Birth Anomalies in Monozygotic and Dizygotic Twins: Results From the California Twin Registry.

BACKGROUND: Inherited factors and maternal behaviors are thought to play an important role in the etiology of several congenital malformations. Twin studies can offer additional evidence regarding the contribution of genetic and lifestyle factors to common birth anomalies, but few large-scale studies have been reported. METHODS: We included data from twins (20,803 pairs) from the population-based California Twin Program. We compared concordance in monozygotic (MZ) to dizygotic (DZ) twins for the following birth anomalies: clubfoot, oral cleft, spina bifida, muscular dystrophy, deafness, cerebral palsy, strabismus, and congenital heart defects. Each birth anomaly was also examined for the associations with birth characteristics (birthweight and birth order) and parental exposures (age, smoking, and parental education). RESULTS: The overall prevalence of any selected birth anomaly in California twins was 38 per 1,000 persons, with a slightly decreasing trend from 1957-1982. For pairwise concordance in 6,752 MZ and 7,326 like-sex DZ twin pairs, high MZ:DZ concordance ratios were observed for clubfoot (CR 5.91; P = 0.043) and strabismus (CR 2.52; P = 0.001). Among the total 20,803 pairs, parental smoking was significantly associated with risk of spina bifida (OR 3.48; 95% CI, 1.48-8.18) and strabismus (OR 1.61; 95% CI, 1.28-2.03). A significant quadratic trend of increasing risk for clubfoot, spina bifida, and strabismus was found when examining whether father smoked, mother smoked, or both parents smoked relative to non-smoking parents (P = 0.029, 0.026, and 0.0005, respectively). CONCLUSIONS: Our results provide evidence for a multifactorial etiology underlying selected birth anomalies. Further research is needed to understand the biological mechanisms.

Prevalence and predictors of recent skin examination in a population-based twin cohort.

BACKGROUND: The incidence of melanoma is increasing worldwide. Guidelines for clinical skin exam for improving early diagnosis of melanoma remain inconsistent, and current data on factors associated with regular skin screening on a population basis are limited. METHODS: We used self-reported data from 50,044 members of the California Twin Program, a population-based cohort of twins born in California between 1908 and 1982, to identify prevalence and determinants of recent clinical screening for skin cancer. RESULTS: Prevalence of skin examination was higher than national estimates, with 32% of respondents of all ages reporting ever having skin examination. Sociodemographic and constitutional risk factors including white race, educational attainment, marital status, and number of large moles were strongly associated with recent screening, as were individual and family history of skin cancer. Lower socioeconomic status, racial/ethnic minority status, and paradoxically, frequent UV-related risk behaviors in adulthood were associated with a lower likelihood of recent screening. CONCLUSIONS: As the evidence concerning the efficacy of skin examination continues to evolve, attention should be paid to motivators and barriers of screening, particularly in high-risk subgroups where lack of screening may contribute to disparate rates of thicker melanomas and lower survival. IMPACT: Our results demonstrate the need for prevention strategies targeted to specific at-risk groups to increase earlier detection leading to improved outcomes.

Childhood infections and adult height in monozygotic twin pairs.

Adult height is determined by genetics and childhood nutrition, but childhood infections may also play a role. Monozygotic twins are genetically matched and offer an advantage when identifying environmental determinants. In 2005-2007, we examined the association of childhood infections with adult height in 140 height-discordant monozygotic twin pairs from the California Twin Program. To obtain information on childhood infections and growth, we interviewed the mothers of monozygotic twins who differed in self-reported adult height by at least 1-inch (2.5 cm). Within-pair differences in the relative frequency of childhood infections were highly correlated, especially within age groups. A conditional logistic regression analysis demonstrated that more reported episodes of febrile illness occurred in the twin with shorter stature (odds ratio = 2.00, 95% confidence interval: 1.18, 3.40). The association was strongest for differences in the relative frequency of infection during the toddler years (ages 1-5: odds ratio = 3.34, 95% confidence interval: 1.47, 7.59) and was similar when restricted to twin pairs of equal birth length. The association was not explained by differential nutritional status. Measures of childhood infection were associated with height difference in monozygotic twin pairs, independent of genome, birth length, and available measures of diet.

The USC Adult Twin Cohorts: International Twin Study and California Twin Program.

