a popular case-control family study where individuals with a disease under study (case probands) and individuals who do not have the disease (control probands) are randomly sampled from a well-defined population. Possibly right-censored age at onset and disease status are observed for both probands and their relatives. For example, case probands are men diagnosed with prostate cancer, control probands are men free of prostate cancer, and the prostate cancer history of the fathers of the probands is also collected. Inherited genetic susceptibility, shared environment, and common behavior lead to correlation among the outcomes within a family. In this article, a novel nonparametric estimator of the marginal survival function is provided. The estimator is defined in the presence of intra-cluster dependence, and is based on consistent smoothed kernel estimators of conditional survival functions. By simulation, it is shown that the proposed estimator performs very well in terms of bias. The utility of the estimator is illustrated by the analysis of case-control family data of early onset prostate cancer. To our knowledge, this is the first article that provides a fully nonparametric marginal survival estimator based on case-control clustered age-at-onset data.

TNF-α-308/-238 polymorphisms are associated with gastric cancer: A case-control family study in China

Associations of TNF-α-308 (rs1800629) and -238 (rs361525) with gastric cancer had the inconsistent indication among different populations. In this case-control family study, 47families were determined with the probands diagnosed with gastric cancer (case family, n=296), accordingly 47families without gastric cancer were matched with the case families by multivariate distribution of age, sex, social class, and pedigree size (control family, n=319). Polymerase chain reaction-restriction fragment length polymorphism (RFLP-PCR) was used to identify the TNF genotype. Chi-square test was used to compare the groups regarding genotype and the allele frequencies, HWE test for Hardy-Weinberg equilibrium. The frequencies of TNF-α-308 GA and AA genotypes were significantly higher in case family than that in control family. The risk of gastric cancer was increased in GA and AA carriers in the first degree (OR=2.06, 95% CI=1.20-3.51 and OR=4.89, 95% CI=2.74-8.74), however the similar result was not found in the second degree. Helicobacter pylori infection status were significantly associated with risk of gastric cancer in first-degree relatives (OR=1.96, 95% CI=1.26-3.05) while no statistical significance was noted in the second-degree relatives. Haplotypes of TNF-α-308/-238 alleles, GA/GG, AA/GG and AA/GA indicated the susceptibilities to gastric cancer with OR and 95% confident intervals resulting 2.07 (1.34-3.21), 4.49 (2.74-7.33) and 4.98 (1.76-14.01) respectively. TNF-α-G308A (rs1800629) polymorphisms are associated with gastric cancer in Chinese population. Haplotypes of TNF-α-308/-238 GA/GG, AA/GG and AA/GA increase the susceptibilities to gastric cancer. The first-degree relatives are more likely to develop into gastric cancer with TNF-α-G308 polymorphisms and H.pylori positive than the second-degree are.

Are Autistic Traits in Youth Meaningful? A Replication study in Non-referred Siblings of Youth with and without Attention-Deficit/Hyperactivity Disorder

Abstract Background We previously described the high prevalence and burden of significant autistic traits (ATs) in youth with attention-deficit/hyperactivity disorder (ADHD). These traits are associated with significantly greater impairment in psychopathological, interpersonal, educational, and neuropsychological functioning. Because the sample consisted of referred ADHD youth, uncertainty remained regarding whether these findings are generalizable to non-referred populations of youths with and without ADHD. Objective The aim of the current study was to assess the prevalence and implications of ATs in a non-referred population of siblings of probands with and without ADHD. Method Participants were non-referred siblings of probands with ADHD (N = 257) and control probands (N = 234) of longitudinal, case-control family studies conducted at Massachusetts General Hospital. Assessments included measures of psychiatric, psychosocial, educational, and cognitive functioning. The presence of significant ATs was operationalized using the Child Behavior Checklist AT profile, which consists of combined aggregate T-scores of ≥ 195 on the Withdrawn, Social, and Thought Problems subscales. Results ATs were significantly more prevalent among the siblings of probands with ADHD as compared with siblings of control probands (6% vs. 1%; P = .02). Siblings of probands with ADHD with a positive AT profile (N = 15) were significantly more impaired than those without an AT profile (N = 242) with regard to psychopathological, interpersonal, educational, and neuropsychological functioning. Conclusions The current study reports a higher-than-expected prevalence of ATs in a non-referred sample of siblings of youth with ADHD, which is consistent with previous findings regarding ATs in a referred sample of youth with ADHD. The presence of ATs is associated with higher levels of morbidity and dysfunction.

