Publications by authors named "Jan Sundquist"

730 Publications

Origins of spousal cross-concordance for psychiatric disorders: a test of the social stress theory for alcohol use disorder.

Psychol Med 2022 Jun 22:1-8. Epub 2022 Jun 22.

Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.

Background: The authors sought to clarify the impact of spousal psychiatric disorders of differing severity [major depression or anxiety disorders (DAD) bipolar disorder or nonaffective psychosis (BPN)] on proband risk for alcohol use disorder (AUD) during marriage.

Methods: In a Swedish cohort ( = 744 628), associations between spousal DAD and BPN and proband AUD were estimated with Cox proportional hazards; associations between parental AUD, proband premarital AUD, and spousal lifetime DAD and BPN were estimated with logistic regression; and whether spousal DAD or BPN causally increased risk for AUD was evaluated with frailty models.

Results: Spousal premarital DAD, spousal marital-onset DAD, and spousal BPN (premarital or marital-onset) were associated with proband AUD during marriage [hazard ratios (HR) range 1.44-3.72]. Those with a parental or premarital history of AUD ( without) were more likely to marry a spouse with DAD or BPN (odds ratios 1.22-2.77). Moving from an unaffected first spouse to a DAD-affected second spouse increased AUD risk in males (HR 2.90). Moving from an unaffected first spouse to a BPN-affected second spouse increased AUD risk (HR 3.96; HR 5.64). Moving to an unaffected second spouse from a DAD-affected first spouse decreased AUD risk, with stronger evidence in females compared to males (HR 0.59; HR 0.28).

Conclusions: Associations between spousal DAD or BPN and proband AUD reflect both selection and causal effects. Marriage to a BPN-affected spouse has a particularly strong effect on AUD risk, with more modest effects for spousal DAD.
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http://dx.doi.org/10.1017/S0033291722001738DOI Listing
June 2022

Is an elevated family-genetic risk for major psychiatric disorders specific to creative occupations?

Psychol Med 2022 Jun 8:1-13. Epub 2022 Jun 8.

Center for Primary Health Care Research, Lund University, Malmö, Sweden.

Background: Despite a large descriptive literature linking creativity and risk for psychiatric illness, the magnitude and specificity of this relationship remain controversial.

Methods: We examined, in 1 137 354 native Swedes with one of 59 3-digit official and objective occupational codes in managerial and educated classes, their familial genetic risk score (FGRS) for ten major disorders, calculated from 1 through 5 degree relatives. Mean FGRS across disorders were calculated, in 3- and 4-digit occupational groups, and then controlled for those whose disorder onset preceded occupational choice. Using sequential analyses, values were evaluated using Bonferroni correction.

Results: 3-digit professions considered to reflect creativity (e.g. 'artists' and 'authors') were among those with statistically significant elevations of FGRS. Among more specific 4-digit codes, visual artists, actors, and authors stood out with elevated genetic risks, highest for major depression (MD), anxiety disorders (AD) and OCD, more modest for bipolar disorders (BD) and schizophrenia and, for authors, for drug and alcohol use disorders. However, equal or greater elevations in FGRS across disorders were seen for religious (e.g. ministers), helping (e.g. psychologists, social workers), and teaching/academic occupations (e.g. professors). The potential pathway from FGRS → Disorder → Occupation accounts for a modest proportion of the signal, largely for MD and AD risk.

Conclusions: While traditional creative occupations were associated with elevated genetic risk for a range of psychiatric disorders, this association was not unique, as similar, or greater elevations were seen for religious, helping and teaching professions and was stronger for internalizing than psychotic disorders.
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http://dx.doi.org/10.1017/S0033291722001349DOI Listing
June 2022

Is an elevated family-genetic risk for major psychiatric disorders specific to creative occupations?

Psychol Med 2022 Jun 8:1-13. Epub 2022 Jun 8.

Center for Primary Health Care Research, Lund University, Malmö, Sweden.

Background: Despite a large descriptive literature linking creativity and risk for psychiatric illness, the magnitude and specificity of this relationship remain controversial.

Methods: We examined, in 1 137 354 native Swedes with one of 59 3-digit official and objective occupational codes in managerial and educated classes, their familial genetic risk score (FGRS) for ten major disorders, calculated from 1 through 5 degree relatives. Mean FGRS across disorders were calculated, in 3- and 4-digit occupational groups, and then controlled for those whose disorder onset preceded occupational choice. Using sequential analyses, values were evaluated using Bonferroni correction.

Results: 3-digit professions considered to reflect creativity (e.g. 'artists' and 'authors') were among those with statistically significant elevations of FGRS. Among more specific 4-digit codes, visual artists, actors, and authors stood out with elevated genetic risks, highest for major depression (MD), anxiety disorders (AD) and OCD, more modest for bipolar disorders (BD) and schizophrenia and, for authors, for drug and alcohol use disorders. However, equal or greater elevations in FGRS across disorders were seen for religious (e.g. ministers), helping (e.g. psychologists, social workers), and teaching/academic occupations (e.g. professors). The potential pathway from FGRS → Disorder → Occupation accounts for a modest proportion of the signal, largely for MD and AD risk.

Conclusions: While traditional creative occupations were associated with elevated genetic risk for a range of psychiatric disorders, this association was not unique, as similar, or greater elevations were seen for religious, helping and teaching professions and was stronger for internalizing than psychotic disorders.
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http://dx.doi.org/10.1017/S0033291722001349DOI Listing
June 2022

Is an elevated family-genetic risk for major psychiatric disorders specific to creative occupations?

Psychol Med 2022 Jun 8:1-13. Epub 2022 Jun 8.

Center for Primary Health Care Research, Lund University, Malmö, Sweden.

Background: Despite a large descriptive literature linking creativity and risk for psychiatric illness, the magnitude and specificity of this relationship remain controversial.

Methods: We examined, in 1 137 354 native Swedes with one of 59 3-digit official and objective occupational codes in managerial and educated classes, their familial genetic risk score (FGRS) for ten major disorders, calculated from 1 through 5 degree relatives. Mean FGRS across disorders were calculated, in 3- and 4-digit occupational groups, and then controlled for those whose disorder onset preceded occupational choice. Using sequential analyses, values were evaluated using Bonferroni correction.

Results: 3-digit professions considered to reflect creativity (e.g. 'artists' and 'authors') were among those with statistically significant elevations of FGRS. Among more specific 4-digit codes, visual artists, actors, and authors stood out with elevated genetic risks, highest for major depression (MD), anxiety disorders (AD) and OCD, more modest for bipolar disorders (BD) and schizophrenia and, for authors, for drug and alcohol use disorders. However, equal or greater elevations in FGRS across disorders were seen for religious (e.g. ministers), helping (e.g. psychologists, social workers), and teaching/academic occupations (e.g. professors). The potential pathway from FGRS → Disorder → Occupation accounts for a modest proportion of the signal, largely for MD and AD risk.

Conclusions: While traditional creative occupations were associated with elevated genetic risk for a range of psychiatric disorders, this association was not unique, as similar, or greater elevations were seen for religious, helping and teaching professions and was stronger for internalizing than psychotic disorders.
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http://dx.doi.org/10.1017/S0033291722001349DOI Listing
June 2022

Predicting the Onset of Opioid Use Disorder in the Swedish General Population.

