Genetic loci associated with skin pigmentation in African Americans and their effects on vitamin D deficiency.
Genetic loci associated with skin pigmentation in African Americans and their effects on vitamin D deficiency.
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DOI：
10.1371/journal.pgen.1009319
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发表时间：
2021-03
期刊：
影响因子：
4.5
通讯作者：
Kittles RA
中科院分区：
文献类型：
--
作者：
Batai K;Cui Z;Arora A;Shah-Williams E;Hernandez W;Ruden M;Hollowell CMP;Hooker SE;Bathina M;Murphy AB;Bonilla C;Kittles RA
最近在非洲后裔人群中进行的全基因组关联研究（GWAS）发现了与皮肤色素沉着相关的新位点。然而，基因组变异如何影响皮肤色素沉着，以及这些皮肤色素沉着基因变异如何影响血清25（OH）维生素D变异，尚未在非洲裔美国人（AAs）中进行研究。为了进一步了解影响人类皮肤色素沉着和血清25(OH)D变化的遗传因素，我们对395个AAs进行了皮肤色素沉着的GWAS研究，并对681个AAs进行了复制研究。然后，我们测试了鉴定的变异是否与AAs子集（n = 591）的血清25(OH) D浓度相关。使用窄带反射计测量皮肤色素沉着，黑色素指数（M-Index）。进行多元回归分析以确定与m指数相关的变异，并评估其在调整人群分层和相关混杂变量后的血清25(OH)D变异中的作用。SLC24A5基因附近的一个变异（rs2675345）与M-Index的相关性最强（P = 4.0 × 10−30）。SLC24A5、SLC45A2和OCA2的变异共同占皮肤色素沉着变异的很大比例（11%）。这些变异对m指数的影响存在性别差异（交互作用P = 0.009）。然而，西非血统（WAA）也占m指数方差的很大比例（23%）。高WAA和高遗传评分（由与M-Index相关的顶级变异计算）的aa之间的M-Index也存在差异，这表明其他未知的与WAA相关的基因组因素可能导致皮肤色素沉着的变化。m指数与血清25(OH)D浓度无关，但遗传评分与维生素D缺乏（血清25(OH)D水平低于12 ng/mL）显著相关（OR, 1.30; 95% CI, 1.04-1.64）。这些发现支持了一种假设，即皮肤色素沉着的进化是对高纬度环境中皮下维生素D合成需求增加的反应。对非洲裔美国人进行了皮肤色素沉着的全基因组关联和复制研究，然后评估了皮肤色素沉着基因在血清维生素D变异中的意义。SLC24A5附近的变异rs2675345与皮肤色素沉着的相关性最强。使用来自3个基因组区域（SLC24A5， SLC45A2和OCA2）和西非基因组血统的顶级变异计算的遗传评分占皮肤色素变异的很大比例。遗传评分和皮肤色素沉着之间的关联模式在男性和女性之间是不同的，这表明性别和遗传变异之间存在相互作用。来自相同的3种皮肤色素基因变异的遗传评分也与严重维生素D缺乏症有关，定义为血清25(OH)D水平<12 ng/mL。然而，皮肤色素沉着和维生素D途径基因变异在血清维生素D变异中所占的比例虽小，但却很重要。结果表明，基因组变异强烈控制皮肤色素沉着，也影响血清维生素D水平。
A recent genome-wide association study (GWAS) in African descent populations identified novel loci associated with skin pigmentation. However, how genomic variations affect skin pigmentation and how these skin pigmentation gene variants affect serum 25(OH) vitamin D variation has not been explored in African Americans (AAs). In order to further understand genetic factors that affect human skin pigmentation and serum 25(OH)D variation, we performed a GWAS for skin pigmentation with 395 AAs and a replication study with 681 AAs. Then, we tested if the identified variants are associated with serum 25(OH) D concentrations in a subset of AAs (n = 591). Skin pigmentation, Melanin Index (M-Index), was measured using a narrow-band reflectometer. Multiple regression analysis was performed to identify variants associated with M-Index and to assess their role in serum 25(OH)D variation adjusting for population stratification and relevant confounding variables. A variant near the SLC24A5 gene (rs2675345) showed the strongest signal of association with M-Index (P = 4.0 x 10−30 in the pooled dataset). Variants in SLC24A5, SLC45A2 and OCA2 together account for a large proportion of skin pigmentation variance (11%). The effects of these variants on M-Index was modified by sex (P for interaction = 0.009). However, West African Ancestry (WAA) also accounts for a large proportion of M-Index variance (23%). M-Index also varies among AAs with high WAA and high Genetic Score calculated from top variants associated with M-Index, suggesting that other unknown genomic factors related to WAA are likely contributing to skin pigmentation variation. M-Index was not associated with serum 25(OH)D concentrations, but the Genetic Score was significantly associated with vitamin D deficiency (serum 25(OH)D levels less than 12 ng/mL) (OR, 1.30; 95% CI, 1.04–1.64). The findings support the hypothesis suggesting that skin pigmentation evolved responding to increased demand for subcutaneous vitamin D synthesis in high latitude environments. Genome-wide association and replication study for skin pigmentation was performed in African Americans, and then the implication of the skin pigmentation genes in serum vitamin D variation was assessed. A variant, rs2675345, near SLC24A5 showed the strongest associations with skin pigmentation. A Genetic Score calculated using the top variants from 3 genomic regions, SLC24A5, SLC45A2 and OCA2, and West African genomic ancestry together account for a large proportion of skin pigmentation variation. The pattern of association between the Genetic Score and skin pigmentation was different between men and women suggesting an interaction between sex and genetic variation. The Genetic Score from the same 3 skin pigmentation gene variants was also associated with severe vitamin D deficiency, defined as serum 25(OH)D levels <12 ng/mL. However, skin pigmentation and vitamin D pathway gene variants account for a small but significant proportion of serum vitamin D variation. The results suggest that genomic variations strongly control skin pigmentation and also influence serum vitamin D levels.
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