TGF-β1 polymorphisms and familial aggregation of liver cancer in Guangxi, China

The goal of present study was to investigate the relationship between polymorphisms of TGF-β1 and familial aggregation of liver cancer in Guangxi Zhuang, Han, and Yao populations. We conducted a population-based case-control family study of liver cancer in Guanxi, China. A total of 214 individuals from 37 case families were surveyed for polymorphisms in TGF-β1. We genotyped six functional TGF-β1 polymorphisms: rs1800469, rs2241715, rs2241716, rs11466345, rs8105161, and rs747857. Levels of TGF-β1, hepatitis B surface antigen, and anti-hepatitis C virus in all serum samples were detected using the enzyme-linked immunoassay method, and presence of hepatitis B virus (HBV) DNA was determined using polymerase chain reaction amplification. A standardized questionnaire was used to collect information from subjects, including alcohol consumption, smoking, eating, and water drinking habits. The results were compared with those from 214 control individuals. The results showed that the TGF-β1 genotypes rs1800469, rs2241715, rs2241715, and rs8105161 were more frequent in patients than in controls. The risk factors for familial aggregation of liver cancer in Guangxi were determined, from high to low, to be: drinking sugared beverages > alcohol consumption > HBV DNA-positive > rs1800469 TT homozygous genotype > rs2241715 TT homozygous genotype. The results suggested that TGF-β1 rs1800469 TT and rs2241715 TT homozygote genotypes represent the genetic factors underlying familial clustering of liver cancer in Guangxi, and that drinking water use, alcohol consumption, and testing positive for HBV DNA are the main environmental factors contributing to familial aggregation of liver cancer in Guangxi.

Familial correlations of onset age of hepatocellular carcinoma: a population-based case-control family study.

BackgroundThere was lack of evidence for familial aggregation in onset age of hepatocellular carcinoma (HCC) in Chinese population. We conducted a population-based case-control family study to examine familial correlation of age of HCC onset in Taixing, China.MethodsA total of 202 cases and 202 matched controls as well as their relatives were included in the study. Lifetime cumulative risks of HCC were estimated using the Kaplan-Meier approach. Cross ratios (CRs) were obtained from stratified Cox proportional hazard models, to assess the familial correlation of onset age.ResultsThe mean age of HCC onset was decreased as increasing number of HCC cases in a family. The onset age was the earliest for first-degree relatives, intermediate for second-degree relatives, and latest for non-blood relatives (spouse) (log-rank test, P<0.01). The onset age was significantly correlated between probands and their relatives. In stratified Cox proportional hazard models, the CRs for the probands versus their fathers, mothers, siblings and uncles/aunts were 6.25 (95% confidence interval (CI): 1.84–21.25), 9.81 (95% CI: 1.24–77.56), 6.22 (95% CI: 1.37–28.36) and 3.24 (95% CI: 1.26–8.33), respectively. After adjustment for hepatitis B virus infection, the CRs remained significant.ConclusionThis current study suggested a significant correlation of onset age for HCC among blood relatives. Familial HCC cases yielded earlier age of onset and their relatives have higher HCC risk in early age, highlighting intensive surveillance should be start at an earlier age for individuals with family history of HCC.

Dysfunction of mitochondria due to environmental carcinogens in nasopharyngeal carcinoma in the ethnic group of Northeast Indian population

Nasopharyngeal carcinoma (NPC) is a rare cancer worldwide, but in India, NPC is uncommon in its subcontinent except in the north-eastern part of the country. NPC is thought to be caused by the combined effects of environmental carcinogens, genetic susceptibility and Epstein-Barr virus (EBV). This is the first study that aimed to examine the selected risk factors, mostly dietary, viral environmental, metabolic gene polymorphisms, mitochondrial DNA (mtDNA) copy number variation and their risk, in subjects who are highly prone to NPC in the ethnic groups of Northeast India, which has included cases, first-degree relatives and controls. The cases and controls were selected from three ethnic groups (Manipuri, Naga and Mizo) of Northeast India with high prevalence of NPC. This case-control family study includes 64 NPC patients, 88 first-degree relatives and 100 controls having no history of cancer. PCR-based detection was done for EBV-latent membrane protein 1 (LMP1) gene and glutathione S-transferase Mu 1 (GSTM1)-glutathione S-transferase theta 1 (GSTT1) polymorphism. A comparative ΔCt method was used for the determination of mtDNA content. An increased risk of 2.00-6.06-folds to NPC was observed with those who intake smoked meat and fish, salted fish and fermented fish; betel nut chewers; tobacco smokers; alcohol drinkers; and those who have kitchen inside the living room, glutathione S-transferase null genotype and EBV infection. The risk of NPC increased in cases with decreased mtDNA copy number (P trend = 0.007). A significant difference between GST null genotypes and EBV infection with mtDNA content was found in the cases (P < 0.0001). The understandings of environment-genetic risk factors and their role in the etiology of NPC are helpful as preventive measures and screening.