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Lactase Persistence, Dietary Intake of Milk, and the Risk for Prostate Cancer in Sweden and Finland

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Lactase Persistence, Dietary Intake of Milk, and the Risk for Prostate Cancer in Sweden and Finland 956 Lactase Persistence, Dietary Intake of Milk, and the Risk for Prostate Cancer in Sweden and Finland Suvi Torniainen,1 Maria Hedelin,3 Ville Autio,4 Heli Rasinpera¨,1 Katarina Augustsson Ba¨lter,3 A˚ sa Klint,3 Rino Bellocco,3,8 Fredrik Wiklund,3 Pa¨r Stattin,9 Tarja Ikonen,6 Teuvo L.J. Tammela,7 Johanna Schleutker,5,6 Henrik Gro¨nberg,3 and Irma Ja¨rvela¨1,2 1Department of Medical Genetics, University of Helsinki; 2Laboratory of Molecular Genetics, Helsinki University Central Hospital, Helsinki, Finland; 3Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; 4Research Unit, Tampere University Hospital; 5Department of Clinical Chemistry, Tampere University Hospital; 6Laboratory of Cancer Genetics, Institute of Medical Technology and 7Department of Urology, Tampere University Hospital and Medical School, University of Tampere, Tampere, Finland; 8Department of Statistics, University of Milano-Bicocca, Milan, Italy; and 9Department of Surgery and Perioperative Sciences, Urology and Andrology, Umea˚University Hospital, Umea˚, Sweden Abstract Prostate carcinoma is the most common cancer in men. Its controls (Cancer Prostate in Sweden I study) using a primary pathogenesis is mostly unknown. Dairy products questionnaire. Only the consumption of low-fat milk was containing lactose have been suggested to be risk factors for found to be associated with increased risk of prostate cancer prostate cancer. Digestion of lactose is dependent on lactase [odds ratio (OR), 1.73; 95% confidence interval (95% CI), 1.16- activity in the intestinal wall. A single nucleotide polymor- 2.39]. A statistically significantly higher (P < 0.01) lactose phism C to T residing 13,910 bp upstream of the lactase gene intake was observed among subjects with high lactase activity has been shown to associate with the developmental down- (C/T and T/T genotypes) compared with those with low lactase regulation of lactase activity underlying persistence/non- activity (C/C genotype). Lactase persistence did not associate persistence trait. To find out whether lactase persistence is with increased risk for prostate carcinoma in the Finnish (OR, related to the risk for prostate cancer, we genotyped 1,229 1.11; 95% CI, 0.83-1.47; P = 0.488) or in the Swedish populations Finnish and 2,924 Swedish patients and their 473 Finnish and (OR, 1.16; 95% CI, 0.91-1.46; P = 0.23). In conclusion, lactase 1,842 Swedish controls using solid-phase minisequencing. To persistence/nonpersistence contains no risk for prostate can- explore if dairy products have an association with prostate cer. Analysis of different milk products showed some evi- cancer, we analyzed the milk consumption in the Swedish dence for low-fat milk as a potential risk factor for prostate study consisting of 1,499 prostate cancer patients and 1,130 cancer. (Cancer Epidemiol Biomarkers Prev 2007;16(5):956–61) Introduction Prostate cancer is the most common malignancy among men in humans able to digest lactose throughout life (lactase developed countries (1). Both endogenous factors (family persistence), and this mutation is particularly common in the history, hormones, ethnicity, and oxidative stress) and exog- populations in the Nordic countries. The diagnosis of low enous factors (nutrition and lifestyle) have been suggested as lactose absorbing capacity has been based on lactose tolerance risk factors but the primary etiology is thus far unknown. High test or breath hydrogen test with varying specificity and dairy product intake has been associated with an increased sensitivity (13). Data are contradictory about the effect of risk of prostate cancer in case-control as well as cohort studies lactase enzyme activity on the absorption of calcium in milk: (2-7). In two recent meta-analyses, high intakes of dairy decreased calcium absorption has been reported in lactase- products and calcium were associated with a slightly increased deficient subjects (14); however, contrary data has also been risk of prostate cancer (4, 8). In Scandinavian countries, presented (15, 16). prostate cancer is the most frequently diagnosed cancer in A single nucleotide polymorphism C/TÀ13910 (rs4988235), men (9, 10); likewise, the consumption of dairy products is the residing 13,910 bp upstream of the lactase-encoding gene highest in the world (11). (LCT), has been shown to associate with lactase persistence/ Lactose is the main sugar of milk that is digested by the nonpersistence trait (17). Many functional studies have shown LCT lactase enzyme to glucose and galactose in the intestinal wall. that the C/TÀ13910 variant regulates the expression of the Lactase