Family history of cancer in children with acute leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma: the ESCALE study (SFCE)

The role of a family history of cancer in the etiology of childhood hematopoietic malignancies was investigated using the data from the ESCALE study. ESCALE, a population-based case-control study, was carried out in France over the period, 2003-2004. A total of 773 cases of acute leukemia (AL), 130 of Hodgkin's lymphoma (HL), 163 of non-Hodgkin's lymphoma (NHL) and 1,681 population-based controls were included. The controls were randomly selected from the French population and were frequency matched with the cases on age and gender. Cancer history in first- and second-degree relatives was reported by the mothers in a structured telephone questionnaire that was the same for the cases and controls. Odds ratios (ORs) were estimated using an unconditional regression model taking into account the stratification variables and potential confounders. A family history of cancer was associated with an increased risk of HL (OR = 1.5 [1.0-2.2]) and NHL (OR = 1.8 [1.3-2.5]), but not AL (OR = 1.0 [0.9-1.2]). The ORs were higher when at least 2 relatives had a history of cancer or when 1 case occurred before age 46 years. Only HL was significantly associated with a family history of hematopoietic malignancies (OR = 2.0 [1.0-3.8]), mainly because of a significant association with a history of HL (OR = 5.4 [1.3-22]). In conclusion, the study findings support the hypothesis of familial susceptibility to childhood lymphoma, but do not suggest familial susceptibility to childhood AL.     

The effect of atopy,childhood crowding,and other immune-related factors on non-Hodgkin lymphoma risk

Objective Since adult immune responsiveness is influenced by early childhood exposures, we examined the role of family size, history of atopic disease, and other childhood immune-related exposures in a multi-center case–control study of NHL. Methods Interviews were completed with 1,321 cases ascertained from population-based cancer registries in Seattle, Detroit, Los Angeles and Iowa, and with 1,057 frequency-matched controls, selected by random-digit dialing and from the Medicare files database. Multivariable logistic regression was used to estimate risk. Results A history of any allergy (excluding drug allergies), decreased risk of all NHL (Odds Ratio [OR] = 0.7, 95% Confidence Interval [CI] = 0.6–1.0), diffuse large B-cell lymphoma [DLBCL] (OR = 0.6, 95% CI = 0.4–0.9), and follicular NHL (OR = 0.7, 95 CI = 0.5, 1.0). A similar effect was observed for hay fever. A history of eczema was associated with an increased risk of follicular lymphoma (OR = 1.9, 95% CI = 1.1–3.4), but not DLBCL (OR = 1.1, 95% CI = 0.6–2.0). Asthma did not affect risk. Youngest compared to oldest siblings had a 90% increased risk of DLBCL (95% CI = 1.2–3.1; p for trend with increasing birth order = 0.006), but not follicular lymphoma (OR = 1.1, 95% CI = 0.6–1.8). Conclusions We infer that some childhood and immune-related factors may alter NHL risk.     

Non-Hodgkin's lymphoma among asthmatics exposed to pesticides

We conducted a pooled analysis of population-based case-control studies in Iowa, Minnesota and Nebraska to investigate whether asthma modifies risk of non-Hodgkin's lymphoma (NHL) associated with pesticide exposures. Cases (n = 872) diagnosed with NHL from 1980 to 1986 and frequency-matched controls (n = 2,381) randomly selected from the same geographic areas as the cases were included. Information on use of pesticides and history of asthma was based on interviews. Unconditional logistic regression was used to calculate ORs, adjusted for age, state and vital status. Of all subjects, 177 (45 cases, 132 controls) reported having been told by their doctor that they had asthma. Subjects with an asthma history had a nonsignificantly lower risk of NHL than nonasthmatics (OR = 0.6, 95% CI 0.3-1.4), and there was no main effect of pesticide exposure (OR = 1.0, 95% CI 0.8-1.2). However, asthmatics tended to have larger ORs associated with exposure to pesticides than nonasthmatics. The OR among asthmatics was 1.8 (95% CI 1.1-3.2) for ever-use of crop insecticides, 2.7 (95% CI 1.0-7.2) for chlordane, 2.4 (95% CI 1.0-5.7) for lindane and 3.7 (95% CI 1.3-10.9) for fonofos. Among nonasthmatics, ORs were 1.1 (0.9-1.3), 1.5 (1.1-2.2), 1.3 (0.97-1.8) and 1.6 (1.0-2.4), respectively. Although there is limited power for assessing interaction, our results suggest that the risk of NHL among asthmatics with pesticide exposure may be higher than among nonasthmatics with pesticide exposure.     