J Stud Alcohol Drugs 2022 05;83(3):332-341

Center for Primary Health Care Research, Lund University, Malmö, Sweden.

Objective: Given the public health importance of opioid use disorder (OUD), we sought to understand better its risk predictors in the Swedish general population.

Method: We examined the Swedish population, born 1950-1970 ( = 2,092,359), and followed through 2018. Using Cox, logistic, and co-sibling models, we explored associations between a wide range of putative risk factors and a first onset of OUD--assessed through medical, criminal, and pharmacy registers--in the entire cohort and in the cohort wherein prior cases of drug use disorder (DUD) were censored.

Results: OUD was predicted by the following four risk factor domains: (a) externalizing syndromes, especially prior non-opioid DUD; (b) psychopathology; (c) psychosocial factors, including social class and immigrant and marital status; and (d) serious injuries and pain diagnoses. When predicting OUD as the first form of DUD, the importance of pain diagnoses as a predictor increased. Co-sibling analyses suggested that the association of some of these risk factors with OUD onset was likely largely causal, whereas others were a mixture of causal effects and familial confounding. An aggregate risk score from these individual risk factors had reasonable receiver operating characteristic (ROC) curve performance.

Conclusions: OUD is a multifactorial syndrome for which risk can be meaningfully predicted by prior externalizing syndromes, internalizing and psychotic psychopathology, indicators of psychosocial status, and predictors of pain diagnoses. Some important differences were seen in the prediction of any OUD onset versus OUD onset as the first form of DUD. Much of the effect of these predictors appear, in co-sibling analyses, to likely reflect causal influences.
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May 2022

Narcolepsy among first- and second-generation immigrants in Sweden: A study of the total population.

Acta Neurol Scand 2022 May 11. Epub 2022 May 11.

Center for Primary Health Care Research, Lund University, Malmö, Sweden.

Aims: To study incident narcolepsy in first- and second-generation immigrant groups using Swedish-born individuals and native Swedes as referents.

Methods: The study population included all individuals registered and alive in Sweden at baseline. Narcolepsy was defined as having at least one registered diagnosis of narcolepsy in the Swedish National Patient Register. The incidence of narcolepsy in different immigrant groups was assessed by Cox regression, with hazard ratios (HRs) and 95% confidence intervals (CI). The models were stratified by sex and adjusted for age, geographical residence in Sweden, educational level, marital status, co-morbidities, and neighbourhood socioeconomic status.

Results: In the first-generation study, 1225 narcolepsy cases were found; 465 males and 760 females, and in the second-generation study, 1710 cases, 702 males and 1008 females. Fully adjusted HRs (95% CI) in the first-generation study was for males 0.83 (0.61-1.13) and females 0.83 (0.64-1.07), and in the second-generation study for males 0.76 (0.60-0.95) and females 0.91 (95% CI 0.76-1.09). Statistically significant excess risks of narcolepsy were found in first-generation males from North America, and second-generation males with parents from North America, and second-generation females with parents from Latin America.

Conclusions: There were only significant differences in incident narcolepsy between native Swedes and second-generation male immigrants. The observed differences can partly be explained by differences in Pandemrix® vaccinations and are probably not attributable to genetic differences between immigrants and natives.
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http://dx.doi.org/10.1111/ane.13633DOI Listing
May 2022

Familial Risks for Liver, Gallbladder and Bile Duct Cancers and for Their Risk Factors in Sweden, a Low-Incidence Country.

Cancers (Basel) 2022 Apr 12;14(8). Epub 2022 Apr 12.

Center for Primary Health Care Research, Lund University, 205 02 Malmö, Sweden.

We used the Swedish Cancer Registry data to address familial risks for concordant (same) and discordant (different) hepatobiliary cancers, including their associations with any other cancers and with known risk factors. Risks were also assessed between spouses. The analysis covered Swedish families and their cancers between years 1958 and 2018. Adjusted familial risks were expressed as standardized incidence ratios (SIRs). Familial SIRs for concordant hepatocellular carcinoma (HCC) were 2.60, and for gallbladder cancer they were at the same level (2.76). Familial risk was also found for intrahepatic bile duct cancer and for female extrahepatic bile duct cancer. HCC was associated with lung and cervical cancers; extrahepatic bile duct and ampullary cancers were associated with colon and pancreatic cancers, suggesting Lynch syndrome. Among spouses, hepatobiliary cancer was associated with HCC, stomach, pancreatic, cervical and upper aerodigestive tract cancers. Among risk factors, family members diagnosed with alcohol-related disease showed association with HCC. The observed familial risks for hepatobiliary cancers were relatively high, and considering the poor prognosis of these cancers, prevention is of the utmost importance and should focus on moderation of alcohol consumption, vaccination/treatment of hepatitis viral infections and avoidance of overweight and other risk factors of type 2 diabetes.
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http://dx.doi.org/10.3390/cancers14081938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9030935PMC
April 2022

The association of mitochondrial DNA copy number with incident mental disorders in women: A population-based follow-up study.

J Affect Disord 2022 07 13;308:111-115. Epub 2022 Apr 13.

Center for Primary Health Care Research, Lund University/Region Skåne, Malmö 20502, Sweden; Department of Family Medicine and Community Health, Department of Population Health Science and Policy Icahn School of Medicine at Mount Sinai, New York, USA; Center for Community-based Healthcare Research and Education (CoHRE), Department of Functional Pathology, School of Medicine, Shimane University, Japan.

Background: Available evidence suggests that mitochondrial DNA copy number (mtDNA-CN) may differ among patients with mental disorders compared to the general population. However, whether mtDNA-CN is independently associated with the subsequent incidence of mental disorders remains unclear.

Material And Methods: We used droplet digital PCR to measure the absolute mtDNA-CN in DNA samples obtained from a population-based follow-up study, which included a total of 2354 middle-aged women (52-63 years) who were free of mental disorders at baseline. After 17 years (median) of follow-up, 727 participants were diagnosed with mental disorders.

Results: In the univariate Cox regression, lower baseline mtDNA-CN (mtDNA-CN < 117) was associated with a higher risk of mental disorders (HR = 1.16, p = 0.047). In addition, smoking, marital status and sleeping quality were associated with both mtDNA-CN and mental disorders. After adjusting for these variables, the association between mtDNA-CN and mental disorders decreased and became non-significant (HR = 1.07, p = 0.36). Stratification of data according to the subtype of mental disorders, showed that low mtDNA-CN was associated with a higher risk of alcohol or drug use disorders (HR = 1.82, p = 0.045 after adjusting).

Conclusion: In the present study, we could not find any independent association between mtDNA-CN blood and the most common mental disorders in a population-based follow-up study of Swedish women, except for alcohol and drug use disorders. The use of blood mtDNA-CN as a biomarker of mental disorders, in addition to other risk factors, needs to be further examined in future studies.
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http://dx.doi.org/10.1016/j.jad.2022.04.064DOI Listing
July 2022

Novel cardiovascular biomarkers associated with peripheral arterial disease in men screened for abdominal aortic aneurysm.

Vasa 2022 May 7;51(3):167-173. Epub 2022 Apr 7.

Department of Acute and Internal Medicine, Skåne University Hospital, Lund University, Malmö, Sweden.

