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Major gene evidence after MTHFR-segregation analysis of serum homocysteine in families of patients undergoing coronary arteriography

 Sun Jee  ;  Kyung Song  ;  Won Shim  ;  Hyun Kim  ;  Il Suh  ;  Jung Park  ;  So Won  ;  Terri H. Beaty 
 HUMAN GENETICS, Vol.111(2) : 128-135, 2002 
Journal Title
Issue Date
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Child ; Chromosome Segregation/genetics* ; Coronary Angiography ; Coronary Artery Disease/genetics* ; Coronary Artery Disease/metabolism ; Coronary Artery Disease/pathology ; Family ; Female ; Folic Acid/blood ; Genotype ; Homocysteine/blood* ; Humans ; Male ; Methylenetetrahydrofolate Reductase (NADPH2) ; Middle Aged ; Mutation/genetics* ; Oxidoreductases Acting on CH-NH Group Donors/genetics* ; Oxidoreductases Acting on CH-NH Group Donors/metabolism ; Pedigree ; Vitamin B 12/blood
Homocysteine ; Homocysteine Level ; Segregation Analysis ; Serum Folate ; MTHFR Gene
Elevated levels of homocysteine is a risk factor for coronary artery disease. Polymorphic alleles in the MTHFR genes that cause recessively inherited increased homocysteine level can explain only a small proportion of the observed variation in homocysteine level. To investigate additional genetic influences, we examined environmental, familial, and genetic influences on serum homocysteine levels in 661 family members of 112 probands who underwent elective coronary arteriography. Maximum likelihood methods were used to fit several genetic and non-genetic models of inheritance to these data to determine if an unobserved Mendelian major gene could explain the familial homocysteine distribution. Adjustments for age, lifestyle (smoking and alcohol consumption), serum folate and vitamin B12, and the measured genotype effect of the MTHFR C677T mutation was carried out separately for males and females using multiple regression models for homocysteine, before and after log-transformation prior to this segregation analysis. After excluding the effects of mutations in the MTHFR genes, we found evidence of a major gene acting in a co-dominant manner. Estimated mean homocysteine levels for the three putative genotypes (LL, LH, and HH) were 8.0, 10.1, and 15.9 µmol/l, respectively, with relative frequencies of 56.8%, 37.2%, and 6%, respectively. Our analysis suggested the presence of a co-dominantly expressed major gene, in addition to the effects of the MTHFR C677T mutation. The results of this study also indicated that multifactorial inheritance was supported more strongly than Mendelian inheritance alone. Our findings may have implications for attempts to identify new homocysteine susceptible genes.
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4. Graduate School of Public Health (보건대학원) > Graduate School of Public Health (보건대학원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Preventive Medicine (예방의학교실) > 1. Journal Papers
Yonsei Authors
Suh, Il(서일) ORCID logo https://orcid.org/0000-0002-9689-7849
Jee, Sun Ha(지선하) ORCID logo https://orcid.org/0000-0001-9519-3068
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