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Development of Lentigines in German and Japanese Women Correlates with Variants in the SLC45A2 Gene

2011; Elsevier BV; Volume: 132; Issue: 3 Linguagem: Inglês

10.1038/jid.2011.350

1523-1747

Andrea Vierkötter, Ursula Krämer, Dorothee Sugiri, Akimichi Morita, Ai Yamamoto, Natsumi Kaneko, Mary S. Matsui, Jean Krutmann,

Acne and Rosacea Treatments and Effects

oculocutaneous albinism 4 single-nucleotide polymorphism underwhite TO THE EDITOR Pigment spots (lentigines), a prominent extrinsic skin aging sign, develop earlier and are more pronounced in Asian than in Caucasian skin (Goh, 1990Goh S.H. The treatment of visible signs of senescence: the Asian experience.Br J Dermatol. 1990; 122: 105-109Crossref PubMed Scopus (76) Google Scholar; Zhao et al., 1998Zhao P. Zhu X. Liu Y. et al.Solar ultraviolet radiation and skin damage: an epidemiological study among a Chinese population.Arch Environ Health. 1998; 53: 405-409Crossref PubMed Scopus (20) Google Scholar; Eun, 2001Eun H.C. Cutaneous photodamage in Asians.J Dermatol. 2001; 28: 614-616Crossref PubMed Scopus (15) Google Scholar. Skin pigmentation is likely to influence the manifestation of hyperpigmentation (Halder and Ara, 2003Halder R.M. Ara C.J. Skin cancer and photoaging in ethnic skin.Dermatol Clin. 2003; 21: 725-732Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, and thus in the present study, we asked whether genetic variants related to skin pigmentation might provide one possible explanation for ethnic differences in lentigines. The report presented here is based on a study conducted in the JAGE study cohort (Extrinsic skin aging study of JApanese and GErman women), which included 39 German women from Düsseldorf and 48 Japanese women from Nagoya (Perner et al., 2011Perner D. Vierkötter A. Sugiri D. et al.Association between sun-exposure, smoking behaviour and plasma antioxidant levels with the different manifestation of skin ageing signs between Japanese and German women - a pilot study.J Dermatol Sci. 2011; 62: 138-140Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, allowing for comparison of lentigines occurrence, genotype distribution, and its association between these two ethnic groups. The sample size of this study was small; thus, in order to validate the association between lentigines occurrence and genotypes for the German subjects, we examined data obtained from a separate but similar cohort. The SALIA study cohort (Study on the influence of Air pollution on Lung function, Inflammation and Aging), containing data from 372 German women (Vierkötter et al., 2010Vierkötter A. Schikowski T. Ranft U. et al.Airborne particle exposure and extrinsic skin aging.J Invest Dermatol. 2010; 130: 2719-2726Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar, was used as an independent validation sample for the German women of the JAGE study. This procedure is commonly used to avoid errors of over-interpretation from small sample numbers. In both cohorts, lentigines were quantified by SCINEXA (Vierkötter et al., 2009Vierkötter A. Ranft U. Krämer U. et al.The SCINEXA: a novel, validated score to simultaneously assess and differentiate between intrinsic and extrinsic skin ageing.J Dermatol Sci. 2009; 53: 207-211Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, Vierkötter et al., 2010Vierkötter A. Schikowski T. Ranft U. et al.Airborne particle exposure and extrinsic skin aging.J Invest Dermatol. 2010; 130: 2719-2726Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar and DNA was isolated from blood samples. As skin pigmentation is a polygenic trait, we selected 25 single-nucleotide polymorphisms (SNPs) with a functional relevance on melanin synthesis in eight different candidate genes (MC1R, ASIP, TYR, TYRP1, TYRP2, TPCN2, P, SLC45A2) and determined genotypes by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (Jaremko et al., 2005Jaremko M. Justenhoven C. Abraham B.K. et al.MALDI-TOF MS and TaqMan® assisted SNP genotyping of DNA isolated from formalin-fixed and paraffin-embedded tissues (FFPET).Hum Mutat. 2005; 25: 232-238Crossref PubMed Scopus (40) Google Scholar. SNPs that did not fulfill the Hardy–Weinberg equilibrium (n=0) or that had a call rate of <90% (n=1) were excluded from further analysis. Confounding factors known to influence lentigines formation, including age, skin type, and sun exposure, were assessed by means of a questionnaire. First, we tested for ethnic differences in the genotype distribution by χ2-test. Further, associations between lentigines occurrence and genetic variants were determined for the two ethnic groups of the JAGE study separately and further in the German women of the SALIA study by multiple linear regression analysis by adjusting for age and further adjusting for skin type and sun exposure. Both cohort studies were approved by local ethics committees. The Declaration of Helsinki Principles was followed and all study participants