Peripheral arterial disease (PAD) is a common atherosclerotic disease with severity ranging from asymptomatic to chronic limb threatening ischemia. The aim of the present cross-sectional study was to identify novel biomarkers associated with PAD. Levels of 91 cardiovascular specific proteins in plasma samples were measured by the Proseek Multiplex CVD III panel from a cohort consisting of 267 65-year-old men recruited from a screening program for abdominal aortic aneurysm (AAA) Levels of protein biomarkers were compared in men with and without PAD (defined as an ankle brachial index of <0.9) and their diagnostic potential was calculated by receiver-operating characteristic analysis. The prevalence of PAD was 14.2% (38/267). After adjustment for multiple comparisons, levels of the following 11 biomarkers remained significantly higher (<0.0001) in patients with PAD: secretoglobin family 3A member 2, osteoprotegerin, urokinase-type plasminogen activator surface receptor, serum macrophage chemokine ligand 16, matrix metalloproteinase 9, p-selectin, growth differentiation factor 15, elafin, cystatin B, trefoil factor 3, and fatty acid-binding protein 4. Multivariable logistic regression analysis (adjusted for smoking, use of antihypertensive and lipid-lowering medication, and metformin) showed that 11 biomarkers were significantly associated with higher risk of PAD with odds ratios ranging from 1.6 to 2.4. Area under curve calculated by receiver operating characteristic curve analysis (diagnostic value) for each protein biomarker ranged from 0.63 to 0.74. We have identified multiple proteins with a potential to be diagnostic biomarkers for PAD, and further research is warranted to clarify their potential predictive and prognostic value.
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http://dx.doi.org/10.1024/0301-1526/a000999DOI Listing
May 2022

A distinctive profile of family genetic risk scores in a Swedish national sample of cases of fibromyalgia, irritable bowel syndrome, and chronic fatigue syndrome compared to rheumatoid arthritis and major depression.

Psychol Med 2022 Mar 31:1-8. Epub 2022 Mar 31.

Center for Primary Health Care Research, Department of Clinical Sciences, Lund University Clinical Research Centre (CRC), Box 50332, SE-202 13Malmö, Sweden.

Background: Functional somatic disorders (FSD) feature medical symptoms of unclear etiology. Attempts to clarify their origin have been hampered by a lack of rigorous research designs. We sought to clarify the etiology of the FSD by examining the genetic risk patterns for FSD and other related disorders.

Methods: This study was performed in 5 829 186 individuals from Swedish national registers. We quantified familial genetic risk for FSD, internalizing disorders, and somatic disorders in cases of chronic fatigue syndrome (CFS), fibromyalgia (FM), and irritable bowel syndrome (IBS), using a novel method based on aggregate risk in first to fifth degree relatives, adjusting for cohabitation. We compared these profiles with those of a prototypic internalizing psychiatric - major depression (MD) - and a somatic/autoimmune disorder: rheumatoid arthritis (RA).

Results: Patients with FM carry substantial genetic risks not only for FM, but also for pain syndromes and internalizing, autoimmune and sleep disorders. The genetic risk profiles for IBS and CFS are also widely distributed although with lower average risks. By contrast, genetic risk profiles of MD and RA are much more restricted to related conditions.

Conclusion: Patients with FM have a relatively unique family genetic risk score profile with elevated genetic risk across a range of disorders that differs markedly from the profiles of a classic autoimmune disorder (RA) and internalizing disorder (MD). A similar less marked pattern of genetic risks was seen for IBS and CFS. FSD arise from a distinctive pattern of genetic liability for a diversity of psychiatric, autoimmune, pain, sleep, and functional somatic disorders.
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http://dx.doi.org/10.1017/S0033291722000526DOI Listing
March 2022

Incident cases of vision impairment and blindness among adult foreign-born and Swedish-born individuals: A national Swedish study.

Eur J Ophthalmol 2022 Mar 30:11206721221090700. Epub 2022 Mar 30.

Center for Primary Health Care Research, 5193Lund University, Malmö, Sweden.

Purpose: To analyse risk of vision impairment (VI) and blindness in adult foreign-born individuals and Swedish-born individuals.

Methods: A nationwide study of individuals 18 years of age and older (N = 6,042,891; 2,902,918 men and 3,139,973 women) in Sweden. VI (in general) and blindness was defined as at least one registered diagnosis in the National Patient Register between January 1, 1998 and December 31, 2015. Cox regression analysis was used to estimate the relative risk (hazard ratios (HR) with 95% confidence intervals (CI)) of incident VI in foreign-born compared to Swedish-born individuals. The Cox regression models were stratified by sex and adjusted for age, co-morbidities, and for sociodemographic status.

Results: A total of 14,597 cases (6433 men and 8164 women) of VI were registered, with an age-standardized incidence per 100,000 person-years of 10.37 in men and 11.03 in women. VI (in general) was more common in immigrants, fully adjusted HRs (95% CI) were for immigrant men 1.38 (95% CI, 1.29-1.48) and women 1.24 (95% CI, 1.16-1.32), with significantly higher HRs among men and women from Eastern Europe, Africa, Latin America and Asia. Higher risks of blindness were also seen for immigrant men, HR 1.75 (95% CI 1.36-2.25), as well as for the other degrees of VI among immigrant men, HR 1.36 (95% CI 1.26-1.47), and immigrant women, HR 1.26 (95% CI 1.18-1.35).

Conclusions: We observed a generally higher risk of VI among foreign-born men and women, especially from some regions.
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http://dx.doi.org/10.1177/11206721221090700DOI Listing
March 2022

Risk of Gynecological Cancers in Cholecystectomized Women: A Large Nationwide Cohort Study.

Cancers (Basel) 2022 Mar 14;14(6). Epub 2022 Mar 14.

Institute of Medical Biometry, University of Heidelberg, 69120 Heidelberg, Germany.

: Gallstones affect women more frequently than men, and symptomatic gallstones are increasingly treated with surgical removal of the gallbladder (cholecystectomy). Breast, endometrial, and ovarian cancer share several risk factors with gallstones, including overweight, obesity, and exposure to female sex hormones. We intended to assess the association between cholecystectomy and female cancer risk, which has not been comprehensively investigated. We investigated the risk of female cancers after cholecystectomy leveraging the Swedish Cancer, Population, Patient, and Death registries. Standardized incidence ratios (SIRs) adjusted for age, calendar period, socioeconomic status, and residential area were used to compare cancer risk in cholecystectomized and non-cholecystectomized women. During a median follow-up of 11 years, 325,106 cholecystectomized women developed 10,431 primary breast, 2888 endometrial, 1577 ovarian, and 705 cervical cancers. The risk of ovarian cancer was increased by 35% (95% confidence interval (CI) 2% to 77%) in the first 6 months after cholecystectomy. The exclusion of cancers diagnosed in the first 6 months still resulted in an increased risk of endometrial (19%, 95%CI 14% to 23%) and breast (5%, 95%CI 3% to 7%) cancer, especially in women cholecystectomized after age 50 years. By contrast, cholecystectomized women showed decreased risks of cervical (-13%, 95%CI -20% to -7%) and ovarian (-6%, 95%CI -10% to -1%) cancer. The risk of ovarian cancer increased by 35% in a just short period of time (6 months) following the surgery. Therefore, it is worth ruling out ovarian cancer before cholecystectomy. Women undergoing cholecystectomy showed an increased risk of breast and endometrial cancer up to 30 years after surgery. Further evaluation of the association between gallstones or gallbladder removal on female cancer risk would allow for the assessment of the need to intensify cancer screening in cholecystectomized women.
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http://dx.doi.org/10.3390/cancers14061484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8946708PMC
March 2022

Prostate cancer incidence and survival in relation to prostate cancer as second cancer in relatives.

