Генетический контроль N-гликозилирования белков плазмы крови человека

Гликозилирование является важной модификацией белков, которая влияет как на их физико-химические свойства, так и на выполняемые ими биологические функции. Масштабные популяционные исследования показали, что уровни различных N-гликанов белков плазмы крови ассоциированы с риском развития ряда мультифакторных заболеваний человека. Найденные ассоциации стали основанием для рассмотрения N-гликанов в качестве потенциального источника биомаркеров и терапевтических мишеней. Биохимические пути N-гликозилирования хорошо изучены, однако понимание механизмов общей и тканеспецифической регуляции этих биохимических реакций in vivo весьма ограниченно. Это затрудняет как интерпретацию наблюдаемых ассоциаций уровней N-гликанов с заболеваниями человека, так и разработку биомаркеров и молекулярных мишеней на их основе. Прогресс в области технологий анализа N-гликозилирования белков позволил к началу 2010-х годов проводить исследования регуляции N-гликозилирования с помощью методов генетического анализа, в том числе полногеномного исследования генетических ассоциаций. Применение этих методов дает возможность находить новые, ранее неизвестные регуляторы N-гликозилирования и расширяет представление о роли N-гликанов в контроле мультифакторных заболеваний и комплексных признаков человека. В данном обзоре мы рассматриваем современное состояние исследований генетического контроля популяционной изменчивости уровней N-гликозилирования белков плазмы крови человека. Описаны современные физико-химические методы измерения N-гликомного профиля, приведены базы данных, содержащие гены, вовлеченные в биосинтез N-гликанов. Систематизированы результаты исследований вклада средовых и генетических факторов в популяционную изменчивость N-гликанов, а также результаты картирования геномных локусов N-гликанов методом полногеномного исследования ассоциаций. Представлены результаты последующих функциональных исследований in vitro и in silico, позволивших предложить новые гены-кандидаты, регулирующие N-гликозилирование белков. В заключение кратко показан текущий прогресс в области гликогеномики человека и описаны возможные пути дальнейших исследований N-гликома.

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