The study of twin subjects permits the documentation of crude heritability and may promote the identification of specific causal alleles. We believe that at the current time, the chief research advantage of twins as subjects, especially monozygotic twins, is that the commonality of their genetic and cultural identity simplifies the interpretation of biological associations. In order to study genetic and environmental determinants of cancer and chronic diseases, we developed two twin registries, maintained at the University of Southern California: The International Twin Study (ITS) and the California Twin Program (CTP). The ITS is a volunteer registry of twins with cancer and chronic disease consisting of 17,245 twin pairs affected by cancer and chronic disease, respectively, ascertained by advertising in periodicals from 1980-1991. The CTP is a population-based registry of California-born twin pairs ascertained by linking the California birth records to the State Department of Motor Vehicles. Over 51,000 individual California twins representing 36,965 pairs completed and returned 16-page questionnaires. Cancer diagnoses in the California twins are updated by regular linkage to the California Cancer Registry. Over 5,000 cancer patients are represented in the CTP. Twins from both registries have participated extensively in studies of breast cancer, melanoma, lymphoma, multiple sclerosis, systemic lupus erythematosus, diabetes mellitus type 1, mammographic density, smoking, and other traits and conditions.

Prostate cancer and ambient pesticide exposure in agriculturally intensive areas in California.

In a population-based case-control study in California's intensely agricultural Central Valley (2005-2006), the authors investigated relations between environmental pesticide/fungicide exposure and prostate cancer. Cases (n = 173) were obtained from a population-based cancer registry, and controls (n = 162) were obtained from Medicare listings and tax assessor mailings. Past ambient exposures to pesticides/fungicides were derived from residential history and independently recorded pesticide and land-use data, using a novel geographic information systems approach. In comparison with unexposed persons, increased risks of prostate cancer were observed among persons exposed to compounds which may have prostate-specific biologic effects (methyl bromide (odds ratio = 1.62, 95% confidence interval: 1.02, 2.59) and a group of organochlorines (odds ratio = 1.64, 95% confidence interval: 1.02, 2.63)) but not among those exposed to other compounds that were included as controls (simazine, maneb, and paraquat dichloride). The authors assessed the possibility of selection bias due to less-than-100% enrollment of eligible cases and controls (a critical methodological concern in studies of this kind) and determined that there was little evidence of bias affecting the estimated effect size. This study provides evidence of an association between prostate cancer and ambient pesticide exposures in and around homes in intensely agricultural areas. The associations appear specific to compounds with a plausible biologic role in prostate carcinogenesis.

The expanding melanoma burden in California hispanics: Importance of socioeconomic distribution, histologic subtype, and anatomic location.

BACKGROUND: The incidence patterns and socioeconomic distribution of cutaneous melanoma among Hispanics are poorly understood. METHODS: The authors obtained population-based incidence data for all Hispanic and non-Hispanic white (NHW) patients who were diagnosed with invasive cutaneous melanoma from 1988 to 2007 in California. By using a neighborhood-level measure of socioeconomic status (SES), the variables investigated included incidence, thickness at diagnosis, histologic subtype, anatomic site, and the relative risk (RR) for thicker (>2 mm) versus thinner (≤ 2 mm) tumors at diagnosis for groups categorized by SES. RESULTS: Age-adjusted melanoma incidence rates per million were higher in NHWs (P < .0001), and tumor thickness at diagnosis was greater in Hispanics (P < .0001). Sixty-one percent of melanomas in NHWs occurred in the High SES group. Among Hispanics, only 35% occurred in the High SES group; and 22% occurred in the Low SES group. Lower SES was associated with thicker tumors (P < .0001); this association was stronger in Hispanics. The RR of thicker tumors versus thinner tumors (≤ 2 mm) in the Low SES group versus the High SES group was 1.48 (95% confidence interval [CI], 1.37-1.61) for NHW men and 2.18 (95% CI, 1.73-2.74) for Hispanic men. Patients with lower SES had less of the superficial spreading melanoma subtype (especially among Hispanic men) and more of the nodular melanoma subtype. Leg/hip melanomas were associated with higher SES in NHW men but with lower SES in Hispanic men. CONCLUSIONS: The socioeconomic distribution of melanoma incidence and tumor thickness differed substantially between Hispanic and NHW Californians, particularly among men. Melanoma prevention efforts targeted to lower SES Hispanics and increased physician awareness of melanoma patterns among Hispanics are needed.

Interaction of area-level socioeconomic status and UV radiation on melanoma occurrence in California.