Cancer Med 2022 May 21;11(10):2117-2124. Epub 2022 Mar 21.

Center for Primary Health Care Research, Lund University/Region Skåne, Malmö, Sweden.

Objectives: To investigate if the risk of prostate cancer (PC) differs based on the order of primary PC diagnosed in first-degree relatives (FDRs) given possibly different risk factors for PC as first primary cancer (PCa-1) and second primary cancer (PCa-2).

Subjects And Methods: In this Swedish nationwide cohort, PC diagnosis was followed for among 149,985 men with one FDR affected by PCa-1, 10,972 with one FDR affected by PCa-2 and 2,896,561 without any FDRs affected by cancer in a maximum of 57 years. PC patients were further followed for death due to PC since diagnosis. Relative risk (RR) of PC was estimated with Poisson regression and hazard ratio (HR) with Cox proportional hazard model.

Results: Compared to men without any FDRs affected by cancer, the RRs of PC in men with one FDR affected by PCa-1 and PCa-2 were 2.12 (95% confidence interval [CI]: 2.07-2.17) and 1.69 (1.54-1.85), respectively. The risk in men with one FDR affected by PCa-2 was significantly lower than those with one FDR affected by PCa-1 after additionally adjusting for family relationship (father-son and brothers) and age at diagnosis of PC in FDR (RR , 0.85, 95% CI, 0.78-0.94). PC patients with a family history of PCa-2 were more likely to be detected at late-stage and less likely to be diagnosed by screening, compared to those with a family history of PCa-1. Patients whose PC was diagnosed after the diagnosis of PCa-1 in FDRs had a better survival than those without a family history of cancer (HR, 0.88, 95% CI, 0.80-0.97), but no such association was observed among patients with a family history of PCa-2.

Conclusion: Our study indicates a discrepancy between PC risks associated with a family history of PCa-1 and PC-2 and the reason behind it may be multifactorial.
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http://dx.doi.org/10.1002/cam4.4591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9119351PMC
May 2022

Prostate cancer incidence and survival in relation to prostate cancer as second cancer in relatives.

Cancer Med 2022 May 21;11(10):2117-2124. Epub 2022 Mar 21.

Center for Primary Health Care Research, Lund University/Region Skåne, Malmö, Sweden.

Objectives: To investigate if the risk of prostate cancer (PC) differs based on the order of primary PC diagnosed in first-degree relatives (FDRs) given possibly different risk factors for PC as first primary cancer (PCa-1) and second primary cancer (PCa-2).

Subjects And Methods: In this Swedish nationwide cohort, PC diagnosis was followed for among 149,985 men with one FDR affected by PCa-1, 10,972 with one FDR affected by PCa-2 and 2,896,561 without any FDRs affected by cancer in a maximum of 57 years. PC patients were further followed for death due to PC since diagnosis. Relative risk (RR) of PC was estimated with Poisson regression and hazard ratio (HR) with Cox proportional hazard model.

Results: Compared to men without any FDRs affected by cancer, the RRs of PC in men with one FDR affected by PCa-1 and PCa-2 were 2.12 (95% confidence interval [CI]: 2.07-2.17) and 1.69 (1.54-1.85), respectively. The risk in men with one FDR affected by PCa-2 was significantly lower than those with one FDR affected by PCa-1 after additionally adjusting for family relationship (father-son and brothers) and age at diagnosis of PC in FDR (RR , 0.85, 95% CI, 0.78-0.94). PC patients with a family history of PCa-2 were more likely to be detected at late-stage and less likely to be diagnosed by screening, compared to those with a family history of PCa-1. Patients whose PC was diagnosed after the diagnosis of PCa-1 in FDRs had a better survival than those without a family history of cancer (HR, 0.88, 95% CI, 0.80-0.97), but no such association was observed among patients with a family history of PCa-2.

Conclusion: Our study indicates a discrepancy between PC risks associated with a family history of PCa-1 and PC-2 and the reason behind it may be multifactorial.
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http://dx.doi.org/10.1002/cam4.4591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9119351PMC
May 2022

Familial Mortality Risks in Patients With Ischemic Stroke: A Swedish Sibling Study.

Stroke 2022 05 2;53(5):1615-1623. Epub 2022 Feb 2.

Center for Primary Health Care Research, Lund University/Region Skåne, Malmö, Sweden.

Background: The influence of familial factors on the prognosis of ischemic stroke (IS) is unknown. This nationwide follow-up study evaluated familial mortality risks of IS among Swedish sibling pairs hospitalized for IS.

Methods: We linked Swedish nationwide registers for the identification of 1380 Swedish born sibling pairs (2760 cases), where both siblings were hospitalized for first-time IS between 1991 and 2010. Median age was 62 years (range, 26-78 years). Sibling pairs with cancer were excluded. Familial hazard ratios (FHRs) for mortality after first IS hospitalization were determined with Cox regression. The influence of proband survival after IS was categorized as short sibling survival (<1, 2, 3, 4, or 5 years) or long sibling survival (≥1, 2, 3, 4, or 5 years) after IS. FHRs were adjusted for age at onset, sex, education, county, year of diagnosis, days of hospitalization, and comorbidities.

Results: Short sibling survival (ie, <3 or <4 years) after IS was associated with an adjusted FHR of 1.29 (95% CI, 1.05-1.58) and 1.24 (95% CI, 1.02-1.51), respectively, for overall mortality after IS. Stratified analysis showed that short sibling survival (ie, <2-<5 years) was stronger and significant only among younger individuals (<62 years) and males. Highest FHR for short sibling survival (ie, <4 years) was 1.42 (95% CI, 1.08-1.88) for younger individuals and 1.50 (95% CI, 1.21-1.87) for males. For young male subjects, FHR was 1.80 (95% CI, 1.33-2.46). In the adjusted model, mortality was also associated with sex, education, age at onset, year of diagnosis, days of hospitalization, coronary heart disease, diabetes, dementia, heart failure, obesity, alcoholism, and hyperlipidemia.

Conclusions: Our results suggest that family history of short survival in siblings after IS is associated with mortality after IS for younger male subjects. Additional studies are needed to characterize possible genetic and nongenetic familial environmental causes of this association.
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http://dx.doi.org/10.1161/STROKEAHA.121.035669DOI Listing
May 2022

Differences in genetic risk score profiles for drug use disorder, major depression, and ADHD as a function of sex, age at onset, recurrence, mode of ascertainment, and treatment.

Psychol Med 2022 Jan 31:1-13. Epub 2022 Jan 31.

Center for Primary Health Care Research, Lund University, Malmö, Sweden.

Background: Do genetic risk profiles for drug use disorder (DUD), major depression (MD), and attention-deficit hyperactivity disorder (ADHD) differ substantially as a function of sex, age at onset (AAO), recurrence, mode of ascertainment, and treatment?

Methods: Family genetic risk scores (FGRS) for MD, anxiety disorders, bipolar disorder, schizophrenia, alcohol use disorder, DUD, ADHD, and autism-spectrum disorder were calculated from 1st-5th degree relatives in the Swedish population born 1932-1995 (n = 5 829 952). Profiles of these FGRS were obtained and compared across various subgroups of DUD, MD, and ADHD cases.