gave written consent. The mean age of JAGE study subjects was 49 years (range: 32–71 years), whereas the SALIA study participants were older, with a mean age of 74 years (range: 68–79 years). In the JAGE study, we confirmed previously described ethnic differences in lentigines manifestation (Nouveau-Richard et al., 2005Nouveau-Richard S. Yang Z. Mac-Mary S. et al.Skin ageing: a comparison between Chinese and European populations. A pilot study.J Dermatol Sci. 2005; 40: 187-193Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar; Tschachler and Morizot, 2006Tschachler E. Morizot F. Ethnic differences in skin aging.in: Gilchrest B.A. Krutmann J. Skin Aging. Springer, Heidelberg-Berlin2006: 23-32Crossref Scopus (33) Google Scholar. Japanese women showed 4.3-fold more lentigines on cheeks than age-matched German women (P<0.001). There was no significant difference in the occurrence of lentigines on the forehead. In contrast, Japanese women showed significantly fewer lentigines on their arms and hands than age-matched German women. The genotype distributions of the selected SNPs in the JAGE and SALIA study populations (Table 1) were not significantly different from that found in the respective populations of the HapMap project. Significant differences in 12 SNPs were detected between Japanese and German women of the JAGE study (Table 1). From these 12 SNPs, rs26722 in the SLC45A2 gene was the only genetic variant associated with the occurrence of lentigines. In Japanese women, the AA genotype of this SNP was associated with a higher number of lentigines on cheeks in comparison with the GG genotype (P=0.02; Figure 1). Only two German women of the JAGE study were heterozygous GA and none were homozygous AA, and thus no further analysis could be performed in this group. In the SALIA cohort, however, 367 women were carriers of the GG variant and five of the GA variant; GA carriers had more lentigines on the back of arms and hands than GG carriers, but not on cheeks (Figure 1). Associations in German women did not reach significance because of the low abundance of the A variant. None of the associations described above changed more than 10% when further adjusted for skin type and sun exposure.Table 1SNPs in genes coding for factors of melanin synthesis with significantly different genotype distribution in German versus Japanese women of the JAGE studyGeners number of SNPStudy populationDistribution of genotypes in the JAGE study (n (%))χ2-Test for ethnic difference in the JAGE studyGGGTTTP<0.001MC1Rrs1805005German30 (76.9)9 (23.1)0 (0)Japanese48 (100)0 (0)0 (0)TYRrs1042602CCCAAAGerman17 (47.2)16 (44.5)3 (8.3)P<0.001Japanese48 (100)0 (0)0 (0)rs1126809GGGAAAGerman14 (37.8)21 (56.8)2 (5.4)P<0.001Japanese48 (100)0 (0)0 (0)rs1393350GGGAAAGerman15 (38.5)19 (48.7)5 (12.8)P<0.001Japanese48 (100)0 (0)0 (0)TYRP1rs1408799CCCTTTGerman21 (55.3)15 (39.5)2 (5.3)P<0.001Japanese0 (0)0 (0)48 (100)TPCN2rs35264875AAATTTGerman28 (71.8)11 (28.2)0 (0)P<0.001Japanese48 (100)0 (0)0 (0)rs3829241GGGAAAGerman15 (38.5)14 (35.9)10 (25.6)P=0.002Japanese34 (70.8)12 (25.0)2 (4.2)Prs1667394AAAGGGGerman27 (69.2)12 (30.8)0 (0)P<0.001Japanese3 (6.3)16 (33.3)29 (60.4)rs1800414AAAGGGGerman39 (100)0 (0)0 (0)P<0.001Japanese9 (18.8)27 (56.3)12 (25.0)rs7495174AAAGGGGerman35 (89.7)4 (10.3)0 (0)P<0.001Japanese7 (14.6)22 (45.8)19 (39.6)SLC45A2rs16891982CCCGGGGerman0 (0)4 (11.1)32 (88.9)P<0.001Japanese47 (100)0 (0)0 (0)rs26722CCCTTTGerman37 (94.9)2 (5.1)0 (0)P<0.001Japanese19 (39.6)22 (45.8)7 (14.6)Abbreviation: SNP, single-nucleotide polymorphism. Open table in a new tab Abbreviation: SNP, single-nucleotide polymorphism. SLC45A2 was initially identified as being the human homolog of Slc45a2 gene mutated in the mouse underwhite (uw) phenotype, and also mutated in oculocutaneous albinism 4 (OCA4; Newton et al., 2001Newton J.M. Cohen-Barak O. Hagiwara N. et al.Mutations in the human orthologue of the mouse underwhite gene (uw) underlie a new form of oculocutaneous albinism, OCA4.Am J Hum Genet. 2001; 69: 981-988Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar. The murine uw genotype leads to generalized hypopigmentation of the eyes and fur (Sweet et al., 1998Sweet H.O. Brilliant M.H. Cook S.A. et al.A new allelic series for the underwhite gene on mouse chromosome 15.J Hered. 1998; 89: 546-551Crossref PubMed Scopus (31) Google Scholar, and OCA4 causes hypopigmentation and ocular abnormalities in humans (Newton et al., 2001Newton J.M. Cohen-Barak O. Hagiwara N. et al.Mutations in the human orthologue of the mouse underwhite gene (uw) underlie a new form of oculocutaneous albinism, OCA4.Am J Hum Genet. 2001; 69: 981-988Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar. However, the molecular function of SLC45A2 remains unknown. Homolog studies have predicted the MATP-coding region of SLC45A2 structure to be a 12-transmembrane-spanning protein (Fukamachi et al., 2001Fukamachi S. Shimada A. Shima A. Mutations in the gene encoding B, a novel transporter protein reduce melanin content in medaka.Nat Genet. 