Exposure to childhood infections and risk of Epstein-Barr virus--defined Hodgkin's lymphoma in women

The role of Epstein-Barr virus (EBV) in Hodgkin's lymphoma (HL) etiology remains unresolved as EBV is detected in only some HL tumors and few studies have tried to reconcile its presence with factors suggesting viral etiology (e.g., childhood social class, infection history). In a population-based case-control study of San Francisco Bay area women, we analyzed interview data by tumor EBV status. Among 211 young adult cases, EBV-positive HL (11%) was associated with a single vs. shared bedroom at age 11 (OR = 4.0, 95% CI 1.1-14.4); risk was decreased for common childhood infections (OR = 0.3, 95% CI 0.1-1.0), including measles before age 10, but not with prior infectious mononucleosis (IM), which is delayed EBV infection. No study factors affected risk of young adult EBV-negative HL. Among 57 older adult cases, EBV-positive HL (23%) was unrelated to study factors; EBV-negative HL was associated with a single bedroom at age 11 (OR = 3.6, 95% CI 1.5-9.1) and IM in family members (OR = 3.1, 95% CI 1.1-9.0). Thus, delayed exposure to infection may increase risk of EBV-positive HL in young adults, but risk patterns differ in younger and older women for both EBV-positive and -negative HL. Late EBV infection does not appear relevant to risk, suggesting that other pathogens impact HL etiology in affluent female populations. Inconsistency of findings with prior studies may reflect failure of study risk factors to proxy meaningful exposures, risk differences by gender, or selection or misclassification bias. Null findings for EBV-negative HL indicate that etiologic models should be reconsidered for this common form.     

Non-Hodgkin's lymphoma, obesity and energy homeostasis polymorphisms

A population-based case-control study of lymphomas in England collected height and weight details from 699 non-Hodgkin's lymphoma (NHL) cases and 914 controls. Obesity, defined as a body mass index (BMI) over 30 kg m(-2) at five years before diagnosis,, was associated with an increased risk of NHL (OR = 1.5, 95% CI 1.1-2.1). The excess was most pronounced for diffuse large B-cell lymphoma (OR = 1.9, 95% CI 1.3-2.8). Genetic variants in the leptin (LEP 19G > A, LEP -2548G > A) and leptin receptor genes (LEPR 223Q > R), previously shown to modulate NHL risk, as well as a polymorphism in the energy regulatory gene adiponectin (APM1 276G>T), were investigated. Findings varied with leptin genotype, the risks being decreased with LEP 19AA (OR = 0.7, 95% CI 0.5-1.0) and increased with LEP -2548GA (OR = 1.3, 95% CI 1.0-1.7) and -2548AA (OR = 1.4, 95% CI 1.0-1.9), particularly for follicular lymphoma. These genetic findings, which were independent of BMI, were stronger for men than women.     

Asthma history, occupational exposure to pesticides and the risk of non-Hodgkin's lymphoma

We previously reported that, although asthma did not increase the risk of non-Hodgkin's lymphoma (NHL), the risk from pesticide exposures was higher among asthmatics than that among nonasthmatics. To further evaluate this finding, we analyzed data from a population-based case-control study of NHL conducted in Iowa, Detroit, Los Angeles and Seattle. Cases (n = 668) diagnosed with NHL from 1998 to 2000 and controls (n = 543) randomly selected from the same geographical areas as that of the cases were included in this analysis. Odds ratios (OR) for the risk of NHL from potential occupational exposure to pesticides tended to be higher among asthmatics (OR = 1.7; 95% CI 0.3-9.1) when compared with that among nonasthmatics (OR = 0.9; 95% CI 0.6-1.5). The risks of NHL associated with pesticide exposure were also higher among asthmatics who had history of hospitalization (OR = 2.1; 95% CI 0.2-29.0) or daily medication for asthma (OR = infinite) than those among asthmatics who did not have such histories. Our results support the previous finding that the risk of NHL from pesticide exposure may be greater among asthmatics.     