enzyme activity is high at birth but down-regulated gene (17-22). The C/TÀ13910 genotype defines lactose malab- after weaning in most of the world’s populations, the condition sorbers (lactase activity <10 units/g protein) and the C/TÀ13910 called adult-type hypolactasia or lactase nonpersistence (12). and T/TÀ13910 genotypes define lactose absorbers (lactase z A mutation has occurred in human history that has made some activity 10 units/g protein), meaning that C/TÀ13910 and T/TÀ13910 genotypes always have normal lactase activity, whereas C/CÀ13910 genotype always has a declined lactase Received 11/27/06; revised 2/26/07; accepted 3/1/07. activity (17, 18, 21, 23). The C/TÀ13910 variant is the major Grant support: Sigrid Juse´lius Foundation, Helsinki, Finland; Helsinki University Hospital variant of lactase persistence/nonpersistence in North Euro- Research Funding, University of Helsinki, Helsinki, Finland; Helsinki University Research Funding, Foundation for Nutrition Research, Helsinki, Finland; the Alfred Kordelin pean populations. Several other variants close to the C/TÀ13910 Foundation, Helsinki, Finland; Reino Lahtikari Foundation, Tampere, Finland; The Academy variant has been recently identified in African populations of Finland grant 211123(J. Schleutker); Medical Research Fund of Tampere University Hospital; and grants from the Swedish Cancer Foundation (Cancerfonden). (24, 25). However, their correlation with lactase activity The costs of publication of this article were defrayed in part by the payment of page charges. remains to be clarified. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. We hypothesize that the high incidence of prostate cancer in Section 1734 solely to indicate this fact. the Nordic countries is partially driven by high dairy (milk) Note: S. Torniainen and M. Hedelin contributed equally to this work. intake, explained by the high prevalence of lactase persistence Requests for reprints: Irma Ja¨rvela¨, Department of Medical Genetics, University of Helsinki, PL104, 00251 Helsinki, Finland. Fax: 358-9-191-25105. E-mail: [email protected] in our populations. This study addresses the question of Copyright D 2007 American Association for Cancer Research. whether there exists an association between the C/T-13910 doi:10.1158/1055-9965.EPI-06-0985 genotypes reflecting lactase activity and the risk of prostate Cancer Epidemiol Biomarkers Prev 2007;16(5). May 2007 Downloaded from cebp.aacrjournals.org on September 24, 2021. © 2007 American Association for Cancer Research. Cancer Epidemiology,Biomarkers & Prevention 957 Table 1. Selected baseline characteristics of prostate cancer The Finnish material consisted of 1,229 unselected, consecu- cases and controls in the Swedish CAPS and Finnish studies tive patients with prostate cancer with the mean age of 69.0 years (range 45-94 years). The DNA samples from unselected Characteristics Sweden Finland consecutive prostate cancer patients were collected from Controls Cases Controls Cases patients diagnosed with pathologically verified prostate cancer during 1999 to 2002 at the Tampere University Hospital, which Age, mean (y) 67.365.9 NA 69.0 serves as a regional referral center in the area for all patients BMI, mean (kg/m2) 26.2 26.3— — Education, n (%) with prostate cancer. Thus, we obtained a population-based Compulsory school 0-9 y 352 (45) 619 (45) — — collection of patients. For the Finnish subjects with prostate Upper secondary 10-12 y 334 (43) 544 (40) — — cancer, clinical characteristics collected include age, prostate- University z13y 96 (12) 194 (14) — — specific antigen, tumor-node-metastasis stage, WHO grade, Missing 5 (0.6) 5 (0.4) — — and Gleason score. The population controls consisted of 473 Country of birth, n (%) Sweden 731 (93) 1,295 (95) — — DNA samples from anonymous, voluntary, and healthy male Other European countries 49 (6) 62 (4.6) — — blood donors (18-65 years old) from the same region, obtained Missing 7 (0.9) 5 (0.4) — — from Blood Center of the Finnish Red Cross in Tampere. Smokers, n (%) The study protocol was accepted by the local ethical Never 297 (38) 528 (39) — — committees and written informed consent was obtained from Ever 478 (61) 815 (60) — — all study participants in both the Finnish and Swedish studies. Missing 12 (1) 19 (1) — — n Prostate cancer stage, (%)* Dietary Assessment. The self-administered questionnaire Localized — 1,570 (56) — 677 (55) Advanced — 1,193(42) — 552 (45) assessed known and potential risk factors for prostate cancer Unknown — 53(2) — 0 (24). The questionnaire included a validated food frequency questionnaire to measure average intake of foods and Abbreviations: NA, not available; BMI; body mass index. beverages during the preceding year (29). Participants were *See Materials and Methods for definition of prostate cancer stage. asked how much, on average, they
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