Results: Differences in FGRS profiles for DUD, MD, and ADHD by sex were modest, but they varied substantially by AAO, recurrence, ascertainment, and treatment with scores typically higher in cases with greater severity (e.g. early AAO, high recurrence, ascertainment in high intensity clinical settings, and treatment). However, severity was not always related to purer genetic profiles, as genetic risk for many disorders often increased together. However, some results, such as by mode of ascertainment from different Swedish registries, produced qualitative differences in FGRS profiles.

Conclusions: Differences in FGRS profiles for DUD, MD, and ADHD varied substantially by AAO, recurrence, ascertainment, and treatment. Replication of psychiatric studies, particularly those examining genetic factors, may be difficult unless cases are matched not only by diagnosis but by important clinical characteristics. Genetic correlations between psychiatric disorders could arise through one disorder impacting on the patterns of ascertainment for the other, rather than from the direct effects of shared genetic liabilities.
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http://dx.doi.org/10.1017/S0033291721005535DOI Listing
January 2022

Differences in genetic risk score profiles for drug use disorder, major depression, and ADHD as a function of sex, age at onset, recurrence, mode of ascertainment, and treatment.

Psychol Med 2022 Jan 31:1-13. Epub 2022 Jan 31.

Center for Primary Health Care Research, Lund University, Malmö, Sweden.

Background: Do genetic risk profiles for drug use disorder (DUD), major depression (MD), and attention-deficit hyperactivity disorder (ADHD) differ substantially as a function of sex, age at onset (AAO), recurrence, mode of ascertainment, and treatment?

Methods: Family genetic risk scores (FGRS) for MD, anxiety disorders, bipolar disorder, schizophrenia, alcohol use disorder, DUD, ADHD, and autism-spectrum disorder were calculated from 1st-5th degree relatives in the Swedish population born 1932-1995 (n = 5 829 952). Profiles of these FGRS were obtained and compared across various subgroups of DUD, MD, and ADHD cases.

Results: Differences in FGRS profiles for DUD, MD, and ADHD by sex were modest, but they varied substantially by AAO, recurrence, ascertainment, and treatment with scores typically higher in cases with greater severity (e.g. early AAO, high recurrence, ascertainment in high intensity clinical settings, and treatment). However, severity was not always related to purer genetic profiles, as genetic risk for many disorders often increased together. However, some results, such as by mode of ascertainment from different Swedish registries, produced qualitative differences in FGRS profiles.

Conclusions: Differences in FGRS profiles for DUD, MD, and ADHD varied substantially by AAO, recurrence, ascertainment, and treatment. Replication of psychiatric studies, particularly those examining genetic factors, may be difficult unless cases are matched not only by diagnosis but by important clinical characteristics. Genetic correlations between psychiatric disorders could arise through one disorder impacting on the patterns of ascertainment for the other, rather than from the direct effects of shared genetic liabilities.
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http://dx.doi.org/10.1017/S0033291721005535DOI Listing
January 2022

The association of zonulin-related proteins with prevalent and incident inflammatory bowel disease.

BMC Gastroenterol 2022 Jan 3;22(1). Epub 2022 Jan 3.

Department of Clinical Sciences Malmö, Center for Primary Health Care Research, Institutionen För Kliniska Vetenskaper, Malmö (IKVM), Lund University, Inga-Marie Nilssons gata 53, Wallenberg Laboratory, plan 5, Box 50332, 202 13, Malmö, Sweden.

Background: Current evidence regarding the association of serum zonulin-related proteins (ZRP) levels with prevalent inflammatory bowel disease (IBD) is contradictory. Moreover, the association with the subsequent risk of incident IBD is still unexplored. This study aimed to investigate the association of serum ZRP levels with both prevalent and incident IBD.

Method: The study included a total of 130 women (51-61 years) from the Women's Health in Lund Area (WHILA) study, which included 18 prevalent IBD (diagnosed before baseline) and 47 incident IBD diagnosed during the 17 years (median) follow-up and age- and sampling time-matched controls. Serum ZRP was tested in all participants by ELISA.

Results: The serum ZRP levels were significantly higher in prevalent IBD compared to their matched controls (63.2 ng/ml vs 57.0 ng/ml, p = 0.02), however, no evidence of a difference in ZRP levels was found between the women who developed IBD during the follow-up period and their matched controls (61.2 ng/ml vs 59.7 ng/ml, p = 0.34). Using linear mixed models, we found that the association between serum ZRP levels and prevalent IBD (β = 6.2, p = 0.01), remained after adjusting for potential confounders. Conditional logistic regression models showed no evidence of an association between ZRP level and incident IBD (OR 1.03, p = 0.34).

Conclusion: Higher serum ZRP levels were associated with prevalent IBD, but not with incident IBD in our study samples.
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http://dx.doi.org/10.1186/s12876-021-02075-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8725386PMC
January 2022

Genetic and environmental influences on the progression from alcohol use disorder to alcohol-related medical conditions.

Alcohol Clin Exp Res 2021 12 19;45(12):2528-2535. Epub 2021 Dec 19.

Center for Primary Health Care Research, Lund University, Malmö, Sweden.

Background: Medical conditions related to alcohol use disorders (AUD) represent a substantial public health concern. However, only a subset of individuals with AUD develop these conditions and the extent to which genetic and environmental factors that are shared with AUD, versus those distinct from it, contribute to this progression has not yet been determined.

Methods: Using data from Swedish national registries for a cohort born from 1932 to 1970 (N = 1,319,214, 48.9% women), we conducted twin-sibling biometric model fitting to examine the genetic and environmental sources of variance that contribute to the liability to alcohol-related medical conditions (AMC). Progression to AMC, determined using medical registry data, was contingent on an AUD registration, which was determined using medical and criminal registry data.

Results: We identified AUD registrations in 3.2% of women and 9.2% of men. Among individuals with an AUD registration, 14.4% of women and 15.4% of men had an AMC registration. In the final models, we constrained the beta pathway from AUD to AMC and the genetic and unique environmental paths to be equal across sexes. The beta path was estimated at 0.59. AMC was modestly heritable in women (A = 0.32) and men (A = 0.30). The proportion of total heritability unique to AMC was 39.6% among women and 41.3% among men. A higher proportion of total environmental variance was unique to AMC: 76.7% for women and 77.2% for men. In a sensitivity analysis limited to liver-related AMC, we observed similar results, with a slightly lower beta path from AUD to AMC (0.46) and higher proportions of AMC-specific genetic (70.0% in women; 71.7% in men) and environmental (84.5% in both sexes) variance.

Conclusions: A moderate-to-substantial proportion of genetic and environmental variance that contributes to AMC risk is not shared with AUD, underscoring the need for additional gene identification efforts for AMC. Furthermore, the prominent influence of environmental factors specific to AMC provides a promising area for the identification of prevention targets. We did not observe significant sex differences in the etiology of AMC, although follow-up is warranted in other well-powered studies.
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http://dx.doi.org/10.1111/acer.14731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8712390PMC
December 2021

Familial Segregation of Venous Thromboembolism in Sweden: A Nationwide Family Study of Heritability and Complex Segregation Analysis.

J Am Heart Assoc 2021 12 16;10(24):e020323. Epub 2021 Dec 16.

Center for Primary Health Care Research Lund University/Region Skåne Malmö Sweden.