Maternal smoking during pregnancy and childhood lymphoma: a meta-analysis

Results from epidemiological studies exploring the association between childhood lymphoma and maternal smoking during pregnancy have been contradictory. This meta-analysis included all published cohort (n = 2) and case-control (n = 10) articles; among the latter, the data of the Greek Nationwide Registry for Childhood Hematological Malignancies study were updated to include all recently available cases (-2008). Odds ratios (ORs), relative risks and hazard ratios were appropriately pooled in three separate analyses concerning non-Hodgkin lymphoma (NHL, n = 1,072 cases), Hodgkin lymphoma (HL, n = 538 cases) and any lymphoma (n = 1,591 cases), according to data availability in the included studies. An additional metaregression analysis was conducted to explore dose-response relationships. A statistically significant association between maternal smoking (any vs. no) during pregnancy and risk for childhood NHL was observed (OR = 1.22, 95% confidence interval, CI: 1.03-1.45, fixed effects model), whereas the risk for childhood HL was not statistically significant (OR = 0.90, 95% CI: 0.66-1.21, fixed effects model). The analysis on any lymphoma did not reach statistical significance (OR = 1.10, 95% CI = 0.96-1.27, fixed effects model), possibly because of the case-mix of NHL to HL. No dose-response association was revealed in the metaregression analysis. In conclusion, this meta-analysis points to a modest increase in the risk for childhood NHL, but not HL, among children born by mothers smoking during pregnancy. Further investigation of dose-response phenomena in the NHL association, however, warrants accumulation of additional data.     

Hodgkin's lymphoma mortality in the Americas, 1997–2008: Achievements and persistent inadequacies

Although therapeutic advancements have made Hodgkin's lymphoma (HL) a largely curable disease, trends in HL mortality have been variable across countries. To provide updated information on HL mortality in the Americas, overall and 20–44 years age‐standardized (world population) mortality rates from HL were derived for the 12 Latin American countries providing valid data to the World Health Organization database and with more than two million of inhabitants. For comparative purpose, data for the United States and Canada were also presented. Trends in mortality over the 1997 to 2008 period are based on joinpoint regression analysis. Declines in HL mortality were registered in all Latin American countries except in Venezuela. In most recent years, HL mortality had fallen to about 0.3/100,000 men and 0.2/100,000 women in Argentina, Brazil, Chile, Colombia, Ecuador and Guatemala, that is, to values similar to North America. Despite some declines, rates remained high in Cuba (1/100,000 men and 0.7/100,000 women), Costa Rica and Mexico as well as in Venezuela (between 0.5 and 0.6/100,000 men and between 0.3 and 0.5/100,000 women). In young adults, trends were more favorable in all Latin American countries except Cuba, whose rates remained exceedingly high (0.8/100,000 men and 0.6/100,000 women). Thus, appreciable declines in HL mortality were observed in most Latin America over the last decade, and several major countries reached values comparable to North America. Substantial excess mortality was still observed in Cuba, Costa Rica, Mexico and Venezuela, calling for urgent interventions to improve HL management in these countries.     

Personal and family history of autoimmune diabetes mellitus and susceptibility to young-adult-onset Hodgkin lymphoma

Young-adult-onset (15-44 years of age) Hodgkin lymphoma (HL) is believed to arise as a consequence of late primary infection in susceptible individuals. The properties of this susceptibility remain little understood. We have previously reported an increased occurrence of HL in patients with rheumatoid arthritis and among their offspring, suggesting that susceptibility to autoimmunity might be of importance also in the pathogenesis of HL. To explore this hypothesis, we assessed the association of personal and family history of diabetes mellitus, with risk of subsequent HL in a population-based case-control study, including as cases all individuals diagnosed with HL above 15 years of age 1964-1999 (n = 6,873) in Sweden, and matched population controls (n = 12,565). First-degree relatives of cases and controls were identified through linkage with the Multi-generation Register. We identified discharges listing diabetes mellitus through linkage with the Inpatient Register (1964-2000). We used odds ratios (OR) as measures of relative risk. Cases with young-adult-onset HL were less likely to have a personal (OR =0.5, 95% CI 0.2-1.1) or family (OR =0.7, 95% CI 0.6-0.8) history of diabetes mellitus. In contrast, HL diagnosed at older ages was neither associated with a personal (OR =1.0) nor family (OR =1.0) history of diabetes mellitus. These findings suggests that characteristics of the immune system associated with conditions such as diabetes mellitus type I are of importance in the pathogenesis of young-adult-onset HL.     

