Extended genetic effects of ADH cluster genes on the risk of alcohol dependence: from GWAS to replication

Abstract

Alcohol dependence (AD) is a multifactorial and polygenic disorder involving complex gene-to-gene and gene-to-environment interactions. Several genome-wide association studies have reported numerous risk factors for AD, but replication results following these studies have been controversial. To identify new candidate genes, the present study used GWAS and replication studies in a Korean cohort with AD. Genome-wide association analysis revealed that two chromosome regions on Chr. 4q22-q23 (ADH gene cluster, including ADH5, ADH4, ADH6, ADH1A, ADH1B, and ADH7) and Chr. 12q24 (ALDH2) showed multiple association signals for the risk of AD. To investigate detailed genetic effects of these ADH genes on AD, a follow-up study of the ADH gene cluster on 4q22-q23 was performed. A total of 90 SNPs, including ADH1B rs1229984 (H47R), were genotyped in an additional 975 Korean subjects. In case-control analysis, ADH1B rs1229984 (H47R) showed the most significant association with the risk of AD (p = 2.63 × 10(-21), OR = 2.35). Moreover, subsequent conditional analyses revealed that all positive associations of other ADH genes in the cluster disappeared, which suggested that ADH1B rs1229984 (H47R) might be the sole functional genetic marker across the ADH gene cluster. Our findings could provide additional information on the ADH gene cluster regarding the risk of AD, as well as a new and important insight into the genetic factors associated with AD.

Genetics of Alcohol Use Disorder

“…Bu SNP fonksiyonel bir varyant olan ADH1C (arg272gln) ile bağlantı eşitsizliği (LD: linkage disequilibrium) durumundadır. Park ve arkadaşları bir Doğu Asya örnekleminde kromozom 4q22-q23'teki ADH gen kümesinde çok sayıda nominal anlamlı SNP tespit etmiş, ayrıca ADH7'deki rs1442492 ve rs10516441 ile ALDH2'de rs671 polimorfizmlerini genom çapı anlamlı bulmuşlardır (73). Benzer bir şekilde, Doğu Asyalılarla yapılan başka GWAS çalışmalarında ALDH2*2 varyantı olan rs671 azalmış AKB riski ile ilişkili bulunmuştur (72,74,75).…”

“…Benzer bir şekilde, Doğu Asyalılarla yapılan başka GWAS çalışmalarında ALDH2*2 varyantı olan rs671 azalmış AKB riski ile ilişkili bulunmuştur (72,74,75). 2 GWAS çalışmasında ADH1B*2 SNP rs1229984 AKB gelişimine karşı koruyucu olarak gösterilmiştir (73,75). Gelernter ve arkadaşlarının yaptığı yakın zamanlı bir çalışmada bir Avrupa kökenli Amerikalı populasyonda SNP rs1229984'ün AKB riskini azalttığı bulunmuştur.…”

Variation in gastric alcohol dehydrogenase and the risk of alcohol dependence

“…Przykładowo zwiększenie aktywności ADH7 skutkujące szybszym przekształcaniem etanolu do aldehydu octowego skraca czas intoksykacji etanolem oraz potęguje dolegliwości tzw. zespołu dnia następnego związane z nagromadzeniem aldehydu octowego [2,14,[30][31][32][33]. Objawia się on przyspieszoną akcją serca, zaczerwienieniem twarzy, uczuciem rozbicia, zaburzeniem koncentracji, sennością, apatią, czego konsekwencją jest zespół nietolerancji alkoholu [34].…”

Patrones de consumo y genotipos determinantes de la tolerancia al alcohol: estudio en estudiantes universitarios de Santiago de Chile

“…La presencia de la enzima ADH4 determina metabolización eficiente del etanol en episodios de intoxicación, asocián-dose así a fenotipo de "riesgo", ya que permitiría un mayor consumo de alcohol a largo plazo 4,5 . La DA o alcoholismo es una enfermedad compleja y multifactorial debido a la interacción de factores ambientales y genéticos 1,[8][9][10][11][12] . La OMS publicó un estudio sobre los patrones de consumo de alcohol en adultos, donde se destaca el alto consumo y patrones riesgosos tanto para Europa como América; por el contrario, destaca el bajo nivel que se presenta en Asia 13 .…”