Background This is the first nationwide segregation analysis that aimed to determine whether familial venous thromboembolism (VTE) is attributable to inheritance and/or shared environment, and the possible mode of inheritance. Methods and Results The Swedish Multi-Generation Register was linked to the Swedish patient register for the period 1964 to 2015. Three generational families of Swedish-born individuals were identified. Heritability was examined using Falconer regression. Complex segregation analysis was conducted using the Statistical Analysis for Genetic Epidemiology software (version 6.4, 64-bit Linux). Among the 4 301 174 relatives from 450 558 pedigrees, 177 865 (52% women) individuals were affected with VTE. VTE occurred in 2 or more affected relatives in 61 217 (13.6%) of the pedigrees. Heritability showed age and sex dependence with higher heritability for men and young individuals. In 18 933 pedigrees, VTE occurred only in the first generation and was not inherited. Segregation analysis was performed in the remaining 42 284 pedigrees with inherited VTE and included 939 192 individuals. Prevalence constraints were imposed in the models to allow for the selection of the pedigrees analyzed. The sporadic nongenetic model could be discarded. The major-type-only model, with a correlation structure compatible with some polygenic effects, was the preferred model. Among the Mendelian models, the mixed codominant (plus polygenic) model was preferred. Conclusions This nationwide segregation analysis of VTE supports a genetic cause of the familial aggregation of VTE. Heritability was higher for men and younger individuals, suggesting a Carter effect, in agreement with a multifactorial threshold inheritance.
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http://dx.doi.org/10.1161/JAHA.120.020323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9075256PMC
December 2021

Association of circulating let-7b-5p with major depressive disorder: a nested case-control study.

BMC Psychiatry 2021 12 9;21(1):616. Epub 2021 Dec 9.

Center for Primary Health Care Research, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden.

Background: Major depressive disorder (MDD) is one of the most common psychiatric disorders and is a great disease burden. However, its underlying pathophysiology and aetiology remain poorly understood. Available evidence suggests that circulating microRNAs (miRNAs) are associated with MDD, but it is still unknown whether miRNAs can predict subsequent incident MDD.

Methods: In this nested case-control study, a total of 104 individuals, who were free of MDD at baseline, from the Women's Health in Lund Area (WHILA) cohort were included. Among them, 52 individuals developed MDD (cases) during the 5 years follow-up and 52 individuals did not develop MDD (controls). Plasma expression levels of miR-17-5p, miR-134-5p, miR-144-5p, let-7b-5p and let-7c-5p at baseline were assessed using qRT-PCR. Logistic regression was used to estimate the odds of developing MDD among individuals with different levels of miRNA expression.

Results: Plasma expression levels of let-7b-5p were significantly lower (p = 0.02) at baseline in cases compared to controls. After adjustment for age and BMI, let-7b-5p was negatively associated with odds for developing MDD (OR = 0.33, p = 0.03, 95% CI = 0.12-0.91). Moreover, let-7b-5p expression levels showed a trend over time with larger differences between cases and controls for the earlier cases (MDD diagnosis <2 years from baseline) than MDD cases developed later (MDD diagnosis 2-5 years from baseline).

Conclusions: These findings show that lower plasma levels of let-7b-5p are associated with a higher future risk of MDD. Results need to be validated in a large cohort to examine its potential as a peripheral biomarker for MDD.
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http://dx.doi.org/10.1186/s12888-021-03621-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8662878PMC
December 2021

Role of mitochondrial DNA copy number in incident cardiovascular diseases and the association between cardiovascular disease and type 2 diabetes: A follow-up study on middle-aged women.

Atherosclerosis 2022 01 1;341:58-62. Epub 2021 Dec 1.

Center for Primary Health Care Research, Lund University/Region Skåne, Malmö, 20502, Sweden. Electronic address:

Background And Aims: Mitochondrial DNA copy number (mtDNA-CN) is a surrogate biomarker of mitochondrial dysfunction and is associated with type 2 diabetes (T2D) and cardiovascular disease (CVD). However, despite being associated with both CVD and T2D, it is not known what role mtDNA-CN has in the association between T2D and CVD. Our aims were to investigate whether, (1) baseline mtDNA-CN is associated with CVD incidence and (2) mtDNA-CN has a role as a mediator between T2D and CVD.

Method: We quantified absolute mtDNA-CN by droplet digital PCR method in a population-based follow-up study of middle aged (52-65 years) women (n = 3062). The median follow-up period was 17 years.

Results: Our results show that low baseline levels of mtDNA-CN (<111 copies/μL) were associated with an increased risk of CVD (HR = 1.32, 95% CI = 1.08; 1.63) as well as with specific CVDs: coronary heart disease (HR = 1.28, 95% CI = 0.99; 1.66), stroke (HR = 1.26, 95% CI = 0.87; 1.84) and abdominal aortic aneurysm (HR = 2.61, 95% CI = 1.03; 6.62). The associations decreased but persisted even after adjustment for potential confounders. Furthermore, our results show that the total effect of T2D on future risk of CVD was reduced after controlling for mtDNA-CN and the proportion mediated by mtDNA-CN was estimated to be 4.9%.

Conclusions: Lower baseline mtDNA-CN is associated with incident CVD and may have a mediating effect on the association between T2D and CVD; however, this novel observation needs to be confirmed in future studies.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.11.020DOI Listing
January 2022

Pre-term delivery and long-term risk of heart failure in women: a national cohort and co-sibling study.

Eur Heart J 2021 Nov 24. Epub 2021 Nov 24.

Department of Family Medicine and Community Health, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, Suite L5-40, New York, NY 10029, USA.

Aims: Women who deliver pre-term have higher future risks of hypertension and ischaemic heart disease, but long-term risks of heart failure (HF) are unknown. We examined these risks in a large national cohort.

Methods And Results: All 2 201 284 women with a singleton delivery in Sweden during 1973-2015 were followed up for inpatient or outpatient HF diagnoses through 2015. Cox regression was used to compute hazard ratios (HRs) for HF associated with pregnancy duration, adjusting for other maternal factors. Co-sibling analyses assessed for confounding by shared familial (genetic and/or environmental) factors. In 48.2 million person-years of follow-up, 19 922 women were diagnosed with HF (median age: 60.7 years). Within 10 years after delivery, the adjusted HR was 2.96 [95% confidence interval (CI): 2.48-3.53] for HF associated with pre-term (gestational age: <37 weeks) compared with full-term (39-41 weeks) delivery. Stratified HRs were 4.27 (2.54-7.17) for extremely pre-term (22-27 weeks), 3.39 (2.57-4.48) for moderately pre-term (28-33 weeks), 2.70 (2.19-3.32) for late pre-term (34-36 weeks), and 1.70 (1.45-1.98) for early term (37-38 weeks). These HRs declined but remained elevated at 10-19 years (pre-term vs. full term: HR: 2.19; 95% CI: 1.94-2.46), 20-29 years (1.80; 1.67-1.95), and 30-43 years (1.56; 1.47-1.66) after delivery, and were not explained by shared familial factors.

Conclusion: Pre-term and early term delivery were associated with markedly increased future hazards for HF, which persisted after adjusting for other maternal and familial factors and remained elevated 40 years later. Pre-term and early-term delivery should be recognized as risk factors for HF across the life course.

Key Question: What are the long-term hazards for heart failure (HF) across the life course in women who deliver preterm?