Population-based study of lymphoma in Germany: rationale, study design and first results

A multi-centre, population-based case-control study of lymphoma among adults was conducted in Germany from 1999-2003. The study comprised 700 incident cases (Hodgkin lymphomas and non Hodgkin's lymphoma, NHL) in the age range 18-80 years and 700 age-, sex- and area-matched controls obtained from population registries. Diagnosis was based on the REAL/WHO classification. Information on demographic characteristics, lifestyle, medical history and occupation was obtained by in-person interviews. Each participant was asked for a 24 ml blood sample. First results are focused on basic demographic characteristics, contact to animals, childhood diseases and vaccinations. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. The ORs for lymphoma were decreased for exposure to sheep and goats (OR = 0.7; 95% CI = 0.5-0.9), for rabbits and hare (OR = 0.7; 95% CI = 0.5-0.9), measles infection (OR = 0.6; 95% CI = 0.5-0.9), Bordetella pertussis infection (OR = 0.7; 95% CI = 0.6-0.95), and tetanus vaccination (OR = 0.5; 95% CI = 0.3-0.9). Increased risk of lymphoma was associated with exposure to cattle (OR = 1.3; 95% CI = 1.03-1.7) and immunization for tuberculosis (OR = 1.5; 95% CI = 0.997-2.4). The results of this study are partly consistent with the hygiene hypothesis. The inconsistencies of some of the findings with an explanation by the Th1/Th2 paradigm, however, warrant further research and may indicate that broader explanatory concepts are needed.     

Hepatitis C virus and risk of non-Hodgkin lymphoma in British Columbia, Canada

We investigated Hepatitis C virus (HCV) seropositivity and the risk of non-Hodgkin lymphoma (NHL) in a population-based case-control study in British Columbia, Canada. Cases were aged 20-79, diagnosed between March 2000 and February 2004, and resident in greater Vancouver or Victoria. Cases with HIV or a prior transplant were excluded. Controls were chosen from the Client Registry of the British Columbia (BC) Ministry of Health, and were age/sex/region frequency matched to cases. Antibodies for HCV were measured in 795 cases and 697 control subjects. HCV seropositivity was 2.4% in cases and 0.7% in controls [odds ratio (OR) = 2.6, 95% confidence interval (CI) = 0.9-7.4]. A significantly elevated risk was observed for B-cell lymphoma (OR = 2.9, 95%CI = 1.0-8.6). The highest risks were associated with diffuse large B-cell lymphoma (OR = 7.3, 95%CI = 2.1-25.0) and marginal zone lymphoma (OR = 6.1, 95%CI = 1.1-33.9). Our results provide further evidence that HCV infection contributes to NHL risk.     

Hepatitis C infection and risk of malignant lymphoma

The association between hepatitis C virus (HCV) infection and risk of malignant lymphoma remains controversial, perhaps due to small-sized studies and low prevalence of HCV in the general population. On the basis of a large Danish-Swedish population-based case-control study, 2,819 lymphoma patients and 1,856 controls of second-generation Danish-Swedish origin were screened for HCV infection using an enzyme-linked immunosorbent assay and a confirming recombinant immunoblot assay (RIBA) test. Positive samples were tested with real-time PCR for the presence of HCV RNA. The association between HCV infection and risk of malignant lymphoma was assessed by logistic regression. When intermediate RIBA test results were interpreted as positive, anti-HCV antibody positivity was associated with a nonsignificant increased risk of non-Hodgkin lymphoma (NHL) overall (odds ratio (OR) = 2.2; 95% confidence interval (CI) 0.9-5.3; n = 20 cases), of B-cell lymphomas combined (OR = 2.4 [1.0-5.8]; n = 20) and of lymphoplasmacytic lymphoma (OR = 5.2 [1.0-26.4]; n = 2). No patients with T-cell or Hodgkin lymphoma were HCV-positive. A more conservative definition of HCV positivity (disregarding intermediate RIBA results) resulted in an OR = 1.6 (0.3-8.5; n = 5) for NHL overall. When the definition was further restricted to require HCV RNA positivity, OR was 1.7 (0.2-16.2; n = 3) for NHL overall. Our findings from a population with a low prevalence of HCV suggest a positive association between HCV and risk of NHL, in particular of B-cell origin.     

Genetic variants in caspase genes and susceptibility to non-Hodgkin lymphoma

The caspase proteins are essential for the regulation of normal B cell development and regulation of apoptosis. We investigated five single nucleotide polymorphisms in four key caspase genes, CASP3 [Ex8-280C>A (rs6948) and Ex8+567T>C (rs1049216)], CASP8 Ex14-271A>T (rs13113), CASP9 Ex5+32G>A (rs1052576) and CASP10 Ex3-171A>G (rs3900115) to determine whether they alter risk for non-Hodgkin lymphoma (NHL) in a population-based case-control study of women in Connecticut (461 cases and 535 controls). Variants in CASP3 and CASP9 were significantly associated with a decreased risk for NHL, particularly follicular lymphoma [e.g. CASP3 Ex8+567T>C odds ratio (OR)(CC+TC) = 0.4, 95% confidence interval (CI) = 0.3-0.7; and CASP9 Ex5+32G>A OR(AA+AG) = 0.6, 95% CI = 0.4-1.0]. Further, variants in CASP3, CASP8 and CASP10 were associated with a decreased risk of marginal zone lymphoma and variants in CASP3 and CASP10 were associated with a lower risk of chronic lymphocytic leukemia and related subtypes. The striking protective associations observed for polymorphisms in all four genes for NHL and/or one or more subtypes suggest that genetic variation in CASP genes may play an important role in the etiology of NHL.     

Tobacco smoking, alcohol drinking and Hodgkin's lymphoma: a European multi-centre case-control study (EPILYMPH)

We analysed the effects of tobacco and alcohol in the aetiology of Hodgkin's lymphoma (HL), based on 340 cases and 2465 controls enrolled in Spain, France, Italy, Germany, Ireland and Czech Republic, between 1998 and 2004. Current smokers showed a significantly increased odds ratio (OR) of HL of 1.39 (95% confidence interval (CI) = 1.04-1.87). Analyses were also conducted separately for subjects younger than 35 years (179 cases) and for older subjects (161 cases). For subjects below age 35, no association was observed between tobacco and HL, whereas for older subjects, ever-smokers experienced a doubled risk of HL as compared to never smokers and the OR of HL for current smoking was 2.35 (95% CI = 1.52-3.61), with suggestion of a dose-response relationship. A protective effect of alcohol was observed in both age groups. The OR for ever-regular drinking was 0.58 (95% CI = 0.38-0.89) for younger subjects and 0.50 (95% CI = 0.34-0.74) for older subjects. There was no evidence of interaction between tobacco and alcohol. Our results are consistent with previous studies, suggesting a protective effect of alcohol on HL. An effect of tobacco was suggested for HL occurring in middle and late age, although this finding might have occurred by chance.     

Cancer risks among relatives of children with Hodgkin and non-Hodgkin lymphoma

A role for genetic susceptibility in the aetiology of childhood lymphomas was investigated in 454 families of children with histologically confirmed Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) from Northwest England. Cancers in parents were obtained from the UK National Health Service Central Register and in other close relatives by interview with the parents. The cancer incidence among relatives was compared with expected incidence based on cancer registry data for England. There were 197 cancers in relatives (SIR 1.0 95% CI 0.8-1.1). In families of children with HL, there was an excess of HL in the first degree relatives (SIR 5.8 95% CI 1.2-16.9). Excesses of HL diagnosed under population median age (SIR 4.1 95% CI 1.1-10.6) were seen among all relatives and relatives of children who were below the median age at diagnosis (SIR 5.5 95% CI 1.1-16.0). In families of children with NHL, there were non-significant excesses of central nervous system (CNS) tumours in the first degree relatives (SIR 2.9 95% CI 0.8-7.4) and in the second and third degree relatives (SIR 1.5). There were significant excesses of CNS tumours diagnosed under the population median age (SIR 2.8 95% CI 1.1-5.8) in all relatives. Excess CNS tumours were also seen among relatives of children below the median age at diagnosis (SIR 3.2 95% CI 1.1-7.6). In conclusion, genetic susceptibility in some families of children with lymphoma might be operating, but aetiologies in HL and NHL appear to be different. Possible interpretations of our findings, in the context of putative genetic and infectious aetiologies, are discussed.     

Tobacco and non-Hodgkin's lymphoma: combined analysis of three case-control studies (United States)

The role of tobacco in the etiology of non-Hodgkin's lymphoma (NHL)was evaluated in a combined analysis of data from three population-basedcase-control studies conducted in four midwestern states of the UnitedStates: Nebraska, Iowa, Minnesota, and Kansas. Interviews were obtained from1,177 cases (993 men, 184 women) and 3,625 controls (2,918 men, 707 women )or, if deceased, from their next-of-kin. Overall, there was no associationbetween NHL and tobacco use (odds ratio [OR] = 1.0, 95 percent confidenceinterval [CI] = 0.8-1.1) or cigarette smoking (OR = 1.0, CI = 0.8-1.1). Aslight negative association evident in analyses by intensity and duration ofsmoking was not present when interviews from proxy respondents wereeliminated. There was a suggestion of a positive association between smokingand NHL among women (OR = 1.3, CI = 0.9-1.9), although there was no clearexposure-response relationship. This large case-control analysis provides noevidence that smoking is linked to the development of NHL among men. Thepossible role of smoking in the etiology of NHL among women needs furtherevaluation.     

Risk of lymphoma subtypes after solid organ transplantation in the United States

Background:

Solid organ transplant recipients have high risk of lymphomas, including non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). A gap in our understanding of post-transplant lymphomas involves the spectrum and associated risks of their many histologic subtypes.

Methods:

We linked nationwide data on solid organ transplants from the US Scientific Registry of Transplant Recipients (1987–2008) to 14 state and regional cancer registries, yielding 791 281 person-years of follow-up for 19 distinct NHL subtypes and HL. We calculated standardised incidence ratios (SIRs) and used Poisson regression to compare SIRs by recipient age, transplanted organ, and time since transplantation.

Results:

The risk varied widely across subtypes, with strong elevations (SIRs 10–100) for hepatosplenic T-cell lymphoma, Burkitt''s lymphoma, NK/T-cell lymphoma, diffuse large B-cell lymphoma, and anaplastic large-cell lymphoma (both systemic and primary cutaneous forms). Moderate elevations (SIRs 2–4) were observed for HL and lymphoplasmacytic, peripheral T-cell, and marginal zone lymphomas, but SIRs for indolent lymphoma subtypes were not elevated. Generally, SIRs were highest for younger recipients (<20 years) and those receiving organs other than kidneys.

Conclusion:

Transplant recipients experience markedly elevated risk of a distinct spectrum of lymphoma subtypes. These findings support the aetiologic relevance of immunosuppression for certain subtypes and underscore the importance of detailed haematopathologic workup for transplant recipients with suspected lymphoma.     

Sun exposure and non-Hodgkin lymphoma: a population-based, case-control study

To investigate the association between sun exposure and risk of non-Hodgkin lymphoma (NHL) by histologic subtypes and to explore whether or not vitamin D intake modify sun-NHL association, we analysed data from a population-based, case-control study conducted in Nebraska between 1999 and 2002. Information on sun exposure during the spring, summer, fall and winter was collected from 387 cases and 535 controls by telephone interview. We found no association between seasonal sun exposure and risk of NHL. Vitamin D intake was also not associated with NHL risk, nor does it modify the sun-NHL association. In contrast, total hours of sun exposure was inversely associated with the risk of NHL (odds ratio (OR)=0.7 comparing >30h/week to <14h/week, 95% confidence interval (CI)=0.5-1.1). Sun exposure was associated with a lower risk of NHL among farmers (OR=0.8, 0.5-1.3 for 14-30h/week; OR=0.6, 0.3-0.9 for >30h/week; p-trend=0.02), but not among non-farmers. Total hours of sun exposure was also inversely associated with risk of diffuse large B-cell lymphoma and T-cell lymphoma. In conclusion, our data suggest that total hours of sun exposure is associated with a lower risk of NHL, and the inverse association is not modified by vitamin D intake, is stronger among farmer, and may vary by subtypes.