BACKGROUND: Melanoma incidence has been correlated strongly and positively with both socioeconomic status (SES) and lower latitude and other measures of ambient UV radiation (UVR). However, because high-SES populations may be colocated in areas of high UVR, we assessed their joint influences on melanoma occurrence to better target subpopulations for melanoma education and screening. METHODS: We obtained from the California Cancer Registry information regarding 23,564 incident cases of invasive cutaneous melanoma among non-Hispanic white residents between January 1, 1998, and December 31, 2002. We geocoded each case based on residence at diagnosis and linked previously tested neighborhood measures of SES and average annual UVR to calculate age-adjusted incidence rates, rate ratios, and the corresponding 95% confidence intervals. Poisson regression was used to calculate multivariately adjusted rate ratios. RESULTS: UVR was significantly and positively associated with melanoma incidence only among persons living in the top 40% of California neighborhoods ranked by SES. People in neighborhoods of the highest SES and UVR categories had 60% higher rates of melanoma than those from neighborhoods in the lowest categories (rate ratio, 1.60; 95% confidence interval, 1.02-2.51). CONCLUSION: Our findings indicate that UVR and SES interact to influence melanoma occurrence and suggest that socioeconomic gradients in melanoma incidence are not explained entirely by UVR. IMPACT: Cancer prevention and early detection educational efforts should be targeted to high-SES groups in areas of high UVR exposure. Contextual measures of both SES and UVR should be considered important determinants of melanoma occurrence in future studies.

Use of an electrostatic dust cloth for self-administered home allergen collection.

Most epidemiologic studies employ a vacuum cleaner used by a trained technician to collect household allergens. This approach is labor intensive, equipment dependent, and impractical if study subjects reside over a wide geographic area. We examined the feasibility of a self-administered dust collection method, using an electrostatic cloth sent by conventional mail, to obtain allergen measurements. Thirty-two nonasthmatic twins from the California Twin Program wiped areas in the family room, kitchen, and bedroom, according to standardized instructions, and returned the cloths by mail. Allergen concentrations for Der-p-1, Der-f-1, Fel-d-1, and Bla-g-2 were determined using ELISA, and intrahouse and room-to-room concentrations were compared. Der-p-1 and Fel-d-1 were found in most homes, with highest concentrations in bedrooms and kitchens, respectively. Der-f-1 and Bla-g-2 were rarely found. Intrahouse Der-p-1 and Fel-d-1 concentrations were highly correlated and statistically significant (for Der-p-1, bedroom vs. kitchen, p=.0003, bedroom vs. family room, p=.0001, and family room vs. kitchen, p=.002; for Fel-d-1, bedroom vs. kitchen, p=.0004, bedroom vs. family room, p<.0001, and family room vs. kitchen, p=.0001). Reported cat ownership was strongly correlated with household Fel-d-1 concentrations (p<.005). In another comparison from different homes of children enrolled in the La Casa atopy prevention study, allergen concentrations measured from dust collected by a single operator from the left and right half of the same room in 21 homes were compared. Levels of Bla-g-2, Der-p-1, and Fel-d-1 concentrations collected from right and left halves of the same room were highly correlated, with r2 ranging from .7 to .9, and were highly statistically significant (all p values<.01). We conclude that nonintrusive and self-administered dust collection, using commercially available electrostatic dust cloths, sent by conventional mail services, is a promising alternative to technician-collected vacuumed dust for measuring indoor allergens in population-based studies, although further validation of the method is necessary.

Interleukin-6-related genotypes, body mass index, and risk of multiple myeloma and plasmacytoma.

Interleukin-6 (IL-6) promotes normal plasma cell development and proliferation of myeloma cells in culture. We evaluated IL-6 genotypes and body mass index (BMI) in a case-control study of multiple myeloma and plasmacytoma. DNA samples and questionnaires were obtained from incident cases of multiple myeloma (n = 134) and plasmacytoma (n = 16; plasma cell neoplasms) ascertained from the Los Angeles County population-based cancer registry and from siblings or cousins of cases (family controls, n = 112) and population controls (n = 126). Genotypes evaluated included IL-6 promoter gene single nucleotide polymorphisms (SNP) at positions -174, -572, and -597; one variable number of tandem repeats (-373 A(n)T(n)); and one SNP in the IL-6 receptor (IL-6ralpha) gene at position -358. The variant allele of the IL-6 promoter SNP -572 was associated with a roughly 2-fold increased risk of plasma cell neoplasms when cases were compared with family [odds ratio (OR), 1.8; 95% confidence interval (95% CI), 0.7-4.7] or population controls (OR, 2.4; 95% CI, 1.2-4.7). The -373 9A/9A genotype was associated with a decreased risk compared with the most common genotype (OR for cases versus family controls, 0.4; 95% CI, 0.1-1.7; OR for cases versus population controls, 0.3; 95% CI, 0.1-0.9). No other SNPs were associated with risk. Obesity (BMI >or= 30 kg/m(2)) increased risk nonsignificantly by 40% and 80% when cases were compared with family controls or population controls, respectively, relative to persons with a BMI of <25 kg/m(2). These results suggest that IL-6 promoter genotypes may be associated with increased risk of plasma cell neoplasms.