Key Finding: Preterm and early term delivery were associated with ∼3- and 1.7-fold adjusted hazards for HF in the next 10 years vs. full-term delivery. These hazards declined but remained elevated 40 years later, and were not explained by shared familial factors.

Take Home Message: Preterm and early term delivery were associated with increased future hazards for HF, which persisted for 40 years after adjusting for other maternal and familial factors. Preterm and early term delivery should be recognized as lifelong risk factors for HF.
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http://dx.doi.org/10.1093/eurheartj/ehab789DOI Listing
November 2021

Family history of breast cancer as a second primary malignancy in relatives: a nationwide cohort study.

BMC Cancer 2021 Nov 12;21(1):1210. Epub 2021 Nov 12.

Center for Primary Health Care Research, Lund University/Region Skåne, Jan Waldenströms gata 35, 205 02, Malmö, Sweden.

Background: With the increasing number of breast cancer (BC) diagnosed as a second primary malignancy after a first primary non-breast cancer (BCa-2), it is unclear about the familial risk of BC among women with a first-degree relative (FDR, parents or siblings) affected by a BCa-2.

Methods: In this Swedish nationwide cohort study, 5315 women with a FDR affected by BCa-2 and 115,048 women with a FDR affected by BC as the first primary cancer (BCa-1) were followed for the first primary invasive BC diagnosis. Relative risk (RR) of BC was estimated through Poisson regression by using 2,743,777 women without a family history of cancer as reference. The risk was stratified by the diagnostic age of BC in FDR, proband type, the time interval between the first primary cancer and BCa-2 in FDR as well as the site of first primary cancer diagnosed in FDR before BCa-2. We also calculated the cumulative incidence of BC from birth to a specific age for the three groups.

Results: The cumulative incidence from birth to age 70 was 10% among women with a family history of BCa-2. The RR of BC with a family history of BCa-2 (RR, 1.68, 95%CI, 1.49 to 1.88) was comparable to that with BCa-1 (1.68, 1.63 to 1.73). The risk was largely consistent irrespective of proband type. The age of onset of BCa-2 in FDR (RR , 1.72 vs. RR 1.67) had less influence on the risk compared to BCa-1 in FDR (1.89 vs. 1.63). In the analysis stratified by the time between the first primary cancer and BCa-2 in relatives, the risks were largely similar. For the site of first primary cancer diagnosed in FDR before BCa-2, the increased BC risk was found in women whose FDRs were diagnosed with first primary gastric, colorectal, endometrial, ovarian, nervous system and endocrine gland cancers, and non-Hodgkin lymphoma.

Conclusions: Women with a family history of BCa-2 have a similar overall BC risk as those with a family history of BCa-1. The risk varied according to the site of first primary cancer diagnosed in FDR before BCa-2.
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http://dx.doi.org/10.1186/s12885-021-08925-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8590230PMC
November 2021

Drug use disorder and risk of incident and fatal prostate cancer among Swedish men: a nationwide epidemiological study.

Cancer Causes Control 2022 Feb 7;33(2):213-222. Epub 2021 Nov 7.

Center for Primary Health Care Research, Department of Clinical Sciences, Lund University/Region Skåne, Malmö, Sweden.

Purpose: Prostate cancer is the second most common cancer in men and a leading cause of cancer mortality worldwide. Men with drug use disorders (DUD) may potentially be at high risk for prostate cancer mortality because of delayed diagnosis and/or undertreatment. In this study, we aimed to investigate prostate cancer incidence, mortality, and stage at time of diagnosis among men with DUD compared to the general male population in Sweden.

Methods: We performed a follow-up study based on Swedish national register data for the period January 1997-December 2016. The study was based on 1,361,532 men aged 50-75 years at inclusion, of whom 9,259 were registered with DUD. Cox regression analysis was used to compute adjusted hazard ratios (HRs) for incident and fatal prostate cancer, and cancer stage at time of diagnosis, associated with DUD.

Results: DUD was associated with a slightly increased risk of incident prostate cancer (HR: 1.07, 95% confidence interval [CI] 1.00-1.14, p = 0.048) and substantially higher risk of fatal prostate cancer (HR: 1.59, 95% CI 1.40-1.82, p < 0.001), adjusted for age, socioeconomic factors, and comorbidities related to tobacco smoking and alcohol use disorder. No association was found between DUD and prostate cancer stage at diagnosis.

Conclusions: Men with DUD have an increased risk of fatal prostate cancer, possibly related to undertreatment in this patient population. Our findings should raise attention among medical staff and decision-makers towards a disadvantaged group of men in need of easily accessible prostate cancer evaluation and treatment.
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http://dx.doi.org/10.1007/s10552-021-01513-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8776671PMC
February 2022

Drug use disorder and risk of incident and fatal prostate cancer among Swedish men: a nationwide epidemiological study.

Cancer Causes Control 2022 Feb 7;33(2):213-222. Epub 2021 Nov 7.

Center for Primary Health Care Research, Department of Clinical Sciences, Lund University/Region Skåne, Malmö, Sweden.

Purpose: Prostate cancer is the second most common cancer in men and a leading cause of cancer mortality worldwide. Men with drug use disorders (DUD) may potentially be at high risk for prostate cancer mortality because of delayed diagnosis and/or undertreatment. In this study, we aimed to investigate prostate cancer incidence, mortality, and stage at time of diagnosis among men with DUD compared to the general male population in Sweden.

Methods: We performed a follow-up study based on Swedish national register data for the period January 1997-December 2016. The study was based on 1,361,532 men aged 50-75 years at inclusion, of whom 9,259 were registered with DUD. Cox regression analysis was used to compute adjusted hazard ratios (HRs) for incident and fatal prostate cancer, and cancer stage at time of diagnosis, associated with DUD.

Results: DUD was associated with a slightly increased risk of incident prostate cancer (HR: 1.07, 95% confidence interval [CI] 1.00-1.14, p = 0.048) and substantially higher risk of fatal prostate cancer (HR: 1.59, 95% CI 1.40-1.82, p < 0.001), adjusted for age, socioeconomic factors, and comorbidities related to tobacco smoking and alcohol use disorder. No association was found between DUD and prostate cancer stage at diagnosis.

Conclusions: Men with DUD have an increased risk of fatal prostate cancer, possibly related to undertreatment in this patient population. Our findings should raise attention among medical staff and decision-makers towards a disadvantaged group of men in need of easily accessible prostate cancer evaluation and treatment.
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http://dx.doi.org/10.1007/s10552-021-01513-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8776671PMC
February 2022

Conduct Disorder in Immigrant Children and Adolescents: A Nationwide Cohort Study in Sweden.

Int J Environ Res Public Health 2021 10 11;18(20). Epub 2021 Oct 11.

Center for Primary Health Care Research, Lund University, SE-221 00 Malmö, Sweden.

Introduction: Conduct disorder is a psychiatric diagnosis characterized by repetitive and persistent norm-breaking behavior. This study aimed to compare the risk of conduct disorder between first- and second-generation immigrant children and adolescents and their native controls.

Methods: In this nationwide, open-cohort study from Sweden, participants were born 1987-2010, aged 4-16 years at baseline, and were living in the country for at least one year during the follow-up period between 2001 and 2015. The sample included 1,902,526 and 805,450 children-adolescents with native and immigrant backgrounds, respectively. Data on the conduct disorder diagnoses were retrieved through the National Patient Register. We estimated the incidence of conduct disorder and calculated adjusted Hazard Ratios.

