Kauko Heikkilä

IMPORTANCE: Estimates of familial cancer risk from population-based studies are essential components of cancer risk prediction. OBJECTIVE: To estimate familial risk and heritability of cancer types in a large twin cohort. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 80,309 monozygotic and 123,382 same-sex dizygotic twin individuals (N = 203,691) within the population-based registers of Denmark, Finland, Norway, and Sweden. Twins were followed up a median of 32 years between 1943 and 2010. There were 50,990 individuals who died of any cause, and 3804 who emigrated and were lost to follow-up. EXPOSURES: Shared environmental and heritable risk factors among pairs of twins. MAIN OUTCOMES AND MEASURES: The main outcome was incident cancer. Time-to-event analyses were used to estimate familial risk (risk of cancer in an individual given a twin's development of cancer) and heritability (proportion of variance in cancer risk due to interindividual genetic differences) with follow-up via cancer registries. Statistical models adjusted for age and follow-up time, and accounted for censoring and competing risk of death. RESULTS: A total of 27,156 incident cancers were diagnosed in 23,980 individuals, translating to a cumulative incidence of 32%. Cancer was diagnosed in both twins among 1383 monozygotic (2766 individuals) and 1933 dizygotic (2866 individuals) pairs. Of these, 38% of monozygotic and 26% of dizygotic pairs were diagnosed with the same cancer type. There was an excess cancer risk in twins whose co-twin was diagnosed with cancer, with estimated cumulative risks that were an absolute 5% (95% CI, 4%-6%) higher in dizygotic (37%; 95% CI, 36%-38%) and an absolute 14% (95% CI, 12%-16%) higher in monozygotic twins (46%; 95% CI, 44%-48%) whose twin also developed cancer compared with the cumulative risk in the overall cohort (32%). For most cancer types, there were significant familial risks and the cumulative risks were higher in monozygotic than dizygotic twins. Heritability of cancer overall was 33% (95% CI, 30%-37%). Significant heritability was observed for the cancer types of skin melanoma (58%; 95% CI, 43%-73%), prostate (57%; 95% CI, 51%-63%), nonmelanoma skin (43%; 95% CI, 26%-59%), ovary (39%; 95% CI, 23%-55%), kidney (38%; 95% CI, 21%-55%), breast (31%; 95% CI, 11%-51%), and corpus uteri (27%; 95% CI, 11%-43%). CONCLUSIONS AND RELEVANCE: In this long-term follow-up study among Nordic twins, there was significant excess familial risk for cancer overall and for specific types of cancer, including prostate, melanoma, breast, ovary, and uterus. This information about hereditary risks of cancers may be helpful in patient education and cancer risk counseling.

OBJECTIVE: The authors investigated whether self-reported life satisfaction predicted suicide over a period of 20 years (1976-1995) in adults unselected for mental health status. METHOD: A nationwide sample of adults aged 18-64 years (N=29,173) from the Finnish Twin Cohort responded to a health questionnaire that included a life satisfaction scale (score range=4-20, with higher scores indicating greater dissatisfaction) that covered four items: interest in life, happiness, general ease of living, and feeling of loneliness. "Dissatisfied" subjects (life satisfaction score=12-20) were compared to "satisfied" subjects (score=4-6). Mortality data were derived from the national registry and analyzed with Cox regression. RESULTS: Dissatisfaction at baseline (life satisfaction score=12-20) was associated with a higher risk of suicide throughout the 20-year follow-up period (age-adjusted hazard ratio=3.02, 95% confidence interval [CI]=1.83-4.98). The association was somewhat stronger in the first decade (hazard ratio=4.46, 95% CI=1.95-10.20) than in the second (hazard ratio=2.34, 95% CI=1.24-4.45). A dose-response relationship was also found. Men with the highest degrees of dissatisfaction (life satisfaction score=19-20) were 24.85 times as prone to commit suicide as satisfied men during the first 10 years of the follow-up period. Throughout the entire follow-up, life dissatisfaction still predicted suicide after adjusting for age, sex, baseline health status, alcohol consumption, smoking status, and physical activity (hazard ratio=1.74, 95% CI=1.02-2.97). Subjects who reported dissatisfaction at baseline and again 6 years later showed a high suicide risk (hazard ratio=6.84, 95% CI=1.99-23.50) compared to those who repeatedly reported satisfaction. CONCLUSIONS: Life dissatisfaction has a long-term effect on the risk of suicide, and this seems to be partly mediated through poor health behavior. Life satisfaction seems to be a composite health indicator.

Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant).