TY - JOUR
T1 - Major gene evidence after MTHFR-segregation analysis of serum homocysteine in families of patients undergoing coronary arteriography
AU - Jee, Sun Ha
AU - Song, Kyung Soon
AU - Shim, Won Heum
AU - Kim, Hyun Kyung
AU - Suh, Il
AU - Park, Jung Yong
AU - Won, So Young
AU - Beaty, Terri H.
N1 - Funding Information:
Acknowledgements This study was supported by Korean Health 2000 R&D grant number HMP-00-B-21000-0031 and 2001 R&D grant number HWP-00-GN-01-0001, Ministry of Health and Welfare, Republic of Korea. The results of this paper were obtained by using the program package SAGE, which is supported by a US Public Health Service Resource Grant (1 P41 RR03655) from the National Center for Research Resources.
PY - 2002/8
Y1 - 2002/8
N2 - 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.
AB - 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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U2 - 10.1007/s00439-002-0757-8
DO - 10.1007/s00439-002-0757-8
M3 - Article
C2 - 12189485
AN - SCOPUS:0036705558
VL - 111
SP - 128
EP - 135
JO - Human Genetics
JF - Human Genetics
SN - 0340-6717
IS - 2
ER -