Results: Overall, the adjusted risk of conduct disorder was lower among first-generation immigrants and most second-generation immigrant groups compared with natives (both males and females). However, second-generation immigrants with a Swedish-born mother and a foreign-born father had a higher risk of conduct disorder than natives. Similar results were found for sub-diagnoses of conduct disorder.

Conclusions: The higher risk of conduct disorder among second-generation immigrants with a Swedish-born mother and the lower risk among most of the other immigrant groups warrants special attention and an investigation of potential underlying mechanisms.
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http://dx.doi.org/10.3390/ijerph182010643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8535976PMC
October 2021

Types of second primary cancer influence overall survival in cutaneous melanoma.

BMC Cancer 2021 Oct 19;21(1):1123. Epub 2021 Oct 19.

Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120, Heidelberg, Germany.

Background: Favorable survival in malignant cutaneous melanoma (melanoma) has increased the likelihood of second primary cancer (SPC). We assess the influence of patient characteristics at diagnosis of first melanoma and the type of SPC (second melanoma and other SPC) on overall survival.

Methods: We used the Swedish Cancer Registry data to assess overall survival in melanoma for the period 1990 to 2015. Kaplan-Meier curves were plotted and hazard ratios (HRs) were estimated with Cox regression models by considering SPC diagnosis as a time-dependent variable.

Results: A total of 46,726 patients were diagnosed with melanoma, and 15.3% of them developed SPC, among which, two thirds were other SPCs. Second melanomas were diagnosed early (31% during the first year) compared to non-melanoma SPCs (9.5%). Survival for women with second melanoma or other SPC (56 and 21% alive after 25 years of follow-up, respectively) exceeded the male rates (21 and 10%, respectively) but all these figures were lower than for females (60% alive) or males (48%) without SPC. Time dependent analysis showed vastly increased HRs for cancer types that are fatal also as first cancers, but SPC-specific HRs remained relatively uniform, irrespective of SPC diagnosed soon or late after first melanoma. In early-onset melanoma, SPC diagnosis after 10 years may not negatively influence overall survival.

Conclusions: As the overall survival of patients with many types of SPCs is unfavorable, advice about health lifestyle should benefit smoking patients and early detection methods may be recommended for SPCs of the breast, prostate and colorectum.
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http://dx.doi.org/10.1186/s12885-021-08845-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8524825PMC
October 2021

Preterm Delivery and Long-term Risk of Hypertension in Women.

JAMA Cardiol 2022 01;7(1):65-74

Department of Family Medicine and Community Health, Icahn School of Medicine at Mount Sinai, New York, New York.

Importance: Preterm delivery has been associated with future cardiometabolic disorders in women. However, the long-term risks of chronic hypertension associated with preterm delivery and whether such risks are attributable to familial confounding are unclear. Such knowledge is needed to improve long-term risk assessment, clinical monitoring, and cardiovascular prevention strategies in women.

Objective: To examine the long-term risks of chronic hypertension associated with preterm delivery in a large population-based cohort of women.

Design, Setting, And Participants: This national cohort study assessed all 2 195 989 women in Sweden with a singleton delivery from January 1, 1973, to December 31, 2015. Data analyses were conducted from March 8, 2021, to August 20, 2021.

Exposures: Pregnancy duration identified from nationwide birth records.

Main Outcomes And Measures: New-onset chronic hypertension identified from primary care, specialty outpatient, and inpatient diagnoses using administrative data. Cox proportional hazards regression was used to compute hazard ratios (HRs) while adjusting for preeclampsia, other hypertensive disorders of pregnancy, and other maternal factors. Cosibling analyses were assessed for potential confounding by shared familial (genetic and/or environmental) factors.

Results: In 46.1 million person-years of follow-up, 351 189 of 2 195 989 women (16.0%) were diagnosed with hypertension (mean [SD] age, 55.4 [9.9] years). Within 10 years after delivery, the adjusted HR for hypertension associated with preterm delivery (gestational age <37 weeks) was 1.67 (95% CI, 1.61-1.74) and when further stratified was 2.23 (95% CI, 1.98-2.52) for extremely preterm (22-27 weeks of gestation), 1.85 (95% CI, 1.74-1.97) for moderately preterm (28-33 weeks of gestation), 1.55 (95% CI, 1.48-1.63) for late preterm (34-36 weeks of gestation), and 1.26 (95% CI, 1.22-1.30) for early-term (37-38 weeks of gestation) compared with full-term (39-41 weeks of gestation) delivery. These risks decreased but remained significantly elevated at 10 to 19 years (preterm vs full-term delivery: adjusted HR, 1.40; 95% CI, 1.36-1.44), 20 to 29 years (preterm vs full-term delivery: adjusted HR, 1.20; 95% CI, 1.18-1.23), and 30 to 43 years (preterm vs full-term delivery: adjusted HR, 95% CI, 1.12; 1.10-1.14) after delivery. These findings were not explained by shared determinants of preterm delivery and hypertension within families.

Conclusions And Relevance: In this large national cohort study, preterm delivery was associated with significantly higher future risks of chronic hypertension. These associations remained elevated at least 40 years later and were largely independent of other maternal and shared familial factors. Preterm delivery should be recognized as a lifelong risk factor for hypertension in women.
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http://dx.doi.org/10.1001/jamacardio.2021.4127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8515256PMC
January 2022

The impact of sex, age at onset, recurrence, mode of ascertainment and medical complications on the family genetic risk score profiles for alcohol use disorder.

Psychol Med 2021 Oct 8:1-9. Epub 2021 Oct 8.

Center for Primary Health Care Research, Lund University, Malmö, Sweden.

Background: Alcohol use disorder (AUD) is clinically heterogeneous. We examine its potential genetic heterogeneity as a function of sex, age, clinical features and mode of ascertainment.

Methods: In the Swedish population born 1932-1995 (n = 5 829 952), we examined the genetic risk profiles for AUD, major depression (MD), anxiety disorders, bipolar disorder, drug use disorder (DUD), attention deficit-hyperactivity disorder (ADHD) and criminal behavior (CB) in 361 124 cases of AUD subdivided by sex, age at onset (AAO), recurrence, mode of ascertainment and medical complications. Family genetic risk scores (FGRS), calculated from 1st to 5th-degree relatives controlling of cohabitation, assesses genetic risk from phenotypes in the family, not from DNA variants.

Results: FGRS profiles differed modestly across sex with all scores higher in females. Differences were more pronounced for AAO and recurrence with the FGRS for AUD, DUD, ADHD and CB substantially higher in cases with early AAO or high recurrence rates. Genetic profiles differed considerably by mode of ascertainment, with higher FGRS for AUD and most other disorders in patients seen in hospital v. primary care settings. Cases of AUD with medical complications had higher FGRS for AUD. AUD cases comorbid with MD and DUD had higher FGRS risk for AUD, but this genetic may be less specific given increases in FGRS for multiple other disorders.

Conclusions: From a genetic perspective, AUD differs substantially as a function of AAO, recurrence, mode of ascertainment and patterns of comorbidity, suggesting caution in cross-sample comparisons of AUD cohorts that differ in these features.
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http://dx.doi.org/10.1017/S0033291721003317DOI Listing
October 2021
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