2001; 28: 302Crossref PubMed Scopus (183) Google Scholar; Newton et al., 2001Newton J.M. Cohen-Barak O. Hagiwara N. et al.Mutations in the human orthologue of the mouse underwhite gene (uw) underlie a new form of oculocutaneous albinism, OCA4.Am J Hum Genet. 2001; 69: 981-988Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar, but no substrate has been identified. It was originally postulated that MATP cotransports a sugar molecule with a proton (Newton et al., 2001Newton J.M. Cohen-Barak O. Hagiwara N. et al.Mutations in the human orthologue of the mouse underwhite gene (uw) underlie a new form of oculocutaneous albinism, OCA4.Am J Hum Genet. 2001; 69: 981-988Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar, regulating the intramelanosomal pH for optimal tyrosinase activity. Characterization of melanocytes derived from the uw mouse mutant has revealed that although tyrosinase was synthesized at comparable rates to wild type, tyrosinase activity was ∼20% of that found in wild-type melanocytes and was also less enriched in uw melanosomes (Costin et al., 2003Costin G.E. Valencia J.C. Vieira W.D. et al.Tyrosinase processing and intracellular trafficking is disrupted in mouse primary melanocytes carrying the underwhite (uw) mutation. A model for oculocutaneous albinism (OCA) type 4.J Cell Sci. 2003; 116: 3203-3212Crossref PubMed Scopus (146) Google Scholar. SNPs in the SLC45A2 gene have been associated with variations in human hair, skin, and eye color (Newton et al., 2001Newton J.M. Cohen-Barak O. Hagiwara N. et al.Mutations in the human orthologue of the mouse underwhite gene (uw) underlie a new form of oculocutaneous albinism, OCA4.Am J Hum Genet. 2001; 69: 981-988Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar; Nakayama et al., 2002Nakayama K. Fukamachi S. Kimura H. et al.Distinctive distribution of AIM1 polymorphism among major human populations with different skin color.J Hum Genet. 2002; 47: 92-94Crossref PubMed Scopus (54) Google Scholar; Graf et al., 2005Graf J. Hodgson R. van Daal A. Single nucleotide polymorphisms in the MATP gene are associated with normal human pigmentation variation.Hum Mutat. 2005; 25: 278-284Crossref PubMed Scopus (183) Google Scholar, Graf et al., 2007Graf J. Voisey J. Hughes I. et al.Promoter polymorphisms in the MATP (SLC45A2) gene are associated with normal human skin color variation.Hum Mutat. 2007; 28: 710-717Crossref PubMed Scopus (58) Google Scholar. In particular, two nonpathogenic, nonsynonymous polymorphisms in the MATP-coding region have previously been investigated: rs26722 (p.Glu272Lys) and rs1689182 (p.Phe374Leu). Allele frequencies of both polymorphisms were significantly different among populations (Nakayama et al., 2002Nakayama K. Fukamachi S. Kimura H. et al.Distinctive distribution of AIM1 polymorphism among major human populations with different skin color.J Hum Genet. 2002; 47: 92-94Crossref PubMed Scopus (54) Google Scholar. Graf et al., 2005Graf J. Hodgson R. van Daal A. Single nucleotide polymorphisms in the MATP gene are associated with normal human pigmentation variation.Hum Mutat. 2005; 25: 278-284Crossref PubMed Scopus (183) Google Scholar showed that 272Lys and 374Leu are significantly associated with dark hair, skin, and eye color in Caucasians. In our study, a significant association with lentigines on cheeks was detectable for the A allele (=272Lys) of rs26722 in the Japanese women and similar associations were indicated in the German women of the SALIA study for the sites at the back of arms and hands, which are prominent sites for lentigines manifestation in German women. With regard to the second SNP, rs1689182, Japanese women were homozygous GG. In contrast, 32 German women were carriers of the CC genotype and 4 of the CG genotype; those with the CG genotype showed a higher mean number of pigment spots in comparison with the CC carriers (not significant). In conclusion, this study confirms previous studies that showed that lentigines located on the cheeks, often attributed to skin aging, are more frequent in Japanese women than German women (Tschachler and Morizot, 2006Tschachler E. Morizot F. Ethnic differences in skin aging.in: Gilchrest B.A. Krutmann J. Skin Aging. Springer, Heidelberg-Berlin2006: 23-32Crossref Scopus (33) Google Scholar. Moreover, it provides evidence that this ethnic difference might, at least in part, be due to differences in genetic variants that modify melanin synthesis. This work was supported by the Bundesminsterium für Umwelt (BMU), the Deutsche Forschungsgemeinschaft SFB 728, a grant from the Ministry of Education, Culture, Sports, Science, and Technology in Japan, and an unrestricted grant from the Estée Lauder Companies, Inc. We thank T. Illig and N. Klopp (Helmholtz Zentrum Munich, German Research Center for Environmental Health) for measuring the presented SNPs. We also thank all the study participants.