Developing epidemic of melanoma in the Hispanic population of California.

BACKGROUND: Hispanics comprise almost one-third of the population of California, are the most rapidly increasing racial/ethnic group in the state, and represent almost one-third of all Hispanics in the U.S. California has among the highest rates of melanoma in the world, yet little is known about trends in melanoma in its Hispanic population. METHODS: Trends in invasive and in situ melanoma incidence data and melanoma mortality data, between 1988 and 2001, from the California Cancer Registry were analyzed. Trends in the Hispanic population were compared with those in the non-Hispanic white population. Time trends in tumors of differing thicknesses and histology were assessed. RESULTS: There was a statistically significant 1.8% per year increase in incidence of invasive melanomas among Hispanic males and a similar but non-statistically significant increase in invasive melanoma among Hispanic females between 1988 and 2001. Among Hispanic males and females tumors thicker than 1.5 mm at presentation increased at 11.6% per year (95% confidence interval [CI], 8.1, 15.2) and 8.9% per year (95% CI, 4.7, 13.3), respectively. CONCLUSION: Rates of invasive melanoma have increased markedly among Hispanics in California since 1988. In contrast to trends in the non-Hispanic white population, increases in melanoma in Hispanics have been confined to thicker tumors, whose prognosis is poor. We recommend that efforts be undertaken immediately to target both primary and secondary melanoma prevention messages to Hispanic communities.

Twins as willing research participants: successes from studies nested within the California Twin Program.

The California Twin Program (CTP) is a population-based sample of over 52,000 twins in which a number of nested studies are ongoing. We outline our experience to date, providing estimates of crude response rates for a variety of different study designs and protocols. We have experienced very high response rates in our studies to date, even in studies with demanding protocols. Lowest response rates have occurred in studies among afflicted individuals, and in one with an unusual protocol. We have experienced some difficulty in locating original members of the cohort, despite efforts to trace individuals using a variety of sources of information. However, in most analyses, the participating sample of twins does not differ substantially from the underlying sample from the CTP. Future work will focus on improving methods of re-contacting cohort members.

Th1 and Th2 cytokines and IgE levels in identical twins with varying levels of cigarette consumption.

Some have suggested that tobacco smoke may skew the immune system toward a Th2 pattern, however the effects of genetics or childhood exposures could explain these results. We compared PMBC supernatant or serum Th1 (INF-gamma) and Th2 (IL-4, IL-5, and IL-13) cytokine and IgE levels in members of 45 pairs of nonasthmatic monozygotic twins with varying levels of current cigarette consumption to determine if smoking was associated with Th1/Th2 function after accounting for genetic factors. A statistically significant dose-response was observed between levels of smoking and IL-13 (p=0.05). Mean IL-13 level among heavy smokers (20+ cigarettes/day) was 146% higher than that among nonsmokers (+26.2 pg/mL; p=0.04). The mean IL-5 level among heavy smokers was 166% higher than that among light (<20 cigarettes/day) smokers (+3.4 pg/mL; p=0.03). No statistically significant differences in INF-gamma, IL-4, or IgE levels were observed. Smoking appears to be associated with increased levels of IL-13.

The occurrence of chronic disease and other conditions in a large population-based cohort of native Californian twins.

We describe the prevalence of chronic diseases and conditions in a large cohort of twins, which has been developed to facilitate studies of the role of genetics and environment in the development of disease. The California Twin Program (CTP) comprises twins born in California between 1908 and 1982. Birth records from all multiple births (256,616 in total) were linked (multiple times between 1990 and 2001) with the California Department of Motor Vehicles (DMV) roster of licensees to obtain address information. The linkages have revealed 161,109 matches and, because of less complete DMV records in some years, were less successful in older females than in all others. To date over 51,000 of these twins have completed a detailed 16-page mailed risk factor questionnaire. Based on estimates of numbers of individuals receiving a questionnaire, our crude response rates are as high as 63.6% (among females currently in their 50s), with an overall crude response rate of 37.9%. Similar to our previous report regarding the first 42,000 twins, the current group who have completed the questionnaire are representative of the population from which they were drawn (in terms of age, sex, race and residential distribution). Self-reported disease frequencies are provided, along with current estimates of future cancer incidence and mortality rates likely to be observed in the group. We outline our plans for cohort expansion, additional studies using the cohort, and future plans for inviting collaboration.